PED21 • Pediatric Special Offer

Table of Contents

PED21 • Pediatric Special Offer

How to Receive Credit

NetCE 5 Hour Course #92453 • Type 2 Diabetes in Youth: A Growing Concern

92453 • Type 2 Diabetes in Youth: A Growing Concern

1. INTRODUCTION

2. ETIOLOGY

3. PATHOPHYSIOLOGY

4. LONG-TERM COMPLICATIONS

5. RISK FACTORS FOR TYPE 2 DIABETES IN YOUTH

6. CLINICAL PRESENTATION

7. DIAGNOSIS AND SCREENING

8. TREATMENT

9. REDUCTION AND MONITORING OF LONG-TERM COMPLICATIONS

10. DEVELOPMENTAL ISSUES

11. COUNSELING PARENTS OF CHILDREN AND ADOLESCENTS WITH TYPE 2 DIABETES

12. PREVENTION OF TYPE 2 DIABETES IN YOUTH

13. SUMMARY AND CONCLUSION

14. RESOURCES FOR CHILDREN WITH DIABETES

Works Cited

Evidence-Based Practice Recommendations Citations

NetCE 10 Hour Course #32263 • Newborn Assessment

32263 • Newborn Assessment

1. INTRODUCTION

2. PRENATAL HISTORY

3. PLACENTAL EXAMINATION

4. IMMEDIATE POST-BIRTH CARE

5. APGAR SCORE

6. NEWBORN SCREENING

7. PERIODS OF REACTIVITY

8. ASSESSMENT OF ATTACHMENT

9. GENERAL APPEARANCE ASSESSMENT

10. GENERAL MEASUREMENTS

11. GESTATIONAL AGE ASSESSMENT

12. SKIN ASSESSMENT

13. HEAD ASSESSMENT

14. EYE ASSESSMENT

15. EAR ASSESSMENT

16. NOSE ASSESSMENT

17. MOUTH ASSESSMENT

18. NECK ASSESSMENT

19. NEUROLOGIC EXAMINATION

20. CHEST ASSESSMENT

21. EVALUATING THE RESPIRATORY SYSTEM

22. EVALUATING THE CARDIOVASCULAR SYSTEM

23. ABDOMEN ASSESSMENT

24. GENITOURINARY SYSTEM ASSESSMENT

25. EXTREMITIES, BACK, AND SPINE ASSESSMENT

26. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

NetCE 15 Hour Course #92343 • Childhood Leukemias and Lymphomas

92343 • Childhood Leukemias and Lymphomas

1. INTRODUCTION

2. OVERVIEW OF CHILDHOOD LEUKEMIAS AND LYMPHOMAS

3. TYPES OF LEUKEMIA

4. TYPES OF LYMPHOMA

5. IDENTIFYING LEUKEMIAS AND LYMPHOMAS

6. DIAGNOSIS OF LEUKEMIAS

7. DIAGNOSIS OF LYMPHOMA

8. COMMUNICATION WITH THE PATIENT AND FAMILY

9. TREATMENT APPROACHES

10. SUPPORTIVE CARE

11. PALLIATIVE AND END-OF-LIFE CARE

12. PSYCHOSOCIAL ISSUES FOR THE PATIENT AND FAMILY

13. LONG-TERM HEALTH CARE FOR CHILDHOOD CANCER SURVIVORS

14. CASE STUDIES

15. CONCLUSION

16. RESOURCES FOR FAMILIES WITH A CHILD OR ADOLESCENT WITH LEUKEMIA OR LYMPHOMA

Works Cited

Evidence-Based Practice Recommendations Citations

PED21 • Pediatric Special Offer

Susan Semb, MSN, CDCES

Nicole F. Keehn, RN, MSN, PsyD

Katrina Lieben, MSN, CNM

www.netce.com

Copyright © 2025 NetCE, All rights reserved.

PED21 • Pediatric Special Offer

Expiration Date: 02/28/2022

How to Receive Credit

To complete this Special Offer for continuing education credit please go to http://www.netce.com/specials in your browser.

For assistance with receiving continuing education credit, please contact us at help@netce.com.

92453 • Type 2 Diabetes in Youth: A Growing Concern

Susan Semb, MSN, CDCES

www.netce.com

Copyright © 2021 NetCE, All rights reserved.

Because diabetes is a long-term illness that requires lifestyle adaptation, this course will discuss interventions within the context of the developmental issues of childhood and adolescence. Further attention will be given to the impact that this chronic disease has upon the family as well as the importance of family support in its management. Upon completion of this course, the reader will have an increased understanding of the growing trend in type 2 diabetes among youth, its causes, and the implications related to its management and prevention.

Table of Contents

92453 • Type 2 Diabetes in Youth: A Growing Concern

Course Overview

Audience

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planners

Division Planners Disclosure

Director of Development and Academic Affairs

Director Disclosure Statement

About the Sponsor

Disclosure Statement

Implicit Bias in Health Care

1. INTRODUCTION

PREVALENCE

IMPACT

2. ETIOLOGY

3. PATHOPHYSIOLOGY

PREDIABETES

MAIN CLASSES OF DIABETES

4. LONG-TERM COMPLICATIONS

MICROVASCULAR COMPLICATIONS

MACROVASCULAR COMPLICATIONS

5. RISK FACTORS FOR TYPE 2 DIABETES IN YOUTH

6. CLINICAL PRESENTATION

ACANTHOSIS NIGRICANS

POLYCYSTIC OVARY SYNDROME

NONALCOHOLIC FATTY LIVER DISEASE

7. DIAGNOSIS AND SCREENING

CRITERIA FOR SCREENING

DIAGNOSTIC CRITERIA

8. TREATMENT

BEHAVIOR/LIFESTYLE MODIFICATION

EDUCATION

BLOOD GLUCOSE MONITORING

MEDICAL NUTRITION THERAPY

PHYSICAL ACTIVITY

MEDICATIONS

TREATMENT OF MENSTRUAL IRREGULARITIES ASSOCIATED WITH PCOS

9. REDUCTION AND MONITORING OF LONG-TERM COMPLICATIONS

ROUTINE MONITORING

HYPERTENSION TREATMENT

DYSLIPIDEMIA TREATMENT

10. DEVELOPMENTAL ISSUES

SCHOOL-AGED CHILD (6 TO 12 YEARS OF AGE)

ADOLESCENT (13 TO 18 YEARS OF AGE)

11. COUNSELING PARENTS OF CHILDREN AND ADOLESCENTS WITH TYPE 2 DIABETES

OVERINDULGENCE

RIGIDITY AND PERFECTIONISM

TRANSITIONING FROM PEDIATRIC TO ADULT CARE

12. PREVENTION OF TYPE 2 DIABETES IN YOUTH

13. SUMMARY AND CONCLUSION

14. RESOURCES FOR CHILDREN WITH DIABETES

Works Cited

Evidence-Based Practice Recommendations Citations

92453 • Type 2 Diabetes in Youth: A Growing Concern

Education Category. Pediatrics

Release Date. 03/01/2021

Expiration Date. 02/29/2024

Course Overview

Because diabetes is a long-term illness that requires lifestyle adaptation, this course will discuss interventions within the context of the developmental issues of childhood and adolescence. Further attention will be given to the impact that this chronic disease has upon the family as well as the importance of family support in its management. Upon completion of this course, the reader will have an increased understanding of the growing trend in type 2 diabetes among youth, its causes, and the implications related to its management and prevention.

Audience

This course is designed for all pediatric and medical/surgical staff as well as counselors, therapists, and social workers who work with youth with type 2 diabetes.

Course Objective

The purpose of this course is to introduce the reader to nursing and health care issues related to type 2 diabetes in children and adolescents. As the prevalence of this problem continues to grow, the need to understand how we can prevent and treat this condition becomes more imperative.

Learning Objectives

Upon completion of this course, you should be able to:

1. Describe the relationship between obesity, the modern lifestyle, and type 2 diabetes in youth.

2. Differentiate important characteristics of prediabetes, type 1 diabetes, and type 2 diabetes.

3. Identify microvascular and macrovascular complications of diabetes.

4. Discuss major risk factors associated with type 2 diabetes in youth.

5. Identify clinical presentation and diagnostic criteria of type 2 diabetes in youth.

6. Discuss the importance of diet and exercise as a primary treatment modality for type 2 diabetes in youth.

7. Identify pharmacologic approaches to type 2 diabetes in youth.

8. Describe standards of care for the monitoring and prevention of long-term complications of type 2 diabetes.

9. Describe appropriate counseling interventions for parents of children with diabetes.

Faculty

Susan Semb, MSN, CDCES, is a retired RN who received her Master's degree in nursing from the University of San Diego. Her nursing experience includes direct patient care, case management, staff development, program development, and health education. She spent the majority of her nursing career working as a diabetes educator in the health education department of a major health maintenance organization. Ms. Semb has also authored other continuing education courses for nurses published by NetCE and contributed to nursing books and other publications. In her retirement, Ms. Semb enjoys travel, line dancing, and pursuing an interest in antiques and vintage items.

Faculty Disclosure

Contributing faculty, Susan Semb, MSN, CDCES, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Division Planners

Jane C. Norman, RN, MSN, CNE, PhD

Alice Yick Flanagan, PhD, MSW

Division Planners Disclosure

The division planners have disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Director of Development and Academic Affairs

Sarah Campbell

Director Disclosure Statement

The Director of Development and Academic Affairs has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

About the Sponsor

The purpose of NetCE is to provide challenging curricula to assist healthcare professionals to raise their levels of expertise while fulfilling their continuing education requirements, thereby improving the quality of healthcare.

Our contributing faculty members have taken care to ensure that the information and recommendations are accurate and compatible with the standards generally accepted at the time of publication. The publisher disclaims any liability, loss or damage incurred as a consequence, directly or indirectly, of the use and application of any of the contents. Participants are cautioned about the potential risk of using limited knowledge when integrating new techniques into practice.

Disclosure Statement

It is the policy of NetCE not to accept commercial support. Furthermore, commercial interests are prohibited from distributing or providing access to this activity to learners.

Implicit Bias in Health Care

The role of implicit biases on healthcare outcomes has become a concern, as there is some evidence that implicit biases contribute to health disparities, professionals' attitudes toward and interactions with patients, quality of care, diagnoses, and treatment decisions. This may produce differences in help-seeking, diagnoses, and ultimately treatments and interventions. Implicit biases may also unwittingly produce professional behaviors, attitudes, and interactions that reduce patients' trust and comfort with their provider, leading to earlier termination of visits and/or reduced adherence and follow-up. Disadvantaged groups are marginalized in the healthcare system and vulnerable on multiple levels; health professionals' implicit biases can further exacerbate these existing disadvantages.

Interventions or strategies designed to reduce implicit bias may be categorized as change-based or control-based. Change-based interventions focus on reducing or changing cognitive associations underlying implicit biases. These interventions might include challenging stereotypes. Conversely, control-based interventions involve reducing the effects of the implicit bias on the individual's behaviors. These strategies include increasing awareness of biased thoughts and responses. The two types of interventions are not mutually exclusive and may be used synergistically.

1. INTRODUCTION

PREVALENCE

Diabetes is a chronic illness that affects 34.2 million people in the United States [1]. The vast majority have type 2 diabetes, a condition that usually affects people older than 45 years of age. While type 1 diabetes accounts for about 5% of all diagnosed diabetes, an estimated 210,000 individuals younger than 20 years of age in the United States are diagnosed with type 2 diabetes every year [2]. Although the numbers do not suggest an epidemic, they do represent an unprecedented worldwide rise in type 2 diabetes among children and adolescents over the past 30 years. Prevalence increases with age, tripling between 10 to 14 years of age and 15 to 18 years of age. For reasons that remain unclear, adolescent girls have a 60% higher prevalence rate than adolescent boys [3]. The Centers for Disease Control and Prevention have projected that type 2 diabetes in persons younger than 20 years of age in the United States will increase 673% by 2060 [75]. Unfortunately, the rise in incidence of type 2 diabetes among youth is accompanied by a severe shortage of pediatric endocrinologists [8].

In the United States, the incidence of type 2 diabetes is greater in children of certain ethnic groups [3]. Among youth 10 to 19 years of age, type 2 diabetes represents 4.5% of the cases of diabetes in Non-Hispanic whites, 37.8% in Non-Hispanic blacks, 20.9% in Hispanics, 11.9% in Asian/Pacific Islanders, and 32.8% among Native Americans [4]. The problem is not limited to the United States. In fact, indigenous children around the world bear the greatest burden of youth-onset type 2 diabetes [3,5]. There is considerable variation in the prevalence of type 2 diabetes depending upon ethnicity and geographical region. Rates are lowest in Europe but increasing in China and India, which is concerning, given their large populations [6,7].

IMPACT

The potential burden of type 2 diabetes in youth is enormous. This disease is associated with serious, long-term complications, such as blindness, end stage renal disease, lower extremity amputation, and the development of cardiovascular disease. Experts believe that the progression of the disease in children may be more rapid and more severe than in adults [3]. In addition to the more well-known consequences of uncontrolled diabetes, research indicates that obese adolescents with type 2 diabetes may have diminished cognitive performance and brain abnormalities as indicated by magnetic resonance imaging studies. These brain abnormalities include reduced white matter and an increased amount of cerebrospinal fluid space [9,10,11].

Diabetes accounts for an overall economic burden of more than $327 billion annually, including a disproportionate use of hospital inpatient care, outpatient and physician office care, emergency visits, skilled nursing days, and home health visits [1]. In addition to these economic costs, diabetes takes an incalculable toll on the individual in terms of lost productivity, disability, decreased quality of life, and early mortality. People with diabetes have healthcare costs that are more than two times greater than those without diabetes [12].

The majority of spending for diabetes goes toward the treatment of long-term complications, such as blindness, renal failure, heart disease, hypertension, and amputation [1]. When the disease begins earlier in life, it is more likely to require more protracted treatment with increased economic, social, and personal burden. Furthermore, many children with type 2 diabetes are undiagnosed due to the asymptomatic nature of the disease, increasing the risk for undetected and untreated long-term complications.

2. ETIOLOGY

Why has there been an escalation in the prevalence of type 2 diabetes in this previously unaffected population? The answer to this question appears to be closely related to features of our modern way of life. Increased body weight is strongly associated with type 2 diabetes in youth, pointing to lifestyle as a causative factor. Childhood obesity has more than tripled since the 1970s [13].

Modern eating habits are characterized by the consumption of calorie-laden convenience foods that are high in fat and sugar and low in fiber. Studies have shown that children and adolescents with type 2 diabetes eat more saturated fat than recommended and have inadequate intake of fiber, grains, fruits, and vegetables [14]. Not surprisingly, the combination of these factors has resulted in high rates of overweight and obesity in all age groups, including children. Excessive consumption of foods high in fat and sugar and low in fiber is associated with substantial increases in the risk for diabetes. Obesity alone can have serious consequences for children, including an increased risk for early adult cardiovascular disease.

Adequate physical activity in young people is essential in preventing type 2 diabetes. It is well known that exercise not only helps offset adiposity but enhances insulin sensitivity in young people [15]. In addition to poor eating habits, children have fewer opportunities to burn calories on a daily basis. Television, computers, telephones, and electronic devices provide the primary source of leisure activity for most young people today, while the typical family does not engage in physical activity sufficient to offset the consumption of high-calorie diets. According to government statistics, only 25% of students in grades 9 through 12 are engaged in an adequate amount of moderate-intensity physical activity [16]. Further, coronavirus disease 2019–2020 (COVID-19) increases risk factors for obesity in youth due to increased stress related to academic and social changes as well as decreased physical activity. Online education does not provide physical education classes, recess time, and normal levels of active movement for school-aged children and adolescents [17].

The correlation between obesity, sedentary lifestyle, and type 2 diabetes is clear. Obesity and inactivity are known to significantly impair the body's ability to utilize insulin. This results in a condition known as insulin resistance, which plays an important role in the development of type 2 diabetes and its associated complications.

3. PATHOPHYSIOLOGY

Diabetes is a metabolic disorder, affecting the way that the body uses food for energy. The primary pathology of diabetes is the body's inability to properly metabolize carbohydrates. In normal physiology, carbohydrates are broken down into glucose molecules that are absorbed in the small intestine, making them available for use by the tissues. In order to be converted to energy for use by the body, the glucose must enter the cell through specific sites called insulin receptors. These receptors can only channel glucose into the cell when insulin is present and properly utilized. This process is often conceptualized as a key (insulin) that opens the door (receptor), allowing glucose to enter the cell and be utilized.

Diabetes occurs when one or more of the following situations exist:

- There is a lack or deficiency of insulin present, causing the receptors on the cells to remain unused.

- There are too few insulin receptors available for the needs of the body, or the existing receptors do not function properly.

- The liver does not properly regulate and store the amount of glucose in the blood; it allows stored glucose to be released when blood levels are already above normal.

PREDIABETES

In the United States, an estimated 88 million people older than 18 years of age have prediabetes [1]. Although more study is needed, it is estimated that about one in six adolescents have prediabetes [1]. Prediabetes is defined by a blood glucose level that is higher than normal but not high enough to meet the diagnostic criteria for diabetes. Having prediabetes greatly increases the risk for later development of type 2 diabetes, and most people with type 2 diabetes have had prediabetes prior to the onset of diabetes.

Evidence Based Practice Recommendation

The American Diabetes Association defines persons at increased risk for diabetes (prediabetes) as those with impaired fasting glucose and/or impaired glucose tolerance and/or A1c 5.7% to 6.4%. Prediabetes should not be viewed as a clinical entity in its own right but rather as an increased risk for diabetes and cardiovascular disease.

https://care.diabetesjournals.org/content/44/Supplement_1

Last Accessed: February 11, 2021

Level of Evidence: Expert Opinion

Prediabetes is an asymptomatic condition and can only be detected by laboratory testing. Prediabetes includes any one of the following findings of increased risk for diabetes [18]:

- Impaired fasting glucose (IFG), defined as fasting plasma glucose (FPG) 100–125 mg/dL

- Impaired glucose tolerance (IGT), defined as a postprandial blood glucose 140–199 mg/dL

- Hemoglobin A1c between 5.7% and 6.4%

The harmful effects of high blood glucose begin at much lower levels than those established to define diabetes. In other words, complications of diabetes begin early in the course of glucose intolerance—often before diabetes is diagnosed. Studies suggest that when blood glucose is higher than normal and remains untreated, patients have a greater risk for developing the microvascular and macrovascular complications associated with diabetes [19,20,21]. Research confirms that long-term damage to the body, especially to the heart and circulatory system, can occur during prediabetes [22]. Although many patients with prediabetes may inevitably develop type 2 diabetes, the Diabetes Prevention Program (DPP) has shown that it is possible to delay or even avoid progression completely by implementing lifestyle modification that leads to healthy weight loss [23]. Healthcare professionals must provide preventive care to individuals who have prediabetes in order to minimize the impact of this condition.

MAIN CLASSES OF DIABETES

The Centers for Disease Control and Prevention (CDC) defines diabetes as, "a chronic (long-lasting) disease that affects how your body turns food into energy" [24]. The CDC divides the various existing types of diabetes into three main classes:

- Type 1 diabetes

- Type 2 diabetes

- Gestational diabetes

The majority of cases are either type 1 or type 2 diabetes. Other types of diabetes include diabetes that are chemically induced or that occur from genetic defects, other diseases, or infections.

Previously, type 1 was known as "juvenile-onset" diabetes, while type 2 was referred to as "adult onset" diabetes. However, these terms are no longer appropriate due to the fact that children and adolescents are now developing what was formerly known as adult onset diabetes in increasing numbers.

Type 1 Diabetes

The presence or absence of endogenous, or internally produced, insulin in the body is the defining factor that differentiates type 1 and type 2 diabetes (Table 1). Type 1 diabetes is an autoimmune disease that leads to the destruction of the insulin-producing beta cells of the pancreas, resulting in a complete absence of endogenous insulin [24]. It has traditionally been associated with onset in people younger than 30 years of age. Until recently, it was the only type considered prevalent in children. In this type of diabetes, insulin therapy is required and is the only appropriate pharmacologic option. Without insulin therapy, the person with type 1 diabetes will develop ketoacidosis, a life-threatening condition characterized by high blood glucose levels and a buildup of acids in the blood that will result in death if not treated.

Table 1: TYPE 1 VS. TYPE 2 DIABETES: WHAT ARE THE DIFFERENCES?

Characteristics

Type 1

Type 2

Formerly known as

"Juvenile onset" diabetes

"Adult onset" diabetes

Etiology

Autoimmune disorder

Usually insulin resistance

Pathophysiologic basis

Insulin deficiency: pancreas stops producing insulin, resulting in a complete absence of endogenous insulin

Insulin resistance: body cells cannot utilize insulin that is made by the body

Insulin deficiency: pancreas eventually produces less insulin due to "pancreatic fatigue"

Risk factors

Family history

Environmental factors

Sedentary lifestyle

Family history

Overweight or obesity

Adiposity

Female sex

Low socioeconomic status

Unhealthy sleep patterns

Stress

Hispanic, African American, Pacific Islander, Native American race

Treatment

Insulin therapy (always)

Diet (primarily carbohydrate management)

Increased physical activity

Nutrition therapy (calorie control for weight management and carbohydrate management)

Increased physical activity

Oral medications (in some cases)

Insulin therapy (in some cases)

Associated conditions

High risk for ketoacidosis with hyperglycemia

Metabolic syndrome, characterized by insulinemia, dyslipidemia, and hypertension

Source: Compiled by Author

Typically, children diagnosed with type 1 diabetes are not overweight and report recent weight loss at presentation. However, it is important to note that as the general population has become increasingly overweight, increasing numbers of children with type 1 diabetes are overweight at the time of diagnosis. Polydipsia and polyuria, along with extreme fatigue, are often present when a child is first diagnosed with type 1 diabetes. The duration of these symptoms prior to diagnosis is usually short and often accompanied by the onset of ketoacidosis.

Type 2 Diabetes

Evidence Based Practice Recommendation

When diagnosing diabetes in a child or young person, the National Guideline Alliance recommends assuming type 1 diabetes unless there are strong indications of type 2 diabetes. The possibility of type 2 diabetes should be considered in children and young people with suspected diabetes who:

- Have a strong family history of type 2 diabetes

- Are obese at presentation

- Are of black or Asian family origin

- Have no insulin requirement or have an insulin requirement of less than 0.5 units/kg body weight/day after the partial remission phase

- Show evidence of insulin resistance (e.g., acanthosis nigricans)

https://www.nice.org.uk/guidance/ng18

Last Accessed: February 11, 2021.

Level of Evidence: Expert Opinion

Because it is a relatively new phenomenon, there is still much to learn about the epidemiology and pathophysiology of type 2 diabetes in children. While it closely resembles that of adults, youth-onset type 2 diabetes displays unique aspects, such as rapidly progressive beta-cell decline and accelerated development of diabetes complications [18,25,26]. According to the CDC, type 2 diabetes in children is usually diagnosed between 10 and 19 years of age. Risk factors include obesity, having a family member with type 2 diabetes, and being born to a mother with gestational diabetes. After 10 years of age, being a member of minority populations, such as Hispanic, African American, Asian/Pacific Islander, and American Indian, greatly increases the risk for development of type 2 diabetes in youth [27]. Whether it occurs in adults or children, most cases of type 2 diabetes begin with insulin resistance. In this condition, the pancreas initially continues to produce insulin, but the tissues are unable to use it. This may be due to a scarcity of receptors on the cells or because the receptors do not function well. Reasons for poorly functioning receptors include adiposity, muscular inactivity, and genetic factors. The beta cells of the pancreas respond to insulin resistance by producing even more insulin in an attempt to compensate. However, much of the insulin remains unused and blood levels of insulin are temporarily high (hyperinsulinemia). After a period of manufacturing large amounts of insulin, the beta cells of the pancreas eventually become exhausted, the amount of endogenous insulin greatly declines, and clinical diabetes ensues. In some cases, type 2 diabetes can be managed with a combination of diet, exercise, and oral medications. Many times, insulin therapy is required to control blood glucose levels and to prevent long-term complications of the disease. Individuals with type 2 diabetes usually produce enough insulin to prevent ketoacidosis. Therefore, they are not truly "insulin dependent," even if they do use insulin therapy to control blood glucose.

The distinction between type 1 and type 2 diabetes in children can sometimes be difficult and complicated. Since the 1980s, the rates of both type 1 and type 2 diabetes in children have increased concurrently with obesity rates in children. Autoantigens and ketosis are often present in young patients with type 2 diabetes, pointing to the possibility that obesity may be driving the autoimmune beta-cell failure that underlies type 1 diabetes [18,28]. Furthermore, type 2 diabetes in children is often not detected until glucose levels are extremely high, with resulting ketoacidosis, a condition most commonly found in type 1 diabetes [29]. While challenging, proper diagnosis at onset is critical for the education and treatment of the patient.

4. LONG-TERM COMPLICATIONS

Generally, the long-term complications of diabetes are grouped according to whether they are the result of large-vessel or small-vessel damage by the disease process. The problems related to small vessel damage are termed "microvascular complications," while "macrovascular complications" refers to large vessel disease. Both types of complications are of significant concern with regard to type 2 diabetes in children because they have an increased risk of these complications early in the course of their disease [30]. Risk factors for the development of long-term complications in youth are incompletely understood and long-term outcome data are scarce [30]. However, evidence of microvascular complications and risk markers for macrovascular complications are often present at the time of diagnosis of type 2 diabetes in youth [31]. According to the Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) study, at the time of enrollment, 14% of participants had a blood pressure at the 95th percentile or greater; 13% had microalbuminuria; 80% had a low HDL cholesterol level; and 10% had high triglycerides [32]. Similar findings appeared in a population of Canadian First Nation youth with type 2 diabetes. Thirty-seven percent had elevated triglycerides, and 12% and 14% of male and female youth, respectively, had systolic blood pressure greater than the 95th percentile [33]. This population also exhibited renal and neurologic complications within 5 years of diabetes diagnosis, and major complications (e.g., dialysis, blindness, amputation) started to manifest 10 years following diagnosis [30,34].

MICROVASCULAR COMPLICATIONS

Uncontrolled hyperglycemia over a number of years is known to cause damage to the small vessels that supply the retina of the eye (retinopathy), the nephrons of the kidney, and the motor, sensory, and autonomic nerves. There is evidence that these complications are especially aggressive in young people with type 2 diabetes; they are also highly prevalent [30,31,35]. The United Kingdom Prospective Diabetes Study demonstrated that intensive treatment of type 2 diabetes in adults can significantly lower the risk for developing diabetes-related eye, kidney, and nerve disease. The findings from this study included a 25% reduction of microvascular disease in subjects who maintained long-term glycemic control [36].

MACROVASCULAR COMPLICATIONS

The development of serious large vessel disease is also a possible effect of diabetes. Macrovascular complications of diabetes involve the cardiovascular, cerebral vascular, and peripheral vascular systems, leading to high incidences of myocardial infarction, stroke, and lower extremity disease.

While the injurious effects of hyperglycemia on large blood vessels are believed to play a significant role in the development of large vessel disease, hyperinsulinemia is also responsible for other damaging effects to the cardiovascular system. Resulting from insulin resistance, high levels of insulin in the blood are associated with a series of adverse metabolic changes that greatly increase the risk for cardiovascular disease; these changes characterize the metabolic syndrome. This cluster of disorders includes two major independent risk factors for myocardial infarction: hypertension and dyslipidemia.

A person has metabolic syndrome if he or she has any three of the following risk factors [37,38]:

- In adults, waist circumference more than 40 inches for men or more than 35 inches for women, indicating excess visceral fat. This is known as the round or "apple" body shape.

- Dyslipidemia (Table 2)

- Triglycerides greater than 150 mg/dL

- High-density lipoprotein (HDL) cholesterol less than 40 mg/dL in men or less than 50 mg/dL in women

- Blood pressure greater than 130/85 mm Hg

- FPG greater than 100 mg/dL

Table 2: DYSLIPIDEMIA

Definition

One or more abnormalities in the circulating blood fats (LDL-C, HDL-C, and triglycerides).

Significance

Lipid abnormalities are a leading factor in the development of arteriosclerosis, a major risk factor for cardiovascular disease.

LDL-C

A lipoprotein that deposits (plaque) in artery walls, leading to inflammation and atherosclerosis. The development of plaque can cause blockage, or rupture of plaque can cause blood clots. The desired blood level is <100 mg/dL.

HDL-C

The so-called "good cholesterol" may help remove excessive amounts of LDL-C, resulting in reduced plaque formation. The desired level is >50 mg/dL for women and >40 mg/dL for men. Low HDL-C levels are associated with the development of cardiovascular disease.

Triglycerides

Another undesirable fat whose exact role in the development of coronary artery disease is not well understood. Elevated levels are often found in people with type 2 diabetes. The desired blood level is <150 mg/dL. Levels >1,000 mg/dL are sometimes found in people with type 2 diabetes, placing them at high risk for pancreatitis.

Source: Compiled by Author

The presence of metabolic syndrome is a signal of the need for lifestyle modification. Weight loss, exercise, and a low-fat diet can often improve metabolic abnormalities without medication. Even a reduction in sitting time and sedentary pastime can have a positive effect metabolic risk factors [38].

5. RISK FACTORS FOR TYPE 2 DIABETES IN YOUTH

Risk factors for the development of type 2 diabetes in young people have been identified. These include [5,28,39,40]:

- Overweight or obesity: A clear correlation exists between the incidence of obesity and the development of type 2 diabetes in all age groups, including children and adolescents. Central adiposity, characterized by a concentration of fat in the torso and abdominal region, is also specifically associated with insulin resistance. Excess fat cells are believed to interfere with insulin utilization and cause insulin resistance.

- Ancestry: Insulin sensitivity appears to vary among ethnic groups. Preliminary population studies on the incidence of type 2 diabetes in youth indicate that this disorder appears in significantly higher rates in Native Americans, African Americans, Hispanics, and Pacific Islanders.

- Family history: Type 2 diabetes is more likely to occur in those who have a first- or second-degree relative with the disease. An estimated 45% to 80% of children with type 2 diabetes have at least one parent who also has the disease. Furthermore, obesity has a familial tendency.

- Developmental stage: Most new cases of type 2 diabetes in young people are diagnosed after the onset of puberty, with a mean age of diagnosis of approximately 13.5 years. During normal adolescence, there is an approximate 50% decrease in insulin sensitivity. It is believed that this is related to the increased production of growth hormone during the pubescent years.

- Gender: The occurrence of type 2 diabetes is more frequent in girls and young women than in boys and young men. Girls are typically more insulin-resistant than boys when controlled for body mass index.

- In utero exposure to diabetes: Having a birth mother with pre-existing or gestational diabetes also increases the risk for diabetes.

Risk factors that negatively impact the health outcomes of youth with type 2 diabetes include [31]:

- Socioeconomic status (i.e., parental income, education, employment)

- Sleep abnormalities

- Chronic exposure to environmental and social stressors

6. CLINICAL PRESENTATION

Many children are asymptomatic at the time they are diagnosed with type 2 diabetes. However, about 20% present with the signs and symptoms of ketoacidosis and glucose levels greater than 600 mg/dL. Many children complain of increased thirst and urination at the time of diagnosis, and some will report an unintentional weight loss over the previous weeks or months [29]. Comorbidities that may be present with diagnosis are early signs of renal insufficiency and retinopathy, hypertension, dyslipidemia, depression, and eating disorders. Other important clinical features frequently found in children newly diagnosed with type 2 diabetes include features or causes of insulin resistance syndrome, such as acanthosis nigricans, polycystic ovary syndrome (PCOS), and fatty liver disease.

ACANTHOSIS NIGRICANS

Acanthosis nigricans is a skin condition characterized by brownish-black patches, usually found on the back of the neck, in the axillae, and on areas exposed to repeated friction. They are slightly raised lesions that feel velvety to touch. Presence of the condition is considered a marker of hyperinsulinemia, and it develops in some cases of type 2 diabetes in children. This sign is most frequently recognized in obese, dark-skinned individuals and occurs more frequently in African Americans than in other ethnic groups. Parents of children with this condition often mistake acanthosis nigricans for poor hygiene and attempt to treat it with vigorous scrubbing and topical medications or cleansers. Some schools have initiated screening procedures for acanthosis nigricans, as many obese children who go on to develop type 2 diabetes present with only this sign [29].

POLYCYSTIC OVARY SYNDROME

PCOS is a disorder of the female reproductive system and is closely associated with insulin resistance. It is characterized by chronic anovulation, resulting in scanty or infrequent menstruation. In patients with PCOS, estrogen levels are usually normal while androgen levels are high. The elevated androgen levels can result in acne and hirsutism.

NONALCOHOLIC FATTY LIVER DISEASE

Nonalcoholic fatty liver disease is a chronic inflammatory process of the liver often associated with insulin resistance. Chronic hepatic inflammation can lead to liver dysfunction and ultimately failure. Evaluation for nonalcoholic fatty liver disease should be done at the time that type 2 diabetes is diagnosed in a child and annually thereafter [5].

7. DIAGNOSIS AND SCREENING

CRITERIA FOR SCREENING

The American Diabetes Association (ADA) recommends the screening of asymptomatic high-risk youth for type 2 diabetes every three years, beginning at 10 years of age or the onset of puberty, whichever occurs first. For the purposes of screening criteria, the ADA considers children at high risk if they are overweight (BMI >85th percentile) or obese (BMI >95th percentile) and have one or more of the following additional risk factors [18]:

- Family history of type 2 diabetes in a first- or second-degree relative

- Native American, African American, Hispanic, Asian, and/or Pacific Islander race or ethnicity

- Signs of insulin resistance, including acanthosis nigricans, hypertension, dyslipidemia, small-for-gestational-age birth weight, or PCOS (as evidenced by menstrual irregularities and/or hirsutism)

- Maternal history of diabetes or gestational diabetes during the child's gestation

DIAGNOSTIC CRITERIA

The diagnostic criteria for diabetes in youth are the same as those established for adults and can be assessed using any of the tests listed in Table 3.

Table 3: DIAGNOSTIC TESTING FOR DIABETES

Diagnostic Test

Criteria for Prediabetes

Criteria for Diabetes

A1c

5.7% to 6.4 %

≥6.5%

Oral glucose tolerance test

140–199 mg/dL two hours after ingestion of glucose liquid

≥200 mg/dL two hours after ingestion of glucose liquid

Fasting plasma glucose

100–125 mg/dL

≥126 mg/dL

Random blood glucose

N/A

≥200 mg/dL and the presence of one or more symptoms of hyperglycemia

Source: [18,41]

Hemoglobin A1c

This test reports the average amount of glucose that has adhered to the red blood cells over the previous two to three months (Table 4). In 2010, the ADA recognized an A1c value that is greater than or equal to 6.5% as diagnostic for diabetes [18,41]. This value continues to be diagnostic for diabetes [18].

Table 4: THE HEMOGLOBIN A1cTEST

What is hemoglobin A1c?

The measurement of hemoglobin A1c concentration provides a valid and reliable indication of a person's overall blood glucose control in the two- to three-month period prior to the test. Large studies have demonstrated that people with diabetes who are able to maintain an average value of 7% or less over 10 or more years have a greatly reduced risk for the microvascular complications of diabetes. It has been shown that for every percentage point decrease in A1c (e.g., 9% to 8%), there is a 35% reduction in the risk of complications.

If a patient is performing self-monitoring of blood glucose, why is the A1c test necessary?

Self-monitoring of blood glucose using a meter gives information about the blood glucose level at a specific moment in time. While this is very useful for the day-to-day management of diabetes, it does not give collective information that can predict the risk for development of long-term complications. By taking into account all times for all days during the two- to three-month period, the A1c gives a better indication of overall glycemic control.

How does the test work?

The test works by measuring the amount of glucose that is chemically attached to red blood cells (RBCs). RBCs that have been exposed to high amounts of glucose over their lifespan will have more glucose attached to them. Because the average life of an RBC is approximately 90 days, the A1c indicates glycemic control over this time period. Results of the A1c are expressed as a percentage and reflect the relative amount of glucose that has been in the blood over the past two to three months.

Source: Compiled by Author

Oral Glucose Tolerance Test

The oral glucose tolerance test (OGTT) requires patients to fast for eight hours, then to drink a liquid containing 75 grams of glucose dissolved in water. The test is performed by measuring the plasma glucose levels two hours after drinking the liquid. A diagnosis of diabetes is made when the result is greater than or equal to 200 mg/dL [18,41].

Fasting Plasma Glucose

To measure FPG, patients are required to fast for at least eight hours, after which a simple blood test is performed. This test is most accurate when administered in the morning. Although it is not as sensitive as the OGTT, it is the preferred method of testing because of its cost-effectiveness and convenience. Diabetes is diagnosed when FPG is greater than or equal to 126 mg/dL [18,41].

Random Blood Glucose

A random blood glucose (RBG) test, also known as a simple blood test, is taken regardless of when food was last consumed. It is generally administered when an individual presents with the following symptoms of hyperglycemia:

- Increased urination

- Unexplained weight loss

- Fatigue

- Blurred vision

- Increased hunger

- Sores that do not heal

An RBG result that is greater than or equal to 200 mg/dL is diagnostic for diabetes [18,41].

8. TREATMENT

The primary means for treating type 2 diabetes in youth is lifestyle management, which includes youth-oriented, culturally appropriate self-management education and support, and weight loss through a healthy eating plan coupled with increased daily physical activity. Blood glucose monitoring is important in providing feedback to the individual on how these changes affect glycemia. Clinical practice guidelines from the American Academy of Pediatrics (AAP) recommend starting metformin in newly diagnosed patients with an A1c of 6.5% or greater [42]. This recommendation also is supported by the ADA [18].

The ultimate goal in managing type 2 diabetes in people of all ages is to prevent or reduce the long-term complications that are associated with this disease. As stated, two major factors warrant vigorous efforts to minimize the risk of both small- and large-vessel complications in young patients with type 2 diabetes [31]:

- The complications have been found to be especially aggressive in this population.

- The earlier the age of onset, the sooner patients will suffer from the devastating complications of diabetes, substantially increasing the burden of the disease on the individual and on society.

Successful management of type 2 diabetes in youth includes [5]:

- Weight loss

- Increasing physical activity

- Normalizing glycemia

- Control of comorbidities, such as hypertension, dyslipidemia, nephropathy, and fatty liver disease

The ADA recommends that a reasonable A1c target for most children and adolescents with type 2 diabetes treated with oral agents alone is <7%. More stringent A1c targets (e.g., <6.5%) may be appropriate for select individual patients if the targets can be achieved without significant hypoglycemia or other adverse effects. Less stringent A1c goals (e.g., <7.5%) may be appropriate if there is increased risk for hypoglycemia. A1c targets should be individualized, taking into account the relatively low rates of hypoglycemia in youth-onset type 2 diabetes [18]. The International Society for Pediatric and Adolescent Diabetes (ISPAD) recommends an overall A1c goal of less than 7.0% for all age-groups [5].

BEHAVIOR/LIFESTYLE MODIFICATION

A family-centered approach is recommended for treating type 2 diabetes in youth [42]. Many families are greatly challenged by the lifestyle changes that are necessary to manage type 2 diabetes in children. Changes in daily habits, such as those involving food and activity, are difficult for people in general because they reflect embedded psychologic, social, and cultural influences. Therefore, psychologists, social workers, registered dieticians, and exercise physiologists play valuable roles in the interdisciplinary diabetes care team.

Readiness to change refers to the theory that people move through a series of stages as they give up unhealthy behaviors and adopt those that are health-enhancing. James Prochaska's behavioral change model has been widely used in many areas of health education, including in diabetes self-management. There are five identified stages that people go through when they are trying to change behaviors (Table 5). For each stage of change, certain interventions on the part of the healthcare provider are recommended. By employing these interventions, healthcare professionals can help "meet" the families within their own particular stage of change at any given time [43].

Table 5: STAGES OF BEHAVIOR CHANGE

Stage

Patient Characteristics

Interventions

Precontemplation

Denies there is a problem

Defensive

Noncompliant

Explore the problem

Offer information

Provide support and empathy

Contemplation

Aware of problem

Actively considers change

Some ambivalence/anxiety

Employ questioning that will increase awareness of the problem

Help build confidence in ability to make changes

Acknowledge efforts to seek information

Preparation

Ready to take action

Makes at least one recent attempt to change

Provide encouragement

Action

Strong commitment to change

Restructures lifestyle/environment to accommodate change

Confidence in ability to be successful

Help provide strategies to remove or reduce negative behavioral triggers

Maintenance

Maintains healthy behaviors for six months or more

Help maintain focus

Help review and renew commitment

Address relapse events

Source: [43]

According to the American Academy of Pediatrics, parenting skills are the key to success in treating childhood obesity. They recommend the following parental interventions in helping to change behavior in children [44]:

- Using praise to cultivate and maintain desirable behavior

- Using physical activity time with parents as a reward for good behavior

- Establishing daily meal and snack times

- Offering only healthy options

- Asking children to offer rewards to parents for positive changes in the parents' behavior

EDUCATION

A family approach to health education is essential, as the lifestyle changes required to manage the child's diabetes will have an impact on the entire family. Parental education should include an assessment of existing knowledge about eating, weight, and health. Research has indicated that most parents of obese or overweight children do not consider their children overweight and do not believe that this is a health problem [45]. Therefore, many will need help in understanding that the child is overweight and that the problem must be addressed. Furthermore, there may be a misconception, especially in some cultures, that being overweight is a sign of good health. If this is the case, there will be a need to educate parents regarding the dangers of diabetes and heart disease related to being overweight in a culturally sensitive way.

In addition to lifestyle modification, comprehensive education for young people with type 2 diabetes and their families should include the following components:

- Blood glucose monitoring

- Blood glucose target ranges

- Signs, symptoms, causes, and treatment of hyperglycemia and hypoglycemia

- Prevention of long-term complications

- Management of associated health problems, such as hypertension and dyslipidemia

BLOOD GLUCOSE MONITORING

Self-monitoring of blood glucose (SMBG) provides immediate feedback on the impact of various daily influences, such as food, activity, and medications, on blood glucose levels. For many individuals, this is an empowering activity that provides a sense of control in the management of the disease. By keeping blood glucose levels near normal as much as possible, patients with diabetes can reduce their risk for acute and chronic complications.

Children and adolescents with type 2 diabetes should monitor their blood glucose levels frequently to assess the quality of their control. The AAP recommends that patients with newly diagnosed type 2 diabetes perform fingerstick blood glucose monitoring before meals and at bedtime until glycemic control is achieved [42].

Target ranges for children with type 2 diabetes who monitor blood glucose are not specified in the practice guidelines published by the ADA and the ISPAD. As with adults, the overall goal is to maintain blood glucose as close to normal as much as possible, without excessive hypoglycemia, and to prevent long-term complications.

MEDICAL NUTRITION THERAPY

Achieving and maintaining a reasonable body weight is the major therapeutic goal in the management of type 2 diabetes in youth. Other goals of medical nutrition therapy include normalizing blood glucose (without excessive hypoglycemia) and maintaining healthy lipid and blood pressure values while allowing for normal growth and development [14,18].

Even minor reductions in weight can significantly improve blood glucose control. A weight-loss plan for a child should be developed and supervised by a registered dietician to ensure a nutritionally adequate meal plan that allows for growth and development while moderately restricting calories [29]. Clinic-based weight management programs appear to be effective in improving the metabolic profile of obese children, if they remain in a supervised program for several years. Results of a pilot program in Philadelphia suggest that an informal, nonintensive program of regular clinician contacts over two years can be more effective than intensive time-limited programs. In this study, the greatest improvements in children's metabolic profile correlated with frequency of visits to the healthcare provider [46].

The safest and most efficacious method for losing weight is to decrease caloric intake from fat and sugar while increasing fiber intake and physical activity [5]. Although weight loss is the goal, the primary focus of treatment should be on healthy eating and physical activity. Providing the family with restrictive lists of forbidden and allowable foods is not recommended. Instead, overall changes in lifestyle should be promoted [18]. Encouraging positive changes in food consumption patterns improves the chances of successful, long-term weight management by working on the modification of unhealthy behaviors. Family involvement in the nutritional management plan is vital for the successful implementation of behavior changes in the child. This supports the patient with diabetes and treats or prevents obesity and obesity-related health conditions in the entire family.

An appropriate meal plan is based upon an assessment that includes family preferences, timing and location of meals and snacks, cultural preferences and restrictions, food preparation practices, and readiness to change. Dietary recommendations should always be culturally appropriate and sensitive to the financial situation of the family. In order to be successful, a weight-loss program requires frequent interaction with the patient, continuous monitoring, and positive reinforcement. Counseling interventions should include encouraging family-style meals that are low in fat and smaller in portion size [18]. It is also important to help the family increase its awareness of their snacking behaviors and to offer strategies for making healthy changes. Because many people engage in eating that has nothing to do with hunger, families should be offered tactics for changing these habits as well.

Guidelines for facilitating healthy eating-related behaviors in youth include:

- Help set realistic goals. Goals should be oriented to behavior rather than outcomes. An example of a behavior goal might be, "I will eat a piece of fruit every day as my after-school snack." Avoid outcome-oriented goals such as, "I will lose 5 pounds this month," which tend to be less supportive of behavioral change and less empowering for the individual.

- Start slowly, focusing on two or three behavior changes at a time. A plan to make a comprehensive change in a person's eating habits tends to overwhelm and is more likely to result in failure.

- If developmentally appropriate, ask the patient to keep a food diary and review this with the patient. This is often considered the first step in the behavior change. Parents can help younger patients with this.

- Avoid the term "diet." Promote obesity management as a lifelong process. Focus on lifestyle changes that will improve glycemic control and long-term, overall health.

- Focus on a general understanding of the principles of good nutrition instead of handing out food lists and diet sheets. General instructions might include recommendations to reduce portion sizes, reduce the intake of fatty and processed foods, and increase the intake of fiber and fresh produce.

- Develop reward systems for appropriate behavior. Rewards could include earning a trip to an amusement park or getting a special toy. Reward charts can help track progress, providing feedback and a source of motivation.

Guidelines for Facilitating Nutritional Management

Nutritional recommendations should come primarily from a registered dietician who has expertise in the area of growth and child development. Dieticians should be a part of an interdisciplinary diabetes care team [18]. However, access to a dietician is not economically feasible for some patients whose healthcare plans do not cover this service or those who live in remote areas. In many instances, and in various settings, a nurse or counselor may assume responsibility for teaching dietary management to patients with diabetes. The following information is not intended nor is it able to replace the expertise of a dietician. But because not all patients have access to a dietician, the following information is provided as a guide to start or supplement education for nutritional management. General guidelines that encourage healthier eating habits to promote weight loss and prevent cardiovascular disease include [5,14,18,29,47]:

- Reduce, then eliminate, caloric beverages (except skim or low-fat milk) from the diet. Appropriate replacements include water, sparkling water, and herbal tea.

- Limit fast foods and fried food.

- Provide food in appropriate portion sizes. Serve portion-controlled snacks on a plate or bowl, not directly from the package.

- Eat a healthy breakfast every day.

- Provide meals on schedule and as a family unit, with no other activities, such as television, taking place at the same time.

- Increase intake of vegetables, unsweetened breakfast cereals, and hot food items that are high in fiber and low in saturated fat. Diets high in these types of foods have been associated with improved glucose tolerance.

- Keep unhealthful foods, such as snack items that are high in saturated fat and sugar, out of the house.

- Do not force children to finish meals if they are not hungry.

- Do not reward children with candy or sweets, especially for finishing meals.

- Provide more foods in their natural state. Have healthful snacks such as fruits, vegetables, and whole grain foods prepared and available as after-school snacks.

- Provide healthful, home-packed lunches to avoid consumption of foods that are high in fat and sugar and are available in many school cafeterias, food courts, and vending machines.

- Plan ahead for parties and other special occasions where high-calorie foods will be available: Have a light snack before attending the party, so food can still be enjoyed at the event, but in smaller quantities.

- Eat smaller meals for the remainder of the day to "save" some calories for the special event.

- Learn how to exchange party foods for other foods on the daily meal plan. Sweets can occasionally be exchanged for other carbohydrate foods on the meal plan.

PHYSICAL ACTIVITY

Physical activity counteracts both insulin resistance and obesity, making it an essential component for both the prevention and treatment of type 2 diabetes. A study presented at the 2010 ADA annual meeting revealed that obese boys who engaged in aerobic and resistance exercise decreased their total body fat, visceral fat, and insulin resistance, even without any changes in diet. The study also indicated that resistance exercise training is appealing to boys and that it expends similar energy to aerobic training in this population [48].

The CDC and the ADA recommend that children and adolescents get at least 60 minutes of physical activity every day [18,49]. Children should be encouraged to participate in sustained activities that use large muscle groups on a daily basis. Aerobic exercise should make up most of the 60 minutes of daily exercise. This should include vigorous intensity exercise at least three days per week. Children should have muscle-strengthening exercise at least three days per week as part of their 60 minutes per day [18]. This could include push-ups and climbing on playground equipment. Bone-strengthening exercise is recommended three days per week, included in the 60 minutes per day requirement [18]. Bone-strengthening exercises include weight-bearing exercise, such as jumping rope and running.

Extended periods of inactivity should be avoided. A 2010 study showed that adolescent boys with two or more hours a day of television or computer screen time are at greater risk for insulin resistance and other markers of metabolic syndrome [50]. A 2017 study found several factors that contribute to prolonged screen time and physical inactivity, including the youth's socioeconomic status, unhealthy food habits, and urban residence (with less exposure to other children) [51]. Overall physical activity can be increased by helping young people find ways to be more active in everyday activities, such as using stairs instead of the elevator, walking instead of riding, and playing outside as much as possible.

Because they are typically not motivated by long-term benefits, young people will not usually be interested in exercising for health reasons. Instead, activities must offer the immediate reward of being fun as well as developmentally appropriate. Physical activities that an adolescent or child may enjoy include dancing, jumping rope, swimming, skating, skateboarding, and team sports. Children and adolescents who have been sedentary should increase activity levels in increments to reach the overall recommendation of 60 minutes per day [16].

Family involvement in the activity plan is recommended to provide support to the child with diabetes and to promote the overall health of the family [14]. Exercising with others, such as parents and friends, promotes the pleasurable aspects of the program and validates its importance [51]. Because finding time to exercise can be challenging for many families, quality school programs that encourage physical activity are also very important. Children should be encouraged to participate in as many different sports as possible. Most importantly, the child must enjoy whatever activities are being encouraged to ensure that he or she will want to continue with them on a regular and consistent basis.

Reduced exercise tolerance is a problem in most overweight children with type 2 diabetes. Walking is considered one of the best forms of activity for those who are exercise intolerant. Walking regimens must be started slowly and engaged in for short periods of time to build tolerance.

Obese children are likely to be uncomfortable participating in organized sports activities. Therefore, other ways of being active should be encouraged. Obese children should begin with a limitation on access to television and increasing non-weight-bearing activities such as swimming, cycling, and paced walking [16].

MEDICATIONS

Evidence suggests that type 2 diabetes in youth is different not only from type 1 diabetes but also from type 2 diabetes in adults. Additionally, given the current obesity epidemic, distinguishing between type 1 and type 2 diabetes in children can be difficult [18]. Accurate diagnosis is critical. Although general treatment goals for patients with the two diagnoses are the same, specific treatment regimens differ markedly between patients with type 1 and type 2 diabetes.

The ADA recommends the initiation of pharmacologic therapy, in addition to lifestyle therapy, at diagnosis of type 2 diabetes [18]. Insulin therapy should be initiated for children and adolescents who are ketotic, in diabetic ketoacidosis, or whose disease cannot be clearly identified as either type 1 or type 2 diabetes [3,5,18]. After acidosis is resolved, metformin should be initiated while subcutaneous insulin therapy is continued [18]. Patients treated with insulin therapy who do not meet glycemic targets should be moved to multiple daily injections with basal and premeal bolus insulins [18]. Patients initially treated with insulin and metformin who meet glucose targets (based on SMBG) can be tapered over two to six weeks by decreasing the insulin dose 10% to 30% every few days [18].

Table 6 lists various medications used in the treatment of type 2 diabetes, although many are not labeled for use in children. Metformin and insulin are approved for children with type 2 diabetes [18,29]. In addition, the GLP-1 agonists dulaglutide, extended-release exenatide, and liraglutide are approved for use in children 10 years of age and older if glycemic targets are not met with metformin (with or without insulin) and if the child's medical and family history allow [18,52]. In metabolically stable patients, metformin, if not contraindicated and if tolerated, is the preferred initial pharmacologic agent for the treatment of type 2 diabetes [18].

Table 6: PHARMACOLOGIC TREATMENT OF TYPE 2 DIABETES

Agent

Mechanism of Action

Route

Possible Side Effects and Patient Education Needs

Insulin

Allows glucose to enter cell for conversion to energy

Subcutaneous

Injection techniques

Risk for hypoglycemia; instruct on signs, symptoms, treatment, and prevention

Biguanides (metformin)

Regulates release of stored glucose from liver

Increases insulin sensitivity

Oral

Caution against the use of alcohol, especially binge drinking.

Most common side effects are headache, nausea, vomiting, and diarrhea, but they subside within weeks of starting therapy.

Diminished appetite with resulting weight loss may occur.

Medication should be withheld when undergoing procedures that utilize radio contrast material.

Lactic acidosis is a very rare but life-threatening risk; instruct patient on treatment and on signs and symptoms, which include myalgia, fatigue, dizziness, difficulty breathing, and gastrointestinal discomfort.

Sulfonylureasa (glipizide, glyburide)

Increases insulin secretion from pancreas

Regulates glucose output from liver

Increases insulin sensitivity

Oral

Risk for hypoglycemia increases with inadequate caloric intake, strenuous exercise, or concurrent use of other hypoglycemic agents; instruct on signs, symptoms, treatment, and prevention.

Thiazolidinedionesa (pioglitazone)

Increases insulin sensitivity

Regulates glucose output from liver

Oral

Risk for hypoglycemia with concurrent use of insulin or sulfonylureas; instruct on signs, symptoms, treatment, and prevention.

May cause fluid retention.

May cause rare, but serious, effect on the liver; regular monitoring of liver function is necessary.

Incretin mimetics or GLP-1 analoguesa (exenatide, dulaglutide, liraglutide)

Increases insulin secretion from pancreas

Subcutaneous

Injection techniques

Inject with meals

Risk for hypoglycemia with concurrent use of sulfonylureas; instruct on signs, symptoms, treatment, and prevention.

Modest weight loss may occur.

Use with metformin and/or sulfonylureas.

Most common side effect is nausea, which tends to improve over time as optimal dosage is reached.

Dipeptidyl peptidase-4 (DPP-4) inhibitorsb (sitagliptin)

Increases insulin secretion from pancreas

Decreases glucagon secretion from pancreas

Oral

May cause mild headache, stuffy or runny nose, sore throat, or diarrhea.

Take with or without food.

aOnly liraglutide is labeled for pediatric use.

bOff-label for pediatric use.

Source: [18,29,52,53]

Metformin acts by decreasing the amount of glucose produced by the liver and improving insulin sensitivity. For adolescents using metformin, it is important to screen for alcohol abuse, including binge drinking, as this medication is contraindicated in those with moderate-to-heavy alcohol use. Besides being effective in lowering blood glucose levels, metformin has other advantages:

- Metformin does not put the child at risk for hypoglycemia when used as the sole pharmacologic agent to treat diabetes. This is especially important in pediatric patients who typically do not appreciate the seriousness of hypoglycemia or respond appropriately to its symptoms.

- Metformin has a beneficial effect on the lipid profile, potentially lowering both low-density lipoprotein cholesterol (LDL-C) and triglyceride levels.

- Metformin may aid in weight loss.

- Metformin may normalize ovulatory function in girls with PCOS.

When monotherapy with metformin does not result in appropriate glucose control after three months, other oral medications such as thiazolidinediones, sulfonylureas, incretin mimetics, or sodium-glucose co-transporter 2 inhibitors may be added. Further, insulin may be used alone or with oral medications [5,18]. A combination of metformin plus rosiglitazone has been found to be more effective than metformin alone [32]. Use of medications not approved by the FDA for youth with type 2 diabetes is not recommended outside research trials [18].

The most common and serious side effect of using insulin is hypoglycemia. An important consideration in any age group, it is of special concern in children because they are believed to be less careful about preventing and recognizing the symptoms [54]. When insulin is used, parents and children must be educated on the signs, symptoms, causes, and treatment of hypoglycemia (Table 7).

Table 7: MANAGEMENT OF HYPOGLYCEMIA

Definition

Blood glucose less than 70 mg/dL

Signs and symptoms

Shakiness, sweating, confusion, irritability, weakness, hunger, blurred vision

Treatment (for children older than 6 years of age and adults)

15 grams of fast-acting carbohydrate

Sources include:

- 3 to 4 glucose tablets or glucose gel equivalent to 10 to 15 grams

- 4 to 6 ounces fruit juice

- 6 to 8 ounces skim milk

- 4 to 5 ounces regular soft drink

- 5 to 6 hard candies

Follow-up

Recheck blood glucose 15 minutes after initial treatment. If the level is still less than 70 mg/dL, treat again with 10 to 15 grams of fast-acting carbohydrate. When blood glucose is greater than 70 mg/dL, eat the regularly scheduled meal or snack.

Prevention

Do not skip meals. If a meal will be delayed, eat a snack.

Check blood glucose before exercise. If it is less than 100 mg/dL, have a snack.

Use abdomen for insulin therapy for more consistency of absorption. Rotate sites within the abdominal area.

Carry a source of fast-acting carbohydrate and wear medical identification at all times when exercising.

Make sure that coaches, teachers, and other supervising adults are aware of the signs, symptoms, prevention, and management of hypoglycemia.

Source: Compiled by Author

TREATMENT OF MENSTRUAL IRREGULARITIES ASSOCIATED WITH PCOS

Oral contraceptive agents with low androgenic activity are often prescribed to normalize menstrual cycles in cases of PCOS. Metformin can also increase menstrual regularity. Often prescribed in tandem, oral contraceptives and metformin appear to work synergistically in normalizing reproductive function. Metformin should be prescribed with caution in sexually active young women with PCOS, as this could increase the risk for unplanned pregnancy. Counseling on abstinence, safer sex practices, and birth control options is strongly indicated in teens.

9. REDUCTION AND MONITORING OF LONG-TERM COMPLICATIONS

ROUTINE MONITORING

The prevention and control of long-term complications in young patients with diabetes is of vital importance due to the increased risks associated with earlier disease onset. The coexistence of obesity, hypertension, and dyslipidemia, which are common in children with type 2 diabetes, greatly increases the risk for cardiovascular disease. Because of the seriousness of these complications, hypertension and dyslipidemia must be aggressively treated and should be considered as important as blood glucose control. These comorbidities are often already present at the time of diagnosis. Therefore, the ADA recommends that blood pressure measurement, fasting lipid profile, microalbuminuria assessment, and dilated eye exam be performed at the time of diagnosis [18]. In addition to cardiovascular risk, hypertension is a risk factor for the development of eye and kidney disease. Routine preventive care can often delay or slow the progression of complications by ensuring early treatment. The routine preventive care schedule recommended for all patients with diabetes consists of [3,5,18]:

- Annual dilated eye exam or less frequent monitoring when advised by an eye care professional

- Annual screening for early, microscopic protein loss from the kidneys (microalbuminuria)

- Annual lipid panel if lipids are abnormal, or if LDL-C levels remain less than 100 mg/dL, repeat lipid profile every five years

- Blood pressure monitoring at each office visit

- Foot exam at each office visit, including annual test for sensation using a monofilament

- Hemoglobin A1c test every three months

HYPERTENSION TREATMENT

Careful control of blood pressure is imperative for the prevention of early-onset cardiac and renal disease in this population [18]. One large study concluded that strict blood pressure management in adults with type 2 diabetes was related to a significant reduction in cardiovascular morbidity, including a 44% reduction in stroke and a 56% reduction in heart failure [55]. Therefore, blood pressure should be monitored regularly and treated aggressively in children with diabetes when either the diastolic or systolic reading is consistently above the 90th percentile for age, sex, and height [18]. Nonpharmacologic measures to reduce blood pressure include dietary intervention and physical activity aimed at weight control. If target blood pressure is not achieved after six months of lifestyle intervention, medication may be initiated [18].

Angiotensin-converting enzyme (ACE) inhibitors are generally considered first-line pharmacologic agents to treat hypertension in young people with type 2 diabetes [18]. These agents are preferred because, in addition to their lowering effects on blood pressure, they are known to have an independent renal protective function when microalbuminuria is present. Patients of childbearing potential should be advised that these medications have potential teratogenic effects and pregnancy should be avoided while taking them.

DYSLIPIDEMIA TREATMENT

Dyslipidemia outweighs all other risk factors for the development of cardiovascular disease in adults with type 2 diabetes. There is increasing evidence that the atherosclerotic process is present in childhood, beginning as early as 10 years of age [56]. Lipid disorders occur comorbidly in most people with type 2 diabetes, including children. Like hypertension, lipid disorders must be treated aggressively. Optimal goals for children and adolescents are LDL-C less than 100 mg/dL, HDL-C greater than 35 mg/dL, and triglycerides less than 150 mg/dL [18].

First-line therapy for dyslipidemia includes lifestyle management aimed at optimizing glucose control and weight loss through healthy eating and increased physical activity. If LDL-C remains greater than 130 mg/dL after six months of dietary intervention, treatment with statins is indicated, with a goal of LDL-C less than 100 mg/dL [18].

The American Heart Association has established these dietary recommendations for preventing cardiovascular disease [47]:

- Consume an overall diet rich in fruits, vegetables, whole grains, fat-free and low-fat dairy foods, legumes, and lean protein.

- Include fish, especially oily fish, at least twice a week.

- Limit total fat intake to less than 25% to 35% of total calories each day.

- Minimize intake of excess calories, saturated and trans fats, cholesterol, salt, alcohol, and sugar.

10. DEVELOPMENTAL ISSUES

Type 2 diabetes in young people occurs more commonly in late childhood or adolescence due to hormonal changes during this stage of life. The developmental issues of children during these years can complicate the attainment of therapeutic goals. For example, a young person is more likely to be motivated by the short-term gratification of consuming high-fat snacks while watching television than the long-term benefits of following a healthier food and activity plan. For this reason, members of this age group tend to be poorly adherent to the types of self-care behaviors recommended to manage diabetes.

SCHOOL-AGED CHILD (6 TO 12 YEARS OF AGE)

Parents still take major responsibility for the healthcare needs of school-aged children, including responsibility for what foods are eaten. However, the school-aged child's environment is expanding, with more activities out of the home and away from parents. The importance of the peer group and fear of being different from others are basic developmental issues in this age group. At the same time, these children are especially impressionable to the examples set by parents and other adults. As adolescence approaches, the importance of body image intensifies. Children at this age also begin experimenting with independent decision making and may begin to challenge authority. By 12 years of age, most children can manage their own insulin therapy, but parents must supervise to ensure that doses are not missed or forgotten.

School Concerns

Every child's school should be informed that he or she has type 2 diabetes. While most school professionals understand the fundamentals of type 1 diabetes, many may be unaware of type 2 diabetes as an emerging phenomenon. School personnel may require education on how this disorder differs from type 1 diabetes. For example, they may not understand that a child with diabetes being managed by a food and activity plan will not be at risk for hypoglycemia if he or she skips a snack. On the other hand, if the child uses sulfonylurea medication or insulin to manage diabetes, school personnel must be aware of the potential for hypoglycemia, including its signs, symptoms, causes, prevention, and treatment. By federal regulation, schools must allow children to monitor blood glucose in the classroom and take appropriate action during the school day to prevent or treat hypoglycemia and hyperglycemia. Printed information for school personnel about children with diabetes is available from the ADA [57].

ADOLESCENT (13 TO 18 YEARS OF AGE)

Even without having to face a chronic illness, adolescence is a complex time for many. Major issues during this stage of life include hormonal fluctuations and sexual development, changes in body image, and strong peer influences. The struggle for independence from parents and other authority figures may lead some adolescents to ignore treatments and falsify blood glucose results. Basic identity issues are important during this time and extend into young adulthood. Risk-taking is a characteristic at this stage, and substance abuse is a well-known related problem. Substance misuse may interfere with the treatment plan and can even be the source of dangerous interactions if the patient is using certain types of medications to manage diabetes. Healthcare providers should be aware of these developmental issues and plan to spend quality, one-on-one time with adolescents to explore the barriers to self-care that are perceived by the patient. Parents need support and guidance during this time as well.

Sexual Identity

Sexual development and related identity issues are at the forefront of adolescent development. Responsible management of all women with diabetes who are in the childbearing years includes preconception planning, as poor glycemic control significantly increases the risk for childbirth complications and fetal anomalies. Sexuality education for adolescents should include discussion of abstinence, contraception, and infection prevention. For those who are already sexually active or are planning to become sexually active, methods of contraception should be discussed [58]. Patients being treated with metformin for PCOS should be cautioned that as the symptoms of PCOS subside, fertility normalizes and the risk for pregnancy will significantly increase with unprotected intercourse.

Approaches to Adolescents with Diabetes

Adolescents should be allowed as much control as possible in the management of diabetes while being assisted to set goals. Using food and exercise logs may be useful in this population because they provide a sense of control and feedback that validates their efforts. Because adolescents often resent dependence upon adults, it is counterproductive to strictly supervise their goals and activities. Experts suggest giving young people goals to reach and allowing them to make their own choices about how they will accomplish them [54].

11. COUNSELING PARENTS OF CHILDREN AND ADOLESCENTS WITH TYPE 2 DIABETES

Having a child with diabetes places stress on the family and usually requires behavioral adjustments. Parents need support because the manner in which they relate to the child with diabetes will affect how the child deals with the disease. Parents need to help their children accept and adjust to the diagnosis and to engage them, along with the entire family in behavior modification. Parents may react with feelings such as guilt or embarrassment, especially if they perceive that they are to blame for the contributing lifestyle features that increased the child's risk for type 2 diabetes. Parents may respond to the stress of having a child with diabetes with a variety of coping behaviors. Two common parental coping strategies, overindulgence and rigidity, represent opposite ends of the continuum.

OVERINDULGENCE

Evidence Based Practice Recommendation

The National Guideline Alliance recommends giving children and young people with type 2 diabetes and their family members or carers (as appropriate) information about local and/or national diabetes support groups and organizations, and the potential benefits of membership.

https://www.nice.org.uk/guidance/ng18

Last Accessed: February 11, 2021

Level of Evidence: Expert Opinion

Some parents may think that the recommended lifestyle changes may be too difficult for the child to handle. They may also feel sorry for the child and fear that the child is fragile due to his or her illness. In this case, they may respond inappropriately by failing to place limits on the child's eating or by forgoing blood glucose monitoring because it hurts. If parents seem overindulgent, the appropriate intervention is to explore the reasons why they behave this way. Are they afraid? Do they lack confidence? Do they feel guilt? What is their readiness to change? Feelings of fear or lack of confidence can often be overcome with education and support. Teach parents that their behavior may be reinforcing their child's own sense of inadequacy. Always identify the stage of change that the family is in and provide interventions accordingly.

RIGIDITY AND PERFECTIONISM

Some parents may cope by trying to achieve perfection in meeting therapeutic goals. This is manifested by rigid adherence to diet and unrealistically expecting blood glucose values to be within the target range all of the time. In these cases, parents should be educated that their child's self-esteem may be threatened by the overemphasis on treatment. They can also be educated that it is appropriate to make compromises in the meal plan as long as the overall eating pattern is healthy. For example, cake and ice cream for a birthday may add calories and raise blood sugar, but consumption of these types of food can occasionally be accommodated by working them into the entire day's meal plan and by maintaining or increasing physical activity.

Reassure these parents that "ideal" control is not necessary all of the time, and encourage them to work with the child for the best control. Also educate parents that blood glucose target ranges are usually guidelines to strive for and that occasional out-of-range results will not adversely affect health in the long run. Caution them to avoid words like "cheating" and "bad blood sugar," as this may be construed by the child as personal failure or misbehavior. Parents and healthcare providers can help the child avoid some of these detrimental feelings by reminding him or her that the target levels are used as a guide and are not a reflection of failure [59].

TRANSITIONING FROM PEDIATRIC TO ADULT CARE

As youth move from childhood to adolescence, diabetes management is gradually shifted from parent to child. However, this shift often occurs more abruptly as teens enter the developmental stage that theorists refer to as "emerging adulthood"—a critical period between 18 and 25 to 30 years of age [18,60,61]. This is generally the time when youth begin to leave their parents' home and must become fully responsible for their diabetes care. These responsibilities include diabetes self-management, making medical appointments, and financing health care (if they are no longer covered by their parents' insurance plans). It is also a time associated with a deterioration in glycemic control; increased occurrence of acute complications; psychosocial, emotional, and behavioral challenges; and the emergence of chronic complications [62,63,64,65]. The transition from pediatric to adult health care often leads to fragmented healthcare delivery, which negatively impacts healthcare quality, cost, and outcomes [66].

To facilitate a seamless transition from pediatric to adult health care, comprehensive, coordinated planning for the transition should begin in early adolescence, preferably at least one year prior to the expected date of transition [67,68]. A discussion of the challenges faced during this period and specific recommendations for managing them may be found in the ADA position statement Diabetes Care for Emerging Adults: Recommendations for Transition From Pediatric to Adult Diabetes Care Systems [63]. Additionally, the Endocrine Society, in collaboration with the ADA and other organizations, has developed transition tools for clinicians, youth, and families that may be accessed at https://www.endocrine.org/improving-practice/patient-resources/transitions [68].

12. PREVENTION OF TYPE 2 DIABETES IN YOUTH

An important topic of research is to determine if type 2 diabetes can be prevented in high-risk individuals. A landmark study involving more than 3,000 adult participants at 27 centers nationwide has concluded that it can. The DPP found that people with IGT coupled with being overweight were able to prevent or delay the onset of type 2 diabetes through a program of weight loss and moderate physical activity [23]. Additional research is needed to evaluate if similar results can be achieved in children.

Due to the complex social and environmental factors that affect youth with type 2 diabetes, individual lifestyle interventions may not be sufficient [31]. The effort to prevent type 2 diabetes in children requires a public health approach. This involves education and legislation that discourages unhealthy food consumption and sedentary activity patterns while providing for healthier alternatives.

Public education should be family-centered and provide children and parents with knowledge and avenues for behavioral change. Information should be made widely available to teach families the importance of consuming healthy diets and engaging in regular physical activity. Furthermore, the public should be made aware of the detrimental impact that aggressive marketing by fast-food restaurant chains and processed food manufacturers has had upon our public health. Many ads for unhealthy foods are aimed at increasing consumption rather than promoting nutrition. The public should know that the low cost and convenience of enhanced portion sizes (e.g., "all you can eat," "super-size") come at the price of serious risk to health. All of these educational approaches should be multicultural in nature, taking into account the various health beliefs and dietary patterns of the populations directly affected by current rates of obesity and diabetes. Legislative action should focus on developing and implementing school- and community-based programs that result in increasing physical activity and preventing obesity by ensuring that all families have access to healthy foods, quality health care, and safe spaces for physical activity [31]. One study of high-risk obese Latino youth found that completion of a 12-week community-based diabetes prevention program resulted in significant decreases in BMI score, BMI percentile, and waist circumference; increases in cardiorespiratory fitness; and decreases in physical inactivity and dietary fat consumption. The community-based program also resulted in significant improvements in insulin sensitivity and reductions in two-hour glucose levels [69].

The CDC has compiled a set of guidelines designed to help schools develop, implement, and evaluate school-based healthy eating and physical activity policies for students [70]. Schools are prime locations for reaching young people at a time when health habits are being established [59,71]. The CDC also offers "BAM!" (Body and Mind). BAM is an online information portal for teachers of students in grades 4 to 8, designed to help these students make healthier lifestyle choices [72]. It is essential that schools provide health education and targeted interventions for at-risk youth. Furthermore, lunch programs should offer healthy choices and strictly limit food that is high in fat and sugar from their cafeterias, food courts, and vending machines. This is especially important today, as many families rely heavily on convenience foods at home, which are often high in fat and low in fiber. Physical education and school-based exercise programs are also very important in promoting the health of our children. Because working parents may not have time to exercise with their children and many children live where it is not safe to exercise outside without adult supervision, it cannot be assumed that children will have access to a physical activity program outside of school. If the health of our children is not enough impetus to provide for physical education, further justification comes from neuroscientific studies showing that exercise promotes brain growth and improved cognitive function [73].

13. SUMMARY AND CONCLUSION

Growth in the number of children being diagnosed with type 2 diabetes is closely related to a significant increase in the rates of overweight and obesity in children. Other risk factors, such as ancestry, family history and gender, are also implicated in the development of type 2 diabetes in youth. Insulin resistance and its relationship to type 2 diabetes has been identified as the primary pathophysiologic factor related to the onset of this disorder. The menacing combination of high insulin levels, high blood pressure, and dyslipidemia in these children is of particular concern, as it greatly increases the risk for early-onset cardiovascular disease and other complications.

Treatment of type 2 diabetes in children and adolescents includes weight loss, increasing physical activity, following a healthy meal plan, and in many cases, medications. Preventing complications such as retinopathy, nephropathy, neuropathy, and cardiovascular disease is a goal of utmost importance in the management of diabetes in young people. A developmental approach is important in offering healthcare interventions to pediatric patients with type 2 diabetes and their families. Furthermore, the importance of family support in managing weight and increasing physical activity is immeasurable. Finally, from a public health perspective, measures to curtail the current growth in the number of children with type 2 diabetes must be taken. The aim of this course has been to provide healthcare professionals with information that will help them understand the causes, treatment, and prevention of this serious problem affecting today's youth.

14. RESOURCES FOR CHILDREN WITH DIABETES

Organizations that are helpful to parents and children with diabetes can be found locally, nationally, and on the Internet.

American Diabetes Association

http://www.diabetes.org

1-800-DIABETES (1-800-342-2383)

The website provides comprehensive information on all aspects of diabetes for healthcare providers and the general public. A chat line and community discussions are available. Includes web page for parents and children. "Imagine Camp" is designed to facilitate an at-home, virtual experience connecting kids and families to help them learn new diabetes management skills that build confidence [74].

Callers to the national telephone number can receive information about all aspects of diabetes management. Local programs include diabetes education classes, youth programs, counseling and support groups, and information services.

Juvenile Diabetes Research Foundation International

https://www.jdrf.org

1-800-533-CURE (1-800-533-2873)

This organization is dedicated primarily to funding and research activities related to finding a cure for type 1 diabetes. The website has pages on treating low blood sugar, dealing with children's feelings, and control through diet and exercise that would be helpful to parents of children with type 2 diabetes.

Children with Diabetes

https://childrenwithdiabetes.com

This is a comprehensive online community for children with diabetes and their families. In addition to news features and education, the site has chat rooms, surveys, polls, and an online specialty store for children with diabetes. Assistance in finding a diabetes camp is also available at this site.

KidsHealth

https://kidshealth.org

A child- and teen-friendly website with information on health topics and healthy living. Includes animation, games, and other interactive, developmentally appropriate content.

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32263 • Newborn Assessment

Nicole F. Keehn, RN, MSN, PsyD

Katrina Lieben, MSN, CNM

www.netce.com

Copyright © 2020 NetCE, All rights reserved.

Every infant presents uniquely and has certain individual needs. While the vast majority of infants transition without problems, some present with anatomic, physiologic, infectious, and developmental issues that must be addressed. The assessment of the newborn should begin with obtaining a health history and include the initial Apgar assessment, the transitional assessment during the periods of reactivity, the assessment of gestational age, and the systemic physical examination. This systematic approach ensures a thorough exam. Nurses in many different areas of nursing conduct newborn assessments. The information provided includes warning signs, which require immediate attention, as well as basic normal assessment findings in the newborn. Due to the large volume of information, this course will cover only the first 24 hours of life.

Table of Contents

32263 • Newborn Assessment

Course Overview

Audience

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planner

Division Planner Disclosure

Director of Development and Academic Affairs

Director Disclosure Statement

About the Sponsor

Disclosure Statement

Implicit Bias in Health Care

1. INTRODUCTION

2. PRENATAL HISTORY

RISK FACTORS

3. PLACENTAL EXAMINATION

4. IMMEDIATE POST-BIRTH CARE

5. APGAR SCORE

6. NEWBORN SCREENING

7. PERIODS OF REACTIVITY

8. ASSESSMENT OF ATTACHMENT

9. GENERAL APPEARANCE ASSESSMENT

10. GENERAL MEASUREMENTS

WEIGHT

LENGTH

HEAD AND CHEST CIRCUMFERENCE

11. GESTATIONAL AGE ASSESSMENT

CASE STUDY

12. SKIN ASSESSMENT

VERNIX CASEOSA

LANUGO

WARNING SIGNS

SKIN TEMPERATURE AND MATURITY

SKIN COLOR

BIRTHMARKS

13. HEAD ASSESSMENT

HEAD SIZE AND SHAPE

CRANIAL STRUCTURE

WARNING SIGNS

14. EYE ASSESSMENT

15. EAR ASSESSMENT

16. NOSE ASSESSMENT

17. MOUTH ASSESSMENT

REFLEXES

18. NECK ASSESSMENT

19. NEUROLOGIC EXAMINATION

WARNING SIGNS

ASSESSING REFLEXES

PAIN RESPONSE

20. CHEST ASSESSMENT

21. EVALUATING THE RESPIRATORY SYSTEM

WARNING SIGNS

INSPECTION

AUSCULTATION

SIGNS OF RESPIRATORY DISTRESS

CAUSES OF RESPIRATORY DISTRESS

22. EVALUATING THE CARDIOVASCULAR SYSTEM

AUSCULTATION

ELECTROCARDIOGRAM

BLOOD PRESSURE

MURMURS

CONGENITAL HEART DEFECTS

ASSESSING THE PULSE AND CAPILLARY REFILL TIME

23. ABDOMEN ASSESSMENT

INSPECTION

AUSCULTATION

PALPATION

NECROTIZING ENTEROCOLITIS

HERNIAS

WARNING SIGNS

24. GENITOURINARY SYSTEM ASSESSMENT

MALE INFANTS

FEMALE INFANTS

25. EXTREMITIES, BACK, AND SPINE ASSESSMENT

INSPECTION

WARNING SIGNS

26. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

32263 • Newborn Assessment

Education Category. Pediatrics

Release Date. 09/01/2020

Expiration Date. 08/31/2023

Course Overview

Every infant presents uniquely and has certain individual needs. While the vast majority of infants transition without problems, some present with anatomic, physiologic, infectious, and developmental issues that must be addressed. The assessment of the newborn should begin with obtaining a health history and include the initial Apgar assessment, the transitional assessment during the periods of reactivity, the assessment of gestational age, and the systemic physical examination. This systematic approach ensures a thorough exam. Nurses in many different areas of nursing conduct newborn assessments. The information provided includes warning signs, which require immediate attention, as well as basic normal assessment findings in the newborn. Due to the large volume of information, this course will cover only the first 24 hours of life.

Audience

This course is designed for all medical-surgical nurses and ancillary nursing personnel involved in the assessment of newborns.

Course Objective

The purpose of this course is to provide an overview of a newborn assessment for all nurses, especially those who either presently care for newborns or those who come in contact with them occasionally.

Learning Objectives

Upon completion of this course, you should be able to:

1. Outline important points of a prenatal history.

2. Describe immediate post-birth care and examination of the placenta.

3. Analyze guidelines and strategies for assigning Apgar scores and the implications of maintaining a thermoneutral environment for the newborn.

4. Discuss the importance of general measure-ments and determination of gestational age.

5. Identify important aspects of the newborn skin assessment.

6. Review key components of the assessment of the newborn's head, face, and neck.

7. Evaluate newborns' reflexes and other relevant neurologic findings.

8. Outline the steps involved in the assessment of the newborn's chest and respiratory system, including identifying signs of respiratory distress.

9. Appropriately evaluate the newborn's cardiovascular system, with attention to potential congenital heart defects.

10. Describe key aspects of the newborn abdomen assessment.

11. Identify warning signs and normal findings when assessing the newborn's genitourinary system.

12. Discuss the inspection of the newborn's extremities, back, and spine.

Faculty

Nicole F. Keehn, RN, MSN, PsyD, received a Master’s of Science, with emphasis on the pediatric critical care population, from Texas Woman’s University in 1993. She completed her doctorate in clinical and neuropsychology at Argosy University in Dallas, Texas. She was employed as the intensive care educator at Texas Children's Hospital in Houston, Texas, and as a clinical nurse in the intensive care unit at Children's Medical Center of Dallas, Texas. Mrs. Keehn is currently a clinical training director of an APPIC internship program and a pre- and post-doctoral psychology supervisor. She is also the managing partner of Lokahi Life Center, PLLC, in Dallas, Texas.

Katrina Lieben, MSN, CNM, received her Bachelor of Science in Nursing from Humboldt State University, California in 1997 and her Master's of Science in Nursing with a nurse midwifery focus from the Frontier School of Midwifery and Family Nursing in 2008. She has worked with mothers and infants her entire career. Ms. Lieben practiced in Ketchikan, Alaska, for more than 10 years, and currently practices midwifery care in Ukiah, California.

Faculty Disclosure

Contributing faculty, Nicole F. Keehn, RN, MSN, PsyD, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Contributing faculty, Katrina Lieben, MSN, CNM, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Division Planner

Jane C. Norman, RN, MSN, CNE, PhD

Division Planner Disclosure

The division planner has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Director of Development and Academic Affairs

Sarah Campbell

Director Disclosure Statement

The Director of Development and Academic Affairs has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

About the Sponsor

The purpose of NetCE is to provide challenging curricula to assist healthcare professionals to raise their levels of expertise while fulfilling their continuing education requirements, thereby improving the quality of healthcare.

Our contributing faculty members have taken care to ensure that the information and recommendations are accurate and compatible with the standards generally accepted at the time of publication. The publisher disclaims any liability, loss or damage incurred as a consequence, directly or indirectly, of the use and application of any of the contents. Participants are cautioned about the potential risk of using limited knowledge when integrating new techniques into practice.

Disclosure Statement

It is the policy of NetCE not to accept commercial support. Furthermore, commercial interests are prohibited from distributing or providing access to this activity to learners.

Implicit Bias in Health Care

The role of implicit biases on healthcare outcomes has become a concern, as there is some evidence that implicit biases contribute to health disparities, professionals' attitudes toward and interactions with patients, quality of care, diagnoses, and treatment decisions. This may produce differences in help-seeking, diagnoses, and ultimately treatments and interventions. Implicit biases may also unwittingly produce professional behaviors, attitudes, and interactions that reduce patients' trust and comfort with their provider, leading to earlier termination of visits and/or reduced adherence and follow-up. Disadvantaged groups are marginalized in the healthcare system and vulnerable on multiple levels; health professionals' implicit biases can further exacerbate these existing disadvantages.

Interventions or strategies designed to reduce implicit bias may be categorized as change-based or control-based. Change-based interventions focus on reducing or changing cognitive associations underlying implicit biases. These interventions might include challenging stereotypes. Conversely, control-based interventions involve reducing the effects of the implicit bias on the individual's behaviors. These strategies include increasing awareness of biased thoughts and responses. The two types of interventions are not mutually exclusive and may be used synergistically.

1. INTRODUCTION

Conducting a thorough neonatal assessment is necessary to ensure that the newborn transitions appropriately to extra-uterine life [1]. Skilled observation should begin at the time of birth and continue frequently during the first 24 hours. Nurses should be aware of the normal features of the transition period in order to detect disorders in adaptation soon after birth [2]. The newborn assessment provides much needed information concerning the state of health of the transitioning newborn as well as a basis with which to formulate further care.

Every infant presents uniquely and has certain individual needs. While the vast majority of infants transition without problems, some present with anatomical, physiologic, infectious, and developmental issues that should be addressed. The assessment of the newborn should begin with obtaining a health history and include the initial Apgar assessment, transitional assessment during the periods of reactivity, assessment of gestational age, and a physical examination. This systematic approach ensures a thorough exam.

Nurses in many different areas of nursing conduct newborn assessments. The information provided in this course includes warning signs, which require immediate attention, as well as basic, normal assessment findings in the newborn. Due to the large volume of information, this course primarily covers the first 24 hours of life.

2. PRENATAL HISTORY

A prenatal history is imperative to the comprehensive care of each newborn and should cover the maternal sequelae, family history, and fetal care history [3]. Maternal history consists of information concerning past pregnancies, including complications, and specifics of labor and maternal illness, including infections and the use of alcohol or drugs [3]. It should also elicit information regarding the current pregnancy, such as the quality and quantity of prenatal care, current laboratory values (including blood type and Rh factor and the results of standard group B streptococcus screening), and the presence of any significant risk factors to the fetus. Obtaining a family history involves inquiring regarding past illnesses, genetic issues, and physiologic problems of parents and siblings [3]. The neonatal history encompasses factors such as vital signs, Apgar scores, required stabilization interventions, and the newborn's general appearance and reaction to the environment [3].

RISK FACTORS

An understanding of the maternal/fetal risk factors is important for the anticipation of possible problems that the infant may experience. Risk factors may be divided into two categories: those that can be modified, such as smoking and drug use, and those that are inherent, such as diabetes and pre-eclampsia.

Smoking

Evidence Based Practice Recommendation

The U.S. Preventive Services Task Force (USPSTF) recommends that clinicians ask all pregnant women about tobacco use, advise them to stop using tobacco, and provide behavioral interventions for cessation to pregnant women who use tobacco.

https://www.uspreventiveservicestaskforce.org/uspstf/recommendation/tobacco-use-in-adults-and-pregnant-women-counseling-and-interventions

Last Accessed: August 10, 2020

Strength of Recommendation: A (The USPSTF recommends the service. There is high certainty that the net benefit is substantial.)

Smoking during pregnancy continues to be an alarmingly common problem. It has been associated with an increased incidence of ectopic pregnancy, preterm birth, low birth weight infants, placental abruption, premature rupture of membranes, and sudden infant death syndrome (SIDS) [4,5,6]. Studies have shown that low birth weight can be attributed to maternal smoking in 20% to 30% of cases [1]. Smoking causes vasoconstriction, resulting in decreased uterine perfusion and decreased oxygen-carrying capacity for the fetus [4,7]. Smoking has also been implicated in poor fetal nutrition, as it interferes with the ability of the fetus to metabolize key vitamins and minerals [4]. Cigarettes contain nicotine, which is a highly addictive substance. Infants of smokers tend to be fussier than those of nonsmokers, and it is thought that they experience nicotine withdrawal symptoms, especially if they are bottle-fed [6].

Drug Use

Illicit drug use can lead to a multitude of problems for the developing fetus. Cocaine, for example, affects all of the user's body systems, including the cardiovascular system, which can lead to heart attack and stroke. It may cause liver disease and perforation of the nasal septum [4]. It is highly addictive. The effect of cocaine on the fetus is directly related to the effect on the mother, including increased blood pressure, which leads to decreased uterine blood flow and perfusion [1]. These effects may lead to preterm labor, low birth weight and length infants, a decreased head circumference, placental abruption, and stillbirth. Additional effects of prenatal cocaine exposure include cerebral infarcts, renal defects, necrotizing enterocolitis (NEC), cardiac anomalies, and mild facial dysmorphic features [1].

Opioid use during pregnancy can be equally devastating. Maternal signs of opioid use include constricted pupils, slurred speech, euphoria, and respiratory depression [4]. Possible effects on the fetus include meconium aspiration, spontaneous abortion, and low birth weight, which may lead to future developmental problems [8,9]. Infants who are born physically dependent on opioids experience intense acute and subacute withdrawal symptoms [8,9,10].

Studies regarding the effect of cannabis use during pregnancy have shown inconsistent results [2,11]. It is thought that smoking cannabis has similar dangers as smoking cigarettes, including increased carbon monoxide levels, which lead to decreased oxygen levels and fetal hypoxia. Some studies have shown that women who smoke cannabis regularly during pregnancy are more likely to give birth to an infant with fetal alcohol syndrome-like characteristics [2]. Other studies have shown that prenatal exposure to cannabis is directly associated with lower birth weight, reduced birth length, and a smaller head circumference [11,186]. Cannabis readily crosses into breast milk, and women that smoke cannabis should be advised against breastfeeding [2].

Diabetes

Gestational diabetes affects up to 9.2% of all pregnancies [12,13]. Factors that place women at higher risk for developing gestational diabetes include age of 25 years or older, obesity, and a family history of type 2 diabetes [4,14]. The infant of a mother with diabetes, regardless of whether the cause is gestational diabetes or pre-existing disease, is affected in a multitude of ways. The effects are more pronounced in "brittle" cases. Fetuses that are continuously exposed to high blood glucose levels will produce more insulin in response, leading to excessive fetal growth and infants who are large for gestational age (i.e., macrosomia) [1,14]. This in turn can place them at higher risk for birth trauma and shoulder dystocia [4]. In the neonatal period, infants of mothers with diabetes are also more likely to experience hypoglycemia that results from the precipitous drop in available blood sugar while they continue to produce excessive amounts of insulin. This can lead to serious neurologic damage with complications including developmental delay, heart failure, and seizures [13,14,15]. Infants of mothers with diabetes are also at higher risk for neonatal jaundice, and women with diabetes are at higher risk for developing pre-eclampsia [4,14]. These infants are also more likely to be obese and develop type 2 diabetes as adults [13].

Pre-eclampsia

Pre-eclampsia is a form of pregnancy-induced hypertension that begins after 20 weeks' gestation. The diagnosis is based on the presence of new-onset hypertension (after 20 weeks' gestation) and at least one of the following: proteinuria; thrombocytopenia; kidney or liver function changes; pulmonary edema; or new-onset, severe, unrelenting headache. Accompanying signs may include headache, visual disturbances, and epigastric pain. Management of pre-eclampsia includes blood pressure control, bed rest, and fluid restriction. The only cure is delivery. The fetus is affected as a result of the hypertension leading to decreased uterine perfusion; chronic hypoxia can result. Infants of women with pre-eclampsia are at higher risk for low birth weight and the catastrophic event of placental abruption [4,16]. Untreated pre-eclampsia may result in eclampsia, which includes the development of seizures. The infant of a woman with eclampsia is at risk for effects of placental abruption, preterm birth, and acute hypoxia [4,16].

Group B Streptococcus

Group B streptococcus (GBS) is a leading cause of early-onset neonatal sepsis causing death to newborns [17,18]. Group B streptococcus is found in the mother's genital tract and rectal area [19]. Colonization is common and generally causes no symptoms in the healthy mother. In its 2010 guidelines, the Centers for Disease Control and Prevention (CDC) recommended universal rectovaginal screening of all pregnant women between 35 to 37 weeks' gestation, with subsequent intrapartum antibiotic prophylaxis; however, in 2019, the American Society for Microbiology (ASM) assumed responsibility for maintaining and updating these guidelines [17,18,143]. The ASM currently recommends screening between 36 weeks to 37 weeks/6days [143]. Universal screening has helped decrease the incidence of early-onset neonatal GBS; however, the incidence of late-onset neonatal GBS has not decreased [17,18,143]. Infants generally become infected during labor and birth due to vertical transmission of the bacteria after the membranes have ruptured; therefore, sepsis is a more likely outcome with delayed delivery after rupture of the membranes. Occasionally, fetuses may become infected during pregnancy.

As noted, there are two different types of GBS infection: early- and late-onset. Early-onset GBS occurs in the first seven days of life and may be detectable in the first six hours [19,20]. It can make a seemingly healthy newborn become ill very quickly. The most common symptoms of early-onset GBS are pneumonia, meningitis, respiratory distress, and sepsis [19,21]. Early-onset GBS has a higher fatality rate than late-onset GBS. Late-onset GBS may not be detected for up to three months and is believed to be transmitted either during birth, through breast milk, or in a nosocomial form [19,21,22]. The most common symptoms are sepsis and meningitis.

GBS sepsis should be considered whenever a newborn demonstrates respiratory distress, temperature instability, or poor feeding. Laboratory values that may be assessed when there is suspicion of GBS include complete blood count with differential, blood culture, chest x-ray, urine culture and analysis, stool culture, and possible lumbar puncture [23]. Treatment of GBS-infected newborns includes IV antibiotics [24].

3. PLACENTAL EXAMINATION

A thorough assessment of the placenta at the time of delivery may assist with age determination and present significant diagnostic information [3]. The placenta should be assessed for size, color, odor, and the presence and number of membranes [3,25].

The ratio of fresh placental weight to infant weight is normally 1:6 in the last trimester. Very large placentas may be indicative of diabetes; very small placentas may be indicative of chronic hypoxia, perhaps caused by hypertension. The placenta should have a uniform thickness throughout; depressions may be from abruption or infarction [3,25,26].

Color may give an estimate of gestational age, as the placenta will become duller with more calcium deposits postdate. Pallor or plethora should be noted as they may indicate fetal blood volume inadequacy or excess and/or hemoglobin status. Staining by meconium or blood through the membranes or of the cord indicates an insult of longer duration. Vernix nodules (or amnion nodosum) indicate prolonged extreme oligohydramnios and pulmonary hypoplasia. An adherent clot suggests that an abruption has occurred. Any of these abnormal findings should be noted [3,25,26].

The placenta should be essentially odorless except for the slight odor of fresh blood. Foul odor indicates infection. This should be noted, and the physician should be informed [3,25,26].

Membranes should be assessed and noted to be present (i.e., not retained inside the uterus). The number of membranes should be determined in the case of multiple gestations [3,25,26].

The umbilical cord should be assessed for appearance, length, and diameter. The appearance of the insertion site should be documented, noting intactness, the number of vessels, and color. The umbilical cord should be a pearl ivory color, and any deviations from this color should be noted. The umbilical cord length is normally between 55 and 60 cm, with 5% of cords shorter than 35 cm and 5% longer than 80 cm [25,26,27]. Shorter length may be the cause of decreased fetal movement, intrauterine constraint, placental abruption, or cord rupture [27]. A longer cord makes entanglement or prolapse more likely. The cord diameter at term is generally about 1.5 cm and should be relatively uniform throughout, without strictures. The Wharton's jelly should be firm, with compression a likely result if the cord is thin [3,26,27].

4. IMMEDIATE POST-BIRTH CARE

Approximately 85% to 90% of infants make the transition from intrauterine to extrauterine life with no assistance necessary [28,29]. However, for the remaining few newborns, some assistance may be required, ranging from simple stimulation to complete resuscitation.

All nurses should be familiar with the ABCs of resuscitation: airway, breathing, and circulation. Because newborns are wet when they are born, they can suffer rapid heat loss if a warm environment is not maintained [28]. Therefore, it is critical to maintain a warm, or thermoneutral, environment for the infant throughout the first hours and days of life. This can be accomplished by placing the infant on the mother's abdomen, with warm blankets placed over them both to maintain body heat. Alternatively, if the need for further intervention is anticipated, or if the caregiver prefers, the infant should be placed on a preheated radiant warmer.

As the infant is being dried with warm blankets, the nurse should also be evaluating the infant's airway, breathing, muscle tone, color, and gestational age. All of these things should be evaluated within the first 30 seconds of life. The airway should be cleared with a bulb syringe or mechanical suction, and the infant should be positioned in such a manner as to facilitate an obstruction-free airway. If, in the initial evaluation, the infant is found to be clear of meconium, is breathing or crying, has good tone, is pink, and appears to be term gestation, then routine care need only be provided [28]. Routine care is comprised of assuring that the infant is warm and dry and keeping the airway clear. According to Neonatal Resuscitation Program standards, further care is warranted if the newborn fails to respond to birth in this positive manner [28].

In the United States, antibiotic eye ointment for the prophylaxis of ophthalmia neonatorum is highly recommended in all newborns [30,31,32]. Ophthalmia neonatorum is the inflammation of the eyes resulting from exposure to gonorrhea or chlamydia as the infant passes through the birth canal and can lead to blindness [30]. Administration of vitamin K intramuscularly is also common in the United States to prevent hemorrhagic disorders [4]. Coagulation alteration is seen predominately in infants in the second or third day of life, specifically because factors VII, VIII, IX, and X are dependent on the synthesis of vitamin K [33,34].

5. APGAR SCORE

In 1953, an anesthesiologist named Virginia Apgar designed a tool for evaluating newborn infants [35]. The Apgar scores grade the infant's response to extrauterine life in five categories [36]:

- Heart rate

- Respiratory effort

- Muscle tone

- Reflex irritability

- Color

There are a maximum of 2 points possible in each category, for a total of 10 possible points. The Apgar determination is completed at one and five minutes of life. It is important to note that resuscitative measures should not be delayed while awaiting the one- and five-minute marks for Apgar determination.

Morbidity and mortality findings have been found to correlate with the five-minute Apgar score [37,38]. The one-minute Apgar score correlates with the pH of cord blood. The lower the score, the more acidotic the infant; in addition, infants with lower scores have worsening cardiorespiratory depression [35]. Some studies have suggested that the Apgar score loses clinical significance for infants of 23 to 25 weeks' gestation who survive their first 24 hours of life [39].

Heart rate can be determined either through auscultation of the apical pulsation or by palpating the umbilical cord. A heart rate greater than 100 beats per minute (bpm) is awarded a score of 2 points. A pulse of less than 100 bpm garners 1 point. An absent heartbeat would obtain zero points [35,36].

Assessment of the respiratory effort requires a multifaceted approach. Movement of air in and out of the lungs may be auscultated at the time that a respiratory rate is obtained. An infant with a good cry is awarded 2 points for respiratory effort. An infant that is making some attempt at breathing but may be categorized as slow or irregular will obtain only 1 point. An irregular breathing pattern, also known as periodic breathing, is a normal finding in some newborns. However, if periodic breathing is associated with nasal flaring, grunting, retractions, cyanosis, or decreased rate, further assessment and intervention may be required. A newborn with an absent respiratory drive will receive zero points [35,36].

The nurse considers muscle tone acceptable if the infant's elbows, hips, and knees are flexed and allow active extension of extremities. The infant should return to the gently flexed position after examination. An attitude of flexion is necessary to obtain 2 points. An infant with some flexion should be assigned 1 point. A limp infant would receive zero points [35,36].

Reflex irritability is noted as the infant reacts to noxious stimulation. An appropriate response to stimuli, such as suctioning or rubbing the soles of the feet, would be for the infant to cry. This response would be awarded 2 points. If the newborn grimaces in response to such stimuli, 1 point would be awarded for effort. If the infant shows no response, then zero points would be awarded [35,36].

Color can be assessed by noting the color of mucous membranes, the trunk, and the soles of the feet. The infant should be pink and not dusky. An infant who is completely pink, including the hands and feet, would be awarded 2 points in this category. An infant that is pink but is acrocyanotic (i.e., has blue hands and/or feet) would receive 1 point. An infant that is blue, gray, or dusky would receive zero points [35,36].

6. NEWBORN SCREENING

Newborn screening programs began in the early 1960s with the development of a screening test for phenylketonuria (PKU) [40]. Newborn screening in the United States is a public health program aimed at the early identification of a variety of serious conditions, including genetic disorders (e.g., cystic fibrosis, hearing loss) and endocrine disorders (e.g., congenital adrenal hyperplasia, primary congenital hypothyroidism) [40,41]. In 2003, all but four states were screening for only six of these disorders. By 2018, most states reported screening for at least 29 (of 35 recommended) genetic and endocrine disorders on the standardized uniform panel of core conditions [41,44].

The adoption of a uniform newborn screening panel has led to earlier lifesaving treatment and intervention for newborns with these disorders [42,43]. The number and types of disorders screened for vary by state, but generally are guided by the Recommended Universal Screening Panel, which was developed by the U.S. Department of Health and Human Services [40,44].

7. PERIODS OF REACTIVITY

All healthy newborns go through predictable periods of alertness and sleep that should be assessed and taken into consideration when performing the comprehensive physical examination. Distressed infants also progress through these stages but at a much slower rate [1]. These stages are called the first and second periods of reactivity.

The first period of reactivity generally lasts six to eight hours. For the first 30 minutes after birth, the newborn is generally very alert and active. The infant will usually have a vigorous suck reflex during this time, and it is generally an excellent time to begin breastfeeding. The infant will have open eyes and will be interested in looking around. Physiologically, the infant's respiratory rate may be increased and the lungs will sound quite wet. The heart rate may be increased, bowel sounds are active, mucus production is increased, and body temperature may be slightly decreased [1,45].

After this initial period of alertness, the newborn will go into a deep sleep that generally lasts from two to four hours, though it may continue much longer. During this period, the infant is very calm. Attempts to stimulate the infant will generally be unsuccessful. Ideally, the physical examination should be completed before this time and the infant can then be left alone to sleep. Physiologically, the infant will experience a decrease in respiratory rate, mucus production, and temperature and will likely not void or stool [1,45].

The second period of reactivity, which usually lasts two to five hours, begins when the newborn wakes from this deep sleep state. The infant is generally very alert once again and showing signs of hunger. This is an excellent opportunity for the infant and family to interact with each other and for the nurse to begin some teaching regarding hunger cues and other ways that the infant may communicate needs. Physiologically, the newborn's heart and respiratory rates increase, the gag reflex is active, and the production of mucus and meconium resumes [1,45].

8. ASSESSMENT OF ATTACHMENT

Throughout the initial postbirth care and physical exam of the newborn, the nurse should be alert for signs of attachment forming between the infant and the parents. It is important for the nurse to look for those behaviors that lead to the successful process of attachment and bonding between parent and infant [1].

Unlike the physical examination, which uses concrete guidelines, the assessment of attachment requires the nurse to observe interactions and speak with the new parents regarding their expectations, dreams, and desires for their infant. This part of the newborn assessment can be challenging in today's hospital environment of shorter stays, but it is imperative in ensuring the well-being of the infant.

The following guidelines may be used when assessing infant-parent attachment [1]:

- When the infant is brought to the parents, do they reach out for the infant and call the infant by name?

- Do the parents speak about the infant in terms of identification (i.e., who the infant looks like; what appears special about their child over other infants)?

- When the parents are holding the infant, what kind of body contact is there? Do they feel at ease in changing the infant's position? Are fingertips or whole hands used? Are there parts of the body they avoid touching or parts of the body they investigate and scrutinize?

- When the infant is awake, what kinds of stimulation do the parents provide? Do they talk to the infant, to each other, or to no one? How do they look at the infant (e.g., direct visual contact, avoidance of eye contact, or looking at other people or objects)?

- How comfortable do the parents appear in terms of caring for the infant? Do they express any concern regarding their ability or disgust for certain activities, such as changing diapers?

- What type of affection do they demonstrate to the newborn, such as smiling, stroking, kissing, or rocking?

- If the infant is fussy, what kinds of comforting techniques do the parents use, such as rocking, swaddling, talking, or stroking?

9. GENERAL APPEARANCE ASSESSMENT

After the prenatal history has been obtained, the placenta has been evaluated, immediate postbirth care has been provided, and Apgar scores assigned, one can proceed with the physical examination. As with other facets of nursing care, the physical assessment always begins with the general appearance.

One important assessment strategy is to discuss the upcoming assessment with the infant's parents. Including the parents during the assessment allows the healthcare provider to point out both normal and abnormal findings. Optimizing this time with the parents assists them in understanding their infant and allows them to ask questions [46].

The following findings are considered warning signs that may be seen during the general assessment [35]:

- Axillary temperature less than 36.1°C or greater than 37.2°C

- Heart rate less than 100 bpm or greater than 160 bpm

- Respiratory rate less than 30 or greater than 60 breaths per minute

- Cyanosis

- Jaundice

- Periods of apnea lasting more than 15 seconds

- Lack of movement or responsiveness

- Hypotonic or hypertonic position

- Lack of interest in environment

Should these findings be noted, they would warrant immediate further investigation and treatment.

As noted, maintaining a thermoneutral environment is an important consideration. The assessment of any newborn should be conducted in a warm, well-lit environment. Cooler environments stress the newborn and may lead to inaccuracies in assessment. For example, incorrect findings may be made if the patient is found to look blue, experience bradycardia, or have cold hands and feet due to a hypothermic environment.

The assessment of the infant can be conducted through inspection, auscultation, and palpation. Inspection should occur before physical contact is made with the infant, though the need may arise to remove blankets, diapers, or clothing in order to complete a thorough inspection. Whenever possible, complete the observation portion of the assessment before touching the newborn. Observe the infant's position, temperament, sleep or wake cycle, color, movement, and respiratory pattern before disturbing the infant. Once the newborn has been disturbed, he or she may become agitated, resulting in a guarded posture, increased respiratory rate, and temperament changes. During the assessment, an inspection of the infant's activity level, color, respiratory effort, ease of movement, and posture should be noted [3]. During inspection, one should also note the appearance of any dysmorphic features. The finding of three or more dysmorphic features may warrant chromosome analysis [29,47].

During inspection, the activity level should be noted for sleep states progressing to irritability during the more intrusive parts of the exam [48]. There are six identified sleep states: deep sleep; active sleep; drowsy, in-between state; awake alert; alert and fussy; and crying [33,48,49]. The infant should be assessed in an awake alert state, which has been identified as the infant being bright, focused, and minimally active [29,33,48,49]. Motor activity, such as tremulousness, irritability, and defensiveness, should be noted both before and during the assessment [48].

Proper lighting is important as the accurate assessment of a newborn's skin can be useful in determining problems. Even if a newborn is slightly icteric at birth, making this determination can be useful in following the infant for potential problems related to jaundice. If the lighting of the examination room is inadequate, the slight appearance of jaundice may be overlooked. Color is important in determining pulmonary and cardiac involvement and thermoregulation, as well as other organ function in the newborn. Changes in the infant's color may occur throughout the exam when the infant cries, becomes cool, or is irritable. Assessment should be made for jaundice, cyanosis, pallor, and plethora [3]. It is important to note that acrocyanosis, the blue or dusky hands and feet with a pink trunk and mucous membranes, is frequently found and does not indicate a major problem.

Respiratory effort should be assessed by noting the rate and quality of breaths. Depth of breathing, retracting, grunting, nasal flaring, head bobbing, and posture changes associated with inadequate effort should be noted. Periodic breathing by the newborn (i.e., taking several breaths in a row then pausing for up to 15 seconds) is a normal finding. However, grunting, flaring, retractions, and head bobbing warrant further investigation [29]. A full discussion of respiratory assessment follows later in this course.

During inspection, resting posture offers many clues to the health of a newborn. In a healthy, full-term newborn, the posture should be that of flexion [1,29]. Muscle tone, including the amount of flexion or extension, should be assessed. Asymmetry of extremities, comparison of upper and lower extremities, and flaccid posture or contraction should be noted and further evaluated during the exam. The newborn's ease of movement should be noted throughout the assessment. The levels of fluidity and spasticity should be observed.

10. GENERAL MEASUREMENTS

General measurements should be performed on each newborn. Infants who are found to have values outside the accepted range may require further evaluation and treatment. Weight, length, head circumference, and chest circumference measurements allow the practitioner to find abnormalities. Plotting these abnormalities provides a quick reference for comparisons with acceptable ranges.

WEIGHT

Birth weight is an important indicator of perinatal morbidity and mortality [2]. When weighing a newborn, it is important to do so when the infant is not wearing a diaper. If a diaper is in place, subtract the weight of the diaper from the total weight. A strategy to prevent weight inaccuracies is to use the same scale each time the patient is weighed. This will control for differences in zero balancing between two scales. If an infant is being weighed on a bed that has a built-in scale, it is important to remove any extra sheets, toys, or diapers. A further consideration in weighing the critically ill newborn is lifting the intravenous infusion lines, as well as other pieces of equipment, such as ventilator tubing, so they do not cause an inaccurately high measurement. A list of the items that the bed was initially zeroed with should be recorded for easy access. These items should remain on the bed during each weighing, so the zero balance of the scale remains at a constant and only the infant's weight is measured. For example, removing a critically ill newborn from the bed each time the weight must be assessed may not be feasible. Instead, the foam mattress and gel devices need not be removed each time the infant is weighed. One of the most important factors in monitoring an infant's fluid balance is weight [50]. Birth weight should be measured soon after birth because the fluid loss that occurs after birth begins fairly rapidly [1].

Classification of weight may be used independent of gestational age. Extremely low birth weight infants weigh less than 1,000 grams, very low birth weight newborns weigh less than 1,500 grams, and low birth weight newborns weigh less than 2,500 grams [51]. Normal weight in a term newborn ranges from 2,500 to 4,000 grams [52,53].

Another common classification system for identifying birth weight-related risk factors uses the terms large for gestational age (LGA), appropriate for gestational age (AGA), and small for gestational age (SGA) (Table 1). An LGA infant weighs more than the 90th percentile at any given gestational age [54]. At term, an LGA infant would be considered one that weighs more than 4,000 grams. An AGA infant is one that falls anywhere between the 10th and the 90th percentile for his or her given age [53]. At term, this would be any infant weighing between 2,500 and 4,000 grams. An SGA infant falls below the 10th percentile for his or her gestational age [53]. At term, an SGA infant weighs less than 2,500 grams. Infants are categorized as term when they are born between the first day of week 37 to 42 weeks of gestation [55]. Before 37 weeks, the newborn may be considered premature, and after 42 weeks, the newborn should be classified as post-term [55] (Table 2). Correctly categorizing the newborn can aid in determining future risk factors.

Table 1: WEIGHT AND PERCENTILE CLASSIFICATIONS

Classification

Birth Weight

Percentile

Small for gestational age (SGA)

<2,500 g

<10th percentile

Appropriate for gestational age (AGA)

2,500–4,000 g

10th to 90th percentile

Large for gestational age (LGA)

>4,000 g

>90th percentile

Source: [54,56]

Table 2: GESTATIONAL AGE CLASSIFICATION

Classification

Gestation

Early-term

37 to <39 weeks

Full-term

39 to <41 weeks

Late-term

41 to <42 weeks

Post-term

42 weeks and beyond

Source: [145]

LENGTH

The most accurate way to measure length is to fully extend the newborn's leg and record the length from the crown of the head to the heel. To establish an accurate measurement, one person should hold the infant in place while another person completes the measurements. To ensure accurate measurements, mark the sheet or the paper on which the infant is lying, at the infant's crown and heel. Acceptable newborn length ranges from 48–53 cm or 19–21 inches [37]. An adjunct to crown-heel measurement is the crown-rump measurement. This particular assessment is useful in determining anatomical abnormalities such as dwarfism [3].

HEAD AND CHEST CIRCUMFERENCE

Head circumference, often referred to as occipital-frontal circumference, may be determined by measuring the circumference of the skull from the frontal to occipital area by placing the tape measure above the ears. It is important to measure the largest part of the head when measuring occipital-frontal circumference. Because of edema and molding due to the birth process, the subsequent occipital-frontal circumference measurements may increase or decrease as much as 2 cm during the first week of life [3]. The head circumference is larger than the abdominal circumference until 32 through 36 weeks' gestation, when it is equal. Acceptable head circumference is 33–37 cm or 13–15 inches [3,37,57,184]

Chest circumference is obtained by measuring around the infant's chest at nipple line midway between inspiration and expiration. Acceptable chest circumference is 30.5–33 cm or 12–13 inches [37,57]. As noted, the head circumference should generally be larger than the chest circumference.

General measurements should be plotted on a standard growth chart and followed over time. Growth charts have been developed to detect nutritional and growth disturbances and are available through the National Center for Health Statistics [58]. The CDC recommends that healthcare providers use the World Health Organization (WHO) growth standards to monitor growth for infants and children ages 0 to 2 years in the United States. For children 2 years of age and older, the CDC recommends that providers use the CDC growth charts [59,60]. For newborns, these charts record [58]:

- Length for age

- Weight for age

- Head circumference for age

- Weight for length

11. GESTATIONAL AGE ASSESSMENT

Protocols vary regarding which infants require gestational age assessment. Some clinicians feel that this assessment should be standard for all newborns, while others use this tool on a case-by-case basis. A gestational age assessment should be performed on any infant that is thought to be premature or when there is a question of gestation. When assessing the gestational age of newborns, the New Ballard Score is often used [3,61]. The New Ballard Score takes into account both neuromuscular and physical maturity [45]. The score sheet includes scales that have grades of -1 through 5. Once the assessment is complete and the scores assigned, the scores are simply added. The total score is then correlated with the corresponding number of weeks to give the clinical determinant of the newborn's age.

Gestational age should be assessed within the first four hours of birth for maximum reliability [33]. The nurse should initially conduct the parts of the examination that can be done without disturbing the infant. This includes the physical maturity section of the New Ballard Score as well as the resting posture component of the neuromuscular maturity section.

CASE STUDY

The following discussion appears in the order in which the examination should be conducted. Please follow along with the New Ballard Score (Figure 1).

Figure 1: NEW BALLARD SCORE

Source : [Reprinted from The Journal of Pediatrics, 11(3), J.L. Ballard, J.C. Khoury, K. Wedif, C. Jarg, B.L. Walsman, and R. Lipp, “New Ballard Score Expanded to Include Extremely Premature Infants.”] Copyright 1991 by Mosby, Inc., with permission from Elsevier.

Resting posture should be evaluated first before the infant is disturbed. The infant should be supine on a flat surface [33]. There are five choices, ranging from 0 points, for a flaccid infant, to 4 points, for a completely flexed infant. Infant A is lying quietly on her back with her arms out to her sides at a greater than 90-degree angle. Her legs are bent at the knee with only a small amount of flexion. She should be awarded 2 points for posture.

The skin should be evaluated next. There are seven subclassifications in the skin category. The extremely premature infant has transparent, friable skin and would be awarded -1 points. The postmature infant presents with leathery, tough, cracked skin and would receive 5 points. Infant A has a fine rash. There appears to be some peeling, with few veins visible on the abdomen. She is awarded 2 points for her skin maturity.

The presence or absence of lanugo (i.e., fine body hair) is evaluated next, with six categories from which to choose. The extremely premature infant is bald, not having had the opportunity to develop lanugo. The postmature infant is also mostly bald because the majority of lanugo has fallen out prior to birth. Infant A has large bald patches but still has a significant amount of hair on her back and ears. She receives 3 points.

Next, the soles of Infant A's feet are examined. Creases begin forming at the top of the newborn's foot and progress to the sole with maturity [33]. There are seven categories from which to choose in this area of assessment, ranging from -2 to 4 points. The extremely premature infant has a smooth sole and should be given points based on the size of the foot. The postmature infant has creases over the entire foot, which often appears cracked and leathery. Infant A has creases over the majority of her foot but not the entire sole. She receives 3 points for her feet.

Observing the presence and size of the breast bud is the next indicator of physical maturity. There are six categories from which to choose in this area. The extremely premature infant will have imperceptible breast buds, while the postmature infant will have well-developed 5–10 mm breast buds and a full areola. Infant A has a noticeable areola and a small bud measuring 2 mm. She is given 2 points.

The development of the newborn's eyes and ears are important markers of gestational age. There are seven categories from which to choose in this area. The extremely premature infant will have fused eyelids; the scoring on these infants is dependent on how tightly or loosely the eyes are closed. The postmature infant will have thick cartilage in the ears and they will be stiff. Infant A has open eyes, and her ears are soft but they do recoil easily. She is awarded 2 points for her eyes and ears.

The last area in the physical maturity assessment is genitalia. There are six categories from which to choose in this area. The extremely premature male infant will have a flat and smooth scrotum; the testes will not have descended into the scrotum. The extremely premature female infant will have an extremely prominent clitoris and flat labia. The postmature male infant will have descended testes and pendulous scrotum with deep rugae. The postmature female will show a labia majora that completely covers her clitoris and labia minora. Infant A has a large labia majora and a small labia minora. Her clitoris is not visible. She is awarded 3 points.

Returning to the neuromuscular maturity section of the New Ballard Score, the square window is measured by bending the wrist and visualizing how far forward the infant's hand can go. The extremely premature infant will have little flexibility in the wrist and show a greater than 90-degree angle. The postmature infant will have great flexibility and the hand will be completely in contact with the forearm. Infant A demonstrates a 30-degree angle when assessing the square window sign. She receives 3 points.

Arm recoil has much to do with the infant's flexion. One performs this test by actively extending the infant's arm to a straight position and letting go in order to evaluate how far back to full flexion the arm returns. In the extremely premature infant, there will be no recoil, and in the postmature infant, there will be full recoil. Again, an observation of the angle determines the point assignment. Infant A recoils to a 140-degree angle. She is given 2 points.

Actively extending the infant's leg and placing the foot near the head may measure popliteal angle. The extremely premature infant will have great flexibility and will be able to demonstrate a completely straight leg in this posture. The postmature infant will show little flexibility and will be unable to extend the knee to greater than 90 degrees. Infant A extends her leg to a 100-degree angle and is given 3 points.

Scarf sign may be measured by extending the infant's arm across the body and measuring how far across the elbow falls. The extremely premature infant will demonstrate great flexibility, and the elbow will be able to stretch all the way across the body. The postmature infant will show little flexibility and will barely get the elbow to meet the inner chest wall. Infant A is able to get her elbow to midline and is awarded 2 points.

The last marker of neuromuscular maturity is the heel to ear sign. This sign is measured by actively extending the infant's foot and attempting to reach the ear. The extremely premature infant will be able to touch his or her foot to the ear, while the postmature infant will be unable to extend a foot anywhere near the ear. Infant A can only extend her foot to a right angle above her body and is given 3 points.

Finally, the points for each category are added to give an estimated gestational age. In our example, Infant A received 15 points in the neuromuscular maturity area and 15 points in the physical maturity section. This is a grand total of 30 points, making her approximately 36 weeks' gestation.

12. SKIN ASSESSMENT

A thorough skin assessment can be an important tool that provides invaluable information. Skin can deliver insight into the newborn's thermoregulation system, tell the experienced practitioner about the newborn's cardiac and respiratory functioning, be an invaluable indicator of gestational age, and be the first indicator of an infectious process.

VERNIX CASEOSA

Vernix caseosa is a lubricant found on the skin or in the skin folds. While usually white, it may be yellow from bilirubin stains or green from meconium staining [34]. It disappears as the fetus ages and, by term, is generally found only in the folds such as the armpit or the groin. Vernix caseosa is almost entirely absent in postmature fetuses and may be an important indicator of gestational age.

LANUGO

Lanugo is the name for the fine hair that covers the body, ears, and forehead of many newborns [3]. Lanugo first develops at 19 weeks' gestation and becomes most obvious at 27 to 28 weeks' gestation. As such, lanugo is an important indicator of gestational age. It may be important for parents to understand that the hair will fall off within the first few weeks of life.

WARNING SIGNS

Warning signs of the skin assessment that would warrant further investigation and/or immediate intervention include:

- Long nails and desquamation, indicating postmaturity

- Thin translucent skin with abundant vernix and lanugo, indicating prematurity

- Pallor, possibly caused by hypothermia, anemia, sepsis, or shock

- Cyanosis, possibly caused by cardiorespiratory disease, hypoglycemia, polycythemia, sepsis, or hypothermia

- Petechiae, possibly caused by thrombocytopenia, sepsis, congenital infection, or pressure sustained during delivery

- Plethora, possibly caused by polycythemia

- Meconium staining, possibly caused by intrauterine asphyxia

- Abnormal hair distribution or extra skin folds, possibly associated with genetic abnormalities

- Poor skin turgor associated with intrauterine growth retardation and hypoglycemia

- Large hemangiomas, which may trap platelets within their borders and cause thrombocytopenia

- Bullae or pustules, possibly caused by staphylococcal infection

SKIN TEMPERATURE AND MATURITY

During the first few moments of life, when the infant is first exposed to the sensation of cold, skin receptors become stimulated. These receptors aid in stimulating the respiratory center to begin the first sequences of breaths and pulmonary gas exchange [37]. A skin temperature range of 36°C to 36.5°C (96.8°F to 97.7°F) is acceptable for the term newborn [37].

In a preterm infant, one will find the skin to be more translucent as opposed to the thick, cracked appearance of the term infant's skin. Being able to visualize vessels through the skin on the abdominal wall is also an age marker [3]. It is easy to see abdominal vessels in preterm infants because of the transparency of the skin. Creases in the sole develop from toe to heel. A decrease in the amount of creasing of the soles of the feet may be a sign of motor deficits [3]. This is based on the belief that foot creasing is caused by movement of the lower extremities, movement of the fetus, and uterine compression. Increased creasing of the sole, generally seen in postmaturity, is also a sign that warrants further investigation.

The assessment of skin turgor may be easily completed along with the assessment of the infant's hydration status, fontanelles, and mucous membranes. The skin turgor test is simple and corroborates the other findings of dehydration. To test the infant's skin turgor, simply pinch the skin. The skin should automatically recoil. If the skin remains "pinched," the infant has poor skin turgor [62].

SKIN COLOR

Color is a valuable finding in the assessment of a newborn. Due to variations in newborns' skin tones, an assessment may vary between healthcare personnel. In this case, an agreement of what to call the color should be noted between personnel so that fluctuations from the baseline color may be quickly identified. If an infant has a normal cardiorespiratory function, the mucous membranes, nail beds, palms of hands, and soles of feet will be pink in lighter-pigmented infants [63]. In darker-pigmented infants, color may be light pink with a yellow or red tinge. It is important to keep in mind that acrocyanosis is a normal finding in the first 24 to 48 hours of life, and an infant can still be considered pink if his/her mucous membranes and trunk remain so, even if the extremities remain blue or pale [64]. Alterations in cardiovascular or respiratory function may present in the form of mottled or dusky skin color. Pallor can be a sign of poor perfusion or anemia. If the infant's skin appears to be pale, then it should be noted and reasons should be identified. Other symptoms of poor skin perfusion are mottling and delayed capillary refilling [63]. Central cyanosis, or a blue color of the face, trunk, or mucous membranes, is not a normal finding and should be acted upon immediately.

Hyperbilirubinemia

Neonatal hyperbilirubinemia, or jaundice, is the yellowish discoloration of an infant's skin and sclera caused by a buildup of the bile pigment bilirubin. Hyperbilirubinemia that is noted in the first 24 hours of life is considered pathologic and should be treated appropriately [65]. Hyperbilirubinemia is a normal variation to a certain degree, and most infants will show some signs during the first week of life [65]. The severity and diagnosis of hyperbilirubinemia is dependent on the bilirubin level at a certain newborn age as well as the presence of risk factors [65,66].

Newborns become jaundiced for two main reasons: immaturity of the liver and/or the excessive amount of fetal hemoglobin that is required in utero. The liver is thought to be one of the last organs to fully mature; therefore, even the full-term infant may be considered to have an immature liver. The liver is where bilirubin, a byproduct of hemoglobin metabolism, is processed, and the immature organ may not be able to keep up with the increased demand that occurs shortly after birth. The increased demand is caused by the breakdown of fetal hemoglobin.

Evidence Based Practice Recommendation

The Academy of Breastfeeding Medicine asserts that clinicians should identify lactation risk factors and assess the infant's weight, hydration, jaundice, feeding activity, and output.

https://abm.memberclicks.net/assets/DOCUMENTS/PROTOCOLS/14-breastfeeding-friendly-physicians-office-part-1-protocol-english.pdf

Last Accessed: August 10, 2020

Level of Evidence: III (Opinions of respected authorities, based on clinical experience, descriptive studies and case reports; or reports of expert committees)

In utero, fetuses are exposed to a much lower partial oxygen pressure (PO_2) than that of the air they begin to breathe as soon as they are born. For this reason, they are in need of a much higher amount of fetal hemoglobin than is necessary after they are born. Fetal hemoglobin has unique characteristics. It has less oxygen carrying capacity, though it does have a greater affinity for the oxygen molecule. Because of the strong oxygen affinity, the oxygen does not unload until the tissue oxygen levels in an infant are lower than they would be in an adult. After they are born, infants begin to rapidly break down the excess hemoglobin to adjust to the much higher PO_2 of the air. When fetal hemoglobin is broken down, the heme is converted to biliverdin and then to unconjugated bilirubin. When the unconjugated bilirubin level exceeds normal, there becomes an increased chance of it depositing in the basal ganglia. Deposition of unconjugated bilirubin in the brain is known as kernicterus, a chronic and permanent form of hyperbilirubinemia that can be life-threatening [66].

For newborns that present with jaundice, the American Academy of Pediatrics (AAP) has several recommendations. Total serum bilirubin or transcutaneous bilirubin levels should be measured within the first 24 hours of life, as observational assessment of the degree of jaundice severity is inaccurate and does not take into account the appearance of infants with darker skin pigmentation [66]. Bilirubin levels should be considered in relation to the age of the newborn (i.e., measured by hours) [66]. Infants younger than 38 weeks' gestation who are breastfed are at greater risk of developing hyperbilirubinemia; these infants require additional observation [66]. All infants should be screened for the risk of developing severe hyperbilirubinemia, and parents should be provided with written and verbal information about neonatal jaundice prior to hospital discharge [66].

Obtaining a thorough history for risk factors of hyperbilirubinemia is essential. The causes of jaundice may be related to Rh incompatibility, abnormal blood cell structures, birth injury, polycythemia, glucose-6-phosphate dehydrogenase or pyruvate kinase deficiency, infection, certain medications, and prematurity [65]. Depending on the cause of the hyperbilirubinemia, treatment includes more frequent feedings, phototherapy, maintaining active bowel routines, and, occasionally, exchange transfusions [65,66].

BIRTHMARKS

When assessing for dysmorphic features of the skin, findings of birthmarks, missing skin, skin tags, vesicles, and lesions should be documented [47]. The use of drawings to better describe abnormal skin findings are helpful [47].

Birthmarks are common in the newborn but may cause considerable anxiety in parents. Some birthmarks involute voluntarily, while others may persist into adulthood [67,68]. The majority of birthmarks are benign; however, some birthmarks may necessitate further investigation to assess their potential for future malignancy or possible underlying conditions. Birthmarks may be divided into three etiologic categories [67]:

- Vascular

- Pigmented

- Abnormal development

Vascular nevi include hemangiomas, nevus flammeus (i.e., port wine stain), and nevus simplex (i.e., stork bite, salmon patch). Pigmented nevi include congenital melanocytic nevi and dermal melanosis (i.e., mongolian spots). Nevi caused by abnormal development, such as supernumerary nipples and lesions along the spine associated with spinal dysraphism, will be discussed in the chest and back assessment sections of this course, respectively.

Vascular Nevi

Strawberry Hemangiomas

Also referred to as strawberry mark, nevus vascularis, capillary hemangioma, or hemangioma simplex, strawberry hemangiomas consist of newly formed capillaries occupying both the dermal and subdermal layers. Strawberry marks are typically raised, sharply demarcated, and bright red. However, these lesions may also present as a patch of pale skin or may not be visible at all [67]. Hemangiomas may be present at birth but most often appear in the first several months of life. They occur most often on the neck and face [68]. Generally, no intervention is required, though many parents will need reassurance that the lesion will involute spontaneously in most cases [67,68]. It is possible for these lesions to compress the eyes, airway, or vital organs, in which case the infant should be referred immediately for treatment, usually with steroid injections or laser therapy [67].

Cavernous Hemangiomas

Cavernous hemangiomas are located in the subcutaneous tissue and generally do not involve the overlying skin, though they may be topped by a strawberry hemangioma or nevus flammeus. Cavernous hemangiomas are composed of a communicating network of interconnected venules. They are often present at birth and undergo a period of rapid growth before they begin to recede on their own. They appear as a reddish-blue, spongy swelling filled with blood. Steroids and/or laser therapy may be used to reduce the size of hemangiomas, especially if their location is obstructive or makes them prone to bleeding [68].

Nevus Flammeus

Nevus flammeus, or port wine stain, is usually observed at birth and is composed of dilated or distended dermal capillaries and postcapillary venules [69]. Most frequently found on the face, nevus flammeus are generally red-to-purple in color, can be of varying size, and are generally unilateral [67]. They are not raised and do not blanch with pressure. Treatment is usually unnecessary unless the lesion is very large or associated with an underlying condition [67]. When it appears along with glaucoma and seizures, nevus flammeus is associated with Sturge-Weber syndrome [69]. An infant with nevus flammeus near the eye should be referred to an ophthalmologist [67].

Nevus Simplex

Nevus simplex, also referred to as stork bites, angel kisses, or salmon patches, appear in 30% to 50% of all newborns [67]. Nevus simplex is generally found at the nape of the neck, but may be also found on the face and scalp. It appears pink in color, blanches with pressure, and is commonly bilateral [67,68]. It has no clinical significance and fades quickly, often having disappeared entirely by 18 months of age [70].

Pigmented Nevi

Congenital Melanocytic Nevi

Most nevi, or moles, do not appear until after birth. However, 0.2% to 2.1% of infants are born with congenital melanocytic nevi [67]. These lesions are usually flat, but some may be raised. They appear brown or black in color and may be hairy. Due to their potential for malignancy, careful consideration regarding management is required. A hairy nevus discovered along the base of the spine is often associated with spina bifida. Infants with large or giant melanocytic nevi should be referred to a surgeon [67].

Dermal Melanosis

Dermal melanosis, or Mongolian spot, is a common finding in infants of Asian, East Indian, or African descent. Caused by melanocytes trapped deep in the skin, these lesions appear flat and bluish-gray or brown and are most commonly found on the back or buttocks. Due to their resemblance to bruises, which may lead to unsubstantiated allegations of child abuse, it is important to document all dermal melanoses in the infant's medical record and explain their presence to the infant's parents. No intervention is required, and most cases resolve by 2 years of age [71].

Common Rashes

Erythema Toxicum Neonatorum

It is estimated that 50% of infants are born with erythema toxicum neonatorum, commonly referred to as newborn rash [72]. The lesions, which may appear as erythematous macules, papules, or vesicles, can appear suddenly in the first three weeks on any part of the body, with the exception of the palms and soles. Although it is not cause for concern in healthy infants, infants who appear ill and have an atypical rash should be tested for fungal, viral, and bacterial infections. The rash has an unpredictable occurrence and presentation. Though it may appear significant to the parents, it requires no treatment and typically resolves within seven days [72,73].

Acne Neonatorum

Acne neonatorum, consisting of closed comedones, is normally found on the forehead, nose, and cheeks. An estimated 20% of infants have acne neonatorum, which is believed to be caused by infant or maternal androgen levels [73]. Parents should be reassured that the acne will resolve with no residual scarring within approximately four months [73].

Milia

Milia are sebaceous glands that are occluded with keratin. They appear as tiny white or yellow papules, approximately 1–2 mm in size, and are generally found on the nose, chin, forehead, and cheeks. They require no special care and usually resolve by 4 weeks of age [34,73].

13. HEAD ASSESSMENT

When assessing the newborn's head, one begins with the general appearance of the head, including the shape, circumference, suture lines, and fontanelle size [74]. Symmetry or asymmetry should be noted, though asymmetry can be a normal variation resulting from the fetal lie in utero. Facial bruising is commonly caused by birth trauma and should be noted. The following section addresses assessment of the newborn's head shape, size, and fontanelles.

HEAD SIZE AND SHAPE

During physical examination, the head should be supported appropriately. The head should move easily from side to side and up and down. Infants may or may not be able to support their heads initially. The shape of each infant's head is unique. After a vertex vaginal delivery, a newborn's head is generally flattened over the forehead and rises to a point at the posterior of the skull over the occiput [1]. This shape reflects the process of molding, where the presenting part engages the cervix and becomes molded to the shape of the cervix. Molding is generally symmetrical in nature and is caused by the skull bones coming together to facilitate birth. The infant is born with a classic "cone head" appearance. This occurrence resolves spontaneously within three to five days and requires no intervention, beyond reassuring parents that their infant's head shape is not permanent [74].

Caput succedaneum and cephalohematoma may occur as a result of birth trauma. Caput succedaneum is the formation of edema of the scalp at the presenting part of the head [34,75]. It has a generally symmetrical appearance and crosses the suture lines. Cephalohematoma, a collection of blood beneath the periosteum, may also occur as a result of increased force to the newborn's head during vaginal birth. It has a generally asymmetrical appearance and does not cross suture lines [75]. It may look like a large "goose egg." It can be very alarming to parents, and they should be reassured that it is normal and will go away without treatment [76].

The occipital-frontal circumference in an AGA infant should measure 33–38 cm [77]. The inexperienced practitioner may require assistance if the infant is moving at the time of examination. As noted, the head circumference is approximately 2–3 cm larger than the chest circumference in newborns. The circumference should be plotted on a growth chart.

CRANIAL STRUCTURE

Important information can be gained by the accurate assessment of both anterior and posterior fontanelles. The fontanelle is best palpated with the second or third finger pad when the infant is quiet and in an upright position [77,78].

The anterior fontanelle, or soft spot, is diamond-shaped and demarcated by the coronal and sagittal sutures. Its anteroposterior measurement is approximately 4–5 cm, and it can be palpated midline, above the forehead [77]. The anterior fontanelle normally closes by 18 months of age [77].

The posterior fontanelle can be palpated midline, toward the back of the head, above the occiput. It is triangular in shape and demarcated by the sagittal and lambdoidal sutures. Its posterolateral measurement is approximately 0.5–2 cm [77]. The posterior fontanelle normally closes by 2 months of age; it is possible for a newborn to be born with a posterior fontanelle already closed [79].

A normal fontanelle should feel soft, yet spongy, and very slightly depressed [80]. A bulging fontanelle appears as a convex shape that feels firm but not spongy. The presence of a bulging fontanelle is indicative of increased intracranial pressure (ICP). Although there are numerous causes, the most common are hydrocephalus, trauma, intracranial hemorrhage, and infections, such as meningitis and encephalitis [74,80]. Accurate diagnosis of the cause of increased ICP may require imaging techniques, such as magnetic resonance imaging, computed tomography, and/or cranial ultrasound [74,79,81]. Crying, lying down, or vomiting can also cause slight bulging of the fontanelle. If the fontanelle returns to normal when the infant is returned to an upright position, it not considered a true bulging fontanelle.

A sunken fontanelle presents as a concave area that feels spongy but depressed. Sunken fontanelles are associated with dehydration and decreased ICP. Decreased peripheral perfusion, poor skin turgor, and sunken eyes may also be present [74]. During fluid resuscitation for dehydration, frequent assessments of the fontanelle can aid in preventing overload.

There are four suture lines that can be palpated: the frontal, coronal, sagittal, and lambdoid sutures. The frontal suture can be felt midline above the eyes running up the forehead and ending at the anterior fontanelle. The coronal suture can be felt from the anterior fontanelle running down the side of the head along the forehead line towards the ears. The sagittal suture can be palpated running midline between the anterior and posterior fontanelle. The lambdoid suture can be felt from the posterior fontanelle running down the head above the occiput towards the area behind the ears [35].

Overriding sutures are a normal finding resulting from birth trauma and molding and usually resolve spontaneously. However, they should be followed closely, and in the event that they do not spontaneously resolve, intervention should be taken to correct the problem. Widely spaced sutures may occur with a bulging anterior fontanelle and are a red flag for increased ICP. In more severe cases of increased ICP, the veins over the scalp may appear enlarged. These infants should receive an infectious disease and metabolic work-up, a standard eye exam, and imaging techniques similar to those used for diagnosing a bulging fontanelle [81].

WARNING SIGNS

During the head assessment, warning signs that warrant further investigation and/or immediate intervention include [35,74,81]:

- Abnormally large fontanelles

- Abnormally small fontanelles

- Suture lines that do not override or are widely spaced

- Bulging fontanelles

- Sunken or depressed fontanelles

- Enlarged veins over the scalp

14. EYE ASSESSMENT

According to the American Academy of Ophthalmology, neonatal conditions that prove to be the most severe and threatening to vision are congenital cataract, retinopathy of prematurity, congenital glaucoma, retinoblastoma, and cerebral visual impairment [82]. There are many risk factors for eye conditions in the newborn, including systemic conditions, neurologic disorders, perinatal complications, and a family history of eye or vision problems [82]. Special attention to eye health should be given to infants who are born prematurely and/or have multiple conditions [82,83].

Following an examination of the general size and appearance of the head, the nurse should assess the eyes. Warning signs should be noted followed by an orderly assessment of eye size, shape, placement, sclera color, and reflexes. Observations of any anomalies should be reported immediately [82].

All regions of the eye should be examined thoroughly for dysmorphic features. Determining the symmetry and completeness of brows and lashes with intact lid margins is important [47]. Initial observations should assess that the eyes are equal in size and placed symmetrically on the face. The outer corner of the eye should be at the same height as the top of the ear, if one were to draw an imaginary line between the two. Low-set ears may be associated with other signs of trisomy 18 or trisomy 21, such as Brushfield spots, a speckling of the iris [75]. Short palpebral fissures are associated with fetal alcohol and other syndromes [84].

When assessing for dysmorphic features, any missing or defective ocular tissue or incomplete development of portions of the eye should be noted as a possible coloboma. Colobomas may involve the eyelid margin or the iris and retina and are associated with several syndromes [85]. The iris may be absent altogether, referred to as aniridia; this most often occurs bilaterally [85].

The upper lid should cover only the top part of the eye. Drooping of the eyelid, or ptosis, may signal neuromuscular weakness [35]. "Doll's eyes" are characterized by a lag in eye movement [86]. This is a normal finding in newborns with muscular immaturity [87].

Epicanthal folds are vertical folds of skin covering the inner canthus of the eye. Epicanthal folds commonly occur among some races (i.e., Asian, Native American) and in newborns of any race prior to the elevation of the bridge of the nose [88]. However, presence of epicanthal folds has also been associated with fetal alcohol syndrome, Down syndrome, and Turner syndrome [88].

Examination of the internal parts of the eye should follow the peripheral examination. Lifting the infant's head while he or she is in the supine position encourages the infant to open its eyes [34]. Term infants are myopic, with a visual acuity of 20/200. Their optimal visual field is approximately 8–12 inches, or about as far away as their mother's face would be during feeding. The lids should unfuse by 28 weeks' gestation, but infants do not have full muscle control of the eyelids at birth. It is also important to assess newborns' tears and exudate. Exudate that is copious, greenish-yellow, or persists or appears after 24 hours of age is a sign of underlying infection [35,85].

The sclera may be white or bluish-white. A yellow appearance of the sclera is indicative of jaundice. Subconjunctival hemorrhage may be present from the pressure of birth. Any irregular shape or unequal size of the iris or pupil should be noted. A white pupil, or cat's eye reflex, indicates abnormalities [85,89]. Downward deviation of the irises exposing the sclera, or sun-setting sign, may be caused by hydrocephalus [90]. When assessing the infant's pupils the terms "equal," "round," "reactive," and "accommodating" can be helpful.

The red reflex is characterized by an equal and round red area of light at the pupil. If a red reflex is absent, white, dull, opaque, or asymmetric, the infant should be further examined for congenital cataracts, and dysmorphia related to chromosomal abnormalities should be considered [35,47,82,85].

There are several eye reflexes that should be examined. The blinking reflex can be tested either by bright light or a light touch. The infant should demonstrate an immediate blink when the eyes are stimulated. The corneal reflex is tested by a light pressure applied to the cornea with a piece of cotton, which should induce an instinctive blink. This reflex is not generally examined unless brain or eye damage is suspected [1]. The pupillary reflex may be determined by shining a light into the eye. The pupil should constrict instantly. Both eyes should be examined in the same manner, with a comparison made between the two. They should have equal size constriction in the same amount of time.

15. EAR ASSESSMENT

Examination of the ears should include size, shape, and location. Ear cartilage becomes firmer as the fetus ages, so preterm infants may have more pliable ears. The placement of the ear should be assessed as it relates to the inner canthus of the eye. A normal ear will at least touch the imaginary horizontal line. If the top of the ear falls below the line, then the ear is considered low set. A low-set ear may indicate chromosomal abnormalities (e.g., Down Syndrome, Turner Syndrome) and may be associated with renal complications [91,92]. The ears can be measured at their longest axis and compared to standardized charts for determination of dysmorphia [47]. Ears are considered small if less than 2.5 cm in the term infant [47].

Evidence Based Practice Recommendation

The USPSTF recommends screening for hearing loss in all newborn infants.

https://www.uspreventiveservicestaskforce.org/uspstf/recommendation/speech-and-language-delay-and-disorders-in-children-age-5-and-younger-screening

Last Accessed: August 10, 2020

Strength of Recommendation: B (There is high certainty that the net benefit is moderate or there is moderate certainty that the net benefit is moderate to substantial.)

In addition to size and position, appearance should also be analyzed for malformations, including absent pinna, abnormal folds, discharge, reddening, or preauricular tags [93]. Abnormal structure may be indicative of other conditions [94,95].

The National Institutes of Health (NIH) and the Joint Committee on Infant Hearing recommend the implementation of universal newborn hearing screening. Since the NIH first endorsed screening all newborns for hearing loss, the number of infants identified as hearing-impaired has increased dramatically [96]. According to the Joint Committee on Infant Hearing, more than 95% of newborns are assessed for hearing loss in the United States. However, nearly one-third of newborns who do not pass initial screening do not have appropriate follow-up to either confirm hearing loss and/or initiate appropriate early intervention services [97]. Technologies used to screen for hearing impairment in this population are auditory brainstem response and otoacoustic emission [97,98].

Infants with normal hearing should have some response to sounds and voices. In newborns, risk factors for hearing loss include a family history of hearing loss, neonatal intensive care stay of greater than five days, aminoglycoside administration of greater than five days, assisted ventilation, ototoxic medications, hyperbilirubinemia, in utero infections, craniofacial malformations, congenital microcephaly, temporal bone abnormalities, and ear anomalies [97]. However, as many as one-half of infants born with hearing loss in the United States have no known risk factors [92].

16. NOSE ASSESSMENT

The nose should be assessed for placement, shape, patency, and the presence of drainage. The nose should be midline on the face. Nares should be symmetrical in placement and size. The assessment for dysmorphic features, such as asymmetric nares or a notched or broad nasal tip, is necessary [47].

A small amount of clear or white discharge from the nose may be noted as a normal finding in the newborn [35,77]. However, copious or discolored nasal discharge may be a sign of congenital syphilis or respiratory problems [77]. Patency may be determined by closing the infant's mouth and assessing the quality of respiratory effort. Obstructing one nare at a time can be useful in determining choanal atresia, which is a blockage in the posterior nasal passage. One can assess the movement of air in and out of the nares by placing a finger under the nares to feel air movement. Obstructed nasal passages are an important finding as newborns are obligatory nose breathers and usually cannot breathe orally even when compromised.

17. MOUTH ASSESSMENT

When examining the mouth of a newborn, symmetry, completeness, size, and color are considerations. The mouth should be midline and symmetrical [77]. Asymmetrical movement may be caused by nerve injury from birth trauma and may include other parts of the face.

Inspect the mouth, lips, tongue, and gums for deformities. If the lighting is poor, a pen light may be used to thoroughly visualize the palate. Gentle assistance should be employed to open the mouth while a second team member completes the assessment. The intactness of the palate may be determined by both visual and tactile strategies. The palate should be palpated for intactness by inserting a gloved finger, soft side up, and feeling the roof of the mouth. Alterations in the shape of the palate may cause breathing or feeding problems. Epstein's pearls, small calcium deposits that form midline on the hard palate, may be present. They will reabsorb within approximately one week [77].

The infant's tongue may appear large for its mouth and shorter than either a child's or an adult's [34,77]. Dysmorphic findings concerning the mouth, tongue, and chin include a flattened or elongated philtrum, disproportionate tongue, small chin, short frenulum ("tongue tie"), and cleft palates and lips [47]. If the infant's mouth remains open and the tongue protrudes, this may be a sign of an existing condition, such as Down syndrome, and should be noted [92].

The color of mucous membranes and lips should be monitored. The colors may be described as dark, purple, dusky, pink, or pale. Using a referenced color gauge or having two nurses assess the infant's color can help with the accuracy. Mucous membranes should be pink and well-hydrated, and a small amount of saliva should be present [77]. If there is a large amount of saliva and the infant is "blowing bubbles," the mouth should be suctioned with a bulb syringe [77]. If this does not resolve the issue, further assessment should be conducted to determine the patency of the esophagus before the infant is allowed to eat.

Observe for natal teeth. While natal teeth occur in normal infants, they are more likely to occur with cleft palate [85]. If teeth are present, they should be noted and reported. Natal teeth are generally removed to prevent a choking hazard, especially if they are loose [77].

REFLEXES

There are several reflexes that should be assessed while examining the mouth. The intensity of the sucking reflex may be described as strong or weak and may be assessed either by placing a finger in the infant's mouth or monitoring feeding. For the critically ill infant who is being fed through a tube, the assessment of the strength of his or her sucking reflex may be determined as the infant sucks on either the feeding tube or the endotracheal tube. A strong suck response occurs when the infant is capable of forming a tight seal around the finger, nipple, or bottle. A weak suck occurs if the infant is either unable to form a seal or unable to suck because of fatigue or deformity. If an alert term infant is unable to suck after many attempts, the infant should be evaluated further.

Assess for a gag reflex by gently stimulating the posterior oral cavity. The infant should have a strong coughing response to the stimulation. If the response is weak, this should also be noted and the appropriate intervention completed. Absence of a gag reflex should be considered an emergency situation because newborns cannot protect their airway without a gag reflex. The extrusion reflex occurs when the infant responds to foreign objects in the mouth by pushing them outward with the tongue.

The rooting reflex is present at birth and assists the feeding process in newborns. To elicit this reflex, the infant's cheek is gently stroked. The normal response is for the infant to turn the mouth in the same direction of the cheek that was stroked and initiate a sucking motion. Variants of this reflex include stroking the upper lip, which should cause the infant to flex his or her head back, and stroking the bottom lip, which should cause the infant to drop his or her jaw. This reflex may be slowed as a result of maternal sedation or a recent feeding. The rooting reflex lasts until approximately 4 to 6 months of age [92,99,100].

18. NECK ASSESSMENT

The neck of the normal newborn is noticeably shorter and more flexible than that of an adult or child. The normal newborn will exhibit creasing and skinfolds on the neck. Infants are generally not capable of supporting their heads at birth and will experience head lag when they are moved to a sitting position from a lying one [33]. Assess lymph nodes and monitor for webbing and any masses [33]. Webbing of the neck, generally noticed from the back of the neck, may be indicative of chromosomal abnormalities [77].

Palpation of each clavicle may help determine intactness. A fractured clavicle may present with an elevation of the bone, or a grating sensation may be felt when manipulated [33]. The newborn should be able to demonstrate free range of motion that is symmetrical.

19. NEUROLOGIC EXAMINATION

The newborn neurologic assessment takes into consideration the immaturity of the neurologic system. As the infant grows and develops, a more certain presentation of the intactness of the neurologic system will surface. When assessing neurologic status, one should be alert for warning signs and then proceed by assessing the newborn's reflexes.

WARNING SIGNS

Warning signs of the neurologic assessment, which would warrant further investigation and/or immediate intervention, include [35,92]:

- Lack of reflex/response to stimuli

- Hypertonic or hypotonic position

- General lethargy

- Pupillary changes

ASSESSING REFLEXES

Assessing primitive reflexes in newborns gives one great insight into the newborn's neurologic status. Reflexes are key to the survival of the newborn and may be the single greatest indicator of neurologic health. Some of the most common reflexes include the Moro, rooting, tonic-neck, stepping, palmar grasp, plantar grasp, and Babinski [92,99,101] (Table 3).

Table 3: PRIMITIVE REFLEXES IN THE NEWBORN

Reflex

Appears

Disappears (Approximate)

Brief Description

Rooting

At birth

Generally becomes voluntary after 3 weeks of age

Turns mouth to the same side of the cheek that is being stroked

Gag

At birth

Continues into adulthood

Strong coughs in response to stimulation of the posterior oral cavity

Extrusion

At birth

3 to 4 months of age

Uses tongue to push foreign objects out of mouth

Moro (startle)

As early as 32 weeks' gestation

6 months of age

When dropped slightly, quickly abducts extremities and forms the index finger and thumb into a "c" shape

Tonic neck (fencing)

Between birth and 2 months of age

4 to 6 months of age

When the infant's head is turned to one side, with the jaw over the shoulder, the arm and the leg on the infant's same side extend while the opposite arm and leg flex

Stepping

At birth

2 months of age

Simulates walking when held in an upright position and the sole of the foot touches a flat surface

Palmar grasp

As early as 28 weeks' gestation

4 to 6 months of age

Wraps fingers around the examiner's finger when it is placed into the infant's palm

Plantar grasp

At birth

8 months of age

Curls toes downward in response to pressure applied to the sole of the foot at the base of the toes

Babinski

At birth

2 years of age

Flexes the big toe when an object is dragged along the sole of the foot from the heel to the head of the 5th metatarsal

Source: [92,99,100,101,102]

During the assessment of all newborn reflexes, considerations of symmetry and the strength of the infant's response should be taken into account. It is important to note that gestational age, but not weight, will directly impact the rate by which the infant responds [103,104]. Infants delivered via cesarean section may have a reduced response to reflex evaluations [105].

Because the assessment of the neurologic system can be rigorous for the infant, it may be recommended to assess the infant's glucose level and special oxygen demands as well as any signs of fatigue before beginning the assessment. The infant should be assessed in an alert state.

Moro Reflex

The Moro reflex, also known as the startle reflex, is generally present from 32 weeks' gestation to six months after birth. The Moro reflex can be assessed by holding the infant in a supine position and, with the head, neck, and spine appropriately supported, allowing the infant to drop slightly. The infant should respond by extending and abducting extremities. The infant should also fan his or her fingers and form a "c" shape with the index finger and thumb. Subsequently, the arms should adduct and the infant should return to a relaxed position. Absence of the Moro reflex may indicate damage to the brain or spinal cord. Absence on only one side of the body may indicate either a broken humerus or scapula or a nerve injury [99].

Tonic Neck Reflex

The tonic neck reflex, commonly referred to as fencing, appears between birth and 2 months of age and disappears at approximately 4 to 6 months of age [99]. To obtain this response, place the infant in a supine position. Rotate the infant's head to one side so the jaw is over the shoulder. The arm and leg on the same side should extend and the arm and leg of the opposite side should flex. Turn the head to the other side and the extremities should mirror this posture.

Stepping Reflex

The stepping reflex is generally present from birth to 2 months of age. This reflex is elicited by holding the infant upright and placing his or her sole of the foot against a hard, flat surface [99]. The infant should respond by alternately flexing and extending the legs to simulate walking.

Palmar and Plantar Grasp Reflexes

Palmar grasp reflex is present from 28 weeks' gestation until four to six months after birth. Pressing the examiner's finger into the palm of the infant's hand may elicit this response [99]. The infant's fingers should flex around the examiner's finger. The plantar grasp is present from birth to 8 months of age. The examiner applies pressure to the bottom of the foot at the base of the toes. The toes should curl downward.

Babinski Reflex

Babinski reflex is generally present from birth to 2 years of age [106]. Babinski reflex is simple yet extremely important in the determination of pathology [102]. The infant should be awake with the head in a midline position for testing. The examiner may drag the wooden or plastic end of a cotton-tipped applicator along the lateral aspect of the sole from the heel to the head of the 5th metatarsal. One study rated the response based on flexion or extension of the great toe and did not gauge the response based on fanning of the other toes [102]. Using the described method, researchers found a 90% response of extension of the great toe. They also found that a small percentage of infants may demonstrate extension at a later age and suggested that other infants may demonstrate extension when in a more awake state. Other studies found similar responses [107,108]. An inappropriate response to this test indicates the need for further neurologic evaluation [106].

PAIN RESPONSE

Pain is an important consideration when assessing an infant's neurologic status. A failure to respond appropriately to painful stimuli can be an indicator of altered neurologic status. The newborn should demonstrate chemical, behavioral, and physiologic responses to pain. Chemical responses are caused from the release of catecholamines, glucagon, growth hormone, cortisol, and aldosterone. This, in turn, results in an increase in metabolic demand, possibly leading to metabolic instability.

Behavioral responses such as facial expression, crying, and body movements are appropriate areas of assessment of pain response in the newborn. Research has shown that body movements such as tremors, twitches, startles, arching, and squirming are not accurate pain indicators; however, limb extensions and finger splays have been shown to be more accurate indicators of pain, especially in preterm infants [109,110,111]. Factors that affect pain response include exposure to multiple painful procedures, lower Apgar scores, earlier gestational age, and illness [109,110]. When assessing behaviors associated with pain in the newborn, these factors should be considered. Physiologic responses also include changes in heart rate, respiratory rate, blood pressure, color, oxygen saturation, vagal tone, and ICP.

20. CHEST ASSESSMENT

A visual inspection of the chest should be completed initially for size, shape, symmetry of movement, and presence of identifying features. The chest should be round and 1–2 cm smaller than the circumference of the infant's head [92]. Chest circumference is obtained by measuring around the infant's chest at the nipple line midway between inspiration and expiration. Measuring the distance between the nipples divided by the chest circumference determines a narrow versus broad chest. In a narrow chest, the internipple distance will be less than 25% of the chest circumference. In a broad chest, the difference will be more than 33% of the chest circumference [47].

Assessment of the infant's breasts should include size, shape, and nipple formation, placement, and number. Breast bud size is an important indicator of gestational age. Some infants are born with supernumerary nipples, usually located vertically, below the normal nipple [92]. These are very rarely associated with any adverse effects or conditions [92,112]. As discussed, they are often mistaken for nevi [67].

Gynecomastia is common in either gender and may be noted as late as the second or third day of life. It is caused by high levels of maternal estrogen that have passed through the placenta, and should resolve spontaneously [1]. Neonatal gynecomastia is often accompanied by galactorrhea, also called pseudomenses milk or "witch's milk" [113]. In infants with galactorrhea, the discharge is usually bilateral. Unilateral, bloody, serous, or purulent discharge should be noted as a sign of an underlying pathologic cause [113]. According to the American Academy of Family Physicians, galactorrhea should also be documented as [113]:

- Scant or abundant

- Expressed or spontaneous

- Intermittent or persistent

If no underlying disease exists, galactorrhea will resolve spontaneously.

21. EVALUATING THE RESPIRATORY SYSTEM

Throughout pregnancy, the fetus receives its oxygen through the umbilical cord from maternal oxygen stores. Oxygenated blood flows from the mother through the uterine artery into the intervillous spaces of the placenta, where gas exchange occurs [33]. Fetal circulation begins with the umbilical vein picking up the oxygen stores from the intervillous spaces of the placenta and transporting them to the fetal heart. Most of the blood bypasses the fetal lungs as they do not have a respiratory gas exchange function [33]. When an infant is born, therefore, a sequence of events must occur in order for the infant to breathe.

In utero, the pulmonary circulation has elevated pressures and low flow states because of high pulmonary vascular resistance [114]. The newborn's pulmonary vascular pressure is partially related to a higher CO_2 from passive maternal oxygenation and is partially related to the pressure applied by amniotic fluid inside the lung [114]. Also, pulmonary vascular pressures are consistently higher than systemic resistance prior to birth [114]. The result is that only 5% to 10% of the entire cardiac output is used for perfusion of the fetal lung [114].

Pressure increases on the fetal chest as the infant is expelled from the uterus during a vaginal delivery. The amniotic fluid inside the lung compartment is pushed out through the airway. Once the infant's head and chest are delivered, the chest re-expands, causing an intake of air to fill the void where amniotic fluid once was [115]. The first few breaths taken by the infant are critical to changes in pressures and functioning of the newborn's pulmonary function. The most common cause of spontaneous pneumothorax in infants is the degree of transpulmonary pressure generated by the first few breaths [116].

The exact stimulant for breathing may not become evident because the newborn is exposed to so many new factors at once, including pain, acidosis, light stimulation, and sensory factors, among others [114,117]. Physical (mechanical) factors that stimulate breathing include the compression of the fetal chest as it moves through the birth canal, and the chest wall recoil, which occurs as the newborn's trunk emerges. Chemical factors, such as the decreases in oxygen concentration and lack of placental blood flow, cause the medulla to stimulate the respiratory center to begin functioning [117]. Once the lungs are open to airflow, the pressure within the capillaries decreases and an increase in the amount of blood to the pulmonary bed occurs [117]. The change in temperature from the intrauterine environment to the extrauterine environment (a decrease of more than 20°F) also works to produce active respiratory effort. An increase in the blood flow to the pulmonary bed occurs as a result of pulmonary vascular relaxation. The pulmonary vascular bed relaxes due to the increase in oxygen saturation that the newborn is able to obtain using his or her circulatory system [114,117].

Due to the difference in fetal hemoglobin and exposure to lower PO_2 levels, laboratory data obtained from the newborn are considerably different than that of an older child or adult. The normal hemoglobin level in the newborn is 17–18 g/dL [33,34]. The newborn is born with up to 90% of fetal hemoglobin. Hematocrit elevation is a normal finding [34].

Leukocytosis of the newborn, caused by increased neutrophil production in the first days of life, is related to the stress of birth [33]. This phenomenon self-corrects in about two weeks.

A thorough evaluation of the infant's respiratory system includes two components. Inspection of the newborn's breathing effort and chest movement begins the process, followed by auscultation of the infant's lung fields. The infant's lungs are positioned anteriorly from above the middle third of the clavicles to the sixth rib at the midclavicular line and to the eighth rib at the midaxillary line. A thorough posterior assessment is warranted as the infant's lower lobes are primarily located posteriorly to the eleventh rib at the vertebral line [50].

WARNING SIGNS

Warning signs of the respiratory assessment, which would warrant further investigation and/or immediate intervention, include [33,35,118]:

- Respiration rate less than 30 or greater than 60 breaths per minute. In some cases, respiratory rates up to 70 breaths per minute in the first few hours of life are acceptable. When assessing rate, a full minute count should be taken to compensate for irregularities in pattern.

- Apnea lasting 20 seconds or longer

- Presence of central cyanosis. Acrocyanosis may be a normal finding in the newborn, but central cyanosis, or the blue or gray coloring of the mucous membranes, trunk, or entire body, is never a normal finding and requires immediate intervention.

INSPECTION

Inspection of the infant's breathing effort and chest movements is ideally done while the infant is at rest. Many newborns experience a breathing pattern commonly known as periodic breathing of the newborn. The infant's breathing pattern may be irregular and include pauses lasting 5 to 15 seconds [119]. Respiratory patterns change in the newborn depending upon the infant's state. If in a deep sleep, the pattern is usually regular; however, it may become irregular with increased motor activity [33]. The work of breathing should be assessed and noted to be unlabored. The infant should appear to be breathing easily. The chest should rise and fall with each breath and be symmetrical in its movement. Chest movement should be synchronized and smooth. Infants in distress may present with lag or seesaw movements of the chest. The assessment of the infant's skin color is necessary as changes in color offer information regarding air exchange [119].

AUSCULTATION

When auscultating neonatal lung fields, it is recommended that a diaphragm stethoscope of 2.5 cm diameter or less be used [50]. When listening with a stethoscope, it is beneficial to first assess one position and then, immediately after, assess the mirror position on the opposite side of the body to determine even the slightest differences in quality. The method of moving the stethoscope in an "S" shaped pattern over the chest is optimal but not always possible if the infant is squirming or has bandages that preclude this systematic manner. Listening along the axilla for resonant sounds can also provide vital information.

The normal newborn may have very noisy or wet-sounding lungs, especially in the first 24 hours of life [119]. In general, there is vast improvement in the noise of the newborn's lungs in the first several hours of life. Abnormal sounds include [119]:

- Stridor: An inspiratory, high-pitched piercing sound usually indicative of an upper airway blockage

- Rales: Low, coarse sounds heard on inspiration or expiration

- Crackles: A cracking or popping sound that occurs when the air that passes through the small airways in the lung is somewhat obstructed by fluid, mucus, or pus at different cycles of inspiration

- Wheezing: A continuous, high-pitched sound heard on inspiration

SIGNS OF RESPIRATORY DISTRESS

The three cardinal signs of respiratory distress in newborns are grunting, nasal flaring, and intercostal retractions. Expiratory grunts occur when the infant attempts to expel trapped air or fetal lung fluid [91]. They may be audible with or without the use of a stethoscope. As they become more severe, grunts can be heard with the unaided ear. Dilatation of the nares, or nasal flaring, may be an early symptom in cases of mild distress and may progress as the infant continues to experience problems with air movement. Flaring occurs when the newborn attempts to bring more air into the lungs. Intercostal retractions are noted as the ribs become visible on inspiration. Intercostal, or xiphoid, retractions may occur and have the appearance of a strong tug at the area of the xiphoid. Retractions are generally described as mild, moderate, or marked.

CAUSES OF RESPIRATORY DISTRESS

Respiratory Distress Syndrome

Respiratory distress syndrome (RDS) is caused by surfactant deficiency and structural immaturity of the infant's lungs [120]. RDS has also been referred to as hyaline membrane syndrome due to the formation of hyaline membranes concurrent with this condition; however, hyaline membranes have also been associated with other respiratory conditions [120]. RDS is the recommended term to distinguish the specific symptoms characteristic of this condition.

The incidence and acuteness of RDS is directly related to gestational age. It is most prevalent in newborns younger than 28 weeks' gestation and/or weighing less than 1,200 g [120]. RDS affects more white infants than infants of other races [121]. Risk factors include maternal diabetes, caesarean delivery devoid of labor, latter born of twins, and familiality [120].

RDS presents either at birth or within the first eight hours of life [120]. If symptoms occur after the first eight hours, then it is unlikely that RDS is the cause. The most common signs of RDS are [120]:

- Tachypnea

- Dyspnea

- Grunting with expiration

- Intercostal retractions with inspiration

- Nasal flaring

- Increasing cyanosis

Oxygen and surfactant therapy are used for support and treatment. Minimizing disturbances, handling the infant gently, and maintaining an ideal body temperature will help reduce the infant's oxygen needs. Infants with RDS need careful fluid management and should be carefully monitored for signs of infection [120].

Transient Tachypnea of the Newborn

Transient tachypnea of the newborn (TTN) is a relatively common condition in near-term infants. It is thought to be caused by residual fluid or debris in the lungs and is more common in infants delivered via cesarean section [33]. TTN occurs more frequently with infant sedation via maternal medication, prolonged labor, fetal macrosomia, and maternal asthma [122].

The condition generally presents as mild respiratory distress with marked tachypnea, in some cases with rates up to 100 to 140 breaths per minute [33]. Though a thorough workup should be done to rule out other causes of respiratory distress, TTN is generally benign and will resolve within 48 to 72 hours [75,122]. Oxygen support may be required in severe cases [33].

Neonatal Sepsis

The presenting sign of sepsis in many newborns is respiratory distress. Therefore, a thorough septic workup is in order in a newborn with signs of respiratory compromise.

Neonatal sepsis is categorized as early onset when it presents within the first seven days of life; most cases present within the first 24 hours [123]. The leading cause of early-onset neonatal sepsis is GBS, followed by Escherichia coli [124]. Events that increase the risk of neonatal sepsis include [122]:

- Maternal infection with GBS during pregnancy

- Premature delivery

- Membrane rupture lasting longer than 24 hours

- Chorioamnionitis

- Frequent vaginal examinations during labor

In addition to respiratory distress, signs of sepsis may include behavioral changes (e.g., lethargy, temperature instability, feeding difficulty), jaundice, and cardiac changes, such as tachycardia or bradycardia. The following manifestations may be observed in neonatal sepsis [1]:

General Signs

- Infant generally "not doing well"

- Poor temperature control (i.e., hypothermia, hyperthermia [rare])

Circulatory System

- Pallor, cyanosis, or mottling

- Cold, clammy skin

- Hypotension

- Edema

- Abnormal heartbeat (i.e., bradycardia, tachycardia)

Respiratory System

- Irregular respirations (i.e., apnea, tachypnea)

- Cyanosis

- Grunting

- Dyspnea

- Retractions

Central Nervous System

- Diminished activity (e.g., lethargy, hyporeflexia, coma)

- Increased activity (e.g., irritability, tremors, seizures)

- Bulging fontanelle

- Increased or decreased tone

- Abnormal eye movements

Gastrointestinal System

- Poor feeding

- Vomiting

- Diarrhea or decreased stooling

- Abdominal distension

- Hepatomegaly

- Hemocult (i.e., positive stools)

Hematopoietic System

- Jaundice

- Pallor

- Petechiae, ecchymosis

- Splenomegaly

Evidence Based Practice Recommendation

The American College of Obstetricians and Gynecologists recommends, regardless of planned mode of birth, all pregnant women undergo antepartum screening for group B streptococcus (GBS) at 36 0/7–37 6/7 weeks of gestation, unless intrapartum antibiotic prophylaxis for GBS is indicated because of GBS bacteriuria during the pregnancy or because of a history of a previous GBS-infected newborn.

https://www.acog.org/-/media/project/acog/acogorg/clinical/files/committee-opinion/articles/2020/02/prevention-of-group-b-streptococcal-early-onset-disease-in-newborns.pdf

Last Accessed: August 10, 2020

Strength of Recommendation: Expert Opinion/Consensus Statement

Although some studies have shown that the use of certain antibiotics may lead to antibiotic resistance and possible damage to the intestine, kidneys, liver, or hearing, antimicrobial therapy is still commonly used to treat sepsis [125]. The American College of Obstetricians and Gynecologists recommends that if the mother is receiving intrapartum antibacterial prophylaxis (IAP) for suspected GBS or chorioamnionitis and the newborn exhibits signs of sepsis, empiric therapy should be administered along with a complete diagnostic evaluation [24,126]. If the infant does not exhibit signs of sepsis but maternal chorioamnionitis is present, empiric therapy and a limited evaluation (i.e., blood culture and complete blood count) are indicated. If the gestational age is less than 37 weeks or the duration of maternal IAP has been less than four hours, a limited evaluation and close observation for a minimum of 48 hours are recommended [24,126]. If neonatal sepsis is suspected, empiric therapy should be administered along with a complete diagnostic evaluation. If there are no signs of sepsis, maternal IAP duration exceeds four hours, and the infant is older than 37 weeks' gestation, no evaluation or therapy is required [24,126]. However, the infant should be closely observed for a minimum of 48 hours. Penicillin is considered the most effective treatment [24,126]. Extreme cases may require assisted ventilation. As sepsis can have an extremely fast onset and cause rapid deterioration, it is imperative that treatment begin immediately.

Meconium Aspiration Syndrome

Meconium aspiration syndrome (MAS) is another cause of respiratory distress in newborns and occurs in approximately 5% of those born with meconium-stained amniotic fluid [127,128]. It is caused by the aspiration of meconium-stained amniotic fluid into the trachea. Meconium staining may be noted by assessing the infant's skin, nails, and umbilical cord and can affect the infant's Apgar score [35]. Presence of meconium may clue the practitioner to assess for tachypnea, hypoxia, and hyper- or hypoventilation [86]. The presence of rales, rhonchi, wheezing, wet sounds with possible retractions, and labored breathing are possible, depending upon the extent of aspiration. Risk factors for MAS include [128]:

- Fetal distress, long labor, or difficult delivery

- Maternal diabetes

- Maternal hypertension

- Low oxygen supply to the infant in utero

Meconium aspiration is associated with asphyxia, but routine intubation and intrapartum suctioning are no longer recommended, regardless of the infant's activity level [127]. Gently clearing the nose and mouth of meconium with a bulb syringe may be warranted. A neonatal advanced life support team should be notified and available to treat a newborn with meconium-stained amniotic fluid [127]. Other treatments for MAS include oxygen therapy, mechanical ventilation, fluid support, a warmer to control temperature, and antibiotics [128,129].

22. EVALUATING THE CARDIOVASCULAR SYSTEM

The fetal cardiovascular system is markedly different from that of the newborn. Because the fetus does not rely upon its lungs for oxygenation, very little blood flows through the pulmonary vasculature. Fetal circulation begins with oxygenated blood traveling to the fetus through the umbilical vein. Note the unusual circumstance of a vein carrying richly oxygenated blood. The blood enters the fetus at the site of the umbilicus and divides into two branches. One branch carries blood to the fetal liver, while the other, larger branch carries blood through the ductus venosus into the fetal vena cava [33]. The oxygen-rich blood then travels to the fetal heart through the right atrium. In an adult, the blood passes into the right ventricle for distribution into the pulmonary vasculature, which would then oxygenate the blood. Because the blood in the fetus is already oxygenated, the majority then passes through the foramen ovale to the left atrium. A small amount of blood does pass into the right ventricle, which pumps the blood into the pulmonary artery to oxygenate the lung tissue. However, the majority of this blood also passes through another duct, the ductus arteriosus, into the aorta for distribution to the body [33]. The deoxygenated blood then leaves the fetus via two umbilical arteries for nutrient and gas exchange in the intervillous spaces of the placenta.

Once the newborn is breathing and maternal blood flow from the umbilicus stops, changes in blood flow, pressures, and volume occur within the heart, causing structural changes. The foramen ovale, which is a naturally occurring atrial septal defect, closes, as does the ductus venosus, due to the changes in pressure and flow [37]. The increase in arterial oxygen tension causes the ductus arteriosus to begin to close at a later time, approximately 12 hours after birth. It is completely closed no later than 21 days after birth [37,130]. The size and shape of the heart changes over a period of time as the left ventricle assumes the primary pumping role.

After the newborn's structural cardiovascular changes occur and the infant is breathing, the pressures in the heart and the volume of blood during flow also shift because of the new route. When the lungs begin receiving a higher concentration of oxygen, the pulmonary vascular bed relaxes, allowing blood to flow through the lungs [130]. Blood through the ductus venosus is halted following the clamping of the umbilical cord. The ductus venosus usually completely closes seven days after birth, though there is no flow through it after the umbilical cord is clamped. When the cord is clamped, it separates the newborn from maternal blood flow, causing systemic vascular resistance to rise. This is due to the increase in pressure of the newborn's circulatory system as opposed to the low pressures in the placenta [130].

It takes time for the fetal right ventricular muscle to remodel itself into the lesser pump side and decrease work [114]. Though the left side of the heart is functioning as in an adult, the muscle mass may not achieve complete dominance over the right ventricle until the sixth month of life [114].

The cardiovascular assessment is composed of auscultation, electrocardiogram (ECG) analysis, blood pressure monitoring, pulse quality, and capillary refill time. However, in the healthy term infant, many practitioners will do little more than auscultation if there are no other signs of problems. Cardiac abnormalities generally present themselves quite obtrusively.

AUSCULTATION

One should note the regularity or irregularity of the rhythm when assessing heart sounds. Noting changes as they associate with breathing patterns will be helpful in identifying the need for further evaluation. Normal heart tones are a result of the heart's valves opening and closing.

Auscultation of heart sounds may be performed in the following sequence [50,131]:

1. The aortic area, which is defined as the second intercostal space at the right of the sternum

2. The pulmonic area, which is located at the second intercostal space to the left of the sternum

3. Erb's point, which is located at the third intercostal space to the left of the sternum

4. The tricuspid area, which is located in the fifth intercostal space to both the left and right of the sternum

5. The apical area, which is found at the fourth intercostal space at the left of the left midclavicular line

The normal heart rate range of an awakened newborn is between 100 to 150 bpm [132]. Bradyarrhythmias occur when the heart rate is less than 60 bpm [133]. If the slow rate is associated with poor systemic perfusion, it should be treated [63]. Tachycardias vary in origin; they may originate from the sinus, supraventricular, or ventricular areas. In infants with tachycardia, the rate is greater than normal for age and is typically greater than 220 bpm [133]. Both bradycardia and tachycardia should be considered as signs of cardiac compromise, noted, and referred for appropriate treatment.

ELECTROCARDIOGRAM

Monitoring the infant's ECG can provide valuable assessment information. The basic ECG cycle consists of a P wave, a QRS, and a T wave. The P wave represents depolarization of both atria. The QRS represents depolarization of the ventricles, and the T wave represents repolarization of the ventricles. Abnormal rhythms may be classified as fast, slow, or pulseless [133]. Rhythm disturbances should be treated if they compromise cardiac output or have the potential to degenerate to a lethal rhythm [133].

BLOOD PRESSURE

Blood pressure monitoring is usually performed to identify low perfusion states associated with decreased vascular volume or decreased cardiac output and also to identify hypertensive states. In healthy term newborns, blood pressure monitoring is rarely performed unless there is an indication of a problem. In the healthy newborn, blood pressure is maintained at a fairly constant level by inter-related changes in resistance and cardiac output. Regional blood flow is determined by metabolic needs and adjusted by changes in resistance rather than pressure. Cardiac output adjusts flow to maintain a fairly constant blood pressure. In cases of severe asphyxia, septic shock, or blood loss, a decrease in blood pressure is a late sign of compromise [134,135]. In the first week of life, blood pressure may be slightly higher in the lower extremities than in the upper extremities [3]. Pulse pressure is obtained by subtracting the diastolic pressure from the systolic pressure. For the term infant, a wide pulse pressure is 25–30 mm Hg, and in the preterm infant, it is 15–25 mm Hg [3]. Multiple readings should be obtained and averaged for the best results [134].

MURMURS

Murmurs occur as blood moves through a highly turbulent area in the heart. Heart murmurs are very common in newborns as their cardiopulmonary systems adjust to extrauterine life [92,136]. These benign murmurs in newborns are usually transient in nature and caused by the foramen ovale not being closed completely. Murmurs are usually benign and not necessarily indicative of heart disease [85]. They generally resolve spontaneously.

Murmurs are classified by intensity (i.e., loudness) from grades 1 to 6. A grade 1 murmur is barely audible and not heard in all positions with the use of a stethoscope. A grade 6 murmur is audible with the stethoscope off the chest [137,138]. The location of the murmur identifies the type of defect. Apical murmurs are indicative of mitral insufficiency, mitral stenosis, subaortic stenosis, aortic insufficiency, aortic ejection click of aortic stenosis, or click or late systolic murmur of mitral valve prolapse [137]. Tricuspid murmurs are indicative of tricuspid insufficiency or stenosis, pulmonary insufficiency, ventricular septal defect, or aortic insufficiency [137]. Aortic murmurs are indicative of aortic insufficiency or aortic stenosis [137]. Pulmonic murmurs are generally caused by pulmonary stenosis or insufficiency, atrial septal defect, pulmonary ejection click, or patent ductus arteriosus [137].

CONGENITAL HEART DEFECTS

In the United States, approximately 1%, or 40,000, of infants born annually have congenital heart defects (CHDs), which are considered the most common type of birth defect [139]. Survival rates of infants born with CHDs have improved over the past several decades. Approximately 75% of infants born with CHDs are expected to survive to 1 year of age and 69% are expected to survive to 18 years of age [140,141]. Family history, maternal diabetes, maternal overweight, maternal obesity, maternal smoking during pregnancy, genetic or chromosomal abnormalities, and maternal exposure to certain drugs or organic solvents may all contribute to the development of CHDs [140,141,142]. Genetic defects are also associated with a higher risk of CHDs. For example, 50% of infants born with Down syndrome also have CHDs [139]. Acute CHD symptoms occur within the first few days of life in approximately one-third of infants [141].

Feeding difficulties are often a first sign, and they may be evident as early as 6 to 12 hours prior to symptoms of heart failure [144]. Because feeding difficulty may be attributed to many different causes, it should exceed 30 minutes and be accompanied by tachypnea, sweating, and subcostal retraction to be considered related to a CHD or heart failure [139,141].

CHDs are classified as acyanotic or cyanotic. Acyanotic defects are usually associated with left-to-right shunting and have symptoms similar to congestive heart failure. Cyanotic defects are characterized by a mixing of oxygenated and unoxygenated blood resulting from the various defects. These defects cause low oxygen-saturated blood to be pumped through the circulatory system.

Acyanotic Defects

Patent Ductus Arteriosus

Patent ductus arteriosus (PDA) is an acyanotic cardiac lesion that occurs when the ductus arteriosus that is present in fetal circulation fails to close completely within 12 hours of birth. It allows for a mixing of oxygenated and deoxygenated blood at the level of the aorta, causing the body and brain to receive blood with a lower PO_2 [139].

PDA has a higher incidence in premature and low birth weight infants, females, exposure to rubella during the first trimester of gestation, and high-altitude births [139,141]. Signs associated with PDA include a grade 2 or 3 murmur and an increased difference between systolic and diastolic pulse pressure [33]. Untreated, PDA can lead to right ventricular failure and pulmonary congestion. Treatment includes medications such as indomethacin or ibuprofen, transcatheter placement, or surgery [139].

Atrial Septal Defect

Atrial septal defect (ASD), another acyanotic cardiac lesion, occurs when the foramen ovale fails to close, leaving an opening between the right and left atrium. This generally results in a left-to-right shunting of blood and is generally asymptomatic initially.

The signs of ASD include a murmur and, eventually, failure to thrive, poor exercise tolerance, and upper respiratory infections [33]. Approximately 50% of ASDs close spontaneously, and approximately 20% resolve within the first year of life [139,140]. Treatment includes catheter and surgical procedures [139].

Ventricular Septal Defect

Ventricular septal defect (VSD) is an acyanotic lesion that occurs due to an abnormal opening between the left and right ventricles. It is more common in male infants than female infants. VSDs vary in size and can lead to left-to-right shunting of blood. These defects are often asymptomatic initially, followed by a degenerative course over the first several weeks to months.

The signs of VSD include a loud murmur, tachypnea, growth failure, feeding difficulties, and eventual heart failure [33]. VSDs can exist without symptoms of heart failure, and as with ASDs, more than 50% close spontaneously. If no signs of heart failure are evident, surgical intervention may be delayed with close follow-up [146]. Because infants with VSDs are often premature and/or tire easily during feedings, nutrition therapy is recommended. Nutrition therapy is considered temporary treatment and may be administered in the form of high-calorie formula, breast milk supplements, and in some cases, tube feeding. If VSD symptoms persist or worsen, surgical intervention is required [146].

Coarctation of the Aorta

Coarctation of the aorta is an acyanotic cardiac lesion that occurs when there is a narrowing of the aorta. It accounts for 5% to 8% of all CHDs [147]. This stricture may cause an obstruction to the blood flow, resulting in increased left ventricular pressure [33]. Signs of coarctation include absent or diminished femoral pulses, murmur, and degeneration into heart failure within the first 7 to 21 days of life [33]. Treatment is surgical [148,149].

Cyanotic Cardiac Lesions

Transposition of the Great Arteries

Transposition of the great arteries (TGA) affects approximately 1 in 3,400 newborns annually and is often accompanied by heart failure [141,150,151]. The aorta and pulmonary artery are switched when they are formed in the embryonic stage. Signs of transposition include cyanosis, hyperpnea, difficulty feeding, and clubbing of the fingers or toes [150,151].

Transposition has been associated with exposure to rubella or other viral illnesses, poor prenatal nutrition, alcoholism, maternal diabetes, and advanced maternal age (i.e., older than 40 years of age) [150,151]. Prostaglandin E is administered intravenously, which maintains a patent ductus arteriosus until transposition is repaired via surgery [150].

Tetralogy of Fallot

The tetralogy of Fallot is the most common cyanotic CHD, occurring in approximately 1 in every 2,500 newborns, although it may not be evident as early as other defects [152,153]. It is characterized by four components: pulmonary stenosis, overriding aorta, right ventricular hypertrophy, and VSD [152,153]. Tetralogy of Fallot has been associated with the same conditions as TGA; however, chromosomal disorders are also common in this population [152].

Infants with tetralogy of Fallot eventually develop what are commonly known as "tet spells," which include hyperpnea, irritability, decreased murmur intensity, and extreme cyanosis in the extremities and mouth during crying, feeding, or exertion [141,152,153]. Infants may also have feeding difficulties, failure to thrive, syncope, clubbing of fingers, or sudden death [152]. Some immediate relief during a spell may be achieved by squatting. For newborns, this maneuver may be accomplished by placing infants on their sides and putting their knees up to their chests. Other interventions that are helpful are slower feedings, smaller and more frequent meals, and comfort measures to minimize anxiety [152].

The tetralogy of Fallot is the most likely CHD to remain untreated past infancy [139,141]. In the past, a palliative surgery was completed to improve blood flow, with complete corrective surgery often postponed until the child reached 3 years of age [141]. Complete surgical repair is now performed during infancy, and infants who have surgery usually do well [139,153]. However, infants too weak or too small to have full surgical repair may still receive the palliative surgery first and the complete surgical repair later [139]. Without surgery, death usually occurs before 20 years of age [153].

ASSESSING THE PULSE AND CAPILLARY REFILL TIME

Peripheral pulses should be assessed for quality and equality. The pulse rate and rhythm should match that of the apical rate and rhythm. Assessing these at the same time can assure mechanical conduction.

Capillary refill time determination is usually performed by applying enough pressure to cause blanching to the dorsum of the foot or palm for approximately five seconds and then tracking the length of time until color uniformity returns. This technique is sometimes used to help assess the newborn cardiovascular status. However, it is considered controversial due to the large variation in the results of studies. Many factors affect refill time, including skin temperature of the examiner's hand; axillary temperature of the newborn; environmental temperature; length of time the examiner applies pressure (i.e., accuracy/ability of the examiner to precisely measure five seconds); body site used; and the firmness of applied pressure [155]. Studies indicate that more research is necessary regarding parameters and diagnostic efficacy before capillary refill time can be recommended as a clinical tool; however, one systematic review suggests that a finger capillary refill time greater than three seconds should be considered abnormal if the test was performed correctly [155,156,157].

23. ABDOMEN ASSESSMENT

Assessing the infant's abdomen includes inspection, palpation, and auscultation. Inspection will include looking at the shape, contour, and movement of the abdomen as well as assessing the umbilical stump. Auscultation should be done for bowel sounds and bruits. Palpation for abdominal masses, as well as for major organs, is an important aspect of the abdominal exam, followed lastly by assessment of the infant's stool.

Assessing stool quantity and quality is an important part of the gastrointestinal assessment. Meconium should be passed within 24 hours [75]. If the infant has not passed meconium within the first 24 hours, a further assessment is warranted to rule out ileus or obstruction. By the second or third day, the infant should begin to have transitional stool, which is green or yellowish and may have a seedy appearance. Within several days to a week, breastfed infants' stools take on the appearance of mustard.

INSPECTION

The first step in assessing the abdomen is inspection. The shape, contour, and movement should be evaluated. The shape should be domed or cylindrical because of immature musculature. There should be no bulging or distention. Distention is one of the first signs of problems. Movement should be fluid and synchronous with chest movement. The presence of localized edema or discoloration is a finding of peritoneal disease [3]. The umbilical stump initially is white and gelatinous in appearance and begins to dry within the first few hours. The umbilical stump should be inspected for the presence of two umbilical arteries and one vein. They make the appearance of a "smiley face," as the musculature in the arteries makes them appear round, like the eyes of a face, and the vein tends to collapse due to lack of musculature. The anus should be inspected for patency and absence of fissures. A digital examination can assist in ruling out complications, if necessary.

AUSCULTATION

Auscultation should be completed before palpation. Listen for the presence of bowel sounds. Bowel sounds should be present approximately one to two hours after birth. In the older newborn, absence of bowel sounds is a significant finding. Auscultation over the kidneys for bruits from renal artery stenosis is important. Auscultation over the liver for bruits may reveal arteriovenous fistula [3].

PALPATION

Palpate and percuss beginning below the umbilicus and proceeding upward. The abdomen should feel soft. Infants may draw their legs up or cry if in pain during palpation of the abdomen. The liver is palpable 1–3 cm below the right costal margin. The most reliable measurement of the liver via palpation and percussion may be obtained in the midlines and below the right costal margin [158,159]. The first step is percussion of the upper and lower borders. In this step, the upper border is defined by percussion in a downward manner while the lower borders are palpated with the fingers in a perpendicular position to the midclavicular line. The second step includes percussion of both upper and lower borders at the position of the midclavicular line. The kidneys are moderately firm and lobulated. The bladder can be assessed for distension by palpating for a firm dome shape midline, in the lower portion of the abdomen.

NECROTIZING ENTEROCOLITIS

Evidence Based Practice Recommendation

According to the American Society for Parenteral and Enteral Nutrition, minimal enteral nutrition should be initiated with in the first two days of life and advanced by 30 mL/kg/day in infants ≥1,000 g at high risk for necrotizing enterocolitis.

https://onlinelibrary.wiley.com/doi/pdf/10.1177/0148607112449651

Last Accessed: August 10, 2020

Strength of Recommendation: Weak

Necrotizing enterocolitis (NEC) occurs most often in very low birth weight and low birth weight infants. In term infants, NEC is associated with the use of concentrated formulas, blood transfusions, NEC outbreak in the healthcare facility, and early use of certain medicines, such as indomethacin and dexamethasone. Early gastrointestinal signs may be ambiguous. Signs of NEC include lethargy, difficulty feeding, bilious emesis, temperature instability, abdominal distention and rigidity, abdominal tenderness, fecal occult blood, and palpable loops in the stool. In the later stages of NEC, a discoloration of the abdominal wall, the labia, or the scrotum may be seen. Because NEC symptoms are similar to other conditions, such as neonatal sepsis, care should be taken to provide immediate and accurate intervention [160,161,162,163].

HERNIAS

Various types of hernias may be seen in newborns, including congenital diaphragmatic hernia, gastroschisis, omphalocele, and umbilical hernia. In some cases, hernias may be diagnosed in utero via ultrasonography. Gastroschisis, omphalocele, and umbilical hernias are apparent through inspection and palpation postnatally.

Congenital diaphragmatic hernia is an anomaly in which the muscular or tendinous parts of the diaphragm do not develop in the fetus and, consequently, abdominal contents protrude into the chest cavity [75]. This intrusion affects the development of other organs, mainly the lungs. It is important to note that congenital diaphragmatic hernia is not readily detectable through inspection and palpation. Signs of diaphragmatic hernia include a flat or scaphoid abdomen, barrel chest, difficult intubation, cyanosis, tachypnea, tachycardia, and bowel sounds that may be auscultated in the thoracic cavity [33,164]. Mortality rates and prognosis are generally poor and have been related to the presence of associated anomalies, prenatal diagnosis, prematurity, low birth weight, and early pneumothorax. Pulmonary hypertension and pulmonary hypoplasia are the recognized pathophysiologic cornerstones [164,165].

Gastroschisis is evident as the infant's intestines protrude from the abdominal wall through a rupture at the umbilical cord, usually on the right side [166,167]. With gastroschisis, intestine loops or other abdominal contents that protrude outside the body are not covered with any membranes and are clearly visible [166]. The risk factors for this type of hernia include young maternal age, low parity, and maternal use of selected drugs. It occurs concomitantly with NEC in approximately 20% of cases [167]. Prognosis is positive, with overall survival rates between 83% and 97% [167].

Omphalocele is similar to gastroschisis, but the protruding contents of the abdomen are usually covered by a very thin layer of tissue and protrude directly through the center of the belly button [168]. An omphalocele appears as a firm mass and, dependent on the size of the rupture, may include the intestines only or other organs, such as the bowel, liver, or spleen [168]. Omphalocele is associated with other conditions, including chromosomal anomalies, congenital diaphragmatic hernia, and cardiac anomalies [168]. Prognosis is linked to associated conditions; for example, prognosis is poor with concomitant cardiac defects, but positive if no associated conditions exist [169].

Umbilical hernias occur as a result of the incomplete closure of the umbilical ring. They present as a bulging of the area around the umbilical stump [169]. The hernia may be more visible when the infant is in an upright position or cries, subsiding when the infant is calm and in the supine position. Cutaneous rupture or damage is rare. It is possible for some umbilical hernias to close spontaneously by 4 years of age, if the rupture is relatively small and no other associated conditions are present [75].

Surgical intervention is necessary for treatment of hernias in most cases and should ensue as early as possible. However, surgical repair may be delayed if more critical concomitant conditions must be managed first, such as cardiac events. Antibiotic therapy may also be used in case of infection or risk of infection. Supportive therapy is often necessary [169].

WARNING SIGNS

Warning signs of the abdominal assessment, which would warrant further investigation and/or immediate intervention, include [35,170]:

- Obvious defects in the abdominal wall, possibly hernia

- Single umbilical artery, associated with congenital, especially renal, anomalies

- Meconium-stained or shriveled umbilical cord, associated with intrauterine growth retardation or perinatal asphyxia

- Imperforate anus, which may be associated with a tracheoesophageal fistula or esophageal atresia

- Hepatosplenomegaly, associated with congenital infections and hemolysis

- Flat or scaphoid-shaped abdomen, which may be associated with a diaphragmatic hernia

- Failure to void within the first 24 hours

- Failure to pass meconium stool within 12 hours

24. GENITOURINARY SYSTEM ASSESSMENT

Observe for color, odor, frequency, and amount of void. Failure to void with in the first 24 hours is considered a warning sign and warrants further evaluation. The normal urine output for an infant is at least 1–2 cc/kg/hour. Output may be as high as 4 cc/kg/hour in the first few days of life [50]. Urine output should be made with a stream of urine under an adequate amount of pressure. Urine is normally straw colored, though variations in color do exist, ranging from clear to amber, and may or may not have sediment.

During the initial head-to-toe assessment of all infants, a thorough examination of genitalia should be completed. The infant's genitalia should be assessed initially for appropriate development and function. Unusual appearance of the genitalia is more often a structural abnormality and not ambiguous genitalia [171]. Accurate diagnosis is vital in order to avoid adverse consequences and undue stress for the family [172,176]. However, a true case of ambiguous genitalia, or disorder of sex development (DSD), may be disturbing to parents and carries lifelong therapeutic and psychosocial implications [172,173]. Immediate intervention is required in newborns with a DSD in order to evaluate adrenal and pituitary function, as certain underlying conditions, such as congenital adrenal hyperplasia, may be life-threatening [154,170,174]. DSDs have variable etiology, ranging from chromosomal abnormalities to maternal ingestion of androgenic steroids or other drugs [175,176].

An expeditious assessment and decision on gender assignment is necessary for improved patient outcome and to ease parental anxiety [154,172,173]. Gender assignment is generally influenced by a variety of aspects, including diagnosis, structure and appearance of the genitalia, surgical alternatives, possible requirement of lifelong therapeutic measures, fertility, and family and cultural views and beliefs [154,172]. Due to the psychosocial implications of DSDs, the AAP issued a policy statement that addresses these implications, including revision and standardization of nomenclature and care [172]. The AAP recommendations for the clinical care of infants with DSDs include [172]:

- Evaluation by an expert should be completed before gender is assigned.

- A center with an experienced, multi-disciplinary team is ideal for evaluation and long-term management.

- A gender should be assigned to all individuals with a DSD.

- Family should be encouraged to participate in the decision-making process; open communication is crucial.

- Family concerns should always be respected and addressed with the highest level of confidentiality.

MALE INFANTS

When examining a male infant, the penis should be midline and straight, with the urethral opening midline at the tip of the penis. Hypospadias occurs when the meatus is located on the ventral surface of the glans, penile shaft, or the perineal area [91]. It may be identified by a groove that extends from the usual area of the meatus interiorly. Epispadias occurs when the urethral meatus occurs on the dorsal surface of the penis [75]. The length of the nonerect penis is 2–3 cm at birth [91]. Until 3 to 4 years of age, the foreskin is usually tight but should not affect the stream of urinary output [91]. The urinary stream should be neither highly pressurized nor of reduced force.

The scrotum should appear loose and pendulous, and each side should be manually assessed to determine the presence of testes. The testes usually descend in the third trimester and are approximately 1 cm in diameter at birth [3,91]. Containing the testes with the index finger and the thumb of one hand at the upper part of the scrotal sac may prevent retraction of the testes during assessment. Undescended testes may or may not be palpable in the inguinal canal. If the testicle cannot be pushed into the scrotum manually, then it is considered undescended. Bilateral undescended testes, micropenis, and/or bifid scrotum should prompt further evaluation [185]. The appearance of rugae may assist in providing information concerning the maturity of the infant. Absence of rugae may be a sign of prematurity [3,91]. Edema of the genital area following birth may be present, especially in breech births, but should resolve in a few days. Hydrocele is the collection of fluid around the testes in the scrotum and a relatively common finding. It can appear quite large and feel tight; diagnosis is made by transilluminating the scrotum. Hydrocele generally resolves on its own and requires no intervention.

FEMALE INFANTS

Appearance of the female genitalia is dependent upon the general nutritional status of the newborn as well as gestational age. The genitalia should be inspected for placement of labia and hymen. The placement of the urinary meatus as well as position of the rectum and length of the perineum should be noted [35]. If the newborn is undernourished, the genital area will appear less developed than it should, with the exception of the clitoris, which may appear to be large because of the underdeveloped state of the surrounding tissues [3,170]. In a healthy term infant, the labia cover the clitoris without fusion. Due to maternal hormone involvement, labia may appear swollen and darker than surrounding tissue [35]. Mucus and possible blood-tinged vaginal discharge called pseudomenstruation may be present for several days [170]. Hymenal tags are common and usually resolve spontaneously within a few weeks [93].

25. EXTREMITIES, BACK, AND SPINE ASSESSMENT

The final portion of the head-to-toe assessment of the newborn is examining the extremities and back. A thorough examination of the arms and legs begins with noting the presence of any warning signs. Attitude, or resting posture, is an important piece of the neonatal evaluation, as is the evaluation of reflexes. The infant should be observed closely for the presence of tremors, and neuromuscular maturity and symmetry should be noted.

INSPECTION

Even in sleep states, the normal resting posture for an infant is flexion. Tone should be assessed in the alert infant. Both decreases and increases in muscle tone can be symptoms of underlying problems and should be further evaluated. Hypotonia, sometimes referred to as low tone, is noted in the "floppy" infant with poor head control and limp extremities. Hypertonia is noted in the infant with tightly flexed upper extremities and extended lower extremities.

Tremors are not considered a normal finding in the newborn; periodic jerking or brief twitching is considered normal [33,35]. If not yet completed, reflexes should also be evaluated, as discussed in the neurologic assessment section of this course. Neuromuscular maturity should be evaluated with the use of age determination scales. Symmetry should be addressed in the alert infant. Bilateral assessment of the infant's reflexes and resting movement can provide a picture of muscular symmetry.

Arms and Hands

The arms and hands should be evaluated for symmetry, webbing, range of motion, and the number of digits [33]. Fingernails are generally long and in need of trimming in the term newborn. The palms should be examined for the presence of a single palmar crease (previously referred to as a "simian" crease) that extends all the way across the hand. A single palmar crease is associated with Down syndrome [177].

Legs

The newborn's legs should be assessed for flexion, symmetry, and length. In some cases, the uterine position can make an infant's foot appear clubbed, such as in the case of metatarsus adductus. The feet should be examined for the presence of metatarsus adductus and club foot [33,170]. With metatarsus adductus, only the front of the foot is turned inward; the back of the foot and ankle remain straight [178]. In cases of true club foot, both the foot and the ankle are turned inward and offer resistance [178].

Developmental Dysplasia of the Hip

Formerly known as congenital hip dislocation, developmental dysplasia of the hip (DDH) is an uncommon finding. However, according to the AAP, ease and efficacy of treatment is directly influenced by how early this condition is diagnosed [179,180]. Diagnosis of DDH is based upon the presence of unstable, subluxated, or dislocated hips or acetabula malformations. The majority (76%) of DDH cases occur in female infants. Other conditions that predispose infants to DDH include [179,180]:

- Breech birth

- Maternal oligohydramnios

- Family history

The Ortolani and Barlow tests are recommended to assist in determining hip instability. Both tests are best performed with an infant relaxed and in the supine position [181]. The Ortolani test begins by holding the infant's thigh with a thumb. Place the index finger of the same hand over the greater trochanter area. Lift and abduct the hip gently and simultaneously push down on the knee. If the hip is not stable, a "clunk" sound will be heard. This sound should not be confused with a click type sound that is sometimes audible from the knee area during this examination [181]. The Barlow test also begins by holding the infant's thigh with a thumb. Use the palm of the same hand to press down on the knee. While applying this gentle pressure, feel for dislocation with the middle finger of the same hand. If the hip is not stable, one should feel the hip dislocate [181]. If findings of the clinical evaluation are unclear, the infant should be re-evaluated at follow-up examinations [179].

Imaging techniques have limited value in newborns. Newborn screening with ultrasonography has led to a high frequency of re-examination and a large number of hips being unnecessarily treated. Ultrasonography is, therefore, recommended only as an adjunct to clinical evaluation "either to clarify suspicious findings on physical examination after 3 to 4 weeks of age or to detect clinically silent DDH in the high-risk infant from 6 weeks to 4 to 6 months of age" [179]. The AAP recommends referral to an orthopedist if limited hip abduction or asymmetric hip abduction is present after four weeks [179]. Infants with risk factors for DDH, a questionable examination, and pediatrician or parental concern should also be referred.

Back and Spine

The back is generally the last part of the newborn that undergoes examination. Skin intactness over the spinal area should be noted as well as curvatures and asymmetry. Assess for hip and shoulder symmetry. Trunk incurvation can be elicited by stroking the infant's back along the spine. The hips should move toward the stimulated side. Gluteal folds should also be symmetrical and may have small dimples within the gluteal crease [170].

When nevi appear midline on the back, they are considered possible cutaneous markers for spinal dysraphism. Other signs include lipomas, dimples (especially if they are connected to the spinal cord), dermal sinuses, tails or skin tags, hypertrichosis, and signs of drainage or local infection. If two or more of these anomalies appear concomitantly, the risk of spinal dysraphism is considered higher. Due to the serious neurologic implications of missed diagnoses of spinal dysraphism, it is important that anomalies be noted and referred appropriately [33,67,182].

WARNING SIGNS

Warning signs of the extremities assessment, which would warrant further investigation and/or immediate intervention, include [35,92]:

- Absence of limbs or digits, usually isolated

- Deformities of digits, including fusion (i.e., syndactyly) and extra digit(s) (i.e., polydactyly), also usually isolated deformities

- Single palmar line associated with Down syndrome

- Lack of movement of limb, possibly from brachial nerve palsy due to excessive traction and flexion of the neck during delivery (arm held adducted and internally rotated) or fracture

- Limited abduction and unequal femur length

- Asymmetrical thigh creases or positive Ortolani maneuver (i.e., clicks indicating developmental dysplasia of the hip)

26. CONCLUSION

A thorough neonatal assessment should be performed on all newborns in the first hours after birth to ensure an appropriate transition to extrauterine life. This assessment should be done systematically so early intervention may be initiated in the event that an abnormality is discovered. The prenatal record should be reviewed whenever possible to be aware of newborn and/or maternal risk factors that may complicate care. Maternal and environmental factors, such as smoking, drug or alcohol use, gestational diabetes, and GBS, are important considerations when assessing newborns. The placenta, examined by either a nurse or the delivering physician, may also give important clues regarding the health of the infant.

Infants should receive expert postbirth care by a person competent in neonatal resuscitation standards. The formal assessment and documentation of the newborn assessment in a timely fashion is essential. Most institutions use standardized forms and charts based on accepted assessment tools, such as the Apgar and the New Ballard scoring methods. Incomplete or incorrect documentation, as well as a lack of follow-up, may have hazardous implications [183]. Apgar scores should be assigned and may indicate future wellness; however, necessary treatment in critical situations should not wait until a score has been established. Any abnormalities should be reported immediately to the physician and appropriate measures should be taken. By following the same consistent approach with each newborn assessment, the nurse can be confident that the highest level of care has been provided for each infant.

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158. Michie C, Alu S, Wild K, Hampsheir R, Chabonnaud P, Harvey D. Should we estimate liver span in the right mid-clavicular line or the midline? J Paediatr Child Health. 1995;31(3):241-244.

159. McMillan JA, Feigin RD, DeAngelis C, Jones MD (eds). Oski's Pediatrics: Principles and Practice. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2006.

160. MedlinePlus. Necrotizing Enterocolitis. Available at https://medlineplus.gov/ency/article/001148.htm. Last accessed July 15, 2020.

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163. Alfa MJ, Robson D, Davi M, Bernard K, Van Caeseele P, Harding GK. An outbreak of necrotizing enterocolitis associated with a novel Clostridium species in a neonatal intensive care unit. Clin Infect Dis. 2002;35(suppl 1):S101-S105.

164. Steinhorn RH. Pediatric Congenital Diaphragmatic Hernia. Available at https://emedicine.medscape.com/article/978118-overview. Last accessed July 15, 2020.

165. Kipfmueller F, Heindel K, Schroeder L, et al. Early postnatal echocardiographic assessment of pulmonary blood flow in newborns with congenital diaphragmatic hernia. J Perinat Med. 2018;46(7):735-743.

166. PubMed Health. Early Birth for Babies with Gastroschisis. Available at https://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0056670/. Last accessed June 20, 2017.

167. Williams T, Butler R, Sundem T. Management of the Infant with Gastroschisis: A Comprehensive Review of the Literature. Available at http://www.medscape.com/viewarticle/458475. Last accessed July 15, 2020.

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Evidence-Based Practice Recommendations Citations

1. U.S. Preventive Services Task Force. Tobacco Smoking Cessation in Adults, Including Pregnant Women: Behavioral and Pharmacotherapy Interventions. Available at https://www.uspreventiveservicestaskforce.org/uspstf/recommendation/tobacco-use-in-adults-and-pregnant-women-counseling-and-interventions. Last accessed August 10, 2020.

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4. ACOG Committee on Obstetric Practice. ACOG Committee Opinion 797: Prevention of Group B Streptococcal Early-Onset Disease in Newborns. Available at https://www.acog.org/-/media/project/acog/acogorg/clinical/files/committee-opinion/articles/2020/02/prevention-of-group-b-streptococcal-early-onset-disease-in-newborns.pdf. Last accessed August 10, 2020.

5. Fallon EM, Nehra D, Potemkin AK, et al. A.S.P.E.N. clinical guidelines: nutrition support of neonatal patients at risk for necrotizing enterocolitis. JPEN J Parenter Enteral Nutr. 2012;36(5):506-523. Available at https://onlinelibrary.wiley.com/doi/pdf/10.1177/0148607112449651. Last accessed August 10, 2020.

92343 • Childhood Leukemias and Lymphomas

Lori L. Alexander, MTPW, ELS, MWC

www.netce.com

Copyright © 2021 NetCE, All rights reserved.

Cancer is the leading cause of death among children 14 years of age and younger and leukemia and lymphoma are among the most prevalent cancers in children. Leukemia and lymphoma may have a genetic basis, and primary care practitioners should know which patients may be at risk for the development of one of these diseases. Also essential is an understanding of appropriate diagnostic testing, as well as the cellular classification, staging, and prognostic variables associated with the disease. A diagnosis of cancer in a child creates devastating effects on the child and his or her family. Because of the key relationship between a pediatrician, family medicine physician, nurses, and a child and his or her family, these practitioners are often an important resource for emotional support, guidance, and referrals. Interventions can also help children with cancer through problems with social interactions and school-related issues. Primary pediatric care must continue during treatment for cancer, and primary care practitioners should understand how leukemia and lymphoma and their treatment affect growth and development and routine preventive measures, such as immunizations. The child's primary care practitioner should also be responsible for maintaining documentation of the child's treatment and providing follow-up care. Over the past several years, research has documented the long-term effects of childhood cancer and its treatment. Studies have shown that more than two-thirds of childhood cancer survivors have serious health conditions, and many have more than one health condition. The specific findings of these studies point to the need for heightened awareness of the health risks for survivors and the value of creating survivorship care plans.

Table of Contents

92343 • Childhood Leukemias and Lymphomas

Course Overview

Audience

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planners

Division Planners Disclosure

Director of Development and Academic Affairs

Director Disclosure Statement

About the Sponsor

Disclosure Statement

Implicit Bias in Health Care

1. INTRODUCTION

2. OVERVIEW OF CHILDHOOD LEUKEMIAS AND LYMPHOMAS

RISK FACTORS

3. TYPES OF LEUKEMIA

ACUTE LYMPHOBLASTIC LEUKEMIA (ALL)

ACUTE MYELOID LEUKEMIA (AML)

4. TYPES OF LYMPHOMA

HODGKIN LYMPHOMA

NON-HODGKIN LYMPHOMA

5. IDENTIFYING LEUKEMIAS AND LYMPHOMAS

6. DIAGNOSIS OF LEUKEMIAS

CLINICAL SIGNS AND SYMPTOMS

DIAGNOSTIC TESTING

CLASSIFICATION

PROGNOSTIC VARIABLES

7. DIAGNOSIS OF LYMPHOMA

HODGKIN LYMPHOMA

NON-HODGKIN LYMPHOMA

8. COMMUNICATION WITH THE PATIENT AND FAMILY

COMMUNICATING EFFECTIVELY

9. TREATMENT APPROACHES

IMPORTANCE OF CLINICAL TRIALS

DISEASE-DIRECTED TREATMENT

TREATMENT OF LEUKEMIAS

TREATMENT OF LYMPHOMA

10. SUPPORTIVE CARE

INFECTION

NEUTROPENIA

ANEMIA OR THROMBOCYTOPENIA

METABOLIC DISTURBANCES

DEEP VEIN THROMBOSIS

11. PALLIATIVE AND END-OF-LIFE CARE

ASSESSING AND MANAGING SYMPTOMS

PSYCHOSOCIAL AND SPIRITUAL ISSUES

PROVIDING END-OF-LIFE CARE

12. PSYCHOSOCIAL ISSUES FOR THE PATIENT AND FAMILY

PSYCHOSOCIAL ISSUES FOR THE PATIENT

PSYCHOSOCIAL ISSUES FOR THE FAMILY AND FAMILY DYNAMICS

13. LONG-TERM HEALTH CARE FOR CHILDHOOD CANCER SURVIVORS

LATE EFFECTS AMONG CHILDHOOD CANCER SURVIVORS

HEALTH PROMOTION AND EDUCATION

CHALLENGES IN PROVIDING HEALTH CARE

14. CASE STUDIES

CASE STUDY 1

CASE STUDY 2

15. CONCLUSION

16. RESOURCES FOR FAMILIES WITH A CHILD OR ADOLESCENT WITH LEUKEMIA OR LYMPHOMA

GENERAL EDUCATION AND ADVOCACY

SURVIVORSHIP

INSURANCE, LEGAL, AND EDUCATIONAL ISSUES

FREE WEEKLONG AND WEEKEND CAMPS

Works Cited

Evidence-Based Practice Recommendations Citations

92343 • Childhood Leukemias and Lymphomas

Education Category. Pediatrics

Release Date. 09/01/2021

Expiration Date. 08/31/2024

Course Overview

Cancer is the leading cause of death among children 14 years of age and younger and leukemia and lymphoma are among the most prevalent cancers in children. Leukemia and lymphoma may have a genetic basis, and primary care practitioners should know which patients may be at risk for the development of one of these diseases. Also essential is an understanding of appropriate diagnostic testing, as well as the cellular classification, staging, and prognostic variables associated with the disease. A diagnosis of cancer in a child creates devastating effects on the child and his or her family. Because of the key relationship between a pediatrician, family medicine physician, nurses, and a child and his or her family, these practitioners are often an important resource for emotional support, guidance, and referrals. Interventions can also help children with cancer through problems with social interactions and school-related issues. Primary pediatric care must continue during treatment for cancer, and primary care practitioners should understand how leukemia and lymphoma and their treatment affect growth and development and routine preventive measures, such as immunizations. The child's primary care practitioner should also be responsible for maintaining documentation of the child's treatment and providing follow-up care. Over the past several years, research has documented the long-term effects of childhood cancer and its treatment. Studies have shown that more than two-thirds of childhood cancer survivors have serious health conditions, and many have more than one health condition. The specific findings of these studies point to the need for heightened awareness of the health risks for survivors and the value of creating survivorship care plans.

Audience

This course is designed primarily for pediatricians, family medicine physicians, nurses, and other healthcare practitioners in the pediatric or family medicine setting. Primary care physicians, other practitioners in primary care, social workers, and marriage and family therapists will also benefit from this course.

Course Objective

All healthcare professionals should understand how pediatric leukemia and lymphoma and their treatment affect growth and development and routine preventive measures and be skilled in discussing emotional well-being and psychosocial issues and in recommending psychosocial interventions. The purpose of this course is to enhance healthcare professionals' understanding of treatment options for childhood leukemias and lymphomas, the effects of treatment on normal growth and development, and the psychosocial effect of cancer on a child and his or her family.

Learning Objectives

Upon completion of this course, you should be able to:

1. Discuss the prevalence and types of childhood leukemia and lymphoma.

2. Identify the clinical signs and symptoms associated with childhood leukemia.

3. Describe the diagnostic testing for and classification of childhood leukemias.

4. Discuss the prognostic variables for childhood leukemias.

5. Describe the clinical presentation, diagnosis, and prognostic variables of Hodgkin lymphoma.

6. Discuss the signs and symptoms, diagnosis, and prognostic variables associated with non-Hodgkin lymphomas.

7. Explain the principles of communicating a diagnosis of childhood cancer.

8. Discuss the importance of clinical trials and the issues unique to trials involving children.

9. Outline the treatment approaches for childhood leukemia and lymphoma.

10. Discuss the various means of supportive care needed for children/adolescents with leukemia or lymphoma.

11. Describe the elements of effective palliation of symptoms in the end of life for children/adolescents with cancer.

12. Recognize the psychosocial and spiritual needs of children/adolescents with cancer and their families.

13. Discuss coping mechanisms of children/adolescents with cancer and their effect on psychosocial adjustment.

14. Explain the psychosocial effect of childhood cancer on family dynamics.

15. Define the most common long-term effects of childhood leukemias and lymphomas and their treatment.

16. Outline recommendations for necessary surveillance and long-term monitoring specific for a child's or adolescent's cancer and treatment.

Faculty

Lori L. Alexander, MTPW, ELS, MWC, is President of Editorial Rx, Inc., which provides medical writing and editing services on a wide variety of clinical topics and in a range of media. A medical writer and editor for more than 30 years, Ms. Alexander has written for both professional and lay audiences, with a focus on continuing education materials, medical meeting coverage, and educational resources for patients. She is the Editor Emeritus of the American Medical Writers Association (AMWA) Journal, the peer-review journal representing the largest association of medical communicators in the United States. Ms. Alexander earned a Master’s degree in technical and professional writing, with a concentration in medical writing, at Northeastern University, Boston. She has also earned certification as a life sciences editor and as a medical writer.

Faculty Disclosure

Contributing faculty, Lori L. Alexander, MTPW, ELS, MWC, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Division Planners

John M. Leonard, MD

Jane C. Norman, RN, MSN, CNE, PhD

Alice Yick Flanagan, PhD, MSW

James Trent, PhD

Division Planners Disclosure

The division planners have disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Director of Development and Academic Affairs

Sarah Campbell

Director Disclosure Statement

The Director of Development and Academic Affairs has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

About the Sponsor

The purpose of NetCE is to provide challenging curricula to assist healthcare professionals to raise their levels of expertise while fulfilling their continuing education requirements, thereby improving the quality of healthcare.

Our contributing faculty members have taken care to ensure that the information and recommendations are accurate and compatible with the standards generally accepted at the time of publication. The publisher disclaims any liability, loss or damage incurred as a consequence, directly or indirectly, of the use and application of any of the contents. Participants are cautioned about the potential risk of using limited knowledge when integrating new techniques into practice.

Disclosure Statement

It is the policy of NetCE not to accept commercial support. Furthermore, commercial interests are prohibited from distributing or providing access to this activity to learners.

Implicit Bias in Health Care

The role of implicit biases on healthcare outcomes has become a concern, as there is some evidence that implicit biases contribute to health disparities, professionals' attitudes toward and interactions with patients, quality of care, diagnoses, and treatment decisions. This may produce differences in help-seeking, diagnoses, and ultimately treatments and interventions. Implicit biases may also unwittingly produce professional behaviors, attitudes, and interactions that reduce patients' trust and comfort with their provider, leading to earlier termination of visits and/or reduced adherence and follow-up. Disadvantaged groups are marginalized in the healthcare system and vulnerable on multiple levels; health professionals' implicit biases can further exacerbate these existing disadvantages.

Interventions or strategies designed to reduce implicit bias may be categorized as change-based or control-based. Change-based interventions focus on reducing or changing cognitive associations underlying implicit biases. These interventions might include challenging stereotypes. Conversely, control-based interventions involve reducing the effects of the implicit bias on the individual's behaviors. These strategies include increasing awareness of biased thoughts and responses. The two types of interventions are not mutually exclusive and may be used synergistically.

1. INTRODUCTION

Cancer is the leading cause of death among children 14 years of age and younger, and leukemia and lymphoma are among the most prevalent cancers in children/adolescents [1,2]. Two types of leukemia—acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML)—and two types of lymphoma—Hodgkin and non-Hodgkin—occur in this population. Each of these diseases is distinct, with variations in etiology, patient characteristics, signs and symptoms, treatment approaches, and outcomes. Primary care practitioners should be able to identify the clinical signs and symptoms that may be indicative of these diseases and have knowledge of diagnostic testing, staging, and prognostic variables. A discussion of all of these aspects is included here, as well as a broad overview of treatment options.

A diagnosis of cancer in a child/adolescent creates devastating effects on him or her, as well as the family. As a result of the key relationship between primary care practitioners and children/adolescents and their families, these clinicians are often an important resource for emotional support, guidance, and referrals. Clinicians should be skilled in discussing emotional well-being and psychosocial issues and in recommending psychosocial interventions to help the patient and family develop coping mechanisms and deal with the disruption to normal family dynamics. Interventions can also help children/adolescents with cancer through problems with social interactions and school-related issues.

Primary pediatric care should continue during treatment for cancer, and clinicians in this setting should understand the effects of leukemia and lymphoma and their treatments on the child's/adolescent's growth and development and on routine preventive measures. In addition, studies have shown higher rates of morbidity and mortality among childhood cancer survivors compared with healthy siblings and the overall (age-matched) population [3,4,5,6,7]. The specific findings of these studies point to the need for heightened awareness of the health risks for survivors and the value of creating survivorship care plans. A discussion of late effects of childhood cancer and its treatment, the maintenance of health documentation, and appropriate follow-up care offers information to help clinicians provide optimal primary care to their patients with childhood leukemia or lymphoma.

2. OVERVIEW OF CHILDHOOD LEUKEMIAS AND LYMPHOMAS

The term "childhood cancer" is used to describe cancers that affect individuals from birth to 19 years of age. Although this age range is wide, cancers that occur throughout these ages have many similarities; however, the physical and psychosocial needs of infants differ greatly from those of young children as well as those of adolescents (defined as 15 to 19 years of age). The incidence of childhood leukemias and lymphoma vary among age groups, as do outcomes. Treatment varies as well, and some adolescents are treated in pediatric clinical practice, while others are treated in adult practices; this difference makes it difficult to evaluate the efficacy of certain treatment protocols and also creates challenges in improving survival rates [8]. In addition, issues related to dependency, access to care, treatment compliance, and decision making differ between children and adolescents with cancer [8,9]. In sum, adolescents represent a distinct population of individuals with cancer, and their unique needs have been recognized, as evidenced by several recent articles and, especially, the 2011 launch of the peer-reviewed journal, the Journal of Adolescent and Young Adult Oncology [10].

In 2021, cancer will be diagnosed in an estimated 15,590 children/adolescents 0 to 19 years of age and will be the cause of 1,780 deaths [2]. Among children 1 to 9 years of age in the United States, cancer is the second leading cause of death (behind unintentional injuries), and it is the fifth leading cause for older children, representing approximately 5.5% of all deaths among individuals 10 to 24 years of age [11]. Hematologic cancers are among the most common childhood cancers in children 0 to 14 years of age; brain and central nervous system tumors and lymphomas are the most common types of cancer diagnosed in adolescents 15 to 19 years of age [2]. Hematologic cancers are classified as leukemia when they involve primarily blood and bone marrow and as lymphoma when they arise from lymph nodes or other organs. Over the years, several systems have been developed to classify hematologic cancers. The uniform standard now used is the World Health Organization (WHO)/Revised European-American Lymphoma (REAL) system, now in its fourth (revised) edition [12,13]. This system differentiates hematologic cancers into four broad categories: myeloid, lymphoid, mast cell, and histiocytic neoplasms. Specific disease entities are further defined within these categories on the basis of morphologic, immunophenotypic, genetic, biologic, and clinical criteria. The hematologic cancers occurring in childhood are predominantly lymphoid or myeloid. The revision clarifies the diagnosis and management of lesions at very early stages and refines the diagnostic criteria for some entities [13].

Lymphoid and myeloid leukemias are further classified as acute or chronic, depending on the maturity of the cells affected and the pace of disease progression; acute leukemia affects immature cells (lymphoblasts) and progresses rapidly, whereas chronic leukemia affects mature cells and progresses more slowly. According to the International Classification of Childhood Cancer (ICCC), leukemia is categorized according to five diagnostic groups. Two of these groups—lymphoid leukemia and acute myeloid leukemia—account for approximately 83% of all leukemias [1].

Acute leukemia is the leading type of childhood cancer, representing 24.3% of all new childhood cancer cases [14]. Lymphoid leukemia is more common in both children and adolescents, with acute lymphocytic leukemia (ALL) accounting for 8.3% of leukemias in children and adolescents, compared with acute myeloid leukemia (AML), which accounts for 3.6% of leukemias in children and adolescents [14]. Chronic lymphocytic leukemia and chronic myeloid leukemia occur primarily in individuals who are at least 50 years of age and are rare in children/adolescents [15]. Because of the rarity of the chronic forms of leukemia in children, the focus in this course is on ALL and AML.

According to the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program, 3,318 children and adolescents were diagnosed with lymphoma between 2009 and 2018 [1]. Hodgkin lymphoma is the most prevalent cancer among adolescents and young adults 15 to 19 years of age, representing 6.7% of all childhood cancers in this age group; non-Hodgkin lymphoma accounts for 4.3% [1]. Among children 14 years of age and younger, non-Hodgkin lymphoma is the more prevalent lymphoma, accounting for 9% of cancers, with Hodgkin lymphoma representing less than 6% [1].

The incidence of pediatric ALL and AML increased significantly between 1975 and 2018. The incidence of non-Hodgkin lymphoma showed no measurable increase, while the incidence of Hodgkin lymphoma has decreased [1]. Mortality associated with pediatric leukemia and lymphoma has also decreased, with the greatest decreases in ALL and AML [1].

RISK FACTORS

Unlike other types of cancers in adults, childhood leukemia and lymphoma are not associated with lifestyle risk factors, but the etiology is unclear. The only clear risk factor for childhood hematologic cancer is an inherited genetic syndrome, especially Down syndrome, which is associated with a 10-fold to 20-fold increased risk of leukemia [16,17,18,19]. Increased risk is associated with several other genetic syndromes as well (Table 1) [17,18,19].

Table 1: GENETIC SYNDROMES ASSOCIATED WITH PEDIATRIC LEUKEMIA AND LYMPHOMA

Genetic Syndrome

Type of Pediatric Leukemia or Lymphoma

Inherited Syndromes

Ataxia-telangiectasia

ALL, AML

Bloom syndrome

ALL, AML

Diamond-Blackfan anemia

AML

Down syndrome

ALL, AML

Familial monosomy 7

AML

Fanconi anemia

AML

Klinefelter syndrome

ALL

Kostmann syndrome (severe congenital neutropenia)

AML

Langerhans cell histiocytosis

ALL

Neurofibromatosis type 1

ALL, AML

Severe combined immunodeficiency syndrome

NHL

Shwachman syndrome

ALL, AML

Acquired Syndromes

Acquired monosomy 7

AML

Amegakaryocytic thrombocytopenia

AML

Human immunodeficiency virus (HIV) infection

NHL

Immunocompromise (drug-related)

NHL

Paroxysmal nocturnal hemoglobinuria

AML

ALL = acute lymphoblastic leukemia; AML = acute myelogenous leukemia; NHL = non-Hodgkin lymphoma.

Source: [17,18,19]

Many factors have been investigated for their role in the development of childhood leukemia and lymphoma, including infection and environmental factors. The combination of genetic susceptibility and an abnormal response to infection is thought to be one cause of leukemia in children 2 to 5 years of age [20,21,22]. In addition, infection with the Epstein-Barr virus (EBV) in the presence of an immunodeficiency condition has been linked to an increased risk of Hodgkin lymphoma, and a history of serologically confirmed infectious mononucleosis significantly increases the risk for EBV-positive Hodgkin lymphoma among young adults [23,24,25,26]. A Children's Oncology Group study found that parental history of autoimmunity and parent or sibling with an allergy is associated with increased risk for EBV-positive Hodgkin lymphoma [27]. Infection in early childhood may reduce the risk of Hodgkin lymphoma, as the incidence is lower for children with many siblings or many playmates [28,29]. With regard to non-Hodgkin lymphoma, the prevalence ranges from 1% to 25% among children/adolescents with primary or acquired immunodeficiency disorders, and a Swedish study demonstrated a significant increase in the risk of non-Hodgkin lymphoma in association with infections in infancy [23,30]

Radiation has emerged as a causal factor of hematologic cancers. Exposure to large doses of radiation, as from such catastrophes as atomic bombs or nuclear reactor accidents, has been associated with higher rates of leukemia and a slightly higher risk for non-Hodgkin lymphoma [31]. Low-dose radiation, from x-rays or radiation therapy, has also been found to be associated with a slight increase in risk for leukemia and lymphoma [31]. However, because of the time needed for disease to develop from such exposure, this cause is not as common in children as it is in adults. Prenatal exposure to radiation has been linked to the development of leukemia, but this cause has been rare since the routine use of preventive measures in performing radiographs on women. In one study, researchers evaluated three types of exposure to radiation: parental exposure before conception, intrauterine exposure, and postnatal exposure. None was found to increase leukemogenesis for children with Down syndrome [32].

Maternal exposure to chemicals and carcinogens during pregnancy has also been evaluated as an etiologic factor for hematologic cancer. Gestational exposure to petroleum products has been associated with an increased risk of infant leukemia, particularly AML and leukemia without mixed lineage leukemia gene rearrangements [33]. In the same study, eight other classes of household chemicals were not found to increase the risk of leukemia. One study explored a possible association between residential proximity to oil and gas development and increased risk for ALL [34]. A meta-analysis found that maternal smoking during pregnancy was associated with a modest increase in risk for non-Hodgkin lymphoma [35].

A family history of Hodgkin lymphoma increases the risk of pediatric Hodgkin lymphoma, with a sevenfold increase in risk for children who have a sibling with the disease [36]. The risk of non-Hodgkin lymphoma is not higher for children who are born to parents who are survivors of non-Hodgkin lymphoma, unless the cancer was associated with a congenital disorder [36].

For reasons that are unclear, the risk of non-Hodgkin lymphoma has been higher among children/adolescents in families with higher parental incomes and educational levels and lower in families with large numbers of children [37]. Other demographic variables may also be risk factors, as the prevalence of childhood leukemia and lymphoma varies according to age, sex, and race/ethnicity, as will be discussed.

The risk factors for childhood hematologic cancers continue to be explored, and it currently appears that a complex set of factors is involved in the development of these diseases.

3. TYPES OF LEUKEMIA

Acute leukemia occurs in approximately 5,470 children and adolescents each year, with most cases occurring in children 1 to 4 years of age. The median age at diagnosis is 6 years of age [1,14]. The incidence is higher for male than female children/adolescents for all races/ethnicities (5.3 per 100,000 vs. 4.3 per 100,000, respectively) [14]. Among racial/ethnic populations of children/adolescents, the incidence of leukemia (all types) is highest for the Asian/Pacific Islander population and lowest for the non-Hispanic black population (Table 2) [1,14].

Table 2: INCIDENCE OF PEDIATRIC LEUKEMIA AND LYMPHOMA ACCORDING TO RACE/ETHNICITY

Cancer Type

Incidence (per 1 million)

Non-Hispanic White

Non-Hispanic Black

Hispanic

Asian/Pacific Islander

Leukemia (all types)

55

35

65

69

Acute lymphoblastic leukemia

40

23

51

44

Acute myeloid leukemia

6

8

7

14

Hodgkin lymphoma

7

6

5

7

Non-Hodgkin lymphoma

9

10

10

12

Source: [14]

ACUTE LYMPHOBLASTIC LEUKEMIA (ALL)

ALL represents a heterogeneous group of biologic subtypes of leukemia and is classified into two principal types depending on the lymphocytes from which it develops. Most cases of B-lymphocyte ALL originate in cells early in the development of B cells and are therefore designated as precursor B-cell type [38]. Research has demonstrated that childhood ALL is initiated in utero, with another event required for full malignant transformation [39,40]. DNA injury leads to the uncontrolled development of leukemic lymphoblasts in the marrow, which causes a deficiency of normally functioning blood cells. As a result, anemia, thrombocytopenia, and neutropenia occur.

ALL accounts for 72% of leukemias in children and adolescents [1]. The incidence of ALL varies according to sex, age, and race/ethnicity. ALL is more common among male children/adolescents (45 per million) than among female children/adolescents (39 per million) [1]. ALL typically develops in children between 1 and 9 years old, with a sharp peak in the incidence for children 1 to 4 years old [1]. The incidence of ALL is highest in the white population, followed by the black and Hispanic populations, with the lowest incidence in the American Indian/Alaska Native population [1].

Advances in treatment since the mid-1970s have improved survival rates for ALL [1]. According to SEER data, the five-year relative survival rate for ALL improved from 41% in 1975–1977 to 72% in 2000–2018 (Table 3) [1]. The observed long-term survival for ALL is 88% at 5 years, with an 82% probability of 10-year survival for children/adolescents who have 5-year survival (Table 4) [1,14].

Table 3: FIVE-YEAR OBSERVED SURVIVAL RATES FOR PEDIATRIC LEUKEMIA AND LYMPHOMA AMONG CHILDREN/ADOLESCENTS (BIRTH TO 19 YEARS OF AGE)

Cancer Type

1975–1977

2000–2018

Acute lymphocytic leukemia

41%

88%

Acute myeloid leukemia

6%

75%

Hodgkin lymphoma

72%

98%

Non-Hodgkin lymphoma

47%

90%

Source: [14]

Table 4: LONG-TERM SURVIVAL IN PEDIATRIC LEUKEMIA AND LYMPHOMA

Cancer Type

5-Year Survival

Acute lymphoblastic leukemia

89%

Acute myeloid leukemia

68%

Hodgkin lymphoma

98%

Non-Hodgkin lymphoma

90%

Source: [1]

ACUTE MYELOID LEUKEMIA (AML)

Pediatric myeloid leukemia refers to a spectrum of hematopoietic malignant diseases, but AML accounts for the majority of cases. Although AML is less prevalent than ALL, AML is more lethal, accounting for approximately 30% of childhood leukemia-related deaths [41]. AML involves the malignant transformation of stem cells or progenitor cells in the bone marrow.

As noted, AML accounts for 3.6% of leukemias in children and adolescents [1]. As with ALL, the incidence of AML varies according to age, but the pattern differs. The incidence of AML is highest for infants and lowest for children 5 to 9 years of age [1]. After 9 years of age, the rate slowly increases throughout adolescence [1]. Unlike ALL, the incidence of AML is similar for male and female children/adolescents (8 vs. 7 per million, respectively) [14]. The incidence is highest in the Hispanic and White populations, but the range across race/ethnicities is narrow [1,14].

The five-year survival rate for AML has consistently been the lowest of all childhood cancers. Although the rate remains low, it has increased substantially, from 46% in 2000 to 63% in 2013 [14]. The observed long-term survival is 68% at five years [1]. A review of data from two AML studies conducted by the Children's Cancer Group (now part of the Children's Oncology Group [COG]) showed that overall survival was substantially higher for white children/adolescents than for black or Hispanic children/adolescents [42]. Because treatment was given according to established cooperative group treatment protocols, compliance rates, access to therapy, type of supportive care, or leukemia phenotype were not likely to be factors in the differences.

4. TYPES OF LYMPHOMA

Lymphomas arise from lymphoid cells. The distinction between Hodgkin and non-Hodgkin lymphoma is defined by the presence of Reed-Sternberg cells in Hodgkin lymphoma [24]. The two types of lymphoma differ from each other in several ways, including clinical behavior, biology, and histopathologic features.

Hodgkin and non-Hodgkin lymphoma occur in approximately 2,420 children and adolescents, and the incidence increases with age, with significant peaks in adolescence [1]. Hodgkin lymphoma accounts for 30% of lymphomas in children and 70% of lymphomas in adolescents, while non-Hodgkin lymphoma accounts for 46% of lymphomas in children and 65% of lymphomas in adolescents [1]. The disease is more common among male children/adolescents (18 per million) than among female children/adolescents (8 per million) [14]. Among racial/ethnic groups, the incidence of Hodgkin and non-Hodgkin lymphoma is highest for non-Hispanic white children/adolescents and lowest for Hispanic children/adolescents [1,14].

As with leukemia, advances in treatment options have improved survival for children/adolescents with lymphoma.

HODGKIN LYMPHOMA

Hodgkin lymphoma was first described in 1832 by Thomas Hodgkin as a "peculiar enlargement" and "affection" of the lymph nodes of the neck and other areas of the body, along with enlargement of the spleen and possibly the liver; there were often deposits of firm tubercle-like nodules in the spleen and liver [24]. The malignant cells, subsequently named Reed-Sternberg cells, arise from B lymphocytes and exist with Hodgkin cells (large, mononuclear cell variants) within an immunoreactive background consisting of lymphocytes, eosinophils, neutrophils, histiocytes, plasma cells, fibroblasts, and collagen [24]. According to the WHO/REAL system, Hodgkin lymphoma may be categorized as nodular lymphocyte-predominant or classical. Classical Hodgkin lymphoma is further categorized into four subtypes: lymphocyte predominant, nodular sclerosis, mixed cellularity, and lymphocyte depleted [43,44]. Two of the four subtypes of classical Hodgkin lymphoma account for most cases in children. Lymphocyte-predominant Hodgkin lymphoma and lymphocyte-depleted Hodgkin lymphoma are both rare in children.

In the United States, the incidence of Hodgkin lymphoma is much lower for children up to 4 years of age than for older children and adolescents. This type of lymphoma is more common among male children/adolescents (8 per million) than female children/adolescents (4 per million) [14]. With regard to race/ethnicity, the incidence of Hodgkin lymphoma is highest in the non-Hispanic white and Asian/Pacific Islander populations and lowest in the Hispanic population [14]. Hodgkin lymphoma is the most curable childhood cancer, with a five-year survival rate of nearly 97% in 2011–2017, an increase from 87% in 1975–1983 [1].

NON-HODGKIN LYMPHOMA

Pediatric non-Hodgkin lymphoma is a heterogeneous group of malignant tumors of lymphoreticular cells that arise from both mature and blastic B cells and T cells [45]. Non-Hodgkin lymphomas in children/adolescents differ from those in adults in that adult lymphomas are more clinically aggressive.

As with Hodgkin lymphoma, the incidence of non-Hodgkin lymphoma increases with age and remains relatively constant across all ages for both boys and girls [1,46]. Non-Hodgkin lymphoma develops nearly twice as often in male than female children/adolescents across all age-groups (15 vs. 6 per million) [14]. The incidence is fairly similar across races/ethnicities, with the highest incidence in the Hispanic and Black populations and the lowest incidence in the non-Hispanic White population [14].

The five-year survival rate for non-Hodgkin lymphoma improved from approximately 74% in 1975–1979 to 90% in 2000–2018 [14].

There are nearly 30 different types of non-Hodgkin lymphoma, but only four are predominant in children: small noncleaved cell lymphoma (Burkitt lymphoma and Burkitt-like lymphoma), lymphoblastic lymphoma, diffuse large B-cell lymphoma, and anaplastic large-cell lymphoma (systemic or cutaneous). Burkitt lymphoma and diffuse large B cell lymphomas both develop from B lymphocytes; anaplastic large-cell lymphoma and lymphoblastic lymphoma typically arise from T cells.

Burkitt Lymphoma

Burkitt lymphoma is the most prevalent type of non-Hodgkin lymphoma among children/adolescents, accounting for approximately 14% of pediatric non-Hodgkin lymphoma in the United States [1]. It most commonly develops in boys 10 to 14 years of age [46]. It is more common in non-Hispanic whites than in Hispanic whites [46]. This type of lymphoma was first noted by Denis Burkitt, who was studying children in Africa [45]. Burkitt lymphoma is endemic in Africa, where it occurs at a very high rate [46,47].

There are clinicopathologic differences between the endemic and sporadic forms of the disease [45]. Burkitt lymphoma most commonly affects the jaw and maxilla of African children, whereas the abdomen is the most common site in children in the United States [47].

Diffuse Large B-Cell Lymphoma

Diffuse large B-cell lymphoma is the second most common non-Hodgkin lymphoma, representing 10% to 20% of pediatric non-Hodgkin lymphoma. It occurs most frequently in adolescents 15 to 19 years of age [46]. This type of lymphoma differs from other types of non-Hodgkin lymphoma in that it grows more slowly and does not usually spread to the bone marrow, central nervous system (CNS), or skin.

Diffuse large B-cell lymphoma is further categorized as nonmediastinal or primary mediastinal. Nonmediastinal disease is more common; primary mediastinal occurs predominately in adolescents [48]. The gene expression profile of this type of non-Hodgkin lymphoma is distinct and suggests a close association with Hodgkin lymphoma [49,50].

Lymphoblastic Lymphoma

Lymphoblastic lymphoma represents approximately 20% of pediatric non-Hodgkin lymphoma [46]. It develops most often in boys, especially in the 10 to 14 year age group [46]. The malignant lymphoblasts are the same as those involved with childhood ALL. If the lymphoblasts involve more than 25% of the bone marrow, the disease is reclassified as leukemia and is treated accordingly. Lymphoblastic lymphoma can arise from early T cells or B cells; precursor B-cell lymphoblastic lymphoma occurs less frequently, representing 2.5% of all non-Hodgkin lymphoma [51].

Anaplastic Large-Cell Lymphoma

Anaplastic large-cell lymphoma accounts for approximately 10% of pediatric non-Hodgkin lymphoma, occurring most often among male adolescents [1,46]. This type of non-Hodgkin lymphoma varies substantially in its clinical presentation, with possible involvement of lymph nodes and extranodal sites, typically bone and skin.

5. IDENTIFYING LEUKEMIAS AND LYMPHOMAS

Leukemia and lymphoma are often not suspected during the evaluation of children because of the rarity of the diseases. This low level of suspicion can make diagnosis in the primary care setting a challenge. In addition, the symptoms associated with these hematologic cancers are typically vague or nonspecific and are similar to those of common childhood conditions. Clinicians in the pediatric and family medicine settings must recognize early signs and symptoms and make appropriate referrals to ensure timely diagnosis and treatment, which are essential for enhancing survival.

Diagnosis begins with a history and physical examination. The subsequent course of diagnostic testing varies among patients and may include:

- Laboratory testing

- Imaging studies

- Evaluation of bone marrow aspirate

- Analysis of cerebrospinal fluid (CSF)

- Biopsy of lymph nodes

- Immunophenotyping

- Cytogenetic testing

- Molecular genetic testing

Some diagnostic procedures are uncomfortable, and children may be fearful and distressed at the prospect of diagnostic testing. Bone marrow aspiration and lumbar puncture are the most feared procedures, and care should be taken to ensure that the child is not in pain during either procedure [52]. The goal of pain intervention in this setting is unconsciousness, amnesia, and analgesia. The drugs used should be available in oral and/or intravenous form, have a rapid onset of action, and be of short duration [53]. Optimum anesthesia will provide the maximum amount of comfort for the child and help him or her cooperate with the procedure. A review demonstrated that mind-body interventions, such as hypnosis, distraction, and imagery, may be useful, either alone or in combination with pharmacologic interventions, in managing procedure-related pain [54]. Preventing pain in diagnostic procedures also has important implications for future care. Children who have a painful experience will be distressed about further diagnostic or therapeutic procedures and will be reluctant to undergo such procedures. The distress related to a painful experience can also manifest several years later, as a painful diagnostic procedure is often recalled as a traumatic event in childhood cancer survivors who experience post-traumatic stress [53].

Specialized testing, such as immunophenotyping, cytogenetic testing, and molecular genetic testing, is complex and beyond the scope of this course. In brief, immunophenotyping is carried out with use of flow cytometry, immunohistochemical assay, or immunophenotyping panel. The results demonstrate the cell lineage of the leukemia or lymphoma (T or B cell origin). Immunophenotyping also demonstrates associations between specific clusters of differentiation antigens and subtypes of disease and is used to diagnose and classify leukemia and lymphoma [55].

Cytogenetic testing identifies chromosomal abnormalities with respect to either number or structure [56]. In addition to conventional cytogenetic methods, molecular cytogenetic methods, such as fluorescent in situ hybridization (FISH); molecular genetic methods, such as reverse transcriptase polymerase chain reaction (RT-PCR) or Southern blot analysis; or DNA probes are used to identify chromosome abnormalities. Molecular studies are expensive and not necessary in all cases. However, they may help to detect translocations involving parts of chromosomes that are too small to be seen with conventional cytogenetic techniques.

The accurate diagnosis of leukemia and lymphoma requires careful evaluation and interpretation of the results of these studies, which, in turn, necessitates consultation with pediatric oncologists with expertise in hematologic malignancies. For this reason, the American Academy of Pediatrics (AAP) recommends that diagnostic testing be carried out in pediatric cancer centers, where the availability of appropriate technology and subspecialists helps to ensure an accurate diagnosis [57,58].

6. DIAGNOSIS OF LEUKEMIAS

CLINICAL SIGNS AND SYMPTOMS

There is a wide variation in the signs and symptoms of leukemia, and the onset is usually acute. However, in some cases, symptoms are insidious and persistent [38]. On average, symptoms are present for four to six weeks before diagnosis and are associated primarily with leukemia-related pancytopenia [19,38]. The clinical manifestations of ALL and AML are similar, although there are some distinctions (Table 5) [19,38,59]

Table 5: CLINICAL MANIFESTATIONS OF ACUTE LYMPHOBLASTIC LEUKEMIA (ALL) AND ACUTE MYELOGENOUS LEUKEMIA (AML)

Clinical Sign/Symptom

ALL

AML

Involvement of central nervous system

Yes (20% to 25%)

Yes (5% to 30%)

History

Low-grade fever; fatigue/weakness

Most common symptom

Yes

Anorexia or weight loss

Yes

Yes

Discomfort in bones and/or joints

Yes

Yes

Easy bruising or increased bleeding

Yes (33%)

Uncommon

Infection

No

Often first presenting symptom

Physical Examination

Pallor

Yes

Yes

Lymphadenopathy

Yes

Yes

Splenomegaly/hepatomegaly

Yes (60%)

Yes (<50%)

Mediastinal mass

Yes (10% to 18%)

Rare

Ecchymoses of skin or mucous membranes

Yes

No

Petechiae

Yes

No

Inflammation/bleeding of gums

No

Yes

Cutaneous rash

No

Yes

Laboratory Values (Median)

Hemoglobin

8 g/dL

8 g/dL

White blood cell count

12 x 10^9/L

20 x 10^9/L

Platelet count

53 x 10^9/L

70 x 10^9/L

Source: [19,38,59]

In taking a history from the child and/or a parent or caregiver, the clinician should determine if any of the following symptoms have been present:

- Fever

- Fatigue or weakness

- General malaise or loss of well-being

- Easy bruising or increased bleeding

- Anorexia or weight loss

- Dyspnea on exertion

- Discomfort in bones and/or joints

- Headache

- Seizures

- Vomiting

A low-grade fever of unknown etiology is the most common symptom associated with ALL [38]. If fever has persisted for more than two weeks, further evaluation for leukemia is warranted. Findings on physical examination that should prompt diagnostic testing for leukemia include pallor, petechiae, ecchymoses of the skin or mucous membranes, or lymphadenopathy (enlargement of more than 2 centimeters). Splenomegaly or hepatomegaly is evident at the time of diagnosis in approximately 60% of children with ALL and in less than half of children with AML [38].

The first sign of AML is often severe infection. Other common signs include swelling, pain, and bleeding of the gums; inflammation of the mucous membranes of the upper airways; and cutaneous rash (reddish papules, plaques, or nodules or maculopapular rash).

A mediastinal mass is rare in children with AML and is found in a small percentage (10% to 18%) of children with ALL [19,38]. With ALL, an enlarged thymus may lead to compression of the trachea or the superior vena cava, which can cause coughing and dyspnea or superior vena cava syndrome, respectively. A chest x-ray should be done if a cough persists for more than two weeks without an identifiable cause [59]. Overt testicular disease is rare (2%) at the time of diagnosis of ALL, but testicular leukemia is identified on evaluation of biopsy specimen in as many as 25% of male children/adolescents [38].

There are some differences between the initial laboratory values for ALL and AML. Although the median hemoglobin is approximately 8 g/dL for both types of leukemia, a higher percentage of children/adolescents with ALL have a hemoglobin of less than 8 g/dL. In addition, AML is associated with higher white blood cell (WBC) and platelet counts [19,38].

Involvement of the CNS is present at the time of the initial diagnosis of leukemia in approximately 20% to 25% of cases of ALL and 5% to 30% of cases of AML [19,38]. Signs of CNS involvement include headache, seizures, vomiting, asthenia, blurred vision, slurred speech, imbalance, cranial nerve palsy, and poor performance in school [19,38].

Many of the symptoms related to leukemia are associated with other diseases and conditions, and care is needed in making a differential diagnosis. Lymphadenopathy may be related to infectious mononucleosis or other infection, but a lack of a response to a routine course of antibiotics should prompt laboratory testing consisting of a complete blood cell count (CBC) with differential and a reticulocyte count. The likelihood of leukemia is high when such testing demonstrates anemia, thrombocytopenia, leukopenia, high mean corpuscular volume, and reticulocytopenia [59]. Light microscopy of stained blood cells can demonstrate leukemic blast cells; blast cells may also be present on the peripheral blood smear. However, blast cells are often present in the bone marrow only.

Children with ALL often have bone and/or joint pain before leukemic blast cells are evident in the peripheral blood, which can prompt evaluation for juvenile rheumatoid arthritis before leukemia. A study showed that for children with bone or joint pain, three factors predicted the diagnosis of ALL: a low WBC count (less than 4,000/mcL), a low-normal platelet count (150,000–250,000/mcL), and a history of nighttime pain [60]. When all three of these factors were present, the sensitivity of a diagnosis of ALL was 100% and the specificity was 85% [60].

DIAGNOSTIC TESTING

Computed tomography (CT), ultrasonography, and magnetic resonance imaging (MRI) can be helpful in detecting leukemic involvement of organs, bone, joints, soft tissue, or brain. Examination of CSF obtained through lumbar puncture can also help to determine whether leukemia involves the CNS [61]. A trephine biopsy should be performed if the tap is dry to differentiate between AML and myelodysplastic syndrome. Differentiation is important for treatment decision making, as myelodysplastic syndrome can only be cured by hematopoietic stem cell transplantation (HSCT) [61].

When the suspicion of leukemia is high on the basis of laboratory testing and/or imaging studies, the child should be referred to a pediatric hematologist or oncologist. Further diagnostic testing begins with bone marrow aspiration. The presence of leukemic blast cells on examination of a bone marrow sample confirms a diagnosis of leukemia. Cells obtained through bone marrow aspiration are also used for cytogenetic examination, immunophenotyping, and other special studies to determine whether the leukemia is lymphocytic or myeloid and to identify the specific leukemia subgroup. Determining this information is important for planning appropriate treatment and providing prognostic information about response to treatment.

CLASSIFICATION

The French-American-British (FAB) Cooperative Group developed a comprehensive classification system for acute leukemias, with three subtypes of ALL based solely on morphologic features and eight subtypes of AML based on morphology and findings of immunohistochemical analysis [62]. However, the discovery that immunophenotypic, cytogenetic, and molecular features of ALL are better than morphology alone for stratifying risk has led to the abandonment of the FAB classification of ALL [63]. The FAB classification for AML is widely accepted (Table 6), but it has been noted that strict application of the system will not allow for the diagnosis and classification of a considerable number of childhood cases [19].

Table 6: FRENCH-AMERICAN-BRITISH (FAB) COOPERATIVE GROUP CLASSIFICATION SYSTEM FOR ACUTE MYELOGENOUS LEUKEMIA AND PREVALENCE OF SUBTYPES

Subtype

Description

Prevalence

M0

Acute myeloblastic leukemia without differentiation; no expression of myeloperoxidase (MPO) at light microscopy level

–

M1

Acute myeloblastic leukemia with minimal differentiation; expression of MPO detected by immunohistochemistry or flow cytometry

18%

M2

Acute myeloblastic leukemia with differentiation

26%

M3

Acute promyelocytic leukemia (APL) hypergranular type

6%

M3v

APL, microgranular variant; cytoplasm of promyelocytes demonstrates a fine granularity, and nuclei are often folded

–

M4

Acute myelomonocytic leukemia (AMML)

17%

M4Eo

AMML with eosinophilia

–

M5a

Acute monocytic leukemia (AMoL) without differentiation (monoblastic)

21%

M5b

AMoL with differentiation

–

M6

Acute erythroid leukemia (AEL)

–

M7

Acute megakaryocytic leukemia (AMKL); flow cytometry is helpful to distinguish blasts from lymphoblasts

7%

Source: [19,62]

Although a comprehensive discussion of the cytogenetic characteristics of leukemia is beyond the scope of the course, an overview of the most common features is helpful in understanding risk, as chromosomal abnormalities are among the most important factors for classifying risk in leukemia [56]. Hyperploidy (more than 50 chromosomes in a tumor cell) is evident in approximately 25% of pediatric ALL but is extremely rare in AML [56]. The most frequent numerical abnormalities in AML are trisomy 8 (three copies of chromosome 8) and acquired trisomy 21 [56].

In infant leukemia (both ALL and AML), abnormality of the mixed-lineage leukemia (MLL) gene at 11q23 is found in nearly 80% of cases [31]. Across all pediatric age groups, the most common structural abnormality in ALL, occurring in approximately 20% to 25% of cases of B-cell ALL, is reciprocal translocation of t(12;21)(p13;q22), which results in fusion of the TEL and AML1 genes. However, TEL-AML1 fusion is rare in T-cell ALL [64]. Several other common abnormalities occur frequently in ALL (Table 7) [56].

Table 7: COMMON CYTOGENETIC FINDINGS IN LEUKEMIA

Type of Leukemia

Cytogenetic Abnormality

Acute lymphoblastic leukemia (ALL)

Hyperploidy

t(12;21)(p13;q22) TEL-AML1 fusion

t(1;19)

t(17;19)(q22;p13.3)

t(9;22)(q34;q11.2) (Philadelphia chromosome)

Aberrations of 12p

Acute myelogenous leukemia (AML)

Trisomy 8

Acquired trisomy 21

t(8;21)

t(15;17)

Aberrations of 11q23

inv(16)

Infant leukemia (ALL and AML)

Abnormality of the MLL gene at 11q23

Source: [56,64,65]

Structural abnormalities are found in approximately 60% of pediatric AML cases and are usually linked to specific subtypes. The most common translocations are t(8;21), which is associated primarily with the M2 subtype, and t(15;17), which is strongly linked to the M3 subtype [56,65]. Other common abnormalities associated with AML are aberrations of 11q23 and inv(16) [56].

PROGNOSTIC VARIABLES

The use of prognostic variables has been of more value in ALL than in AML. Several factors predictive of outcome have enabled the stratification of ALL into high-risk and standard-risk groups, and treatment is planned according to risk [38]. However, studies have been inconsistent in identifying factors present at or shortly after the time of diagnosis of AML that are predictive of outcome [19,66,67,68,69,70,71]. The greatest prognostic factor is the response to treatment [72].

Acute Lymphoblastic Leukemia (ALL)

The following factors have been found to have prognostic significance for children with ALL [72,73]:

- Age at the time of diagnosis

- WBC count at the time of diagnosis

- CNS status at the time of diagnosis

- Subtype of ALL

- Sex

- Race/ethnicity

- Cytogenetic findings

Age at the time of diagnosis is a strong prognostic factor, and the variation in outcome reflects differences in the underlying biology of ALL in different age groups [74,75]. For example, there is a high percentage of favorable cytogenetic features, such as high hyperdiploidy and t(12;21), in children who are 1 to 9 years of age, and the disease-free survival is better for that age group than for infants and older children and adolescents [76,77,78,79]. In addition, the risk of treatment failure is high for infants with ALL, especially infants younger than 3 months of age [80,81,82].

The risk of treatment failure is also high for children with precursor B-cell ALL who have an increased WBC count (more than 50,000/mcL) at the time of diagnosis [79]. In turn, a high WBC count is associated with other high-risk prognostic factors, such as t(4;11) and t(9;22).

The CNS status at the time of diagnosis is described according to results of a nontraumatic diagnostic lumbar puncture, specifically, the number of WBCs and the presence or absence of blasts on cytospin of the CSF sample. CNS3, which is defined as a WBC count of ≥5/mcL and the presence of blasts on cytospin, is associated with a higher risk of treatment failure compared with patients who do not have CNS involvement at the time of diagnosis. CNS2 status (WBC count less than 5/mcL and the presence of blasts) may be associated with a higher risk of relapse, but this risk may depend on treatment [83,84,85]. With respect to the sex of the patient, the prognosis has been slightly better for girls than for boys [86,87,88]. Although testicular relapse is one reason for this difference, relapse in bone marrow and CNS is also more frequent among boys [86,87,88]. Male sex has not been a risk factor in studies in which the event-free survival rate is more than 80% [89,90]. Studies that have examined sex differential for etiologic clues have identified several sex-specific genetic markers for childhood ALL risk [91,92,93,94] .

The role of race/ethnicity as a prognostic variable is unclear. Early studies indicated better survival rates for white children than for black children, and later studies demonstrated lower survival rates for black, Hispanic, and American Indian/Alaska Native children compared with white and Asian/Pacific Islander children/adolescents [95]. However, studies done at St. Jude Children's Research Hospital have indicated no racial/ethnic differences in survival, leading researchers to believe that survival depended instead on access to the same treatment protocols [82,96]. Social, biologic, and pharmacokinetic factors should be explored in an effort to better understand racial/ethnic variations in outcome [97]. Clinical and public health strategies can help improve access to health care, clinical trial enrollment, treatment, and survivorship care for children with ALL [98].

With regard to cytogenetic findings, hyperdiploidy is associated with a highly favorable prognosis and is also associated with other favorable prognostic factors, including an age of 1 to 9 years, a low WBC count, and t(12;21) with the TEL-AML1 fusion gene [76,77,99,100,101,102]. Hypodiploidy has been associated with progressively worse outcomes as the number of chromosomes decreases, with the worst outcome associated with near haploidy (24 to 28 chromosomes) [72,100]. Extreme hypoploidy and presence of the Philadelphia chromosome has been an indicator of very poor prognosis in B-cell ALL [103].

Chromosome translocations may influence prognosis, but other prognostic factors and the type of treatment may determine the effect of a specific translocation. TEL-AML1 fusion has been associated with an excellent outcome [64,77,104]. In contrast, the Philadelphia chromosome is related to an unfavorable prognosis, especially when it occurs in children who have a high WBC count or in whom the response to initial therapy is slow [56,105]. The t(4;11) has also been related to a high risk of treatment failure, and the event-free and overall survival rates are lower for children with Down syndrome and ALL [106,107,108].

Acute Myeloid Leukemia (AML)

The first prognostic factors identified for AML were age, WBC count, and FAB classification at the time of diagnosis, but their ability to predict outcome has been inconsistent [67,68]. A report of 61 children treated between 1976 and 1984 indicated that an age of younger than 2 years at the time of diagnosis, a WBC count of less than 100,000/mcL, and an FAB subtype of M4 or M5 were predictive of an increased risk of relapse and a decreased overall survival [68]. Adolescent patients are at higher risk for treatment-related mortality compared with younger children [109].

In another study of nearly 500 patients treated between 1986 and 1989, univariate and multivariate analyses demonstrated several clinical, morphologic, and cytogenetic factors associated with a lower rate of complete remission, including hepatomegaly, low platelet count (20,000/mcL or less), FAB subtype M5, and trisomy 8 [67]. In addition, a higher platelet count (more than 20,000/mcL) and absence of hepatomegaly were independent prognostic factors of better overall survival [67].

Data for a series of nearly 300 patients treated at St. Jude Children's Research Hospital from 1980 to 1996 indicated that the five-year event-free survival was slightly better for an age of 2 years or younger, an initial WBC count of less than 50,000/mcL, and an FAB subtype of M3 or M5 [19]. Although sex has not been used as a prognostic factor, several studies have suggested that the outcome is more favorable for girls than boys [19,67].

The ability of cytogenetic findings to predict outcome has varied, but they appear to be the best prognostic factors in AML [66,110,111]. In one study, trisomy 8 was the strongest predictor of poor prognosis, and in another, abnormalities of 11q23, q3, or chromosomes 5 or 7 were associated with a high rate of treatment failure [78]. In the series of patients treated at St. Jude, the best outcome was associated with t(9;21), and a favorable outcome has also been associated with t(8;21), t(15;17), and inv(16) [19,66]. Aberrations of chromosome 16q have also been shown to be a prognostic indicator of complete remission and better overall survival [65,67]. For children with monosomy 7, AML progresses rapidly and the response to treatment is poor [56]. In contrast to the situation in ALL, children with Down syndrome and AML have a good response to treatment [67,110]. Advances in technology are allowing researchers to identify other factors associated with outcome, and further studies are needed to confirm the usefulness of these factors as prognostic variables [112].

7. DIAGNOSIS OF LYMPHOMA

The clinical presentation of lymphoma is similar to that of leukemia in several ways, and the course of diagnostic testing is also similar. However, some signs and symptoms of lymphoma are distinct from those of leukemia. Furthermore, there are differences even between the two types of lymphoma, especially with regard to the sites of disease.

Imaging studies are done not only to determine or confirm the presence of lymphoma but also to assess the extent of disease, which assists in staging as well as in establishing a baseline for monitoring response to treatment. As with leukemia, immunophenotyping and cytogenetic analysis are done to determine the cell lineage of disease, evaluate the pattern of CD antigen expression, and identify chromosomal abnormalities. The role of these studies in the diagnosis of lymphoma is not discussed here, as other factors currently play a more significant role in prognosis.

HODGKIN LYMPHOMA

Clinical Signs and Symptoms

Children and adolescents with Hodgkin lymphoma are often asymptomatic, and the disease is frequently an incidental finding during a routine examination or evaluation of an injury. Approximately 25% to 30% of children will have one of three archetypal constitutional symptoms, known as B symptoms: unexplained, intermittent fever of 38 degrees Centigrade; drenching night sweats; or unintentional loss of more than 10% of body weight within the past six months (Table 8) [113]. The suspicion of Hodgkin lymphoma is increased when B symptoms are present with lymphadenopathy or splenomegaly. Patients may also have nonspecific systemic symptoms, such as fatigue and anorexia. In some patients, generalized pruritus may be present for months before lymphadenopathy is found, and excoriations may be evident as a result of excessive scratching [113]. On physical examination, the most common finding is a persistent, painless adenopathy, usually in the supraclavicular or cervical area [59,113]. As noted, reactive lymphadenopathy is common in children/adolescents, making it necessary to carefully evaluate patients to first rule out other infectious or inflammatory conditions. Involvement of the supraclavicular nodes should prompt earlier evaluation for Hodgkin lymphoma, as the cervical nodes are most commonly involved in infection and inflammatory conditions. Infectious mononucleosis can be distinguished from Hodgkin lymphoma by the presence of symmetrical cervical lymphadenopathy with pharyngitis. A tuberculin test may be helpful to rule out tuberculosis, which also may have similar clinical characteristics.

Table 8: CLINICAL MANIFESTATIONS OF HODGKIN AND NON-HODGKIN LYMPHOMA

Clinical Sign/Symptom

Hodgkin Lymphoma

Non-Hodgkin Lymphoma

B-Cell

Lymphoblastic

Anaplastic Large Cell

History

Presence of symptoms

Usually asymptomatic

–

–

Wax and wane for weeks

B symptoms (unexplained fever, night sweats, weight loss)

Occurs in approximately 28%

Occurs in approximately 50%

–

Occurs in approximately 42% to 68%

Other

Pruritus

–

–

–

Physical Examination

Lymphadenopathy

Cervical or supraclavicular, painless

Peripheral

Relatively uncommon

Cervical or axilla, painless

Peripheral (occurs in 88% to 97%)

Most common extranodal site(s)

Lung, liver, bone

Abdomen (Burkitt); neck, mediastinum, throat (DLBCL)

Mediastinum (T cell); head and neck (B cell)

Skin, soft tissue

Splenic involvement

30% to 40%

–

–

11% to 23%

Hepatic involvement

Rare

–

–

15% to 27%

Mediastinal involvement

66%

–

75%

19% to 52%

Other

–

–

Pallor, petechiae, ecchymoses

–

Abnormal laboratory values

Elevated erythrocyte sedimentation rate

Elevated erythrocyte sedimentation rate and lactate dehydrogenase

–

–

DLBCL = Diffuse large B-cell lymphoma.

Source: [113,114,115,116]

Involvement of only lymph nodes and/or the spleen is present in most patients [113]. In general, enlarged lymph nodes are firm and nontender. In advanced disease, enlarged nodes may grow together to form aggregate masses that become attached to underlying tissues [113]. Approximately 15% to 20% of patients will have noncontiguous extranodal involvement, and the lung, liver, bone marrow, and bone are the most common sites of extranodal involvement [117,118]. Extranodal involvement is more commonly associated with the mixed cellularity subtype of Hodgkin lymphoma, whereas involvement of the cervical, supraclavicular, and mediastinal lymph nodes is most often associated with the nodular sclerosis subtype [113].

The mediastinum is involved in about two-thirds of patients [113]. Symptoms accompanying mediastinal involvement may include a persistent, nonproductive cough, dyspnea, or chest pain. Evaluation for Hodgkin lymphoma should be carried out if these symptoms are present, especially if accompanied by B symptoms. It is important to distinguish involvement of the mediastinum from a large, normal thymus or from other mediastinal tumors [24,113]. Morphology, clinical signs, radiographic findings, and immunophenotyping findings must all be evaluated closely to make the distinction.

Non-Hodgkin lymphoma should be considered in the differential diagnosis of Hodgkin lymphoma. One distinguishing feature is the rate of disease progression; involved lymph nodes will grow more rapidly in non-Hodgkin lymphoma than in Hodgkin lymphoma. In addition, abnormal laboratory values are more common with non-Hodgkin lymphoma [113].

Diagnostic Testing

The diagnostic work-up for suspected Hodgkin lymphoma includes laboratory testing and imaging studies to evaluate the site and extent of disease. Laboratory testing should begin with a CBC with differential and an erythrocyte sedimentation rate. The results of the CBC may be nonspecific, demonstrating neutrophilia, eosinophilia, and thrombocytosis [24,113]. Lymphopenia and normochromic normocytic anemia are indicators of extensive disease [119,120]. In the presence of other signs of Hodgkin lymphoma, elevations of the erythrocyte sedimentation rate, lactate dehydrogenase level, and ferritin level may be further indicators of Hodgkin lymphoma [59]. An elevated level of alkaline phosphatase may indicate metastatic bone disease, and further testing should be done to determine if there is skeletal involvement [113].

Evaluation of a bone marrow sample is usually not routinely done. Bone marrow involvement is a characteristic of primarily lymphocyte-depleted Hodgkin lymphoma, which is rare in the pediatric population; approximately 10% to 15% of children/adolescents will have bone marrow involvement at the time of the initial diagnosis [24]. The frequency of bone marrow involvement is higher for older male children who have constitutional symptoms. Bone marrow biopsy should be limited to patients who have B symptoms and in whom advanced disease is suspected [113].

A diagnosis of Hodgkin lymphoma can be confirmed only through evaluation of a specimen from an involved lymph node, and biopsy should be done when there is no response to a course of antibiotics. The biopsy technique depends on the site of the involved node. Excisional biopsy is often the preferred technique, as it allows for better determination of the histologic subtype [113]. However, the least invasive procedure should be used [121,122]. Thus, fine-needle aspiration may be more appropriate if the involved node is in the thoracic or abdominal cavity, and CT can be used to guide biopsy in these situations.

Classification and Staging

As noted, Hodgkin lymphoma is classified histologically according to four subtypes. Nodular sclerosis is the most common subtype, representing approximately 72% of the cases of pediatric Hodgkin lymphoma. This subtype occurs most frequently in adolescents, and the mediastinum is involved in 80% of cases [24]. Mixed cellularity Hodgkin lymphoma accounts for approximately 25% of pediatric Hodgkin lymphoma, most frequently developing in children younger than 10 years of age [24]. It is usually associated with the peripheral lymph nodes of the upper part of the body.

Hodgkin lymphoma is staged according to the Ann Arbor classification system (also referred to as the Lugano classification system), which categorizes the disease as stage I through IV according to the extent of lymph node involvement (Table 9) [123]. The system is based on the premise that Hodgkin lymphoma progresses along contiguous lymph nodes [124]. Within this classification system there are additional designations that are applied to further define symptoms and disease [124].

Table 9: ANN ARBOR CLASSIFICATION FOR STAGING OF HODGKIN LYMPHOMA

Stage

Criteria

I

Involvement of a single lymph node region

II

Involvement of two or more lymph node regions (number to be stated) on the same side of the diaphragm

III

Involvement of lymph node regions on both sides of the diaphragm

IV

Noncontiguous involvement of one or more extralymphatic organs or tissues with or without associated lymph node involvement

Subclassifications

A

Asymptomatic

B

Displaying specific symptoms of unexplained loss of more than 10% of body weight in the six months before diagnosis, unexplained fever with temperatures greater than 38 degrees Centigrade for more than three days, or drenching night sweats

E

Extralymphatic disease resulting from direct extension of an involved lymph node region

S

Involvement of the spleen

Source: [123,125]

Prognostic Variables

Evidence Based Practice Recommendation

According to the National Comprehensive Cancer Network, there is no uniform risk stratification for pediatric Hodgkin lymphoma. However, several factors are considered to confer poor prognosis, including B symptoms, extranodal disease, Ann Arbor stage, gender, and response to initial chemotherapy.

https://www.nccn.org/professionals/physician_gls/pdf/ped_hodgkin.pdf

Last Accessed: August 5, 2021

Level of Evidence: Expert Opinion/Consensus Statement

Prognostic variables have less importance in Hodgkin lymphoma because of advances in treatment, but some variables are helpful in predicting outcome. The most significant prognostic indicator is stage of disease. The outcome associated with stage I, II, or III disease is better than that for stage IV disease [117,126,127]. Studies in which prognostic factors were evaluated in multivariate analysis have demonstrated the following factors to be of import [126,128]:

- Presence of B symptoms

- Mediastinal disease bulk

- Results of laboratory studies

The presence of B symptoms (low-grade fever, night sweats, and weight loss) reflects aggressive disease and has been associated with a worse prognosis [126,128,129]. High tumor burden is also predictive of a worse prognosis; a ratio of mediastinal mass-to-thoracic cavity of more than one-third has been associated with a greater risk of recurrence and with a slightly lower survival rate in several studies [126,129,130]. The number of disease sites may also play a role in predicting outcome. Patients who have fewer than four sites of involvement generally have a better outcome [123,131].

Several laboratory studies, including the WBC count, hemoglobin, erythrocyte sedimentation rate, and serum ferritin level, have also been correlated with a poor prognosis [123,126,132]. In one study, a WBC of more than 13,500/mcL and a hemoglobin level of less than 11.0 g/dL were significantly associated with shorter disease-free survival [126].

The predictive value of patient-related factors such as sex and age is unclear. One study indicated that disease-free survival was better for girls than for boys [126]. Age has been an important indicator in some studies, with 5-year and 10-year survival rates being higher for children 10 years of age or younger than for older children and adolescents (11 to 16 years of age) or young adults [133].

The rate of response to initial cycles of chemotherapy appears to be prognostically important and is being used in the research setting to tailor subsequent therapy, avoid treatment-associated risks that compromise long-term health, and achieve high cure rates [127,134].

NON-HODGKIN LYMPHOMA

Clinical Signs and Symptoms

The clinical evaluation and diagnostic testing for non-Hodgkin lymphoma is similar to that for Hodgkin lymphoma. Lymphadenopathy should be evaluated, and infectious or inflammatory conditions should be ruled out before a biopsy is performed. The sites of disease and associated symptoms vary according to the histopathologic type of non-Hodgkin lymphoma [114,115,116]. Most children/adolescents will have advanced disease at the time of presentation [46,115].

B-Cell Lymphoma (Burkitt, Burkitt-like, and Diffuse Large B-Cell)

Diffuse large B-cell lymphoma and Burkitt or Burkitt-like lymphoma may appear clinically similar, but the former is more often localized [135,136]. The most common site of B-cell lymphoma is the abdomen, and involvement of peripheral lymph nodes is relatively uncommon [46,114]. When present, peripheral lymph node involvement is more likely to be associated with diffuse large B-cell lymphoma, with sites in the neck, mediastinum, or throat [114]. Symptoms associated with B-cell lymphoma in the abdomen include abdominal pain, nausea, vomiting, and diarrhea. A mass may be palpable on physical examination of the abdomen [59,114]. Persistent abdominal pain with vomiting or diarrhea, especially when accompanied by significant weight loss, should prompt further diagnostic testing. Intussusception of the small bowel is common.

Lymphoblastic Lymphoma

In comparison with B-cell lymphoma, the abdomen is rarely involved with lymphoblastic non-Hodgkin lymphoma. Instead, the mediastinum is involved in nearly 75% of children/adolescents with T-cell lymphoblastic lymphoma, as a result of development of the lymphoma from the thymus [46]. The mass forms in the anterior mediastinum. Dyspnea is often the first symptom [115]. Coughing, wheezing, stridor, dysphagia, and superior vena cava syndrome may also be presenting symptoms. Because mediastinal involvement with non-Hodgkin lymphoma progresses more rapidly than with Hodgkin lymphoma, these symptoms may be more severe. Pleural effusion may also occur [46]. Localized lymphoblastic lymphoma may occur in lymph nodes, bone, and subcutaneous tissue. Other lymph nodes, such as the tonsils or neck nodes, are less commonly the primary site of T-cell lymphoblastic lymphoma. Disease spread can be rapid, with the brain, pleura, pericardium, and bone marrow being the most common sites of metastases. Disease is in an advanced stage (stage III or IV) at the time of diagnosis in most cases [115].

In the case of precursor B-cell lymphoblastic lymphoma, disease is usually more limited and involves skin, soft tissue, bone, tonsil, or a sole peripheral nodal region [115].

Anaplastic Large-Cell Lymphoma

The course of symptoms with anaplastic large-cell lymphoma may be indolent, with fever and a waxing and waning of lymphadenopathy [137,138]. Nearly 50% of patients have B symptoms, and 88% to 97% of patients have lymphadenopathy, with the peripheral nodes being involved most often. CNS and bone marrow involvement occur less frequently with anaplastic large-cell lymphoma than with other types of non-Hodgkin lymphoma [46,116,138].

Soft tissue and skin are the most frequent sites of extranodal involvement [46,116,138,139,140]. Cutaneous manifestations may be single or multiple nodules, multiple or disseminated red-yellow papillomatous lesions, or large ulcerated lesions [116]. Other extranodal sites include the gastrointestinal tract, lung, pleura, and muscle.

Diagnostic Testing

As with Hodgkin lymphoma, the diagnostic work-up for suspected non-Hodgkin lymphoma includes laboratory testing, diagnostic imaging, and biopsy of suspicious nodes. A CBC can help distinguish non-Hodgkin lymphoma from infectious or inflammatory adenopathy [115]. A high level of serum lactate dehydrogenase level is often indicative of a large mass, but the level is increased less often in patients with anaplastic large-cell lymphoma than in patients with B-cell lymphoma or lymphoblastic lymphoma [116]. A CSF sample should be examined, and evaluation of biopsy specimens should include histopathologic analysis, immunophenotyping, and cytogenetic and molecular analysis [114,115,116,138].

The use of imaging studies is similar for all types of suspected lymphoma. The choice of study is based on the suspected site of involvement. A chest x-ray or CT of the chest is indicated if a mediastinal mass is suspected, which is often associated with T-cell lymphoblastic lymphoma or diffuse large B-cell lymphoma [114]. MRI of the head and neck should be done if signs or symptoms are suggestive of involvement of neck nodes. The abdomen is the most frequent site of involvement for B-cell lymphoma, making CT of the abdomen perhaps the most valuable imaging study in that setting. CT also is useful for staging the lymphoma and for differentiating the primary cutaneous form from the systemic form [114,141]. Skeletal scintigraphy is useful for detecting bone involvement, such as with anaplastic large-cell lymphoma [138]. Positron emission tomography (PET)/CT scanning has largely supplanted scintigraphy and is highly recommended for patients with suspected non-Hodgkin lymphoma [142,143,144]. PET/CT scanning is also useful for assessing response to treatment and for identifying occult sites of disease. Whole-body scanning may be helpful in detecting disease sites that would otherwise be unidentified [114,141]. If advanced disease is suspected, MRI or CT of the brain should be done [141].

Classification and Staging

Pediatric non-Hodgkin lymphoma is classified as stage I through IV according to the St. Jude staging system, which is similar to the Ann Arbor staging system for Hodgkin lymphoma [145,146]. These stages are [46,145,146]:

- Stage I: Involvement of a single node

- Single tumor outside of the abdomen or chest

- Stage II: Single extranodal tumor with involvement of regional lymph nodes

- Involvement of two nodal regions or more on the same side of the diaphragm

- Two single extranodal tumors, with or without involvement of regional lymph nodes, on the same side of the diaphragm

- Primary tumor (completely resectable) in the gastrointestinal tract, with or without involvement of associated mesenteric lymph nodes

- Stage III: Two single extranodal tumors on opposite sides of the diaphragm

- Involvement of two or more nodal regions above and below the diaphragm

- Primary intrathoracic tumor (mediastinal, pleural, or thymic)

- Extensive primary intra-abdominal disease

- Paraspinal or epidural tumor, with or without involvement of other sites

- Stage IV: Any finding of stage I, II, or III disease with initial involvement of the CNS, bone marrow, or both

Prognostic Variables

As with Hodgkin lymphoma, advances in treatment for non-Hodgkin lymphoma have made prognostic variables less significant [114]. In addition, factors predictive of outcome vary according to the histologic subtype of non-Hodgkin lymphoma.

For B-cell lymphomas, the most important prognostic factor is tumor burden, as determined by either stage of disease or the serum lactate dehydrogenase level [114]. The tumor burden is high for patients with extensive bone marrow involvement (more than 25%) [114]. Serum lactate dehydrogenase level is a well-recognized risk factor that correlates with tumor burden, and a level of more than 1,000 IU/L has been associated with a poor prognosis [48,147,148].

Age and sex have also been evaluated as prognostic factors in B-cell lymphoma; many studies have not found them to be predictive of outcome [114]. In one study involving children/adolescents with diffuse large B-cell lymphoma, the event-free survival was significantly better for male patients than for female patients and the outcome was better for younger girls than for adolescent girls [135]. Again, the universal applicability of these findings is not established.

In an analysis of p12ooled data from three multicenter studies of prognostic variables in anaplastic large-cell lymphoma, multivariate analysis demonstrated that the following factors were significantly associated with a risk for treatment failure [114,140,148,149,150,151]:

- Presence of a mediastinal mass

- Involvement of the lung

- Focal lesions of the liver or spleen (and/or hepatomegaly or splenomegaly)

- Skin involvement

There was no significant effect of age, sex, or stage of disease in any of the studies [46].

In a comprehensive analysis of potential prognostic factors for outcome in lymphoblastic lymphoma, no factor was found to be associated with outcome [152].

8. COMMUNICATION WITH THE PATIENT AND FAMILY

The primary care provider is often in the position to tell parents that the clinical findings and initial testing may indicate a diagnosis of leukemia or lymphoma. Primary care practitioners who have established a relationship with their patients and families are the healthcare professionals most likely to understand the overall health status of the family, family dynamics, and cultural context of the family. They should draw on all of this information to help present the diagnosis in a way that the family can understand. Further diagnostic testing in a pediatric cancer center will help to refine the diagnosis by identifying a specific type of leukemia or lymphoma, and prognosis and treatment options will then be discussed by oncology specialists. Primary care providers should have familiarity with key aspects of the diseases, as they may become a resource for the family during the child's/adolescent's treatment in a pediatric cancer care center. Primary care providers must be able to communicate effectively with parents as well as the child/adolescent with leukemia or lymphoma. Effective communication requires basic physician communication skills as well as specialized skills in delivering bad news.

COMMUNICATING EFFECTIVELY

Effective communication is a cornerstone of the family-physician relationship. Some physician communication behaviors that have been found to be positively associated with health outcomes include empathy, reassurance and support, explanations, positive reinforcement, humor, discussion of psychosocial issues, health education and information sharing, courtesy, and summarization and clarification [153]. Other factors essential for effective communication and a successful relationship are knowledge of the language preference of the patient and family; an understanding of and respect for the family's cultural values, beliefs, and practices (referred to as cultural and linguistic competency); and an awareness of the family's health literacy level [154,155,156].

Language, cultural competency, and health literacy are significant issues, given the growing percentages of racial/ethnic populations. According to U.S. Census Bureau data from 2019, approximately 67.8 million Americans (22% of the population) speak a language other than English in the home, with more than 3.4 million of them (1.1% of the population) reporting that they speak English less than "very well" [157]. Clinicians should ask their patients' parents what language they prefer for their medical care information, as some individuals prefer their native language even though they have said they can understand and discuss such information in English [158]. An example of the effect of limited English proficiency is a study of children/adolescents hospitalized for infections, in which a primary caregiver with limited English proficiency was found to be an important independent risk factor for both a longer hospital stay and fewer home health care referrals [159].

The national standards on Culturally and Linguistically Appropriate Services (CLAS) include four standards related to communication and language access services that are mandated for health care organizations [160]. Although these standards are not mandated for individual health care providers, the Office of Minority Health encourages clinicians to meet the standards to make their practices more culturally and linguistically accessible [160]. These standards are:

- Offering and providing language assistance services, including bilingual staff and interpreter services, at no cost to each patient/consumer with limited English proficiency at all points of contact, in a timely manner during all hours of operation

- Providing patients with both verbal offers and written notices (in their preferred language) that inform them of their right to receive language assistance services

- Ensuring the competence of language assistance provided to limited English proficient patients by interpreters and bilingual staff and avoiding the use of the patient's family and friends as interpreters

- Making easily-understood patient-related materials available and posting signage in the languages of the commonly encountered groups and/or groups represented in the practice area

Studies have demonstrated that the use of professional interpreters rather than "ad hoc" interpreters (family members, bilingual staff, etc.) leads to better outcomes [161,162,163]. In addition, individuals with limited English language skills have indicated a preference for professional interpreters rather than family members [164]. Despite this clear benefit and preference, a survey of more than 900 pediatricians showed that professional interpreters were the third most commonly used resource; bilingual family members were used most often [165]. According to one study, this practice has only modestly improved since 2004 [166]. Professional interpreters have recommended that clinicians can further enhance the quality of care by meeting with interpreters before discussions of bad news and by explicitly discussing with the interpreter whether strict interpretation or cultural brokering is expected [167].

Knowledge of the family's health literacy is important for achieving treatment goals and good outcomes, yet most individuals lack adequate health literacy. According to the 2003 National Assessment of Health Literacy, 14% of individuals in the United States have "below basic" health literacy, which means they lack the ability to understand health information and make informed health decisions [168]. A systematic review of more than 300 studies showed that an estimated 26% of patients had inadequate literacy and an additional 20% had marginal literacy [169]. Health literacy varies widely, according to race/ethnicity, level of education, and gender, and clinicians are often unaware of the literacy level of their patients and family [156,170]. Predictors of limited health literacy are poor self-rated reading ability, low level of education, male sex, and nonwhite race [170,171].

Several instruments are available to test the literacy level, and they vary in the amount of time needed to administer and reliability in identifying low literacy. A review demonstrated that the two most accurate tools for identifying literacy are the Rapid Estimate of Adult Literacy in Medicine (REALM) and the shortened version of the Test of Functional Health Literacy in Adults (S-TOFHLA) [156]. REALM takes 3 minutes to administer, whereas S-TOFHLA takes 7 to 12 minutes to administer [156]. More rapid testing is available since the development of the Newest Vital Sign (NVS), an instrument named to promote the assessment of health literacy as part of the overall routine patient evaluation. The NVS takes fewer than three minutes to administer, has correlated well with more extensive literacy tests, and has performed moderately well at identifying limited literacy [156,170]. Two questions have also been found to perform moderately well in identifying patients with inadequate or marginal literacy: "How confident are you in filling out medical forms by yourself?" and "How often do you have someone help you read health information?" [156].

Clinicians should adapt their discussions and educational resources to a family's identified health literacy level and degree of language proficiency. The use of plain language (free of medical jargon), asking parents to repeat pertinent information, regularly assessing recall and comprehension, providing educational resources in a variety of formats (e.g., print, oral, web-based, video), and using culturally appropriate and translated educational materials, can all help ensure that parents better understand the diagnosis and other aspects of their child's disease and its management, ultimately leading to higher quality care.

Cultural competency is essential for addressing healthcare disparities among minority groups [154]. The AAP Task Force on the Family noted that "nonjudgmental, culturally sensitive, family-oriented care" should be provided by all pediatricians [172]. The task force further noted that providing such care requires that the "family's history, interactions, and preferred solutions are considered, used, and supported" [172]. To that end, primary care providers should assess the family's beliefs and values associated with illness and health care (Table 10).

Table 10: KEY TALKING POINTS TO ASSESS CULTURAL INFORMATION

What behaviors and symptoms of the child are of most concern to the parents?

Why do the parents believe cancer occurred in the child?

How do the parents believe the child is affected by the cancer?

What are the family's beliefs and fears about cancer?

What measures did the parents take to control the symptoms before diagnosis?

What do the parents expect of the medical team?

What are the expected roles of various family members in the healthcare setting?

What are the family's dietary practices?

What are the religious beliefs and/or affiliations and significant religious persons in the family's lives?

Source: [173]

The status of children within the family and community differs among cultures and is a factor in how parents and other family members will respond to a child's illness [174]. Respect for cultural health beliefs and practices is important for many patients from non-Western cultures, and clinicians should be sensitive to culturally defined beliefs about health care [164]. These beliefs may underlie the degree or quality of the parents' involvement in the child's care or noncompliance with treatment or recommendations [174].

Another factor that varies across cultures is the role of decision-makers; an understanding of the family dynamics with respect to decision making is essential [175]. In most cases of children/adolescents with cancer, the parents will be the primary decision-makers. There are three options for decision making: clinician-centered (the clinician makes the decision), informed (the patient/family makes the decision after becoming informed by the clinician and through other sources), and shared (the clinician and patient/family collaborate in the process). Parents differ in their preferences regarding the level of involvement [176,177,178]. The physician should explore the issue of decision making with parents to ensure that their preferred level of involvement is attained.

One study has underscored the need to engage in the preferred decision-making process; the study found that parents' unhappiness with the decision-making process was correlated with optimism about cure [179]. In the study, 61% of parents were more optimistic than their child's physician about the likelihood of cure. Parents who were unhappy with the decision-making process were more apt to be overly optimistic [179]. Studies have also shown that satisfaction with treatment choices is increased when communication in the diagnosis phase has been effective [176].

Delivering Bad News

A cancer diagnosis presents the dual challenge of being both emotionally and intellectually overwhelming. These feelings are heightened for parents of a child/adolescent with cancer. Parents differ in how much information they want or feel they can handle about the diagnosis. Clinicians should ask how much detail the parents wish to hear [176]. Important points for communicating the diagnosis include:

- Use clear, jargon-free language.

- Check often for understanding.

- Offer reassurance and support.

- Encourage questions.

Clinicians should address parents' and patients' fears and reassure them that they will be available throughout the course of treatment [176]. Eliciting and validating emotional reactions at this time will help parents and patients better understand and comply with further diagnostic testing [176].

Guidelines are available to help clinicians deliver bad news in the childhood cancer setting with sensitivity (Table 11) [179,180,181]. However, the stress of receiving bad news, even if the clinician is compassionate and speaks clearly, can prevent patients and family members from retaining needed information [180]. After relating bad news, clinicians can build a partnership by allowing parents to express their feelings and opinions [182]. A pediatric psychologist or family therapist can assist both the child and family in coping with the impact of the diagnosis.

Table 11: GUIDELINES FOR BREAKING BAD NEWS

Formulate a plan. Mentally rehearse the steps of the conversation.

Schedule a time for the discussion to allow all important family members and medical staff to be present.

Meet in a quiet and private setting.

Make arrangements for a professional translator if English is not the first language of the family. Meet with the professional translator before the discussion to discuss expectations.

Preface bad news with a phrase to prepare the family, such as "I wish the results were different, but..."

Communicate clearly and minimize use of technical language.

Let the patient's and family's reactions guide the flow of the conversation. Allow silence.

Be empathetic and acknowledge the family's emotions.

Explain to parents who are worried about the child hearing bad news that age-appropriate, open communication with children allows the practitioner and family to provide the child with comfort and reassurance while removing uncertainty.

Determine the family's level of understanding of the illness/situation to assess misconceptions, aspects of news that will be surprising, and their unique information needs.

Determine if any family members are "numbers people" so they can be provided the type of information with which they feel most comfortable.

Make parents feel that they are part of the team to help their child and that their efforts will help the medical team take care of their child.

Explain to patient and family that they are not to blame for the child's cancer.

Schedule a future meeting to discuss the bad news and options (e.g., in an hour, the next day, the next week).

Source: [179,180,181]

Clinicians should also determine parents' preference for the type and amount of information to be shared with the child. Many parents wish to protect their child by withholding information. This is especially true among some cultures—for example, among Chinese, Japanese, and Greek populations [183]. However, studies have shown that children often recognize the seriousness of their illness and prefer open communication about their disease and prognosis [183,184,185]. Such open exchange of information can help to avoid the fear of the unknown and to preserve the child's trust in his or her parents and/or family and caregivers [183,185]. Even if the child is to be included in the discussion, the best approach may be to sequence some information; that is, to communicate information to parents in separate meetings before communicating it to the child. Parents of children with leukemia have acknowledged the benefits of communicating openly with children, but they noted that their child's presence during discussions of such topics as prognosis, treatment options, and adverse events, restricted their own communication with physicians, made it difficult to concentrate, and interfered with their efforts to care for their child emotionally [186]. Parents also said that separate meetings allowed them to absorb information and to convey it to their child at an appropriate time and in a reassuring way [186].

Parents and clinicians should involve the child in the discussion of the diagnosis using language that is developmentally appropriate for the child, checking often to make sure the child understands. Having the child repeat the information in his or her own words is one way to assess comprehension [183]. The child should also be encouraged to express feelings and concerns. Adolescents and children who are mature enough to understand and reason should be allowed to express their opinions, and healthcare professionals should be advocates for the child's preferences and decisions [178]. Adolescents especially, because of their need for independence, should be given choices about their care, whenever possible, as well as about privacy issues, such as with whom information can be shared [8].

Clinicians should explore ways to best communicate with and educate children/adolescents. Computer-assisted and multimedia educational programs have been shown to enhance cancer-related knowledge among children/adolescents and improve their feelings of control over their health [187].

9. TREATMENT APPROACHES

The goals for treatment of pediatric leukemia and lymphoma have evolved dramatically since the early 1960s, when palliative care was considered to be the rational approach to treatment of leukemia and extensive radiation therapy was used for lymphoma. The search for better curative therapies that do not yield long-term side effects has led to a variety of approaches based on prognostic factors, as well as independent host-related or disease-related factors.

The treatment protocols for pediatric leukemia and lymphoma have been developed and refined by several cooperative groups in the United States and Europe, the most notable of which are COG, the National Cancer Institute, St. Jude Children's Research Hospital, Dana-Farber Cancer Institute Consortium, Medical Research Council Working Party on Childhood Leukemia, European Organisation for Research and Treatment of Cancer—Children's Leukaemia Cooperative Study Group, the French Society for Pediatric Oncology, and the Berlin-Frankfurt-Munster Cooperative Groups. The investigators in these groups are at the forefront of evaluating chemotherapy and radiation doses and combinations to achieve the overall goal of maximizing the potential for cure while minimizing treatment-related toxicity.

The treatment of pediatric leukemia and lymphoma is a complex process that requires the expertise of several pediatric subspecialists, including hematologists/oncologists, diagnostic radiologists, pathologists, radiation oncologists, and surgeons, as well as pediatric nurses, social workers, and other allied healthcare professionals experienced in the care of children with cancer. Superior results have been achieved when treatment is provided at pediatric cancer centers with specialized multidisciplinary teams. Due to these superior results, the AAP developed guidelines recommending that all children and adolescents with cancer be referred to a pediatric cancer center for treatment [57,58]. The AAP notes that, in many cases, all aspects of care should be given at the center but acknowledges that "certain aspects of care may be continued in the office of a primary pediatrician for selected children, after the diagnosis has been established and the treatment plan determined by the pediatric cancer center" [57,58].

Over the years, the treatment of adolescents with leukemia or lymphoma has been the topic of some debate because of the decreased event-free and overall survival among adolescents compared with children [188]. Some adolescents have been treated according to adult protocols, while others have been treated according to pediatric protocols. Almost all retrospective studies comparing outcomes for adult and pediatric protocols have shown a significant benefit to pediatric protocols [70,129,188]. These differences are thought to be related to the substantial differences between adult and pediatric protocols [188].

IMPORTANCE OF CLINICAL TRIALS

Retrospective reviews of data from pediatric cancer clinical trials have demonstrated that the treatment protocols in clinical trials offer a significant survival benefit compared with other treatment approaches [189,190]. Virtually all children with leukemia or lymphoma are eligible for treatment in a clinical trial, yet 40% to 60% do not participate [189,191]. This rate of nonparticipation is even higher outside pediatric cancer centers. In one study of more than 5,000 children/adolescents (birth to 21 years of age), the rate of clinical trial participation was 25% for institutions other than pediatric cancer centers [189]. Participation of children/adolescents in clinical trials, both within and outside of pediatric cancer centers, is higher for leukemia than for lymphoma and for younger children (birth to 5 years) than for older children [189]. The rate of participation among adolescents is substantially lower, ranging from 10% to 15%, and this low rate is of special concern [188].

One systematic review sought to identify the perceptions and attitudes toward clinical trial participation among adolescents and young adults (15 to 39 years of age) [192]. Major themes identified for acceptability of clinical trials included hope for positive clinical affect, altruism, and having autonomy, while potential deterrents included prolonged hospitalization, worry about side effects, and discomfort with experimentation [192]. The findings of one qualitative study suggest that caregivers and providers have work to do in overcoming factors that limit patients' involvement in clinical trial enrollment decision-making [193]. Data from a retrospective study suggest that establishing a joint pediatric/adult oncology program can improve adolescent/young adult enrollment in clinical trials. Fifty-seven patients were referred to an oncology program from 2006 to 2010. Eight were referred for consultation only and not treated. Five of 22 patients (23%) who received treatment at the pediatric cancer center were enrolled onto a clinical trial; 9 of 27 patients (33%) who received treatment at the adult cancer center were enrolled, an increase from the previous three years [194].

Clearly, more children/adolescents should participate in clinical trials to provide the maximum opportunity for cure and long-term survival. Healthcare professionals should encourage parents to seek care at a pediatric cancer center and to ask about clinical trials if the issue is not raised. This is particularly important for older children and adolescents [195]. Assent for clinical trial participation in the pediatric setting differs from its counterpart in the adult setting (informed consent) in many ways and is a complicated issue. The obvious and primary difference between the two settings is the patient's capacity for decision making. It is generally believed that children/adolescents should be involved in the discussion and decision making about medical treatment (including participation in a clinical trial) if the discussion is developmentally appropriate [183,196,197]. Various ages have been suggested as the threshold for sufficient capacity to reason and understand a discussion about a clinical trial and make a decision to participate. The National Commission for Protection of Human Subjects of Biomedical and Behavioral Research, the California legislature, and the AAP have set the threshold for participating in the assent discussion at 7 years of age [196,197]. However, others have argued that a child at this age cannot understand all aspects of a research trial, and the ages of 9 years, 11 years, and 14 years have all been suggested as thresholds [197,198,199]. The age range of 9 to 14 years has been noted as the "transition period," or the ages at which there is the most variability in the capacities of individual children [197]. Studies involving focus groups of healthy adolescents have shown that research concepts such as placebo and randomization are difficult to understand even for teenagers [200]. Clearly, age is but one of several factors that should be considered when determining the appropriateness of engaging a child in the decision-making process; other factors include level of maturity, physiologic and psychologic state, and the child's reasons for his or her preferences [199,201].

In a study of assent discussions involving children/adolescents with leukemia and their parents, the fewest number of clinicians considered the patient alone to be the primary decision-maker [202]. Most clinicians noted that the parents were the primary decision-makers; others indicated that it was a "family" decision to be made jointly between parents and the patient [202]. According to guidelines established by COG, the clinician and parents should seek the child's perspective in a "developmentally, contextually, and culturally sensitive fashion," and the clinician should encourage the parents and patient to make the decision jointly as a family unit [197]. Furthermore, clinicians should advocate for the child if the parents disregard the child's preferences and should ask to speak to the child alone if they think the child is not expressing his or her true perspective in the presence of the parents [197].

Another factor in the issue of clinical trial assent is the high levels of emotion, stress, and anxiety associated with a diagnosis of cancer in a child. These psychosocial factors have been shown to have an effect on comprehension, which, in turn, influences the ability to make a decision [191]. The complexity of treatment options for pediatric cancer and the swiftness with which most decisions must be made also add to the challenge of decision making about clinical trials. Because of these factors, effective clinician-parent communication is essential [176]. In many cases, the intervention of a psychologist or therapist may also be helpful. A study showed that race and socioeconomic status were associated with less information-sharing and partnership-building cues from clinicians and with less participation in the assent discussion by parents [191].

The importance of respect in obtaining assent has been emphasized. Respectful assent involves providing sufficient information about the trial and encouraging the patient and family to ask questions and express concerns [197,199]. Respectful assent also involves responding to dissent [197,199]. The child's participation in a trial should be monitored, and persistent expressions of distress about continued participation should be addressed [197].

In a study to gain the perspective of parents about clinical trial decision making, parents offered several suggestions to improve the process. The most common suggestion was to give parents more time to decide [203]. Parents also suggested that clinicians should [203]:

- Provide more information and repeat it for understanding

- Offer other resources, such as videos and books

- Communicate honestly and with empathy

- Arrange for parents to speak with other parents who have been through the clinical trial decision-making process

Parents who were not native English speakers noted the importance of having a professional interpreter available during the process [203].

Discussion of the trial should be comprehensive and address all facets of treatment, including side effects, long-term effects, and survival expectancy (Table 12). A focus on providing information in the context of informed consent may come at the expense of other communication exchanges that are important to patients, especially in the context of end-of-life decisions [204]. Many parents wish to avoid these topics in an effort to protect their children, but research has shown that children tend to pose these questions themselves and that they benefit from the assent process [183,202,204].

Table 12: KEY ELEMENTS TO BE DISCUSSED ABOUT PARTICIPATING IN A CLINICAL TRIAL

Goals of the trial and treatment

Rationale for treatment

Prognosis (survival and cure)

Importance of the child's best interests

Randomization procedure

Procedures necessary for the research

Anticipated risks and benefits of both experimental and standard treatments

Inconveniences associated with the trial

Alternative procedures or treatments

Voluntariness

Confidentiality

Source: [203,205]

Parents have also noted a need for clearer explanations of the randomization process and of the difference between the clinical trial treatment and standard treatment [205]. Specifically, parents have noted a need to better understand that a clinical trial involves several possible treatment options, one of which is the treatment their child would receive outside of the clinical trial [205]. One analysis identified suggestions for improving the informed consent process by interviewing 57 parents and 20 young adult patients (14 to 21 years of age). A total of 21 suggestions for improvement emerged in three main themes: provision of more information; structure and presentation of the informed consent process; and suggestions for physicians conducting the process. Common suggestions included providing more specific information about the trial, allowing more time for decision making, and using different methods to deliver information [206]. Multimedia approaches to describe research procedures have been shown to enhance overall understanding of both parents and children/adolescents [207].

Although signed assent is not usually required legally, clinicians should document the assent process, including whether the child was invited to participate in the discussion and, if so, the role he or she played in the decision-making process [197].

DISEASE-DIRECTED TREATMENT

As mentioned, treatment regimens for leukemia and lymphoma continue to be refined as the findings of long-term studies demonstrate late effects. For example, high rates of neurocognitive disorders and other effects have been associated with radiation exposure resulting from prophylactic cranial radiation therapy in children with leukemia or radiation to the thorax or head and neck area in children with lymphoma. This has led to the reduction of radiation doses in treatment protocols and/or the use of radiation only for high-risk patients [208,209].

Another well-recognized late effect, anthracycline-related cardiac toxicity, has led to the use of lower doses of anthracycline as well as the use of cardioprotectants (dexrazoxane or enalapril) during anthracycline treatment [210,211,212]. The effects of cardioprotectants require the results of long-term studies, which will not be available for several years.

A detailed discussion of the various protocols that have become standard for the treatment of leukemia and lymphoma is beyond the scope of this course. An overview of the goals and approaches to treatment and the chemotherapy agents used is provided here (Table 13).

Table 13: CHEMOTHERAPY AGENTS USED IN REGIMENS TO TREAT PEDIATRIC LEUKEMIA AND LYMPHOMA

Class of Drug

Name of Drug

Alkylating agents

Busulfan

Carmustine (BCNU)

Chlorambucil

Cyclophosphamide

Ifosfamide

Mechlorethamine

Melphalan

Procarbazine

Antimetabolites

Cytarabine

Mercaptopurine (6-MP)

Thioguanine (6-TG)

Methotrexate

Clofarabine

Cladribine

Fludarabine

Antitumor antibiotics

Bleomycin

Dactinomycin

Anthracyclines

Daunorubicin

Doxorubicin

Epirubicin

Idarubicin

Mitoxantrone

Corticosteroids

Dexamethasone

Prednisone

Enzymes

Asparaginase

Asparaginase (Erwinia asparaginase [recombinant])

Pegaspargase

Epipodophyllotoxins

Etoposide

Teniposide

Topotecan

Heavy metals

Carboplatin

Cisplatin

Plant alkaloids

Vinblastine

Vincristine

Vinorelbine

Source: Compiled by Author

TREATMENT OF LEUKEMIAS

The treatment of leukemia varies according to the type and is risk-adapted. This approach prevents overtreatment of children at low risk for relapse and provides sufficient cytotoxicity for children at high risk for relapse or treatment failure. Investigators continue to explore both different doses of chemotherapy agents, timing and intensity, and different drug combinations to achieve better rates of remission, disease-free survival, and overall survival for children/adolescents with ALL and AML.

With one exception, all types of ALL are treated with an approach that includes the following phases [213]:

- Remission induction therapy (at the time of diagnosis)

- Postinduction therapy (after achieving complete remission), including: Consolidation/intensification therapy

- Continuation (maintenance) therapy

- CNS prophylaxis

The exception to this approach is B-cell ALL. B-cell ALL is histologically similar to Burkitt lymphoma, and it is, therefore, treated according to protocols for advanced Burkitt lymphoma without marrow involvement, which consists of short-term intensive chemotherapy (high-dose methotrexate, cytarabine, and cyclophosphamide) [147,214].

The biologic and molecular characteristics of childhood leukemia are becoming better understood with the advent of genetic technology. As this enhanced knowledge leads to further distinction of subgroups according to molecular characteristics, research is focusing on the development of novel therapies to target molecular abnormalities, a type of treatment that has dramatically changed treatment and outcomes for several types of cancers in adults. Several such drugs are in early studies of children/adolescents with leukemia [215]. Imatinib (an oral drug that has been successful in adults) received FDA approval in 2013 for treatment of pediatric Philadelphia chromosome-positive (Ph+) ALL [216].

Acute Lymphoblastic Leukemia (ALL)

Risk-adapted treatment protocols developed in the 1990s have achieved a cure rate of 80% [96,217]. Most pediatric study groups classify patients with ALL according to three risk categories: standard, high, and very high; COG uses a fourth category for very low probability of relapse [216,218].

In general, treatment of pediatric T-cell or precursor B-cell ALL consists of intensive multidrug chemotherapy for standard-risk patients, allogeneic HSCT for high-risk patients, and antimetabolites for low-risk or very-high-risk patients [38]. All children with ALL receive CNS prophylaxis, primarily with intrathecal chemotherapy [70,213]. Prophylaxis with cranial radiation is reserved for patients at very high risk of relapse, such as patients with CNS involvement at diagnosis or with T-cell ALL [70,213].

Remission Induction

The goals of remission induction therapy are to induce complete remission (defined as eradication of 99% of the initial burden of leukemia cells), to restore normal hematopoiesis, and to regain a normal performance status [38]. This phase of treatment typically lasts four weeks [213]. The rate of complete remission after induction therapy is high, ranging from 96% to 99% [70,213]. Of the patients in whom complete remission is not achieved within the first four weeks of treatment, approximately 50% will experience a toxic death during induction (usually due to infection) and the remaining 50% will have resistant disease [89,152,213,219,220]. The protocols for children with high-risk or very-high-risk ALL and all adolescents with ALL involve treatment with at least four chemotherapeutic agents. These agents most often include a corticosteroid (prednisone or dexamethasone), vincristine, and asparaginase and/or an anthracycline (doxorubicin or daunorubicin) [213]. The COG protocols reserve the use of a four-drug induction for patients with high-risk B-cell ALL and T-cell ALL and do not include administration of anthracycline during induction to patients with standard-risk ALL [213]. Patients treated by three other study groups receive an induction regimen with four or more drugs regardless of presenting features [213]. A meta-analysis of studies comparing the use of dexamethasone or prednisone showed that dexamethasone was more efficacious, with lower rates of events (death from any cause, refractory or relapsed leukemia, second malignancy, and CNS relapse) but no difference in bone marrow relapse or overall mortality [221]. Dexamethasone was associated with higher rates of toxicity, however, and it is not clear whether the short-term benefits found will translate to better overall survival [221]. A randomized trial comparing doxorubicin and daunorubicin given during induction found no difference in efficacy between the agents in early response measures [222]. In June 2021, the U.S. Food and Drug Administration (FDA) approved Rylaze (Erwinia asparaginase [recombinant]) as a component of the multi-agent chemotherapy regimen to treat ALL (and lymphoblastic lymphoma) in adult and pediatric patients (one month and older) who have developed hypersensitivity to Escheria coli-derived asparaginase products [223]. Rylaze was found to maintain a clinically meaningful level of asparaginase activity throughout the entire duration of treatment [223].

The emergence of targeted therapies for treatment of Philadelphia chrome-positive (Ph+) disorders with tyrosine kinase inhibitors (TKIs) represents an important advancement in ALL therapy. Imatinib mesylate is an inhibitor of BCR-ABL tyrosine kinase and, as stated, is approved by the FDA for treatment-naïve patients with pediatric Ph+ ALL [224]. In one study of early response to TKIs during remission induction in children with Ph+ ALL, TKIs (imatinib and dasatinib) produced a marked drop in minimal residual disease levels. At the end of remission induction, 9 of 11 patients who received imatinib or dasatinib and conventional induction chemotherapy had remission, compared with two of 16 patients who received chemotherapy alone. The five-year event-free survival rate was 68.6% for the 11 patients who received TKIs compared with 31.6% for the 19 patients who did not [225].

Consolidation/Intensification Therapy

Consolidation/intensification therapy begins after normal hematopoiesis has been restored. The most commonly used intensification regimen was first introduced by the Berlin-Frankfurt-Munster (BFM) clinical trials group and usually includes methotrexate with 6-mercaptopurine (6-MP) and high-dose asparaginase, followed by reinduction treatment (the same regimen given during the first few months of remission induction therapy). Maintenance typically includes 6-MP, weekly low-dose methotrexate, and sometimes administration of vincristine and a corticosteroid, as well as continued intrathecal therapy [70,213]. This regimen, with variations (e.g., intensification for higher-risk patients, use of escalating doses of methotrexate without leucovorin rescue, elimination or truncation of some phases for lower-risk patients), has been adopted by COG and has been associated with favorable outcomes in children with standard-risk ALL [226,227].

The doses of drugs are increased according to risk, and studies have been done to evaluate the efficacy of higher doses in preventing relapse. Research reported in 2011 demonstrated a significant improvement in event-free survival for children/adolescents with high-risk B-cell ALL when high-dose methotrexate without asparaginase was used compared with standard-dose methotrexate and asparaginase (82% vs. 75%) [228]. Similarly, compared with standard-dose methotrexate, high-dose methotrexate led to significantly better 5-year and 10-year event-free survival for children/adolescents with high-risk T-cell ALL, with rates of 80% vs. 68% and 77% vs. 66%, respectively [229].

In a landmark multicenter COG study of 92 children (1 to 21 years of age) with Ph+ ALL, investigators evaluated whether imatinib (340 mg/m^2 per day) with an intensive postinduction chemotherapy regimen improved outcome. Continuous imatinib exposure improved outcome in patients treated with imatinib for 280 continuous days, with a three-year event-free survival of approximately 80%, more than twice that of historical controls. Three-year event-free survival was similar for patients treated with chemotherapy plus imatinib or sibling donor blood and marrow transplantation. There were no significant toxicities associated with adding imatinib to intensive chemotherapy [230]. A follow-up study found that five-year disease-free survival was similar for patients treated with chemotherapy plus imatinib (70%), sibling donor blood and marrow transplantation (65%), and unrelated donor blood and marrow transplantation (59%). The reinduction rate following relapse was similar to other higher-risk ALL groups [231].

Another study assessed the safety and efficacy of oral imatinib in association with a Berlin-Frankfurt-Munster intensive chemotherapy regimen and allogeneic stem-cell transplantation for patients (1 to 18 years of age) with pediatric Ph+ ALL [232]. Patients were enrolled by 10 study groups between 2004 and 2009, and were classified as either good risk or poor risk according to early response to induction treatment. Good-risk patients were randomly assigned to receive postinduction imatinib with chemotherapy or chemotherapy alone. All poor-risk patients received postinduction imatinib with chemotherapy. All patients received four postinduction blocks of chemotherapy, after which they became eligible for stem-cell transplantation. Four-year disease-free survival was 72.9% in the good-risk/imatinib group compared with 61.7% in the good-risk/no imatinib group. Four-year event-free survival for poor-risk patients was 53.5% [232].

Continuation (Maintenance) Therapy

Continuation therapy usually consists of weekly methotrexate and daily 6-MP for a period of 2 to 2.5 years [70,213]. A review of trials involving more than 10,000 children demonstrated that shorter durations of treatment were associated with a higher risk of relapse and death [233,234].

CNS Prophylaxis

Before the routine use of CNS prophylaxis, relapse involving the CNS occurred in approximately 80% of all patients with complete remission [235]. Preventing relapse of disease in the CNS has led to significant improvement in the rate of isolated CNS relapse, which now ranges from less than 2% to 10% [19,96]. Radiation was first used for CNS prophylaxis, but this approach was associated with significant acute and late morbidity, including neurocognitive impairment, second cancers, and endocrinopathy [70,208]. As such, the use of intrathecal chemotherapy, usually methotrexate or cytarabine, is now used in most cases [213]. Children/adolescents with very-high-risk disease may still benefit from cranial radiation, and most treatment protocols limit the use of radiation to these instances, with the use of lower doses [152,213,236].

Treatment for Relapsed or Refractory Disease

Relapse occurs in approximately 25% of patients with ALL [237]. The most common sites of relapse in ALL are bone marrow, the CNS, and the testicles [237]. For bone marrow relapse, reinduction therapy (usually a four-week course of prednisone, vincristine, and an anthracycline, with perhaps the addition of asparaginase) is followed by postremission chemotherapy [237]. Treatment of CNS relapse usually involves intensive systemic therapy, with cranial or craniospinal radiation delayed for six months [238].

In 2017, the FDA approved the first gene therapy for the treatment of B-cell precursor ALL in children and young adults [239]. Tisagenlecleucel is a genetically modified autologous T-cell immunotherapy used in the treatment of refractory or relapsed disease. With this approach, the patient's T cells are collected and modified to include a chimeric antigen receptor that directs T cells to kill leukemias cells, then infused back into the patient. In one study, the three-month remission rate was 83% [239]. However, tisagenlecleucel is associated with potentially severe side effects, including cytokine release syndrome, neurologic events, serious infections, acute kidney injury, and hypoxia [240].

Isolated testicular relapse usually occurs later than either bone marrow or CNS relapse and is treated with intensive chemotherapy that includes high-dose methotrexate. Patients who do not have a complete remission after induction also receive local radiation therapy [213]. Orchiectomy of the clinically involved testis is performed in some European clinical trial groups, with biopsy of the contralateral testis to determine whether additional local control (i.e., surgical removal or radiation) is needed. One study that examined testicular biopsy at the end of frontline therapy failed to demonstrate a survival benefit for patients with early detection of occult disease [241]. While there are limited clinical data concerning outcome without the use of radiation therapy or orchiectomy, the use of chemotherapy (e.g., high-dose methotrexate) to achieve antileukemic levels in the testes is being tested in clinical trials [213].

Hematopoietic Stem Cell Transplantation

In 2012, the American Society for Blood and Marrow Transplantation (ASBMT) published an update to its 2005 recommendation that HSCT be done after first complete remission of Ph+ ALL when a matched related donor is available [242,243]. Allogeneic HSCT is recommended for children who [243]:

- Are in their second complete remission following an early marrow relapse for B-cell ALL

- Have had failure of primary induction therapy but subsequent complete remission

- Have T-cell ALL in their second complete remission

- Have ALL in their third or greater remission

Allogeneic HSCT is not recommended for patients with T-cell ALL in their first complete remission; patients with the MLL gene plus ALL when it is the sole adverse risk factor; and patients with isolated CNS relapse in B-cell ALL [243]. In general, HSCT approaches benefit only children at high risk for relapse with standard chemotherapy approaches [244].

Infection prophylaxis during HSCT includes confinement in a HEPA-filtered, positive-air-pressure sealed room, strict hand hygiene, antibacterial prophylaxis with fluoroquinolone, and antifungal prophylaxis with fluconazole [245].

Follow-Up and Surveillance

Several organizations have published consensus guidelines for follow-up for late effects following HSCT; however, these guidelines do not address all pediatric-specific challenges to HSCT [246]. The Pediatric Blood and Marrow Transplant Consortium (PBMTC) published six detailed papers to address the lack of detailed pediatric-specific late effects and guidelines for long-term follow-up after HSCT. The PBMTC summary and guideline recommendations provide the most current outline for following up children for late effects after HSCT (Table 14) [247].

Table 14: SELECTED SCREENING RECOMMENDATIONS FOR LATE EFFECTS AFTER HSCT IN PEDIATRIC POPULATION

Effects

Screening

Management

Iron overload

Annual serum ferritin; if elevated, consider T2-weighted MRI

Phlebotomy or chelation

Gastrointestinal

Annual screening for chronic GVHD and hepatitis virus infection

Annual hepatocellular carcinoma screening for high-risk patients (i.e., those with hepatitis C or B infection, obesity, diabetes, or low platelet count)

—

Renal

Monitor urine for albumin:creatinine ratio at day 80 and then annually. If ratio is >30 and <300 mg/g, confirm with two or more tests in 3 to 6 months and monitor every 3 to 6 months. If ratio is >300 mg/g, monitor every 3 to 6 months.

Treat with ACE inhibitor or ARB if albumin:creatinine ratio is >300 mg/g on one occasion or if patient has persistent ratio >30 g/kg on three occasions in a 6-month period and has hypertension.

Pulmonary

Pulmonary function testing for allogeneic recipients twice per year for two years, with consideration for more frequent screening in recipients of mismatched or unrelated donor grafts, or patients with active chronic GVHD. After two years, consider yearly follow-up pulmonary function tests based on symptoms and past measurements.

With a >15% decrease in pulmonary function test values or new pulmonary infiltrate, evaluate for infection/GVHD. Refer to pulmonologist for disease-specific care as needed.

Cardiac

Annual cardiovascular risk assessment

Blood pressure each visit and at least annually

Electrocardiogram/echocardiogram at least every five years, more frequently if patient received anthracycline, total body radiation, or chest radiation

Refer to cardiologist for abnormal or declining cardiac function.

Metabolic

Lipid profile and fasting glucose at least every five years. If abnormal, screen annually.

—

Thyroid dysfunction

Thyroid-stimulating hormone and free thyroxine annually for 10 years after busulfan and for at least 30 years after total body radiation.

Physical examination of thyroid yearly to screen for tumors after total body radiation.

If thyroid-stimulating hormone is high and free thyroxine is normal, either treat or repeat in two months. Replace thyroid as indicated for low levels. Rare secondary thyroid tumors post-TBI can be cured with surgery.

Growth impairment

Accurate measurement of growth yearly through full growth (age 17 years for girls and 19 years for boys). Bone age as needed.

Bone age and referral to an endocrine specialist for a patient not growing appropriately. GH therapy may unmask hypothyroidism.

Low bone mineral density

Dual-energy x-ray absorptiometry scan before HSCT, one year after HSCT, and yearly if z-score is <–1.

Calcium and vitamin D supplementation

Weight-bearing exercise

Avoid smoking, alcohol, and caffeine

For patients with z-score <–2 and/or history of fractures, refer to endocrine specialist.

Osteonecrosis

Consider MRI screen of asymptomatic patients on high-dose steroids

Early MRI screening of any patients with symptoms of joint pain, pain in groin or anterior thigh, or limping

Minimize steroid and alcohol consumption

Offer analgesics

Recommend non-weight-bearing exercise and physical therapy

Refer to orthopedic specialist.

Reproductive risks

Women: monitor for ovarian failure (FSH, assess cycling)

Men: semen analysis

Women: Anti-Müllerian hormone may assess ovarian reserve. Treat ovarian failure with hormone replacement therapy.

Men: If oligospermia noted, may offer intracytoplasmic sperm injection

ACE = angiotensin converting enzyme; ARB = angiotensin receptor blocker; FSH = follicle-stimulating hormone; GH = growth hormone; GVHD = graft-versus-host disease; MRI = magnetic resonance imaging.

Source: [247]

Acute Myeloid Leukemia (AML)

As noted earlier, the event-free and overall survival rates are lower for children/adolescents with AML than for those with ALL. Due to lack of consistent prognostic factors in AML, risk-adapted treatment is not regularly used as it is for ALL; however, risk-adapted and biologically targeted therapies are being tested to improve treatment while sparing normal tissues [41,248]. Optimal treatment of AML requires control of bone marrow and systemic disease [249]. The four-phase approach is not always followed, as the efficacy of the continuation (maintenance) phase has not been proven for the treatment of AML [19,41,249]. The approach to the treatment of AML is similar for all types except for the M3 subtype (acute promyelocytic leukemia), for which chemotherapy is combined with all-trans retinoic acid (ATRA) [19].

The drugs used to treat AML have primarily remained the same, but regimens and timing of treatment have been refined, with current rates of 80% to 90% for complete remission, 30% to 40% for relapse, 45% to 55% for event-free survival, and 55% to 65% for overall survival [41,249].

Induction Therapy

The most effective chemotherapy regimen for induction in AML has been an anthracycline, cytarabine, and etoposide [41,249]. Although the regimens used have differed in many ways, including the cumulative doses of drugs, the choice of anthracycline, and the number of treatment cycles, the results have been relatively similar [41,249].

Consolidation/Intensification Therapy

Studies and one phase III clinical trial have demonstrated that intensive treatment during the consolidation phase leads to decreased relapse rates and better event-free and overall survival for younger patients with AML [19,250]. High-dose cytarabine, usually given with mitoxantrone, has led to improved outcomes for children with high-risk disease [249].

CNS Prophylaxis

Intrathecal chemotherapy is considered by most to be a standard component of treatment of AML, although no studies have compared CNS prophylaxis with no CNS prophylaxis, and it has not been shown to contribute directly to improved survival [19,249]. Cytarabine, methotrexate, or both, along with hydrocortisone, are the preferred agents for prophylaxis [249]. The rate of isolated CNS relapse is reported to be 2% [41]. Cranial radiation is not used for prophylaxis [41,249].

Treatment for Relapsed or Refractory Disease

Most relapses occur during the first year, and the most common site of relapse is the bone marrow (92%) [251]. Relapse occurs in the CNS in 10% to 20% of patients and in the skin in 4%.

Remission induction chemotherapy regimens have included high-dose cytarabine in combination with fludarabine or mitoxantrone [41,249]. Anthracyclines are effective, but the increased risk for cardiotoxicity limits their use in the relapse setting if they have been used for primary treatment [251]. Liposomal daunorubicin has been added to fludarabine plus cytarabine in an attempt to limit cardiotoxicity [41]. However, cure is unlikely with chemotherapy alone for relapsed AML [41]. In 2020, the FDA extended the indication for gemtuzumab ozogamicin to include newly diagnosed CD33-positive AML in pediatric patients 1 month of age and older [252]. The drug was previously approved for children 2 years of age and older with relapsed or refractory AML [249,253]. Efficacy and safety information for the extended indication was supported by data from a multicenter randomized study of 1,063 patients, 0 to 29 years of age, with newly-diagnosed AML. The estimated percentage of patients free of induction failure, relapse, or death at five years was 48% in the gemtuzumab ozogamicin plus chemotherapy arm versus 40% in the chemotherapy alone arm. No difference in overall survival was found between treatment arms. The most common adverse events included cardiotoxicity, hepatotoxicity, infection, fatigue, and fever [253]. In a report from the COG on the efficacy of clofarabine in combination with cytarabine in pediatric patients with recurrent AML, the combination yielded an acceptable response rate without excess toxicity. The nearly 50% survival rate reported suggests that this combination is an effective bridge to HSCT [254]. HSCT is thought to be the only curative treatment for relapse [41,249,250,251,255].

Stem Cell Transplantation

The issue of HSCT in AML, especially with regard to when it should be done, remains a topic of some debate. A meta-analysis demonstrated that transplantation reduced the risk of relapse and significantly improved disease-free and overall survival among many children/adolescents with AML [256]. The review of evidence by the ASBMT led to its recommendation of transplantation after either first or second remission if a matched related donor is available [257]. However, a later meta-analysis showed that transplantation after first complete remission did not lead to significant differences in relapse or disease-free or overall survival compared with no transplantation [258]. Current application of allogeneic HSCT involves incorporation of risk classification to determine whether transplantation should be pursued in first remission [249]. Due to improved outcomes in patients with favorable prognostic features and lack of demonstrated superiority of HSCT, this patient population typically receives matched-family donor HSCT only after first relapse and achievement of a second complete remission [257,259,260,261].

The absence of published recommendations specific for pediatric AML motivated an international group of pediatric hematologists and oncologists to develop evidence- and expert opinion-based consensus recommendations for the management of AML in children [61]:

- For patients with initial hyperleukocytosis and symptomatic coagulopathy and/or leukostasis, emergency strategies should be initiated to reduce the risk of fatal hemorrhage and leukostasis.

- Antifungal prophylaxis (including trimethoprim-sulfamethoxazole for prophylaxis of Pneumocystis jirovecii) should be administered to all children.

- The use of fluoroquinolones may be considered as prophylaxis against Streptococcus viridans and gram-negative sepsis.

Follow-Up and Surveillance

The improved outcome in children with AML over the last 10 years is probably associated with better supportive care strategies [61]. Children with AML who receive treatment with contemporary therapy and remain in remission four years from diagnosis probably are cured. Although late relapses and late deaths from other causes are rare, long-term follow-up of survivors is necessary for the timely management of late adverse effects [262].

TREATMENT OF LYMPHOMA

Hodgkin Lymphoma

Evidence Based Practice Recommendation

The National Comprehensive Cancer Network recommends that treatment of patients with favorable-risk pediatric Hodgkin lymphoma typically involve participation in an ongoing clinical trial.

https://www.nccn.org/professionals/physician_gls/pdf/ped_hodgkin.pdf

Last Accessed: August 5, 2021

Level of Evidence: Expert Opinion/Consensus Statement

Standard treatment options achieve cure in approximately 80% to 90% of children/adolescents with Hodgkin lymphoma. The rates have been better for children 10 years of age and younger than for children older than 10 years of age [113,263]. The German Hodgkin Study Group found that adult treatment protocols were safe and effective treatment options for adolescents with Hodgkin lymphoma [264].

The risk-adaptive approach to the treatment of Hodgkin lymphoma involves planning treatment according to prognostic variables such as stage of disease, presence of B symptoms, and tumor bulk [265]. Disease is classified as being low, intermediate, or high risk. Low-risk disease is defined as localized Hodgkin lymphoma (stage I or II and sometimes IIIA) with no B symptoms or tumor bulk. Intermediate-risk disease usually includes stage I or II disease with unfavorable features (B symptoms, tumor bulk, involvement of three or more lymph node regions, and/or extranodal extension to contiguous structures) [113]. Stages III and IV typically represent high-risk disease.

Favorable-risk (low-risk) disease is defined differently by different clinical trial groups, but for the most part it encompasses patients with localized stage I and II disease without adverse prognostic features (e.g., "B" symptoms, extranodal extension, mediastinal bulky disease). Favorable-risk disease can be treated with reduced therapy, which consists of two to four cycles of multiagent chemotherapy and low-dose (15–25 Gy), involved-field radiation [265,266]. The regimens used most often include etoposide, which has commonly replaced alkylating agents and anthracyclines. Intermediate-risk disease is treated with three to six cycles of compacted, dose-intensive chemotherapy and low-dose, involved-field radiation, usually as consolidation therapy. For high-risk disease, four to six compacted, dose-intensive cycles of chemotherapy in addition to low-dose (15–25 Gy) involved-field radiation therapy to involved sites of disease are recommended [265]. The dose-intensive regimen of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone led to response within four weeks in 74% of children/adolescents with stage IIB or IIIB Hodgkin lymphoma with bulk disease or stage IV disease [267]. When followed by guideline-directed consolidation therapy, the treatment led to overall survival of 97% and five-year event-free survival of 94% [267]. Early response to therapy may be considered in determining the need for radiation in those who have complete remission. Advanced radiation techniques, such as intensity-modulated radiation therapy and proton therapy, may be considered depending on the clinical scenario and if an improvement is expected [265,268].

In addition to disease-related factors, the patient's age and sex are primary considerations. A younger age at the time of diagnosis has implications for musculoskeletal and soft-tissue deformities and cardiovascular dysfunction after radiation and/or chemotherapy with an anthracycline [113]. With respect to the patient's sex, the risk of breast cancer is increased for teenage girls who have radiation to the thorax, and girls are at higher risk of cardiomyopathy as a result of anthracycline use [113]. Alkylating agents lead to a higher prevalence of gonadal dysfunction in boys. The German Paediatric Oncology and Haematology Society pioneered risk- and gender-adapted therapy featuring the vincristine, etoposide, prednisone, and doxorubicin regimen for boys to limit the amount of alkylating agents; girls received vincristine, procarbazine, prednisone, and doxorubicin. The HD-95 trial investigated whether radiation therapy could be omitted in patients achieving a complete remission to chemotherapy. Early results (median follow-up time: three years) indicate a 97% event-free survival rate for favorable-risk patients. There was no difference in outcome between favorable-risk patients treated with chemotherapy alone and those treated with combined-modality therapy [269].

Randomized trials have compared chemotherapy alone with chemotherapy plus low-dose radiation for advanced stage Hodgkin lymphoma. The results have primarily indicated that there is no benefit to the addition of radiation in terms of event-free or overall survival, with one study indicating that the addition of radiation was comparable to the addition of a second chemotherapy regimen [117,270]. Researchers continue to debate the issue of adding low-dose radiation to chemotherapy because of the toxicity associated with each modality [271,272,273]. However, the use of radiation therapy may allow for lower doses of chemotherapy agents. In an effort to cure children with Hodgkin lymphoma with minimal side effects, most treatment approaches entail combined-modality therapy with reduced dose radiation. A number of combined-modality therapy protocols exist, and the decision as to how to incorporate radiation therapy should be made within the context of the protocol followed [265].

Treatment for Relapsed/Refractory Disease

Relapse will occur after first-line treatment in approximately 10% to 20% of children with advanced-stage Hodgkin lymphoma [263]. Relapse occurs most often within four years, but late relapse is not rare [265]. Although chemotherapy with ifosfamide, carboplatin, and etoposide in combination or as single agents is effective, the toxicity profiles of the drugs have led investigators to search for alternative treatments. Vinorelbine, ifosfamide, and high-dose methotrexate have been found to be acceptable, but subsequent relapse after high-dose methotrexate has occurred in as many as 50% of children/adolescents [263]. Nonmyeloablative stem cell transplantation has been used in selected patients with high-risk disease [263]. In addition, two cycles of chemotherapy with dexamethasone, etoposide, cisplatin, high-dose cytarabine, and asparaginase (DECAL) plus maintenance therapy and stem cell transplantation was found to be effective for relapsed Hodgkin lymphoma, with a five-year event-free survival of 26% and five-year overall survival of 31% [274]. The COG has evaluated ABVE-PC (doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide) and its derivatives across all risk groups [275,276,277]. Benefits of this regimen include lower cumulative doses of anthracyclines, alkylating agents, and bleomycin compared with MOPP and ABVD regimens used in prior decades. Lower cumulative doses are expected to translate into long-term reductions in second malignant neoplasms and fewer cardiovascular, pulmonary, and fertility complications [278,279,280].

COG investigated treatment of relapsed/refractory disease with brentuximab vedotin and gemcitabine in 46 children and young adults [281]. Twenty-four of 42 patients treated at the recommended phase II dose of 1.8 mg/kg experienced a complete response within the first four cycles. Four of 13 patients (31%) with partial response or stable disease had all target lesions with Deauville scores of 3 or less after cycle four. By modern response criteria, these are also complete responses, increasing the complete response rate to 28 of 42 patients. There were no treatment-related deaths. The most common adverse events among all patients treated were neutropenia, rash, transaminitis, and pruritus [281]. Trials are ongoing to determine the efficacy and toxicity of combining brentuximab vedotin with chemotherapy. Additionally, phase I/II trials of immune checkpoint inhibitor therapy (with nivolumab and pembrolizumab) for use in childhood refractory/relapsed disease are ongoing [282,283].

Stem Cell Transplantation

HSCT is usually limited to patients who have relapse or in whom disease is refractory to primary conventional therapy [113,127,284].

Follow-Up and Surveillance

Most pediatric patients with Hodgkin lymphoma have a favorable outcome; however, there is increasing concern about risks of carcinogenesis from diagnostic and therapeutic radiation therapy and from post-treatment surveillance imaging. In one study, cumulative radiation dosage from diagnostic imaging examinations and the frequency of relapse detection by these examinations were recorded. In the first two years after therapy, patients in remission received a median of 11 examinations. In 13 of 99 patients who relapsed, approximately 1% of surveillance imaging examinations (e.g., CT scan, positron emission tomography [PET] scan, chest radiographs) identified relapsed disease. Given this very low rate, the financial burden of the tests themselves, the high cure rate, and risks of second malignancy from ionizing radiation exposure, modification of the surveillance strategy is recommended [285].

Non-Hodgkin Lymphoma

With standard treatment options, approximately 75% to 80% of children/adolescents with non-Hodgkin lymphoma will survive at least five years, although the survival rate varies according to subtype [46,135,286]. Age may also be a factor. In one study, the five-year event-free survival rate was approximately 79% for adolescents compared with 85% for patients younger than 15 years of age [287]. However, another study found that age was not a factor in increased risk of treatment failure [148]. Instead, the patient's level of lactate dehydrogenase, mediastinal disease, and combined bone marrow-/CNS-positive involvement were independent risk factors in children with mature B-cell non-Hodgkin lymphoma [148]. Response to treatment also is an important prognostic indicator. With the exception of anaplastic large-cell lymphoma, pediatric non-Hodgkin lymphoma that is refractory to first-line therapy has a very poor prognosis, regardless of histology [288,289,290].

As with Hodgkin lymphoma, the treatment of non-Hodgkin lymphoma is based on the extent of disease, with the intensity of treatment being increased for more extensive disease [291]. Because non-Hodgkin lymphoma in children is considered to be widely disseminated from the outset, even when apparently localized, combination chemotherapy is recommended for most patients [46]. The event-free survival has been better in some studies in which surgical resection was done. So, there may be some value to this approach if resection can be readily accomplished, especially in cases of large tumor masses [114]. Treatment often consists of a cytoreduction phase to reduce tumor burden, followed by a consolidation phase.

For most studies of treatments done in the United States, patients are categorized into three risk groups: low-risk, which is completely resected stage I disease or stage II abdominal disease; high-risk, which consists of CNS involvement with or without bone marrow involvement; and intermediate-risk, which encompasses disease that is not eligible for the other two groups [114]. Treatment also varies according to the pathologic subtype.

B-cell non-Hodgkin lymphoma can be treated with two or three cycles of combination chemotherapy after surgical resection if there is no measurable tumor burden [46,291,292]. The combination of vincristine, cyclophosphamide, doxorubicin, and prednisone has been highly effective in this setting [214]. A single-agent phase II study of rituximab performed by the BFM group showed activity in Burkitt lymphoma [293]. A pilot study from the COG added rituximab to baseline chemotherapy with FAB/LMB-96 therapy in patients with stage III and stage IV B-cell non-Hodgkin lymphoma [294,295]. For higher risk disease, the addition of two or three courses of chemotherapy, high-dose methotrexate, and high-dose cytarabine was also effective [214,296,297].

Good outcomes for treatment of lymphoblastic lymphoma have been achieved with use of ALL-type regimens consisting of an induction phase of multiagent chemotherapy (eight drugs) followed by a consolidation phase and a maintenance phase of two years, with cranial radiation for CNS prophylaxis [51,298]. This approach was superior to short, intensive pulsed chemotherapy regimens [299,300,301]. Good outcomes also have been reported by the COG with use of a Children's Cancer Group (CCG)-modified BFM ALL regimen (prednisone, dexamethasone, vincristine, daunorubicin, doxorubicin, L-asparaginase, cyclophosphamide, cytarabine, methotrexate, 6-mercaptopurine, 6-thioguanine, and reduced number of intrathecal treatments during maintenance) [46]. The study randomized 254 patients to the regimen with intensified intrathecal methotrexate (Arm A1) or an adapted non-Hodgkin lymphoma/BFM-95 therapy with high dose methotrexate in interim maintenance but no intrathecal methotrexate in maintenance (Arm B1). Each cohort was randomized to either more or less intensification (cyclophosphamide/anthracycline) (Arms A2/B2) and CNS radiation therapy for CNS-positive patients only [302]. There was no difference in five-year event-free survival among the four arms. Five-year survival for CNS-positive patients was 63%. There was no difference in outcome based on CNS prophylaxis or intensification for CNS-negative patients [302]. In a COG study of 56 children and adolescents with stages I and II disease who were treated with the modified CCG BFM regimen for two years, the COG reported a five-year event-free survival of 90% and a five-year overall survival of 96% [303].

For patients with a mediastinal mass, radiation targeting the mass is not necessary except as emergency treatment to relieve airway obstruction or superior vena cava syndrome [46,115]. In such cases, low doses of radiation are used. Cranial radiation may be reserved for patients with CNS involvement at the time of diagnosis [301].

Several treatment strategies have been used for anaplastic large-cell lymphoma, and the outcomes have been comparable [46,116,140]. Treatment has been adapted to risk in some cases, usually according to stage of disease [140]. Common agents are corticosteroids, vincristine, doxorubicin, and methotrexate, but the doses have varied substantially. A course of chemotherapy similar to that used for B-cell non-Hodgkin lymphoma, with treatment stratified by stage of disease, was effective for disseminated anaplastic large-cell lymphoma, as was treatment that included a short cytoreduction phase (two chemotherapy cycles) followed by a short maintenance phase (five to seven months) [139,140]. In an international study of systemic childhood anaplastic large-cell lymphoma, 12 of 463 patients had CNS involvement; three of the 12 had isolated CNS disease. Comparative analysis of CNS-positive and CNS-negative patients showed no difference in anaplastic lymphoma kinase positivity, immunophenotype, presence of B symptoms, or other sites of disease. With multiagent chemotherapy, the event-free and overall survival rates of the CNS-positive group at five years were 50% and 74%, respectively [304]. CNS involvement in anaplastic large-cell lymphoma is rare at diagnosis [46].

CNS Prophylaxis

The use of radiation therapy is limited in children with non-Hodgkin lymphoma. Early studies showed that routine CNS prophylaxis had no benefit for patients with low-risk (stage I or stage II) disease [305]. It has been demonstrated that CNS prophylaxis can be omitted in lymphoblastic lymphoma [301,306]. It can also be eliminated for patients with anaplastic large-cell lymphoma and B-cell non-Hodgkin lymphoma, even those who present with CNS disease [140,296]. These findings are supported by data from the Childhood Cancer Survivor Study, which demonstrated that radiation was a significant risk factor for secondary malignancy and death in long-term survivors [307].

Treatment for Recurrent or Refractory Disease

Relapse occurs in approximately 12% of children/adolescents with non-Hodgkin lymphoma [286]. Intensive chemotherapy with drugs that were not used in first-line treatment have been utilized, and stem cell transplantation support has been effective for patients with chemosensitive disease [114,308,309,310,311]. Two cycles of chemotherapy with DECAL, maintenance therapy, and stem cell transplantation was found to be effective for relapsed non-Hodgkin lymphoma, with a five-year event-free survival of 23% and five-year overall survival of 30% [274].

Although outcomes in pediatric B-non-Hodgkin lymphoma have improved with intensive chemotherapy protocols, the long-term adverse effects of therapy and poor outcomes for patients who relapse continue to be challenges [46,312]. One study evaluated the potential risks and benefits of routine relapse surveillance imaging after the completion of therapy among 44 patients with non-Hodgkin lymphoma who were diagnosed and treated at Texas Children's Cancer Center between 2000 and 2011 [312]. Only three of the 44 patients had relapse (6.8%) and none of the relapses were initially diagnosed by CT or PET scans. The median effective radiation dose per patient was 40.3 mSv (range: 0–276 mSv). This study highlights the low relapse rate following complete response at the end of therapy among children/adolescents with B-non-Hodgkin lymphoma, the low sensitivity of early relapse detection by surveillance imaging, and the costs and potential increased risk of secondary malignancies from cumulative radiation exposure from surveillance imaging [312].

10. SUPPORTIVE CARE

Supportive care is integral to the treatment of leukemias and lymphomas and addresses the symptoms and potential complications of both the disease and treatment. Children should be followed closely during active treatment; the primary oncologist usually coordinates this care. However, the child's primary care provider may also be involved, especially if the family's home is far from the pediatric cancer center. In addition, routine visits with the primary care provider should continue for overall health maintenance. These visits provide an opportunity to assess symptom management and the development of complications. Good reciprocal communication between the primary care provider and the primary oncologist is essential. The primary oncologist should send a copy of the patient's treatment plan to the primary care provider, and both clinicians should maintain communication about complications as they occur [313].

Supportive care focuses on the treatment of infection, neutropenia, anemia, thrombocytopenia, and other complications, such as metabolic disturbances and deep vein thrombosis. Also essential is symptom management, which centers on enhancing the quality of life.

INFECTION

Of primary concern during treatment for leukemia or lymphoma is the risk of infection, which is the leading cause of morbidity and mortality among children with cancer [19,314]. Infection is a result of the severe immunosuppression caused by both treatment (chemotherapy and radiation therapy) and the disease process itself. Immunosuppression and associated neutropenia increase the risk for opportunistic infection with bacterial, viral, fungal, and protozoal organisms [314,315]. Most infections that occur in children during or after treatment for leukemia or lymphoma are the same as those found in healthy children [315].

Evidence Based Practice Recommendation

According to the Advisory Committee on Immunization Practices, the measles, mumps, rubella, and varicella vaccine is contraindicated in children with severe immunocompromise (including as a result of leukemia or lymphoma).

https://www.cdc.gov/vaccines/pubs/pinkbook/meas.html

Last Accessed: August 5, 2021

Level of Evidence: Expert Opinion/Consensus Statement

Prevention of infection includes general measures such as meticulous hand hygiene (for the patient and all who come in direct contact) and the avoidance of environments where the risk of infection transmission is high. Playing in dirt or gardens or near construction sites may pose a risk of fungal infection [314]. In addition, it is important to protect the integrity of the skin and mucosal surfaces, as they serve as barriers to infectious pathogens [315]. Proper oral hygiene, with daily tooth brushing and use of chlorhexidine mouth rinse, is important, and rectal suppositories and rectal thermometers should not be used [314]. Unless the child is at high risk for fever and neutropenia, routine prophylaxis against viral, bacterial, and fungal agents is not recommended [315,316,317]. One exception is prophylaxis for Pneumocystis jiroveci, which occurs in 15% to 20% of children treated for ALL [315,318,319]. Prophylactic treatment consists of trimethoprim-sulfamethoxazole (TMP-SMZ), given either daily or on three consecutive days per week [253,319,320]. Treatment with TMP-SMZ on two consecutive days per week has also been shown to be effective [321].

Several trials have shown the efficacy of antibiotic prophylaxis in reducing the incidence of bacterial infections but not in reducing mortality rates. One systematic review evaluated whether there remains a benefit of reduction in mortality when compared with placebo or no intervention [322]. The review included 109 trials (involving 13,579 patients) that were conducted from 1973 to 2010. The reviewers found that, when compared with placebo or no intervention, antibiotic prophylaxis significantly reduced the occurrence of fever, clinically and microbiologically documented infection, and other indicators of infection. There were no significant differences between prophylaxis with quinolone or TMP-SMZ with regard to death from all causes or infection; however, quinolone prophylaxis was associated with fewer side effects leading to discontinuation and less resistance to the drugs thereafter. The benefits of antibiotic prophylaxis outweighed the harms (e.g., adverse effects, development of resistance) because all-cause mortality was reduced [322].

Children receiving treatment for leukemia or lymphoma who have a fever (38.5 degrees Centigrade or two temperatures of at least 38.0 degrees Centigrade within 24 hours) should be evaluated carefully for infection. Vital signs should be assessed, and physical examination should include evaluation of common sites of infection (respiratory system, ears, sinuses) as well as occult sites (mouth, skin, perianal area) [314]. Laboratory testing should include a CBC, blood cultures, urinalysis, and urine culture [314]. The absolute neutrophil count (ANC) should be determined, as neutropenia is the most significant predisposing factor for infection [314,323]. Approximately 70% to 80% of bacterial infections occur in children who have moderate neutropenia [323]. The presence of fever and neutropenia requires hospitalization for empiric treatment with intravenous administration of broad-spectrum antibiotics [324]. One randomized controlled trial evaluated the use of ciprofloxacin in children younger than 18 years of age with ALL or lymphoma who were scheduled to undergo chemotherapy [325]. A total of 95 children were randomized to receive oral ciprofloxacin 20 mg/kg/day (45 children) or placebo (50 children) from the beginning of their chemotherapy. Rectal swab cultures were taken before and at one and/or two weeks after the intervention. Of the 71 patients who developed neutropenia, the proportion of children who developed fever was significantly lower in the ciprofloxacin group than in the placebo group. Ciprofloxacin significantly reduced the occurrence of febrile episodes in patients with ALL in the induction phase of chemotherapy, but not in patients with lymphoma or in the consolidation phase of chemotherapy. Adverse effects were not different between the groups [325].

Evidence Based Practice Recommendation

The Children's Oncology Group recommends obtaining blood cultures at the onset of fever and neutropenia in children with cancer from all lumens of central venous catheters.

https://childrensoncologygroup.org/downloads/COG_SC_FN_Guideline_Document.pdf

Last Accessed: August 5, 2021

Strength of Evidence/Level of Evidence: Strong recommendation, low-quality evidence

The risk of infection is also increased for children who have an indwelling central venous catheter. Indwelling venous catheters are used in most children/adolescents with cancer to facilitate the administration of medications, fluids, and blood products. The risk of infection related to these catheters has ranged from approximately 3% to 60%, and the risk is greater with external catheters than with implanted ones [326,327]. Care of external catheters requires strict adherence to aseptic technique, daily flushing of the catheter, and frequent changes of the sterile dressing [315]. If a fever develops, blood for cultures should be obtained through the catheter and from a peripheral site and empiric treatment with antibiotics should be started. Routine removal of the catheter is not necessary, as nearly 75% of catheter-related infections resolve with the catheter intact [328]. However, if signs of septicemia develop and bacteremia persists 48 hours after the start of antibiotic administration, the catheter should be removed [314]. The catheter should also be removed immediately if the infection is fungal.

The presence of a central venous catheter also requires prophylactic antibiotics before invasive procedures, including dental cleaning or procedures. The prophylaxis used is that recommended by the American Heart Association for children with congenital heart disease: amoxicillin, 50 mg/kg (maximum of 3 grams), given one hour prior to the procedure [329].

NEUTROPENIA

Neutropenia is defined as an ANC of less than 1,000/mcL. An ANC of less than 500/mcL is considered to be moderate neutropenia, and an ANC of less than 200/mcL is severe neutropenia [314]. As noted, neutropenia is a significant factor for the development of infection. In the adult setting, neutropenia is prevented and managed with the use of hematopoietic growth factors, such as granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF). In the pediatric population, clinical protocols for leukemia usually include guidelines for the use of CSFs. Research to evaluate their use has been limited, and the results have varied [326,330,331]. One meta-analysis of 16 randomized controlled trials involving nearly 1,200 children with cancer, primarily leukemia and lymphoma, demonstrated that the prophylactic use of CSFs was associated with a 20% decrease in febrile neutropenia, a lower number of documented infections, and shorter hospital stays [332]. However, other studies, including a meta-analysis, have indicated that CSFs have no significant effect on the incidence of infection [330,333]. It is important also to note that the use of CSFs in children with ALL has been associated with an increased risk for secondary myeloid leukemia or myelodysplastic syndrome [334]. Given these findings, the American Society of Clinical Oncology states that the use of CSFs in children with ALL should be "considered with caution" and recommends that primary prophylaxis with CSFs is "reasonable" for children in whom febrile neutropenia is likely [331]. Secondary prophylaxis with CSFs should be limited to children at high risk [331]. The risk of AML has also led to the recommendation to avoid the routine use of CSFs after induction therapy [326,331]. Pegfilgrastim, a recombinant G-CSF used to prevent neutropenia in adults, has been shown to be safe and effective for children [335].

The International Pediatric Fever and Neutropenia Guideline Panel is a multidisciplinary, multinational group of pediatric oncology and infectious diseases experts. In 2017, the Panel published an updated clinical practice guideline for the management of fever and neutropenia in children with cancer and in HSCT recipients [317]. The Panel addressed risk stratification and evaluation as well as therapeutic interventions, and it made strong or weak recommendations related to initial presentation, ongoing management, and antifungal therapy of pediatric fever and neutropenia. The Panel's strong recommendations are summarized in Table 15[317].

Table 15: INTERNATIONAL PEDIATRIC FEVER AND NEUTROPENIA GUIDELINE PANEL RECOMMENDATIONS FOR THE MANAGEMENT OF FEVER AND NEUTROPENIA IN CHILDREN WITH CANCER

Recommendation

Level of Evidence

Remarks

Initial Presentation of Fever and Neutropenia: Initial Management

Risk stratification: Adopt validated risk stratification strategy and incorporate into routine clinical management

Low-quality evidence

Strategy choice should be determined by validation in similar context; ability to implement based on complexity, availability of required components (e.g., biomarkers)

Evaluation: Obtain blood cultures at onset of FN from all CVC lumens

Low-quality evidence

—

Evaluation: Obtain chest radiography in patients with respiratory signs/symptoms

Moderate-quality evidence

Patients at High Risk for Fever and Neutropenia: Treatment

Use monotherapy with antipseudomonal β-lactam, fourth-generation cephalosporin, or carbapenem as empirical therapy

High-quality evidence

Monotherapy may be not be appropriate for centers with high rate of resistance, or for patients who present with hemodynamic instability

Reserve addition of second gram-negative agent or a glycopeptide for patients who are clinically unstable, when resistant infection is suspected, or for centers with high rate of resistant pathogens

Moderate-quality evidence

Threshold for when rates of resistance are sufficiently high to support empirical combination or glycopeptide therapy has not been established, will vary by institution

Ongoing Management (Excluding Empirical Therapy)

Modification of treatment: In patients who respond to initial empirical antibiotic therapy, discontinue double coverage for gram-negative infection or empirical glycopeptide (if initiated) after 24 to 72 hours if there is no specific microbiologic indication to continue combination therapy

Moderate-quality evidence

Rationale is same as that for recommendation for initial empirical monotherapy. The Panel valued reducing unnecessary antibiotic administration to reduce toxicity, costs, and antibiotic resistance.

Modification of treatment: Do not modify initial empirical antibacterial regimen based solely on persistent fever in children who are clinically stable

Low-quality evidence

Modification of treatment: In children with persistent fever who become clinically unstable, escalate initial empirical antibacterial regimen to include coverage for resistant gram-negative, gram-positive, and anaerobic bacteria

Very low-quality evidence

Cessation of treatment: In all patients, discontinue empirical antibiotics in patients who have negative blood cultures at 48 hours, who have been afebrile for at least 24 hours, and who have evidence of marrow recovery

Low-quality evidence

—

Empirical Antifungal Therapy

Risk stratification: Patients at high risk of IFD are those with AML, high-risk ALL, or relapsed acute leukemia, and children undergoing allogeneic HSCT. Children with prolonged neutropenia and children receiving high-dose corticosteroids are also at high risk of IFD. All others should be categorized as low-risk IFD.

Low-quality evidence

Risk stratification rules are not yet available for prediction of IFD. The Panel recognized that high-risk ALL is a heterogeneous group and this risk may be explained by prolonged neutropenia and corticosteroid administration. No data available to specify which ALL patients is at particular risk of IFD.

Evaluation: Do not use β-D-glucan.

Low-quality evidence

—

Evaluation: Do not use fungal PCR testing in blood

Moderate-quality evidence (new recommendation)

—

Evaluation: In terms of imaging for evaluation of prolonged (≥96 hours) FN in IFD high-risk patients, perform CT of the lungs

Low-quality evidence

Lungs consistently most commonly affected site. Optimal timing of initial and repeated imaging not known.

Treatment: In IFD high-risk patients with prolonged (≥96 hours) FN unresponsive to broad-spectrum antibacterial agents, initiate caspofungin or liposomal amphotericin B for empirical antifungal therapy

High-quality evidence

—

FN = fever and neutropenia; CVC = central venous catheter; IFD = invasive fungal disease; AML = acute myeloid leukemia; ALL = acute lymphoblastic leukemia; HSCT = hematopoietic stem cell transplantation; PCR = polymerase chain reaction; CT = computed tomography

Source: [317]

ANEMIA OR THROMBOCYTOPENIA

Evidence Based Practice Recommendation

According to the Council of Pediatric Hematology/Oncology Centres across Canada, prophylactic platelet transfusions are recommended at a platelet threshold of 10 x 10^9/L for clinically stable pediatric patients receiving chemotherapy for leukemia.

https://www.c17.ca/application/files/2916/2006/0821/C17_Platelet_Guideline_English_Summary_2011.pdf

Last Accessed: August 5, 2021

Strength of Evidence/Level of Evidence: 1C (Strong recommendation, poor-quality evidence)

Myelosuppression caused by chemotherapy may lead to anemia and thrombocytopenia. In these cases, blood products may be needed. No hemoglobin level has been established as a threshold for transfusion of blood; the need for transfusion of packed red blood cells (preferred to whole blood) is based on careful evaluation of individual patients [326]. Transfusion was once done for a hemoglobin of less than 10 g/dL, but most clinicians now consider 7–8 g/dL as the threshold due to the risks associated with transfusions [314,326]. Erythropoietin at a dose of 600 units/kg to 900 units/kg once weekly for 16 weeks has been shown to be safe for increasing the hemoglobin level and decreasing the need for transfusion among children 5 to 18 years of age who were being treated with myelosuppressive chemotherapy for nonmyeloid cancers [336].

As with transfusion of blood products for anemia, the need for transfusion of platelets is based on the individual case. Platelet transfusion is rarely indicated during remission induction for ALL, but prophylactic platelet transfusions are usually given during treatment for AML when the platelet count declines to less than 10,000/mcL [326]. If a child has fever, sepsis, a history of bleeding, severe mucositis, coagulopathy, or hyperleukocytosis, prophylactic transfusion of platelets may be given with the presence of a higher platelet count (for example, 20,000/mcL) [326]. If a child is to have an invasive procedure, a transfusion should be given to maintain a platelet count of 40,000–50,000/mcL [314].

METABOLIC DISTURBANCES

The rapid destruction of malignant cells can lead to a build-up of chemicals in the bloodstream. This accumulation of biochemicals can cause several metabolic disturbances, including hyperuricemia, hyperphosphatemia, hyperkalemia, and hypocalcemia [323,337]. Collectively, these abnormalities comprise tumor lysis syndrome, which is most commonly associated with high tumor burden [114,115]. Prompt management of tumor lysis syndrome is necessary to prevent renal failure. The management approach has involved increased hydration with a hypotonic solution and administration of allopurinol; however, recombinant urate oxidase has been shown to be more effective than allopurinol [114,115,323,337].

DEEP VEIN THROMBOSIS

The risk of deep vein thrombosis is increased for children with a central venous catheter (CVC), and the likelihood of thrombosis is higher for children who have had catheter-related infection or occlusion of the catheter [338]. Deep vein thrombosis (DVT) in these cases usually develops without signs or symptoms. In a study of 21 children with a catheter-related deep vein thrombosis, signs or symptoms occurred in only five [338]. Repeated complications, primarily occlusions, should prompt investigation for thrombosis [314,338]. Treatment consists of a thrombolytic agent, such as tissue plasminogen activator [314,339]. One prospective registry study found that insertion of peripheral central catheters (specifically, Hickman catheters), insertion in an angiography suite, and proximal-tip location significantly increased the risk of symptomatic CVC-related DVT. Positive family history of thrombosis also significantly increased the risk of CVC occlusion [340].

11. PALLIATIVE AND END-OF-LIFE CARE

The term palliative care is often used synonymously with end-of-life care. However, palliative care is increasingly being defined as care that focuses on enhancing the quality of life for the patient (child or adult) and family, regardless of whether curative treatment is being undertaken. As optimally defined, pediatric palliative care [173,341,342,343,344,345,346]:

- Begins at the time of diagnosis

- Is family-centered and includes the child and the child's family, including siblings

- Is delivered by a multidisciplinary team

- Addresses physical symptoms and psychosocial issues

- Addresses the family's spiritual issues (e.g., faith, culture, religion, clergy, questions about the meaning of pain/suffering and death/dying)

- Enhances the quality of life for the patient and family

- Provides assistance with advance care planning and practical concerns (e.g., location of end-of-life care)

Recognizing the need for more effective pediatric palliative care, the AAP issued a statement recommending that "the components of palliative care are offered at diagnosis and continued throughout the course of illness, whether the outcome ends in cure or death. Palliative care should be accessible in any setting, including home, hospital, and school" and should be patient- and family-centered [344,347]. Despite the calls for a family-focused approach to pediatric palliative care, a gap remains between optimal family care and actual practice, due in part to the ambiguity and ambivalence about the meaning of "caring for the family" [346].

Effective communication among all caregivers and between parents and the patient is essential to providing optimum palliative care. The goals of treatment should be clearly articulated among the palliative care team and the family to facilitate collaboration and delivery of care [173]. As much as possible and appropriate, the child should be allowed to participate in discussions about the direction of care [344,348]. Parents have repeatedly stated that compassionate, honest, and complete information, ready access to staff, emotional expression by staff, and staff support are critically important to their ability to make decisions concerning their children. Family needs in this area are high [349,350,351,352].

ASSESSING AND MANAGING SYMPTOMS

The assessment and management of symptoms represent the cornerstone of palliative care [173,353]. Symptom management is crucial not only to relieve physical and psychologic suffering but also to avoid feelings of mistrust and fear [348]. In general, studies have shown that pain, fatigue, and nausea/vomiting are the most common physical symptoms in children being treated for cancer [173,348,354,355,356]. Symptoms differ, however, according to age, the type of cancer, the type of treatment, and the degree of distress they cause. For example, in one study, 35% of children/adolescents 10 to 18 years of age had clinically significant pain, lack of energy, drowsiness, nausea, cough, lack of appetite, and psychologic symptoms; the most distressing symptoms were pain, insomnia, mouth sores, and difficulty swallowing [357]. A similar study of younger children, 7 to 12 years of age, demonstrated lethargy, pain, or insomnia occurring in approximately 33%, with pain, insomnia, pruritus, nausea, sadness, and worry being the most distressing symptoms [358].

Effective management of symptoms requires careful assessment, physical examination, and functional evaluation, all of which should be repeated at regular intervals to ensure ongoing alleviation. Several tools are available to assess pain. However, such tools are lacking for other symptoms, highlighting the importance of the patient's self-report of symptoms. A symptom checklist for children can help facilitate monitoring and self-reporting of symptoms [356]. Symptom management should be timely and include both pharmacologic and nonpharmacologic strategies [173,341,348]. Because stress and anxiety can exacerbate physical symptoms, attention to psychosocial issues is essential for optimum symptom management.

Pain

Pain may be related to treatment, diagnostic procedures, and/or progressive disease. The patient's self-report of pain, when possible, is the most reliable indicator [53,348]. Assessment of pain must be appropriate for each child's age, developmental level, and cultural context. Pain assessment tools have been developed for several different age groups among children/adolescents, from birth to 18 years of age, and for nonverbal or cognitively imp23aired children (Table 16) [53,359,360,361,362,363,364,365,366,367,368]. These tools are designed to either provide a score according to a set of behavioral cues, as in the case of infants and young children, or allow the child to self-report on the intensity and location of pain. Several tools have been modified and validated for use among children/adolescents of different races/ethnicities, including black, Hispanic, Asian, and Alaska Native populations [369,370,371,372].

Table 16: INSTRUMENTS USED FOR PAIN ASSESSMENT IN CHILDREN AND ADOLESCENTS

Age of Child

Assessment Tool

Birth to 3 years of age

FLACC (Face, Legs, Activity, Cry, Consolability)

CRIESa

Neonatal Infant Pain Scale

Children's Hospital of Eastern Ontario Pain Scale (CHEOPS)

3 to 7 years of age

Faces Scale

Oucher

Pain thermometers

Body maps

Older than 7 years of age

Visual analog scale

Verbal response scale

aThe five parameters are crying, requires oxygen to maintain saturation greater than 95%, increased vital signs, expression, and sleepless.

Source: [53,359,360,361,362,363,364,365,366,367,368]

It is also helpful to evaluate behaviors to determine if a young child has pain. Indicators of pain in infants include facial expressions such as frowning, a furrowed brow, a quivering chin, crying, sucking, flexing of fingers and toes, and breath-holding. Behavioral indicators are also important for older children, as they may not admit to having pain because of fear of an injection. Indicators in older children include decreased energy level; decreased eating; lack of interest in usual activities; holding or protecting part of the body; seeking comfort or closeness; and whining or groaning [359,360,361,362,363].

Physical examination and functional evaluation are other components of pain assessment. During the examination, the clinician should watch closely for nonverbal cues that suggest pain. These cues are especially important when examining patients who are unable to verbally communicate. To evaluate how pain may be influencing function, the clinician should watch the patient to see how pain limits movements and should ask the patient or family how the pain interferes with normal activities. Determining functional limitations can help enhance patient compliance in reporting pain and adhering to pain-relieving measures, as clinicians can discuss compliance in terms of achieving established functional goals.

As with adults, using the WHO ladder to manage pain is effective for children [373,374,375]. The WHO ladder involves a three-step approach, with the strength of the analgesic agent increasing according to the severity of pain. There are two important underlying principles of the WHO ladder. First, analgesics should be administered on a regular schedule rather than on an as-needed basis. This approach is not only more effective at controlling pain but also avoids unnecessary pain as a prompt for the next dose. The second principle is that treatment should correspond to the intensity of pain as reported by the patient, regardless of whether treatment at a previous step was carried out [373].

The WHO ladder calls for the use of nonopioid and opioid analgesic agents (Table 17). Rotation of opioids has been found to be effective and can help avoid dose-limiting toxicity [173]. Medications for pain should be given by the easiest, least painful route (oral, sublingual, or parenteral for children with a central venous catheter), avoiding intramuscular injections whenever possible [173,348].

Table 17: PHARMACOLOGIC APPROACHES TO PAIN RELIEF IN CHILDREN AND ADOLESCENTS

Drug (Route)

Typical Initial Dose, Interval

Maximum Dose

Notes

Nociceptive Pain

Acetaminophen (PO, PR)

10–15 mg/kg every 4 to 6 hrs

1.0 g/dose, 4 g/day

Oral form available as tablets, chewable tablets, liquid, and drops

Ibuprofen (PO)

5–10 mg/kg every 8 to 12 hrs

400 mg/dose, 1.2 g/day

Oral form available as tablets, chewable tablets, liquid, and drops

Choline magnesium trisalicylate (PO)

7.5–15 mg/kg every 12 hrs

1.0 g/dose

Oral form available as tablets and liquid

Naproxen (PO)

5–10 mg/kg every 12 hrs

1.0 g/dose

Oral form available as tablets and liquid

Ketorolac (PO, IV, IM)a

0.5 mg/kg every 6 hrs

10 mg/dose (PO);

30 mg/dose (IV)

–

Codeine (PO, SQ, IM)

0.5–1 mg/kg every 3 to 4 hrs

60 mg/dose

Oral form available as tablets and liquid

Tramadol (PO)

1–2 mg/kg every 6 hrs

Titrate

–

Morphine (PO, SL, PR)

0.15–0.3 mg/kg every 3 to 4 hrs

Titrate

Oral form available as tablets and liquid

Morphine (IV, SQ, IM)

0.1 mg/kg every 2 to 4 hrs

Titrate

–

Hydromorphone (PO, PR)

0.03–0.08 mg/kg every 3 to 4 hrs

Titrate

Oral form available as tablets and liquid

Hydromorphone (IV, SQ, IM)

0.015 mg/kg every 2 to 4 hrs

Titrate

–

Methadone (PO)

0.2 mg/kg every 8 to 12 hrs

Titrate

Oral form available as tablets and liquid

Methadone (IV, SQ, IM)

0.1 mg/kg every 8 to 12 hrs

Titrate

–

Fentanyl (Transdermal)

0.5–1 mcg/kg/hr every 48 to 72 hrs

Titrate

–

Fentanyl (Lozenge [sedative])

5–15 mcg/kg every 4 to 6 hrs

Titrate

–

Fentanyl (IV, SQ)

1–2 mcg/kg every 1 to 2 hrs

Titrate

–

Oxycodone (PO)

0.1 mg/kg every 3 hrs

Titrate

Oral form available as tablets and liquids

Neuropathic Pain

Gabapentin (PO)

5 mg/kg every 6 to 8 hrs

3.6 g/day

–

Amitriptyline (PO)

0.2 mg/kg at night

1 mg/kg/night

–

aGive for no more than five days.

PO = by mouth; PR = per rectum; IV = intravenously; IM = intramuscularly; SL = sublingually; SQ = subcutaneously.

Source: [53,348]

There are no randomized controlled trials addressing the management of breakthrough pain in children with cancer. Limited data and considerable experience indicate that breakthrough pain in this patient group is common, underassessed, and undertreated [376]. Clinicians and parents should also be alert to breakthrough pain, which occurred in 57% of children with cancer in one study [377]. The risk of breakthrough pain was higher for younger children (7 to 12 years of age) than older children (13 to 18 years of age). The high rate of breakthrough pain reflects the importance of pain assessment as an ongoing process, with assessment and documentation at regular intervals. The optimum interval varies. In general, patients with more severe disease should be evaluated more frequently. Measures of pain relief should also be documented, especially with regard to efficacy.

An ideal therapeutic agent would be easy to administer and rapid in onset with short duration. The most common and effective strategy seems to be multimodal analgesia that includes an immediate-release opioid (e.g., morphine, fentanyl, hydromorphone) administered intravenously by a patient-controlled analgesia pump, ensuring an onset of analgesic action within minutes. Intranasal fentanyl (or hydromorphone) may be an alternative, but no pediatric data have been published for commercially available fentanyl transmucosal application systems, and these products cannot yet be recommended for use with children with cancer and breakthrough pain [376].

Pain medication should be complemented by nonpharmacologic interventions that are begun early in the course of treatment. These interventions should be age-appropriate. Touch, massage, stroking, and rocking work well for infants, toddlers, and young children; distraction is effective for older children, as are guided imagery, music and art therapy, play therapy, controlled breathing, and relaxation techniques [53].

Fatigue

Fatigue is often described by children as "drowsiness," feeling "sluggish," or having a loss of energy. As many as 70% to 80% of children/adolescents with cancer note one of these feelings, which can be caused by many factors, including medications (chemotherapy agents and opioids), pain, anemia, progressive disease, and psychologic issues [342,348,356]. Tools to assess fatigue, for use by patients (7 to 12 years of age), parents, and healthcare staff, have been developed but require evaluation and validation in prospective studies [378,379]. Signs and symptoms of fatigue include asthenia, sleep disturbances, low energy level, and decreased participation in activities. Gradual increases in exercise and school activities and cognitive-behavioral approaches to improve coping skills may be helpful.

One study evaluated the change in children's and adolescents' fatigue scores during cancer treatment and described possible causes of fatigue [380]. Forty children 7 to 12 years of age, 29 adolescents 13 to 15 years of age, and one parent were included in the study. Cancer-related fatigue was measured using the Child Fatigue Scale, the Adolescent Fatigue Scale, and the Parent Fatigue Scale. Children, adolescents, and parents reported a statistically significant increase in fatigue scores during their treatment, with medical procedures and the hospital environment reported as major causative factors of the fatigue experienced [380]. Results of another study indicate that cancer-related fatigue results in a low health-related quality of life for pediatric patients [381].

Gastrointestinal Symptoms

Nausea and vomiting are the most common gastrointestinal symptoms in the pediatric cancer setting; other symptoms include constipation, diarrhea, and anorexia/cachexia. Nausea and vomiting can be a challenge to assess, especially in young children who are unable to articulate the feeling of nausea. Inactivity, signs of weakness, and/or lack of appetite may indicate nausea. The choice of antiemetic is based on the likely cause of nausea and vomiting [173,348]. The best agents for nausea and vomiting caused by chemotherapy or radiation therapy are 5-HT3 receptor antagonists, such as ondansetron and granisetron. Other choices are prochlorperazine, scopolamine, dronabinol, and metoclopramide [113,173,348,382]. Anticipatory nausea may be alleviated by benzodiazepines and the use of relaxation techniques [323,348]. Use of a hydration fluid may be necessary to prevent dehydration in a child who is vomiting excessively [348]. Taking medications after meals, when possible; eating small, frequent meals; and avoiding strong smells may also help ease nausea [173].

Constipation is also common among children/adolescents with cancer and is usually related to medications, particularly opioids and vincristine [348]. This symptom is often under-recognized or undertreated by clinicians [173]. The optimum treatment for constipation is prevention through a variety of measures, including movement/exercise, adequate fluid intake, and increased fiber intake. Regular use of laxatives is recommended during treatment with opioids [53].

Mucositis

Mucositis occurs in as many as 50% of children/adolescents receiving chemotherapy. It is often associated with radiation therapy to the head and neck area [323,337]. Mucositis can affect the mouth, esophagus, stomach, duodenum, and colon, and the severity depends on the type of chemotherapy used. High-dose methotrexate and high-dose cytarabine are considered the most damaging to mucosa [337]. Small studies have shown that chlorhexidine is beneficial for alleviating mucositis in children, but the results must be confirmed by larger trials [383]. One literature review focused on randomized clinical trials to evaluate the effectiveness of chlorhexidine mouthwash in alleviating mucositis in children receiving chemotherapy [384]. Control groups consisted of placebo, no intervention, or another intervention group. Mucositis was scored using either the WHO scale or the modified Oral Assessment Guide. Five studies fulfilled the inclusion criteria, in which chlorhexidine was evaluated. Four of the five showed a significant preventive effect on the development or severity or mucositis when chlorhexidine mouthwash was used. The remaining study showed no benefit compared with the placebo group [384]. Other helpful measures include the use of ice chips during administration of chemotherapy, excellent oral hygiene, analgesic agents, and avoidance of irritating foods or fluids, such as citrus fruits and juices [323,337].

Pruritus

Pruritus usually occurs as a side effect of medications, especially morphine and other opiates, and may also be associated with progressive lymphoma [53]. Physical manifestations of pruritus include excoriation, erythema, and lichenification; rubbing of the eyes, nose, or skin may also indicate pruritus [248]. Discontinuing use of the causative medication, if possible, is the preferred treatment approach. Moisturizing creams may be used for dry skin, and systemic corticosteroids or antihistamines may be helpful for more severe cases [248].

PSYCHOSOCIAL AND SPIRITUAL ISSUES

Anxiety, worry, and sadness are among the most frequently occurring psychologic symptoms for children/adolescents with cancer [173,348,357]. These emotions are a normal response to many effects of cancer and its treatment, including pain and other symptoms, disease progression, impaired function, isolation, loss of control, concern about parents and other family members, and loss of a "normal" life [173]. Clinicians and other caregivers should address such fears and concerns honestly and should encourage family members to discuss them openly with each other and the patient.

Specially trained members of the palliative care team can play an important role in helping patients and their families deal with psychosocial issues. Child-life specialists and creative art therapists are available in hospital settings to guide patients in expressing their feelings through creativity and imagination [173]. This process can help foster the patient's sense of control and independence and enhance self-esteem [173]. Psychologists on the palliative care team can assess the psychologic needs of both the patient and family and implement interventions as appropriate.

Spiritual support for the child and family is an important component of palliative care and is usually the primary responsibility of a pastoral care worker on the palliative care team. However, all professional caregivers should provide spiritual support. Spirituality transcends religion and involves such concerns as hope, forgiveness, love, and sense of meaning [348]. Caregivers should talk with the patient about his or her dreams and hopes for the future and encourage the patient and family to express spiritual concerns and engage in their religious traditions [345].

PROVIDING END-OF-LIFE CARE

The high survival rates for children with leukemia and lymphoma has of course led to a decreasing number of childhood deaths. Still, 10% to 30% of patients will have relapsed disease and die. Despite the fact that these children would benefit from hospice care delivered by a multidisciplinary palliative care team, studies have shown that most children with cancer die in the hospital [385]. However, one report indicated a significant increase in the number of children/adolescents who died at home since the late 1990s, and a survey of bereaved parents and pediatric oncologists ranked home as their first choice for end-of-life pediatric cancer care [386,387]. Still, hospice care is used by only 5% to 25% of eligible children in the United States and Canada [388].

The movement to formally develop high-quality palliative care programs began in the late 1990s. The AAP issued the first policy statement on pediatric palliative care in 2000. Then in 2003, the Institute of Medicine recommended specialty training in pediatric palliative care and development of collaborative guidelines and protocols tailored to children [389,390]. In 2006, St. Jude Children's Research Hospital (St. Jude) made development of a pediatric palliative care program an institutional priority, with the mission to "provide each child living with or dying from a catastrophic illness with state-of-the-art patient- and family-centered physical, emotional, and spiritual care with the goal to attend suffering, promote healing, and improve quality of life" [391,392,393]. In 2007, St. Jude initiated a one-year pilot project to evaluate the role of pediatric palliative care expertise as part of the interdisciplinary care team. The pilot program was a success, and in 2008, St. Jude fully implemented the Quality of Life Service (QoLS) program throughout the hospital. The program functioned on a consultative basis, working together with patients' primary care teams. QoLS consults included advanced care planning; symptom control; care coordination and continuity; emotional, social, and spiritual support; end-of-life care; and bereavement support in inpatient, outpatient, and home-based settings. The QoLS also provided more than 200 educational offerings across all professions in the institution and partnered with medical and psychosocial providers [394].

In 2016, members of the St. Jude Department of Oncology, Division of Quality of Life and Palliative Care, in collaboration with others, published results of a study that described the institution's eight-year experience integrating palliative care with cancer care for pediatric patients [394]. According to the results, new consults per year increased from 17 in the pilot year to 115 in 2014. Patient encounters increased from 58 in the pilot year to 1,297 in 2014, indicating that the QoLS not only saw more patients but also followed them more regularly and for longer periods of time. Mean encounters per patient by year of initial consult more than tripled, from 5.1 in 2007 to 16.1 in 2014, substantiating that patients were seen with increasing regularity and sustained continuity from the time of consultation [394]. In the early years of the program, the primary patients' goal of care at initial consultation was focused on "comfort only," but this shifted over time to a "goal of cure," which increased from 25% of patients in 2008 to 58% in 2014. Following the pilot year, there was also a shift in patients' location of death from primarily inpatient settings to increased use of outpatient settings. The authors were unable to determine the preferred location of death, but increased use of outpatient locations suggest that increased availability of palliative care services facilitated outpatient end-of-life care and a greater ability to satisfy the preferences of patients and their families [394]. This led the American Society of Clinical Oncology to recommend palliative care services for all high risk oncology patients. Yet, as stated, both adult and pediatric oncologists refer only a small proportion of patients to palliative care services, and then it is late in the disease course when the goal of cure is no longer an option [395,396,397,398].

There is a significant association between race/ethnicity and hospice enrollment, with Latinos enrolled in hospice significantly more often than patients of other races. However, by the time of death, 34% of Latinos and 50% of non-Latinos had withdrawn from hospice [399]. The lack of appropriate end-of-life care has a high price; one study indicated that 89% of dying children suffered "a lot" or "a great deal" from at least one symptom in their last month of life [400]. The findings of that study and others, including the Institute of Medicine (IOM) report When Children Die: Improving Palliative and End-of-Life Care for Children and Their Families, have prompted further research on the topic [343,353,358].

Several barriers to pediatric end-of-life care have been identified (Table 18) [173,343,348,401,402]. Because of the low rate of mortality, the lack of relevant educational programs, and the paucity of palliative care services across the United States, particularly in pediatric facilities, many healthcare professionals are left inexperienced with pediatric end-of-life care [401,402,403,404]. In addition, the availability of sufficiently trained pediatric hospice professionals is limited because of the low rate of hospice admissions for children/adolescents. One survey found that pediatric palliative care is only offered in 58% of Children's Oncology Group institutions caring for children with cancer [402]. Other challenges to providing high-quality care include growing demands for expansive care, discomfort in providing mental health/bereavement services to families, and reimbursement models that do not support comprehensive care [346]. The increasing demand for expansive care, including palliative care services, led St. Jude to expand the QoLS resources, which included: more clinical and research staff; a hospice and palliative medicine fellowship training program; and creation of a home-based palliative care and hospice program in collaboration with the local children's hospital and community hospice [394].

Table 18: BARRIERS TO PEDIATRIC END-OF-LIFE CARE

Rarity of death among children

Immeasurable parental distress at loss of child

Unrealistic expectations or denial of parents

Association of palliative care with "giving up" or hopelessness

Provider sense of failure when a child dies

Difficulty in determining prognosis

Lack of symptom assessment tools

Lack of knowledge regarding pediatric dosing of symptom-relief medications

Fragmentation of medical and psychosocial/spiritual services for children

Lack of adequately trained pediatric hospice professionals

Lack of comprehensive, coordinated pediatric palliative care programs

Inadequate education for providers and families about palliative care

Source: [173,343,346,348,394,398,401,402,404,405,406]

The potential death of a child goes against the natural order and is associated with feelings of distress and failure for parents as well as clinicians. Parents and family members continue to hope for a cure and often see the end of curative therapy as "giving up" [348,407]. In a survey of pediatric oncologists, the most frequently reported barrier to end-of-life care was unrealistic expectations of the family, noted by approximately 48% of respondents [408]. Family denial was another commonly reported barrier, noted by 36% of respondents [408]. Paradoxically, the high rates of cure and long-term survival associated with most pediatric leukemias and lymphomas foster parents' hope for cure [343,407]. Feelings of denial and hope are also factors in late hospice referrals. Most hospice referrals are made at the time of disease progression (44%), at the end of therapeutic options (26%), or at the time of imminent death (20%) [401]. Earlier hospice referral, such as at the time of disease relapse, would enhance the quality of care for children and their families, yet only 2.5% of referrals are made at that time [401]. A survey of pediatric oncologists found that they were less likely to refer patients after chemotherapy had been stopped and more likely to refer at the time of diagnosis of cancer/incurable cancer. They also preferred that "supportive care" be used in place of "palliative care," because the term was negatively perceived by their patients [398].

Clinicians usually recognize the lack of a realistic chance for cure before parents and should talk openly with parents about discontinuing aggressive treatment and directing attention to enhancing the quality of life that remains for the child [409]. At this point, it is helpful to emphasize the importance of alleviating pain and other symptoms and making the child comfortable [173]. In addition, the family should understand that the primary oncologist and/or primary care provider will remain involved in the child's care [173]. Members of the palliative care team should discuss goals of treatment with the family, outline choices for interventions as the end of life draws near, and establish limits of care as the health status changes [173,341].

The symptoms present at the end of life are similar to those that occur during treatment, although research has shown that some are more common or more intense in the end-of-life period [353]. Pain, nausea, drowsiness, and energy loss have been reported by more than half of children/adolescents (6 to 17 years old) with advanced cancer [353,410]. Other common symptoms include dyspnea, weight loss and anorexia, vomiting, and constipation [353]. Bone marrow failure may occur as a result of progressive disease, leading to infection, fatigue, and bleeding [353]. Transfusion of blood products can provide symptomatic relief, and their use should be considered on an individual basis.

In a study in which symptoms among various types of cancer were evaluated, the symptoms most commonly associated with pediatric leukemia and lymphoma during the end-of-life period were pain (95%), weakness (83%), anemia (76%), bleeding (66%), infection (59%), and weight loss and anorexia (56%) [353]. Overall, symptom management was more effective for children with leukemia or lymphoma than for children with solid tumors, but weakness and anorexia remained intractable among all patients [353]. How aggressively symptoms are treated will depend on many factors, including how close the child is to death and the defined limits of care. The underlying goal is to keep the child as comfortable as possible. In addition to the management of symptoms, "comfort interventions" should be integrated into care (Table 19) [411].

Table 19: COMFORT CARE INTERVENTIONS

Intervention

Description

Quiet presence

Sit quietly to provide calming influence and comfort that family is near

Massage

Ask the child what he or she would like massaged (e.g., feet, back); play quiet music to aid in relaxation

Touch

Hold hand or gently touch or stroke the child in familiar comforting manner

Music/television/DVD

Play child's favorite music, television show, cartoon, movies for familiar comfort and distraction

Toys/blanket

Provide the child with his or her favorite item for comfort

Picture board

Have family and friends gather pictures of fun past events shared with the child and place the pictures on a bulletin board or poster board near the bed

Books

Ask the child which book he or she would like to hear and read aloud

Family, friends, spiritual support person, pets

Honor the child's requests to see family members, pets, etc.

Source: [411]

Dyspnea is particularly present near the end of life, occurring in approximately 30% of children with leukemia and lymphoma [353,400]. Objective measures of dyspnea do not correlate well with subjective sensation. But because the symptom is extremely distressing and frightening to both the patient and the family, treatment should be directed at alleviating the patient's discomfort and distress promptly [348]. The use of oxygen, opiates, and/or benzodiazepines can provide symptomatic relief [173,348]. Nonpharmacologic interventions include relaxation techniques and the use of fans to blow air across the child's bed [173].

The need for spiritual support is heightened during the end of life as children and family prepare for dying [348]. Faith and the involvement of clergy play a critical role in decision making about end-of-life care [345]. A survey of pastoral care workers indicated that more than half of patients and 60% to 80% of parents had spiritual needs [412]. Because the illness experience, primary fears, and concept of death range according to the child's developmental age, appropriate spiritual interventions vary (Table 20) [173,341,348]. Patients grieve because of the isolation and loss associated with the disease, and the palliative care team should provide support for this process [413]. Many parents avoid talking with their ill child about death for many reasons, primarily because they do not wish to acknowledge the fact to themselves or the child. However, most dying children are aware that they are dying, and talking about it with family can help them to express important feelings and to say good-bye [173,343]. One retrospective study showed that parents who talked with their child about death did not regret it, whereas more than 25% of parents who did not talk to their child about death regretted that decision [413]. In addition, levels of anxiety were higher among parents who did not discuss death with their child. Another retrospective study investigated the rationale and consequences of a parent's decision to discuss death with their child [414]. The study involved bereaved parents of a child who died of cancer. Eighty-six parents of 56 children responded to questions about the topic. Of these, 55 parents of 35 children did not discuss the impending death. Their reasons for not discussing death were varied and included: parents' inability to discuss the impending death; their desire to protect their child; their general views about talking with children; their perceptions of their child's characteristics; the child's unwillingness to discuss death; a lack of opportunity to have the discussion; and the child's disability. The parents who did discuss death with their child generally used symbolic and/or religious narratives, or they discussed the subject directly and briefly. A majority of the parents interviewed felt positive about their ultimate decision [414]. Parents should be encouraged to talk to their spiritual or religious advisor for guidance in how to talk with their child [173]. Strict adherence to Western ethical norms may not always be the best choice for migrant or immigrant patients and their families. Instead, an approach that is based on cultural humility may allow for a greater understanding and improved communication between patient/family and caregivers [415].

Table 20: FEARS, CONCEPTS OF DEATH, AND SPIRITUAL INTERVENTIONS ACCORDING TO DEVELOPMENTAL AGE OF CHILDREN AND ADOLESCENTS

Age

Primary Fears

Concept of Death

Spiritual Interventions

Infant

Separation; strangers

Unable to differentiate death from temporary separation or abandonment

Provide consistent caretakers

Minimize separation from parents and significant others

Decrease parental anxiety

Maintain crib/nursery as "safe place" (no invasive procedures)

Encourage parental presence

Encourage/facilitate use of spiritual support system for the family

Toddler

Separation; loss of control

Recognizes death in terms of immobility

Often viewed as reversible, temporary, or foreign

Minimize separation from parents and significant others

Keep security objects at hand

Provide simple, brief explanations

Explain and maintain consistent limits

Encourage participation in daily care

Provide opportunities for play and play therapy

Reassure the child that disease is not punishment (by God, Higher Power, or other authority figure)

Early school-age child

Bodily injury and mutilation; loss of control; the unknown; the dark; being left alone

Recognizes death in terms of immobility

Often viewed as reversible, temporary, or foreign

Begins to question and develop a mature concept

Do not underestimate level of comprehension

Provide simple, concrete explanations

Provide advance preparation (days for major events, hours for minor events)

Use pictures, models, actual equipment, medical play when providing explanations

When appropriate, initiate discussion of love and caring from Higher Power to relieve anxiety and loneliness

Show behavioral qualities of love, trust, respect, caring, and setting of firm limits and disciplining without anger

School-age child

Loss of control; bodily injury and mutilation; failure to live up to expectations of important others; death

Recognizes all the components of irreversibility, universality, nonfunctionality, and causality

Provide choices whenever possible

Stress contact with school or organized religious peer group

Use diagrams, pictures, and models for explanations

Emphasize the "normal" things the child can do

Reassure child that he/she has done nothing wrong; hospitalization is not punishment

Be alert to anxiety about being punished by deity

Provide appropriate concrete explanations in response to questions regarding spiritual beliefs

Continue spiritual rituals; if appropriate, promote prayer and relationship with child's concept of God

Model behaviors that show forgiveness and acceptance

Adolescent

Loss of control; altered body image; separation from peer group

Speculates on the implications and ramifications of death

Understands effect of death on other people and society as a whole

Future-oriented, difficult to understand reality of death as a present possibility

Allow adolescent to be an integral part of decision making regarding care

Give information sensitively

Allow as many choices and as much control as possible

Be honest about treatment and consequences

Stress what the adolescent can do for himself or herself and the importance of cooperation and compliance

Assist in maintaining contact with peer group

Provide answers without bias and enable participation in discussions of illness in terms of philosophical or spiritual beliefs

Encourage contact with friends and use of spiritual rituals if appropriate

Observe and document verbalizations of adolescent's values and beliefs

Source: [173,341,348]

Bereavement and Grieving

Bereavement and grieving support are other essential components in end-of-life care [173,346,413]. Bereavement care may best address grief by providing family members with outlets to communicate feelings and memories about a dying or deceased child [416,417]. It is important to provide support for siblings, who report often feeling left out and abandoned [346,413]. Despite a growing body of literature substantiating the needs of siblings, they continue to be unmet [418,419,420,421]. Siblings also may experience post-traumatic stress symptoms, poor quality of life, and a sense of aloneness [422]. Healthcare providers can address the needs of siblings by [422,423,424,425]:

- Engaging them in discussions about care

- Providing them with specific caregiving tasks

- Ensuring that they have adequate support (e.g., child life specialist, social worker, support group) and education

- Encouraging them to remain active in activities important to them

- Identifying a "safe adult" in which the sibling can confide

- Making mental health referrals when appropriate

- Asking sibling directly about his or her experiences

Grief can be prolonged and exacerbated by several factors, including the loss of the child's quality of life, the family's dissatisfaction with the provider-family rapport and communication, cultural insensitivity, and lack of follow-up [173]. This finding underscores the need for effective end-of-life care and open, honest, empathic communication from the palliative care team. In addition, caregivers should respect the family's cultural context when designing and discussing treatment plans and goals. Also, it is imperative that family members be allowed to hold their child during and after death and to carry out family, religious, and cultural rituals.

In most cases, the grieving process is considered to be in its end stages when bereaved individuals are comfortable with a restructured lifestyle [426]. However, parental grief related to the loss of a child is generally experienced more intensely and differently than other forms of grief because a child's death is atypical in developed countries [427]. Parents can maintain healthy bonds with their deceased children by sharing memories about their children, writing biographies, performing annual religious rituals, and establishing monetary memorials [428,429]. The maintenance of the connection through conversation appears to aid in healing for grieving parents [429].

Grieving is relieved by the continued involvement and support of the palliative care team and the primary care provider after a child's death [430]. Attendance at a memorial service and handwritten notes of sympathy from the clinician and medical team are valued highly by grieving families [423,431]. The clinician should emphasize the personal strengths of the family that will help them cope with the loss and should offer help with specific issues. The note should also invite the patient to contact the physician or other members of the palliative care team with questions. Provision of bereavement services varies. Programs usually involve contacting the family at regular intervals to provide resources on grieving, coping strategies, professional services, and support groups. Frequent contact with family after death can ensure that families are adjusting to the loss [346]. Referrals for psychosocial and spiritual interventions should be made as early as possible to optimize their efficacy. Bereavement services should extend for at least one year after the patient's death, but a longer period may be necessary.

12. PSYCHOSOCIAL ISSUES FOR THE PATIENT AND FAMILY

Evidence Based Practice Recommendation

The Psychosocial Standards of Care Project for Childhood Cancer recommends that youth with cancer and their family members should routinely receive systematic assessments of their psychosocial health care needs.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6397048

Last Accessed: August 5, 2021

Strength of Recommendation/Level of Evidence: Strong/High

In the 1960s, psychosocial interventions focused on bereavement during palliative care because of the low survival rates for common childhood cancers. Today, the excellent survival rates produced by advances in treatment challenge clinicians with more complicated familial psychosocial issues and increase the need for a variety of intervention strategies.

Addressing psychosocial issues is an integral component of comprehensive cancer care not only to help patients and their families cope with a cancer diagnosis and the stress related to treatment, but also to help alleviate latent psychosocial distress. The diagnosis and course of a child's cancer can detrimentally affect family members' interactions with one another and their social environment. Yet, responding to childhood cancer can prompt positive growth if psychosocial issues are managed effectively. Although many families are resilient, the negative psychosocial consequences for one or more family members touched by a child's cancer can be lasting and severe. Studies have found that the psychologic distress experienced by family members is often greater than that experienced by the patient [432]. For example, parents, who are already distressed by their child's illness also often struggle with conflicted feelings when their role as parent means they must manage the competing needs of various family members. The authors of one qualitative analysis sought to identify parental expectations of support from healthcare providers during a child's life-threatening illness [433]. Based on thematic analyses conducted with data from 31 semi-structured interviews of parents, the authors identified three themes and one overall expectation [433]:

- "Help us survive this."

- "Let's fight together. Please fight with me, not against me, to care for my family."

- "Guide me through the darkness. I am suffering."

The overall expectation was for mutuality with the healthcare providers and healthcare system in order to keep fighting together for the family's survival [433].

Clinicians in the pediatric and family medicine setting are well-positioned to monitor family members' coping abilities and psychosocial states during the trajectory of the illness. Most parents believe that psychosocial issues should be discussed with the child's physician and would find that discussion to be valuable [172]. However, less than 50% of parents raise such topics, and parents report that only 15% to 20% of physicians assess the family's psychosocial issues [172]. Clinicians may be able to provide the auxiliary emotional support and guidance the child and his or her family needs [433,434]. If necessary, they can refer at-risk family members to intervention programs/specialists to improve coping strategies and promote healthy psychologic adjustment.

PSYCHOSOCIAL ISSUES FOR THE PATIENT

The anxiety and stress associated with cancer and its treatment require that patients use effective coping mechanisms. Due to the wide range in age of patients with childhood leukemia and lymphoma, coping mechanisms vary according to a child's level of understanding and stressors. Similarly, the potential late effects and the actions to promote well-being also differ. In addition to disrupting a child's psychologic well-being, the period of cancer treatment affects a child's relationships with peers and school performance. The psychosocial issues discussed in this section focus primarily on issues arising during treatment.

Coping Mechanisms

Coping has been defined as the "constantly changing cognitive and behavioral efforts to manage the specific external and/or internal demands that are appraised as taxing or exceeding the resources of the person" [435]. The two main types of coping are problem-focused and emotion-focused [435]. The goal of problem-focused coping is to change aspects of an event to relieve distress. If the individual cannot manage a stressful event, emotion-focused coping is used to regulate feelings or alter his or her interpretation of the situation. Emotion-focused coping mechanisms intended to alter interpretations are categorized into four control strategies: predictive control, vicarious control, illusory control, and interpretative control [354]. These control strategies are used commonly by children and their parents when coping with cancer [355,356]. Using combinations of problem-solving and emotion-regulating mechanisms to meet each cancer-related challenge decreases short-term distress and promotes healthy social and cognitive development and adaptation [436].

The majority of studies have shown that the psychologic profile of childhood leukemia or lymphoma survivors is similar to population norms, suggesting that most children with leukemia or lymphoma will cope effectively with their cancer experience [437,438]. However, subgroups of these patients are at special risk for poor psychologic outcomes [439,440,441].

As children learn and grow, they construct the world around them differently. Thus, the developmental age at the time of a cancer diagnosis defines the type and complexity of coping mechanisms available to the patient throughout the course of the disease [442,443]. The level of understanding and stressors, coping mechanisms, potential long-term effects, and actions a medical team can take to promote well-being vary according to the developmental age [444,445].

Infants (Birth to 12 Months of Age)

Level of understanding and stressors: The infant's understanding of treatment is limited to pain and comfort. Infants undergoing cancer treatment can have a difficult time developing trust and bonding with parents because medical procedures often separate infants from their parents, disrupt household routines, and cause pain. An infant frequently separated from parents may experience feelings of abandonment [446].

Coping mechanisms: Infants are limited to certain aspects of emotion-focused coping because crying is an emotional release. With few available coping mechanisms, the infant's emotional development and future coping abilities can be affected adversely by cancer.

Potential long-term effects: A child diagnosed with cancer during infancy may experience cognitive delay. Difficulty bonding with parents may affect subsequent developmental stages.

Actions to promote well-being: To offset cancer-related developmental disruptions, the medical team should allow parents to stay in the infant's room and attend to his or her needs, such as feeding, diaper changing, comforting, and bathing. In addition, minimizing the number of staff caring for the child may promote trust and a sense of routine.

Toddler (18 Months to 3 Years of Age)

Level of understanding and stressors: A toddler diagnosed with cancer has different developmental challenges than an infant. However, a toddler still has limited understanding of cancer-related cause and effect and has limited access to coping mechanisms. Because a toddler's sense of time is restricted to the present, the child will likely not grasp that staying still reduces the time and pain associated with treatment. The toddler's level of understanding may exceed his or her ability to communicate, which is another barrier to coping. During this stage of development, a toddler explores his or her sense of self, property, and security. Cancer therapy, however, challenges a toddler's autonomy and feeling of safety. For instance, a toddler will likely say "no" to treatment, only to be vetoed. In addition, the toddler may perceive that his or her parents cannot protect him or her from pain associated with treatment. Although a toddler's understanding of death is minimal, he or she likely has some concept of loss and separation and may fear abandonment when parents are out of sight. The health-related quality of life for toddlers with cancer is significantly worse than that of healthy age-matched controls. Cancer most strongly affects a toddler's sleep, appetite, behavior, and liveliness [447].

Coping mechanisms: A toddler has access to more emotion-focused coping strategies to regulate stress than an infant and has developed some problem-focused strategies. Communication skills, although limited, can be used to express emotions and seek parental support and solace. To gain more control over his or her environment, a child may hold a parent's hand during a painful procedure to know that the parent is near. Pain endured during a procedure may be associated with the staff member providing the respective treatment.

Potential long-term effects: During this stage, a cancer diagnosis may postpone language and motor development as well as bladder and bowel control. Toddlers' development in these areas may regress.

Actions to promote well-being: Parental handling of a toddler's cancer-independent needs should be made routine to minimize the child's feelings of abandonment or insecurity. Motor skill development accelerates at this age; therefore, safe levels of physical activity should be promoted. Also, giving a toddler limited choices, even in the smallest matters, supports their sense of autonomy. For instance, a provider could ask a toddler, "Would you like a bandage with cartoon characters or a regular one?"

Early School-Age (4 to 7 Years of Age)

Level of understanding and stressors: Although the degree of development of a child at 4 years of age may be much different from that of a child at 7 years of age, children of these ages have surpassed the cognitive and emotional development of toddlers. Concepts of empathy and guilt are developing. Injury and death may be believed to be magically reversible, as in many children's cartoons. Patients who are 6 to 7 years of age at the time of a cancer diagnosis have been shown to have poor health-related quality of life with respect to autonomy, motor skills, and cognitive functioning two months after treatment [447].

Coping mechanisms: Early school-age children can cope using emotion-focused methods and some problem-focused strategies. A child in this age category can communicate feelings and needs more clearly than a toddler and has a better understanding of cause and effect. Both of these factors elevate the child's ability to cope actively with stressors and express negative emotions. Children understand the concept of hopefulness during this stage, which can promote a positive outlook and adaptive coping [448]. Regardless of the cancer stressors experienced, patients with a high sense of humor have better psychosocial adjustment and fewer infections [449].

Potential long-term effects: Experiencing leukemia can interfere with the proper development of an early school-age child's social and academic skills [450,451,452,453]. Without honest, age-appropriate discussions about the child's prognostic information and death, the development of thinking based on logic rather than fantasy may be delayed [454]. Children in whom cancer is diagnosed after 5 years of age are more likely to experience post-traumatic stress symptoms because they are able to understand the seriousness of their illness. However, they are also more likely to experience post-traumatic growth, characterized by a positive shift in perspective and priorities, because they can appreciate their inner strength and others' support [455].

Actions to promote well-being: A child may believe that his or her cancer diagnosis and treatments are punishments for bad behavior. Parents should be advised that rewarding good behavior during and after procedures with praise and small rewards (e.g., stickers) can promote a child's healthy development and ability to cope with cancer. Negative behaviors should not receive extra attention. To avoid developmental delay of reality-based thinking, parents should also be advised to answer a child's questions about the cancer honestly and in an age-appropriate manner [454]. Role-play discussions should be performed to assist in understanding how to best tell an individual child distressing news [180]. Discussions should be tempered by the expression of hope, which is a very important coping strategy in any pediatric cancer situation. School attendance should be encouraged because social and academic skills can be developed and peers can serve as an important support system for children with cancer [451]. Animal therapy programs may reduce a young child's emotional distress and promote socialization [456].

School-Age (8 to 12 Years of Age)

Level of understanding and stressors: Compared with self-reports in other developmental age groups, self-reports of children with cancer who are 8 to 12 years of age and secondary assessments were more likely to emphasize emotional distress over physical distress. Emotional stressors include confinement, feelings of alienation, and worries before medical procedures. The pain associated with diagnostic procedures and treatments is the most frequently mentioned physical aspect of cancer-related distress [457]. By 9 years of age, children understand that death is irreversible; however, their concept of the future is still very limited [458]. Some children may try to "protect" their parents from fearing death by avoiding conversations about the subject. However, avoidance of these discussions causes a child to suffer in isolation [185,454].

Coping mechanisms: Communication and logical reasoning skills available to children in this age range promote the development of problem-focused coping. Children may be more interested in learning about their cancer and its treatment because they want to master social and cognitive skills; intellectualizing the problem is one coping strategy children of this age may use. Emotion-focused coping skills are also more advanced because a school-age child is more likely to communicate emotions to seek others' support [457].

Potential long-term effects: Intensive treatments may interrupt the development of social and academic skills. Although the child's communication skills are more sophisticated, sharing concepts that are "too adult" for the child can affect socialization with peers and personality development.

Actions to promote well-being: A cancer diagnosis poses a challenge to a child's desire for equality and fairness. Its effects on schoolwork and physical activity may leave the child feeling inferior to peers, angry, and frustrated [451]. Such emotions may manifest as withdrawal or depression; the child may hide these feelings from parents. Thus, listening carefully and discussing feelings is imperative to understanding the child's problems. Art, writing, music, and dance/movement therapy can provide the child with expressive outlets [459,460,461]. Although children may desire to know all about their illness, parents and the treatment team must provide age-appropriate education. Too much exposure to decision making and adult responsibilities may disrupt a child's socialization with peers. As for any school-age child, school attendance is beneficial for social and academic development, and children should therefore be given the tools necessary to transition back into a school routine [451].

Adolescent (13 to 18 Years of Age)

Level of understanding and stressors: During this stage, adolescents are attempting to individualize themselves. However, identity formation in adolescents with cancer may revolve around their illness. Although adolescents understand death, they may feel it only happens to others. The most frequently reported emotional stressors are worries before medical procedures and feelings of alienation [357,457,462]. Compared with age-matched controls, children 12 to 15 years of age with cancer have a significantly lower health-related quality of life with respect to motor functioning [447].

Coping mechanisms: Coping strategies commonly used by adolescents during treatment include positive thinking, avoiding thoughts of treatment, keeping busy, focusing on positive outcomes, and staying relaxed [462,463,464]. One study found that better problem-solving skills were associated with lower adolescent distress [465]. A systematic review analyzed how childhood cancer patients and survivors communicate about their cancer with family and peers [466]. Participants were adolescents and young adults 16 to 34 years of age. Communication occurred on a spectrum with variations in who the youth shared information with, how often they shared information, and the amount and type of information they shared. The reviewers found that communicating about cancer was a beneficial coping strategy and that it prompted social support and appeared central to significant relationships. Barriers to communication (e.g., fear of stigma, poor peer reactions) hindered the participants' willingness to disclose [466]. Post-treatment coping strategies include negotiating to regain/gain autonomy, cognitive reliving of the cancer experience with peers or the medical team, and forgetting the negative aspects of treatment [463]. Potential long-term effects: One large, retrospective study has suggested that adolescents with cancer achieve autonomy, psychosexual development, and social development at an older age than peers [467]. Diagnosis at adolescence has been linked to an increased risk for the development of post-traumatic stress disorder [440]. However, one study found that personality factors, such as adaptive style, were a stronger determinant of post-traumatic stress than health history [468]. Another study of 435 youth (253 with cancer, 182 healthy controls) found that the relationship between post-traumatic stress symptoms and post-traumatic growth depended on contextual factors and that the majority of the youth (83%) were resilient and able to find benefit from stressful life events [469].

Actions to promote well-being: The physical and emotional changes of this final stage of childhood are conjoined with a desire for private space. However, honoring an adolescent's desire for privacy can be difficult during hospitalizations. A sense of privacy and respect, as well as cooperation, can be maintained by knocking before entering an adolescent's room, asking permission when introducing new people, and being mindful of the adolescent's physical modesty during examinations. To promote treatment compliance in older adolescents, equal medical information should be provided to patients and their parents. Adolescents should have the option to lead treatment discussions in order to enhance feelings of respect, control, and independence. Getting to know others with the same disease, treatment, or situation—especially those who are cured—may help adolescents cope, and emerging technology, cancer-related video games, and social networking are helping adolescents with cancer to better understand their disease, comply with treatment, and connect with one another [9,462,470]. Parents should be dissuaded from controlling treatment discussions and decision making without the adolescent's approval, which can lead to acting-out (externalizing) or internalizing behaviors in the patient.

Gender Differences in Coping Mechanisms

Some studies have shown differences in the coping styles of male and female children/adolescents with cancer. One study found that older female children (12 to 18 years of age) use a wider repertoire of emotion-focused and problem-focused coping strategies than their male counterparts [471]. Among male participants in the study, use of emotion-focused coping was linked to a disposition to experience anger and anxiety but not depression. Emotion-focused coping in the female participants was not associated with these variables. Depressive symptoms were less likely to develop in female participants who used problem-focused strategies.

In another study, male children 11 to 18 years of age were found to use disengagement coping strategies, such as problem avoidance, wishful thinking, social withdrawal, and self-criticism, more often than female children did [472,473]. Engagement coping strategies include problem-solving, cognitive-restructuring, social support, and expression of emotions. Male children were also found to use humor coping significantly more often than girls in a study of children 7 to 14 years of age who had ALL [449,474]. Healthy psychosocial adjustment was strongly correlated to humor coping [449].

Relationships with Peers

Mothers are the most commonly reported source of social support by children/adolescents with cancer. As a child with cancer develops into an adult, however, his or her social support needs extend beyond the family. Socialization with peers contributes to coping abilities and psychologic adjustment of children/adolescents with cancer [475,476,477]. For adolescents 12 to 14 years of age, family-independent social networks are significantly smaller than those of adolescents 15 to 18 years of age, which may contribute to less effective coping. The emotional support of peers is particularly important for continued participation in school and social activities [477]. Hospitalizations, poor physical health/appearance, academic difficulties, and poor parental coping skills can also limit the patient's development of relationships with peers [451,478].

School-Related Issues

Regular attendance at school is difficult during cancer treatment, but clinicians should emphasize to patients and their parents that going to school is an important part of normal life. School can help to reduce the social isolation associated with cancer and enhance the child's self-esteem [314]. School reintegration programs have been found to improve children's psychosocial well-being (anxiety and depression), social well-being (social competence and social support), behavioral problems, and physical competence, but more research is needed to investigate the effects of these and other related interventions [187,479].

In preparing for the child/adolescent to re-enter school, the primary care provider should guide parents in developing questions and issues to discuss with teachers and other personnel at the school. Topics that should be addressed with school personnel include [480]:

- Child's diagnosis and treatment plan

- Information on low blood counts and the risk of infection

- Central venous line issues

- Importance of contacting the parents when the child has a fever

- Immunization restrictions

- Attendance issues

- Administration of medicine

- Activities that the child cannot participate in

- Whether special permission is required to wear a hat or scarf in school

- Whether the child may take extra time to move between classrooms

- Possibility of tutors in specific subjects

Cancer and its treatment are often associated with learning problems, and parents should be aware for the potential for difficulties with handwriting or spelling, reading comprehension, remembering math facts, copying information after seeing it, and completing tasks on time [480].

Psychosocial Interventions

A meta-analysis of the effects of psychosocial interventions on psychologic outcomes in children with cancer showed that patient-oriented therapies do not effectively reduce child distress or improve child adjustment [481]. The authors of the study suggested several reasons for this finding: children with cancer have psychologic outcomes similar to those of healthy children; the average length of follow-up of the studies analyzed was only four months; and most studies used a waitlist/standard care control group instead of a control group with a generic psychosocial intervention providing nonspecific support or attention. Waitlist control groups do not control for nonspecific treatment variables such as social support from other group members or facilitators. One systematic review identified a broad range of psychosocial interventions that could benefit cancer survivors and their families, but concluded that more high-quality studies are needed to optimize the healthcare services that can best support children and their families [482].

PSYCHOSOCIAL ISSUES FOR THE FAMILY AND FAMILY DYNAMICS

Childhood cancer can place every family member at risk for the development of psychosocial problems. Several studies have been conducted to explore the psychosocial dynamics within family units.

Patient and Parents

Parental factors linked to the psychologic outcomes and quality of life for a child with cancer include education, communication styles, and coping strategies [451,472,479,483,484,485,486,487].

- Parental education: Children with cancer are more likely to experience poor psychologic adjustment if their parents' education level does not exceed high school.

- Parental communication styles: Most healthcare professionals agree that parents should talk openly, honestly, and age-appropriately to a child about his or her illness. Open lines of communication protect children with cancer from suffering emotional distress in isolation and promote high-quality care. In addition, poor cancer-related communication is linked to children's and adolescents' noncompliance with cancer treatments.

- Parental coping strategies: Coping mechanisms of parents can be reflected by children with cancer. A correlation study demonstrated similarities in the use of disengagement coping—in particular, problem avoidance—by parents and their adolescent child. Three months after diagnosis, parental differences in information-seeking were correlated with lower quality of life for children with cancer. However, other dissimilarities in maternal and paternal coping mechanisms, such as religious or support-seeking coping styles, do not appear to affect patients' quality of life.

Patient and Siblings

From the diagnosis through the course of a child's cancer, cancer-free siblings of all ages are affected emotionally and often physically. Siblings may suffer from unattended emotional responses, including anger, anxiety, jealously, resentment, depression, and loneliness; difficulties related to the absence of their parents; and reduced school achievement [488]. Immature thinking in young children can lead to thoughts that they caused their sibling's illness. Adverse physical problems experienced by cancer-free siblings are headaches, sleep disruption, and poor eating habits [489]. Most siblings who experience these emotional and physical responses do not suffer long-term problematic outcomes; however, a subset of siblings does experience difficulties [490].

Risk Factors for Poor Psychologic Outcomes for Cancer-Free Siblings

A meta-analysis of 50 studies involving siblings of children with chronic illness showed that internalizing behaviors, especially anxiety and depression, placed healthy siblings at a higher risk of poor psychologic adjustment [491]. The risk of unhealthy psychologic adjustment is also amplified if the ill sibling's cancer alters day-to-day family function. Warmth or closeness between cancer-free siblings (8 to 15 years of age) and their siblings with cancer increases the risk of poor psychologic adjustment; these intimate relationships are associated with decreases in social competence [492]. In addition, the incidence of poor psychologic outcomes in response to guilt and heightened fear of death increases if the sibling with cancer dies [493]. The psychologic adjustment of cancer-free siblings, however, improves with age as a result of the development of protective factors such as increased maturity and capacity to empathize [492,494].

A post-traumatic stress model may best fit the potential psychologic outcomes of cancer-free siblings up to five years after treatment. As a component of the Surviving Cancer Competently Intervention Program randomized trial, 78 sibling participants completed a Post-traumatic Stress Disorder Reaction Index [495,496]. Post-traumatic stress symptoms were experienced by almost half of cancer-free siblings. Moderate-to-severe post-traumatic stress disorder was reported by one-third of cancer-free siblings. Cancer-free siblings who were 7 years of age or older at the time of their sibling's cancer diagnosis reported more severe post-traumatic stress symptoms than those who were 6 years of age or younger at the time of diagnosis. In the same study, cancer-free female siblings indicated more post-traumatic stress symptoms than cancer-free male siblings.

One study explored bereaved siblings' advice to healthcare professionals working with children with cancer and their families [497]. Of the 174 siblings that participated, 108 answered an open-ended question about what advice they would give. The most common advice (given by 56% of siblings) related to their own support. Another one-third wanted professionals to provide them with better medical information. Some siblings wanted to be more involved in their brother's/sister's care and asked that healthcare professionals provide their parents with guidance on how to achieve this. Other common threads were related to psychosocial aspects, for example, siblings' wish for professionals to mediate hope without sacrificing realism and understanding the importance of asking the ill child about the kind of care they wanted [497].

Factors that promote healthy psychologic outcomes in cancer-free siblings are related to support and functioning of the entire family. Specifically, these factors include [498,499,500]:

- More family cohesion and adaptability with less family disruption

- Increased family support resources

- Enhanced communication within the family

Cancer-Free Siblings' Feelings During Treatment

Cancer-free siblings tend to identify themselves through the experiences of other family members during the course of their ill siblings' cancer [501]. When encouraged to discuss their personal experiences and feelings, cancer-free siblings focused primarily on their ill siblings' or parents' experiences, diminishing their sense of self. These patterns were more evident during the ill siblings' hospitalizations and as the physical appearance of their ill siblings worsened. Although cancer-free siblings experience stress similar to their brothers or sisters with cancer, most participants reinforced that their suffering was not justified because they were not experiencing the illness. Healthy siblings worried about the physical and emotional needs and abilities of their ill brothers or sisters following a cancer diagnosis. They said that they often "felt good" during the times they helped the ill sibling feel more comfortable. Yet, most of the cancer-free siblings also indicated that they experienced guilt because they had minimal involvement in taking care of their ill sibling. Although feelings of guilt in cancer-free siblings have not been correlated to negative psychologic outcomes, these feelings should be addressed by parents and clinicians [501].

Parents and Siblings

Numerous studies have shown that cancer-free siblings of children with cancer have the most unmet emotional needs relative to all other members of the family [502]. For children, the family is the primary social support system, and cancer-free siblings receive the least attention when childhood cancer disrupts everyday household life. Cancer-free siblings' emotional responses (e.g., fear, anger, guilt, jealousy, sadness) and health-related responses (e.g., sleeping difficulties, eating problems) are often overlooked or underestimated by parents [489]. These responses are compounded by cancer-free siblings' sensitivities to the parents' cancer-related emotional and practical burdens.

Parental and Self-Reports of Cancer-Free Siblings' Health

Parental and self-reports regarding cancer-free siblings' emotional and physical states also differ. Parents generally report better statuses for their cancer-free children than the children report themselves [503]. However, parents of children with cancer also report that their cancer-free children are "less healthy" than age-matched and sex-matched controls. Despite these reports, parents utilized health care for their cancer-free children less than the parents of matched controls [489]. The relative health of a cancer-free sibling to that of a child with cancer may cause parents to minimize the significance of the cancer-free sibling's health issues. Lack of time, energy, and financial resources may also reduce the parent's efforts to seek health care for a cancer-free child. Furthermore, most cancer-free children attempt to protect their parents' emotions by hiding their own negative emotions and health issues. The findings of a qualitative study suggested that cancer-free siblings valued keeping the family together and the survival of the sibling with cancer similarly [501].

Compared with matched controls, cancer-free siblings of children with cancer report significantly more trouble sleeping (72% compared with 53%) and problems eating (42% compared with 26%) [489]. These complaints are reported more frequently by cancer-free siblings who also report internalizing behaviors than those who engaged in externalizing coping strategies. Cancer-free siblings who present emotional or behavioral problems before the cancer diagnosis are more prone to somatic symptoms and poor psychologic adjustment. Therefore, healthcare practitioners should ask parents if their cancer-free children acted-out or had emotional problems prior to the development of cancer in the ill sibling to help assess the cancer-free child's level of risk for psychosocial issues. Also, clinicians should ask if the cancer-free sibling has any physical complaints in order to evaluate whether he or she needs additional interventions to avoid long-term psychologic repercussions. Parents who understand that their cancer-free child is at risk for psychosocial problems due to a sibling's cancer are more likely to have the child participate in a therapeutic program [503].

Parents

Although parental emotional distress and psychosomatic complaints are high shortly following a child's cancer diagnosis, prospective studies have shown that most survivors' parents adjust within 1 to 10 years [504,505,506]. Still, approximately 25% to 33% of parents face long-term psychologic issues [359,504,506,507]. Healthcare professionals' attention to the specific needs of the family can enhance the family's resilience [508,509,510,511]. Post-traumatic stress disorder is the most common psychologic disturbance for parents of childhood cancer survivors [507,512].

In a prospective and longitudinal study to assess psychologic functioning, parents' somatic symptoms and feelings of anxiety gradually decreased to control group levels by five years after diagnosis [513]. However, 27% of parents still had clinically elevated scores for psychologic distress at that time. When the data were analyzed according to the treatment outcome for the child, psychologic distress was manifested in 23% and 29% of parents of survivors and deceased children, respectively. Fifty percent of parents of children with relapsed disease continued to experience psychologic distress after five years. Higher levels of psychosomatic complaints at the time of the cancer diagnosis and the child's relapse were indicators of higher long-term psychologic risk. The same study found that mothers had higher levels of anxious feelings than fathers; however, all other measures were similar between mothers and fathers. Support-seeking coping strategies have been found to significantly reduce anxiety levels in mothers [514].

Psychosocial Interventions for Families

Therapies that holistically address the family's or the parents' emotional distress and coping skills are most effective for curtailing the intensity of unhealthy psychologic outcomes caused by childhood cancer [481,515,516]. Of interventions that have been studied in randomized trials, two have been shown to offer significant benefit [481]. Mothers of children recently diagnosed with cancer were better able to cope with their cancer-related stressors after receiving problem-solving skills training in conjunction with standard psychosocial care, compared with mothers who received standard psychosocial care alone [515]. The effectiveness of the training was better for Spanish-speaking mothers than English-speaking mothers, and single mothers derived the greatest benefit from the training.

The second intervention with proven efficacy is the Surviving Cancer Competently Intervention Program, a one-day, four-session, family-centered treatment intervention designed to teach coping skills to mothers, fathers, and adolescent survivors [516]. Compared with the control group, fathers derived the most benefit from the program, followed by the adolescent survivors. The coping strategies taught to fathers and survivors allowed them to reframe their reactions to the cancer and to speak more openly with their families about the cancer experience. Mothers did not show improvements with the intervention.

Interventions for siblings have also been effective. A therapeutic peer support camp was shown to improve mental health outcomes for siblings (8 to 13 years of age) of children with cancer [517]. The camp program was designed to decrease stress levels, improve social competence, and enhance knowledge of cancer and its treatment. According to standardized self-report measures, participants in the program demonstrated significantly decreased anxiety, improved social competence, greater social acceptance, and significantly reduced fear of disease [517]. Another study found that structured teaching and psychosocial sessions at a five-day residential summer camp led to significant improvements in knowledge about the sibling's cancer, behavior, social support, self-esteem, attitude, and mood [518]. The improvements represented increases of 5% to 25% over the baseline values and were sustained over a period of one year. One study surveyed children's pain and distress levels immediately before and after a one-hour Kids Kicking Cancer in-person class [519]. Eligible participants were enrolled in standard classes, diagnosed with a chronic health condition (e.g., cancer), or the sibling of a child diagnosed with a chronic health condition, and between 5 to 17 years of age. Pain and distress were reported using Likert-style scales. Friedman test was used to test for overall changes in pain and distress, and within subgroups. A total of 59 youth (19 cancer patients, 17 non-cancer patients, 23 siblings) completed the study. Overall, pain and emotional distress were significantly reduced following a one-hour class, with 50% and 89% of youth reporting a reduction in pain and distress, respectively. The reduction in pain was most pronounced with cancer and non-cancer patients, whereas, the reduction in distress was most pronounced among healthy siblings. Reductions in pain and distress did not significantly differ among subgroups [519].

Resources for Patients and Their Families

Several resources are available to help patients and their families become more knowledgeable about cancer and treatment options, gain support from other families, and obtain help with practical concerns. Educational materials developed by several advocacy organizations are available online, and a list of potentially useful resources is available at the end of this course.

13. LONG-TERM HEALTH CARE FOR CHILDHOOD CANCER SURVIVORS

Approximately 1 in 640 adults 20 to 39 years of age is a survivor of pediatric cancer [520]. Among adolescents 15 to 19 years of age who were diagnosed with cancer from 2008 to 2014 and followed through 2017, 73% had a five-year relative survival rate if diagnosed with leukemia, 89% if diagnosed with non-Hodgkin lymphoma, and 97% if diagnosed with Hodgkin lymphoma [521]. The high (and increasing) number of survivors, as well as the emerging results of myriad late effects of treatment, led to the IOM report Childhood Cancer Survivorship: Improving Care and Quality of Life, published in 2003 [522]. Among the recommendations in that report were:

- Develop evidence-based clinical practice guidelines for the care of survivors of childhood cancer.

- Define a minimum set of standards for systems of comprehensive, multidisciplinary follow-up care that link specialty and primary care practitioners and ensure the presence of such a system within institutions treating children with cancer.

- Evaluate alternate models of delivery of survivorship care.

- Improve awareness of late effects and their implications to long-term health among childhood cancer survivors and their families.

- Improve professional education and training regarding late effects of childhood cancer and their management for both specialty and primary care practitioners.

The long-term follow-up care of childhood cancer survivors is important both to maintain routine care and to monitor for the occurrence of late effects of cancer treatment. Children and adolescents need continuity of routine pediatric care throughout and following their cancer treatment. This need has been emphasized by the AAP, which stated that each child must have a "medical home" for maintenance of health care [523]. Pediatricians, family practitioners, and nurses have an important role in the follow-up care for children with cancer [313,314,520,524]. Children with cancer should have regularly scheduled visits for routine preventive care, such as immunizations and the monitoring of growth and development [314]. In addition, routine pediatric care provides the opportunity to assess the effectiveness of symptom management, monitor treatment-related toxicity, confirm cancer remission, evaluate the psychosocial needs of the patient as well as the family, and promote healthy lifestyle behaviors [313]. Lastly, primary care providers are valuable resources for education and support for the patient and family.

Long-term follow-up healthcare is also crucial for ensuring appropriate surveillance, screening, and preventive care for childhood cancer survivors. The advances in survival for pediatric cancer have allowed investigators to evaluate survivors' health over time. Since the 1980s, long-term studies have identified several, widely varying late adverse effects of treatment. These long-term studies have served two valuable purposes: by identifying the most common treatment-related effects, clinicians can provide better follow-up care and investigators can modify treatment protocols to minimize toxicity for future patients. Many of the studies have involved the Childhood Cancer Survivor Study (CCSS) group, a cohort of more than 20,000 survivors who have survived for more than 5 years after treatment at various institutions and have been followed for 16 to 32 years. The group also includes sibling controls for comparison studies.

Research with the CCSS group has led to the development of evidence-based clinical practice guidelines for childhood cancer survivors [525,526]. The guidelines were developed by an expert panel within COG and are available online [526]. The guidelines facilitate creating a surveillance and follow-up care plan that is individualized according to treatment exposure and risk. The COG Late Effects Committee, in conjunction with Baylor School of Medicine, has developed a web-based interface, Passport for Care, that generates personalized recommendations based on an individual's specific risks [527]. Updates on this interface will be posted on the guidelines website.

LATE EFFECTS AMONG CHILDHOOD CANCER SURVIVORS

Late effects are usually defined as those occurring at least two years after completion of treatment and are chronic and sometimes progressive [52]. These late effects are primary contributors to mortality and morbidity for survivors. Among 20,483 five-year survivors in the CCSS group, mortality was 8.4 times higher for survivors than for the age-, sex-, and year-matched U.S. population [5]. The overall absolute excess risk of mortality was 7.36, which represents an additional seven deaths per 1,000 individuals who were followed up for one year [5]. The leading cause of mortality was recurrent and/or progressive disease (approximately 58%), followed by subsequent neoplasms (19%), circulatory system diseases (7%), and respiratory system diseases (3%) [5]. The cause of mortality varied by sex, with a higher proportion of deaths related to a subsequent neoplasm among female survivors and a higher proportion of cardiac deaths among male survivors [5]. The morbidity related to pediatric cancer treatment has a substantial impact on the health status and quality of life for survivors. Studies have shown that 63% to 75% of childhood cancer survivors have at least one physical or psychosocial late effect and that 28% to 40% have a severe or life-threatening condition [3,4]. However, one study found the incidence of severe or life-threatening conditions to be much higher. Researchers evaluated 14,359 five-year survivors in the CCSS cohort for risk of severe, disabling, life-threatening, and fatal events, and 4,301 siblings were included for comparison [528]. The cumulative incidence of a severe, disabling, life-threatening, or fatal health condition was greater among survivors than siblings (53.6% and 19.8%, respectively) by 50 years of age [528]. Correlation of late effects with primary diagnosis has indicated that leukemia and non-Hodgkin lymphoma are associated with lower burdens of adverse events, whereas the burden associated with Hodgkin lymphoma is often higher than the average burden (Table 21) [3,4,529].

Table 21: COMPARISON OF LATE EFFECTS ACCORDING TO PRIMARY DIAGNOSIS

Measure of Late Effect

Overalla

Leukemia

HL/NHL

Moderate or extreme adverse effect in at least 1 of 6 health status domains

44%

40%

44% / 37%

Burden of Adverse Events

None

20%

26%

19%

High or severe

23%

12%

16%

Chronic Health Condition (Relative Risk)

Any

3.3%

2.2%

4.6% / 3.2%

Severe or life-threatening

8.2%

4.1%

10.2% / 6.8%

Two or more

4.9%

2.8%

8.7% / 4.3%

aIncludes all childhood cancer diagnoses.

HL = Hodgkin lymphoma; NHL = non-Hodgkin lymphoma.

Source: [3,4,529]

Among the most common late effects are [3,4,209,266,313,520,526,529]:

- Subsequent neoplasm

- Cardiac abnormalities

- Abnormal growth and development

- Gonadal dysfunction

- Neurocognitive impairment

- Dental problems

- Psychosocial disorders

Many other less common late effects are also associated with cancer treatment, and survivors at risk should be evaluated accordingly (Table 22 and Table 23). The morbidity rates related to these late effects vary substantially according to many factors, primarily the type of treatment and the primary cancer diagnosis. Knowledge of the specific diagnosis and details of treatment can help clinicians provide preventive care, establish early diagnosis, and implement appropriate interventions.

Table 22: NONMALIGNANT ADVERSE EFFECTS ASSOCIATED WITH CHILDHOOD LEUKEMIA OR LYMPHOMA AND ITS TREATMENT

Organ/System Affected

Late Effect

Causative Agent or Therapy

Blood

Hepatitis B or C, human immunodeficiency virus (HIV)

Transfusion of contaminated blood producta

Bone marrow

Myelodysplasia

Alkylating agents

Acute myelogenous leukemia

Epipodophyllotoxins

Endocrine glands

Pituitary and/or thyroid dysfunction

Radiation

Bones and joints

Abnormal skeletal growth, chronic pain

Radiation

Osteopenia, osteoporosis, avascular necrosis

Radiation, corticosteroids, methotrexate, cyclophosphamide, ifosfamide

Reproductive system

Testes/ovaries dysfunction

Alkylating agents, radiation

Lungs

Fibrosis

Bleomycin, BCNU, radiation

Diffusion abnormalities

Radiation

Cardiovascular System

Heart

Cardiomyopathy, left ventricular dysfunction (subclinical), congestive heart failure

Anthracyclines

Cardiac failure, cardiac arrhythmias

Cyclophosphamide (high dose)

Myocardial infarction, valve disorders, cardiac arrhythmias, constrictive pericarditis

Radiation

Blood vessels

Coronary artery disease

Radiation

Central Nervous System

Brain

Neurocognitive impairment, motor problems, seizures, behavior changes

Methotrexate, cytarabine, radiation

Ears

Scarring of eardrum, build-up of ear wax, damage to middle ear (sense of balance)

Radiation

Hearing loss

Cisplatin

Eyes

Dry eyes, light sensitivity, keratoconjunctivitis, retinopathy

Radiation

Cataracts

Radiation, corticosteroids, busulphan

Nerves

Neuropathy

Cisplatin, vincristine, vinblastine

Digestive System

Oral cavity, teeth

Xerostomia, abnormal dentition, cavities, gingivitis, periodontal disease

Radiation

Intestines

Malabsorption, strictures, chronic diarrhea

Radiation

Liver

Hepatitis, fibrosis, cirrhosis

Methotrexate, BCNU, 6-mercaptopurine, radiation, contaminated blood productsa

Urinary System

Bladder

Hemorrhagic cystitis, cancer

Ifosfamide, cyclophosphamide

Scarring

Radiation

Kidneys

Nephropathy

Radiation, ifosfamide

Fanconi syndrome

Ifosfamide, cisplatin

Reduced filtration

Cisplatin, carboplatin

Hypertension, renal insufficiency

Radiation

Kidney failure (rare)

BCNU, CCNU, methotrexate (high dose)

aFor transfusions given before 1972 (hepatitis B), between 1977 and 1985 (HIV), and before 1993 (hepatitis C).

Source: [3,4,209,266,313,520,526,529,530,531,532,533,534,535]

Table 23: RECOMMENDED SCREENING FOR SURVIVORS OF CHILDHOOD LEUKEMIA AND LYMPHOMA ACCORDING TO CHILDREN'S ONCOLOGY GROUP GUIDELINES

Late Effect

Therapy or Cause

Recommended Screening

Cardiac abnormalities (cardiomyopathy, left ventricular dysfunction [subclinical], congestive heart failure, arrhythmias, myocardial infarction, valve disorders, pericarditis, coronary artery disease)

Anthracyclines, cyclophosphamide (high dose), radiation (mantle, mediastinum, thorax, axilla, abdomen)

Yearly history and physical examination with attention to presence of murmur, S3, S4, increased P2 sound, pericardial rub, rales, wheezes, peripheral edema, jugular vein distention

Baseline echocardiography and electrocardiography, repeated as clinically indicated

Fasting glucose and lipid profile every three to five years

Education about risk of strenuous exercise

Cataracts

Alkylating agents, corticosteroids, cranial, orbital, or eye radiation

Yearly eye examination

Dental problems (abnormal dentition, cavities, gingivitis, periodontal disease, microdontia)

Cranial radiation, bone marrow transplantation, chemotherapy (any)

Dental cleaning every six months

Yearly oral examination

Dyslipidemia

Radiation

Baseline fasting lipid profile every two years

Testicular hormonal dysfunction/impaired spermatogenesis; ovarian hormone deficiencies/reduced ovarian follicular pool

Alkylating agents, radiation (whole abdomen, pelvis)

Yearly evaluation of puberty stage and pace, sexual function, Tanner assessment, testicular volume (male patients)

Baseline levels of FSH, LH, and estradiol (female patients) or testosterone (male patients) at 13 years age (female patients) and 14 years of age (male patients)

Hearing loss, tinnitus, vertigo

Heavy metals, radiation

Yearly assessment of hearing difficulties and otoscopic examination

Complete audiologic evaluation by audiologist, yearly, for patients age ≤5 years

Pure tone audiometry testing at 1,000–8,000 Hz every 2 years for patients 6 to 12 years of age, then every 5 years beginning at 13 years of age

Hepatic dysfunction

Antimetabolites, methotrexate

Yearly examination with attention to jaundice, ascites, hepatomegaly, splenomegaly

Baseline levels of ALT, AST, and bilirubin, repeated as clinically indicated

Hepatitis B or C; HIV

Transfusion of blood products before 1972 (hepatitis B), between 1977 and 1985 (HIV), and before 1993 (hepatitis C)

Hepatitis B surface antigen and core antibody once

HIV 1 and 2 antibodies once

Hepatitis C antibody once

Neurocognitive deficits

Cranial radiation, methotrexate, cytarabine (high-dose IV), neurosurgery (brain)

Formal neuropsychologic evaluation at baseline

Yearly assessment of educational or vocational progress

Peripheral sensory neuropathy

Heavy metals, plant alkaloids

Yearly neurologic examination for two to three years after therapy completed

Psychosocial disorders

Cancer experience

Yearly assessment for depression, anxiety, post-traumatic stress syndrome, and social withdrawal

Pulmonary toxicity (fibrosis, interstitial pneumonitis, obstructive lung disease)

Alkylating agents, bleomycin, radiation (mantle, mediastinum, thorax), hematopoietic cell transplant, thoracic surgery

Yearly pulmonary examination with attention to history of cough, shortness of breath, dyspnea, wheezing

Baseline chest x-ray and pulmonary function tests, repeated as clinically indicated

Renal/bladder damage

Alkylating agents, heavy metals, antimetabolites, radiation (abdomen, pelvis), hematopoietic cell transplant, nephrectomy

Yearly blood pressure, urinalysis

Baseline levels of BUN, creatinine, electrolytes, calcium, magnesium, and phosphate, repeated as clinically indicated

Sinusitis (chronic)

Cranial radiation

Yearly sinus examination with evaluation for history of rhinorrhea and postnasal discharge

Thyroid gland dysfunction

Radiation (head and neck, thorax), thyroidectomy, systemic radiation

Yearly thyroid function studies and evaluation for thyroid hyperplasia

Bone Disorders

Osteopenia, osteoporosis

Radiation, corticosteroids, methotrexate, cyclophosphamide, ifosfamide, hematopoietic cell transplant

Baseline bone density

Yearly musculoskeletal examination

Avascular necrosis

Corticosteroids, hematopoietic cell transplant

Abnormal Growth and Development

Impaired growth

Cranial radiation, corticosteroids, chemotherapy (any), radiation (neck, thorax, whole abdomen)

Yearly height measurements on standardized growth charts

Yearly determination of height, weight, body mass index, and blood pressure

Fasting glucose, serum insulin, and lipid profile every two years (overweight or obese individuals) or five years (normal-weight individuals)

Overweight or obesity

Cranial radiation, diagnosis of acute lymphoblastic leukemia

Second Cancers

Acute myelogenous leukemia, myelodysplasia

Epipodophyllotoxins, alkylating agents, hematopoietic cell transplant

Yearly dermatologic examination (pallor, petechiae, purpura) with evaluation for history of fatigue, bleeding, or easy bruising up to 10 years after treatment

Yearly CBC with differential up to 10 years after treatment

Bladder cancer

Cyclophosphamide, radiation (whole abdomen, pelvis)

Yearly urinalysis and evaluation for history of hematuria, urinary dysfunction

Breast cancer

Radiation of 20 Gy or more (mantle, mediastinum, thorax, axilla)

Yearly clinical breast examination beginning at puberty until 25 years of age, then every six months

Mammography beginning eight years after radiation or at 25 years of age, whichever occurs last

Colorectal cancer

Radiation of 30 Gy or more (whole abdomen, pelvis)

Colonoscopy every five years beginning at 10 years after radiation or at 30 years of age, whichever occurs last

Lung cancer

Radiation

Yearly pulmonary examination

Discuss the benefits and risks/harms of spiral CT scanning for patients at highest risk (e.g., smokers)

Lymphoma

Hematopoietic cell transplant

Yearly physical with attention to lymphadenopathy and splenomegaly

Skin cancer

Radiation (any field)

Yearly dermatologic examination of radiated fields with evaluation for history of skin lesions or changing moles

Solid tumors

Hematopoietic cell transplant

Yearly evaluation for benign or malignant tumors

FSH = follicle-stimulating hormone; LH = luteinizing hormone; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; CBC = complete blood count.

Source: [526]

Subsequent Neoplasms

The occurrence of subsequent neoplasms as a late effect among childhood cancer survivors has been well-documented. Multiple studies have demonstrated that these cancers are a major source of morbidity and mortality for 30 years or longer after treatment [3,266,520,536,537,538,539,540]. The 30-year cumulative incidence is 20.5% for a subsequent neoplasm and 7.9% for a second malignant neoplasm (excluding nonmelanoma skin cancer) [7]. The highest cumulative incidence is associated with Hodgkin lymphoma (18.4%); the incidence is similar for non-Hodgkin lymphoma and leukemia (5.8% and 5.6%, respectively) [7].

The greatest risk factor for a subsequent neoplasm is radiation therapy (relative risk: 2.7), followed by female sex and childhood Hodgkin disease (relative risk: 1.5 for both), and older age at the time of childhood cancer diagnosis (relative risk: 1.3) [7]. It is important to note, however, that changes to treatment protocols over time (e.g., the move to limited use of radiation therapy) may affect risk among children/adolescents treated within the past decade. Overall, the most frequently occurring subsequent solid tumors among childhood cancer survivors are breast, thyroid, and CNS cancers and soft-tissue sarcoma [7,535].

The authors of one study sought to find the incidence and excess risk for breast cancer in women after chest radiation; differences between the clinical characteristics of breast cancer and the outcomes after therapy among these women and in the general population; and potential benefits and harms associated with breast cancer surveillance among women exposed to chest radiation. The cumulative incidence of breast cancer by 40 to 45 years of age ranged from 13% to 20%. The risk for breast cancer increased linearly with radiation dose. The evidence suggests that the characteristics of breast cancer in these women and the outcomes after diagnosis are similar to those of women in the general population [534]. Authors of another study evaluated cumulative breast cancer risk in 1,230 female childhood cancer survivors treated with chest radiation. Survivors who were treated with lower delivered doses of radiation (2–20 Gy) to a large volume (i.e., whole-lung field) had a high risk (43.6%) of breast cancer. The cumulative incidence of breast cancer by 50 years of age was 30%, with a 35% incidence among Hodgkin lymphoma survivors. Breast cancer-specific mortality at 5 and 10 years was 12% and 19%, respectively [532].

The rate of cancer screening among childhood cancer survivors has been lower than optimal, and clinicians should emphasize the importance of screening, given the high risks [541]. Second cancers among childhood cancer survivors call for vigilant screening and surveillance according to individual risk [526,542]. A prospective one-arm study was conducted among a random sample of 72 Hodgkin lymphoma survivors, 27 to 55 years of age, who were at increased risk for breast cancer and/or cardiomyopathy and had not had a screening mammogram or echocardiogram within the prior two years. A one-page survivorship care plan with recommendations for surveillance was mailed to participants. In addition, survivors' primary physicians were contacted and provided patient-specific information. A web-based virtual information center was made available for both survivors and physicians. Outcomes were assessed by telephone six months after the intervention. At six months, 41% of survivors reported having completed the recommended mammogram; 20% reported having an echocardiogram (women 30%, men 10%) [535].

Cardiac Abnormalities

The greatest risk of cardiac abnormality is associated with a high cumulative dose of anthracycline, which is used in treatment regimens for approximately 60% of children and adolescents with cancer [210,211,520,533,543]. In a study of more than 1,300 childhood cancer survivors, the relative risk of cardiac abnormality was reported to be 3.53 in association with use of an anthracycline and 7.41 in association with the combination of an anthracycline and an alkylating agent [4]. The risk of anthracycline-induced cardiac abnormality is increased further by several factors, including female sex, younger age (younger than 5 years) at the time of treatment, and black race [526]. Examples of nonanthracycline agents used in pediatric populations that have been associated with cardiotoxicity include cyclophosphamide, cytarabine, cisplatin, and ifosfamide [544].

A wide range of cardiac abnormalities have been noted in survivors [3,4,209,313,520]. It is well-established that the development of congestive heart failure can occur at any anthracycline dose, but the risk increases with increased cumulative doses, especially doses ≥300 mg/m^2 [545,546,547,548]. A systematic review indicated a rate of subclinical cardiotoxicity of approximately 16% to 28% associated with an accumulated dose of anthracycline of more than 200 mg/m^2 [4]. Among survivors who had been treated with an anthracycline, cardiomyopathy has been identified in as many as 57% and clinical heart failure (usually asymptomatic) in as many as 39% [209,520]. In a study of more than 10,000 survivors, the relative risk of congestive heart failure was 15.1 compared with sibling controls [3]. The more time that has passed since a patient has received treatment with an anthracycline, the higher the patient's risk for developing changes in cardiac function [210,549,550].

Radiation therapy to the thorax has also been associated with cardiac damage, including decreased left ventricular mass, end-diastolic wall thickness, valve defect, and early, significant decline in left ventricular shortening fraction, with elevated body mass index and Hispanic ethnicity identified as independent risk factors [209,520,533]. The use of lower doses of radiation for children with lymphoma has decreased the occurrence of radiation-related cardiac toxicity [209].

The COG guidelines suggest yearly history and physical examination for survivors at risk for cardiac abnormality related to either chemotherapy or radiation [526]. In addition, an echocardiography and electrocardiography should be done at baseline (the beginning of long-term follow-up) and periodically, depending on risk. Survivors should be educated about the risks of strenuous sports or exercise.

Abnormal Growth and Development

The most common abnormalities in growth and development among childhood cancer survivors have been impaired growth (short stature) and obesity.

Impaired Growth

The use of chemotherapy and radiation therapy in children has been associated with impaired growth and short stature as a result of effects on growth centers in the spine and long bones and endocrine organs [266,551,552,553]. Cranial radiation at a dose of more than 18 Gy has been linked to the greatest loss in height. This loss can be caused by several factors, including growth hormone deficiency, precocious or delayed puberty, or hypothyroidism [266,313,526]. Other factors, such as age younger than 4 years, female sex, obesity, concomitant use of corticosteroids, and radiation dose, contribute to risk [266,526,551].

Cranial radiation alone is not the only causative factor, as final height has been compromised in children with ALL regardless of whether radiation was given in addition to chemotherapy [551,552]. Growth is impaired primarily during remission induction therapy, and so-called "catch-up growth" will occur in approximately 70% of children after induction therapy has been completed [520,551,552,553]. However, maintenance therapy with methotrexate and 6-MP may prevent catch-up growth [554]. Catch-up growth does not occur with radiation-induced impairment [552].

Radiation therapy to the head and neck or cerebral cortex can cause hypothyroidism, leading to short stature and poor growth [266,555]. This risk has been somewhat decreased by the use of lower cumulative doses of radiation therapy in treatment protocols for childhood lymphoma [209]. Bone marrow transplantation is also associated with a high risk for severe growth impairment, especially when the conditioning regimen involves total body radiation [266].

Survivors should have regular growth assessment consisting of measurement of height on standardized growth charts [526]. Growth hormone therapy may be beneficial if growth hormone deficiency is found to be the cause of impaired growth [313,520,526]. Although the use of growth hormone therapy was once thought to confer an increased risk of second neoplasms, evidence of this risk has not been demonstrated in large studies [266,313].

Obesity

Obesity is another well-recognized long-term complication in survivors of ALL, occurring in as many as half of long-term survivors [266,313,520]. Weight gain is increased the most during the first year after the end of treatment, and gains continue with time. Several factors have been suggested as the cause of obesity, including treatment with corticosteroids (especially dexamethasone) and cranial radiation [266,520,526].

A meta-analysis of survivors of pediatric ALL found a high prevalence of obesity in ALL survivors regardless of survivors' receipt of cranial radiation, gender, or age at diagnosis [556]. Another study indicated a relative risk of obesity of 1.97 in association with radiation therapy to the head and neck, cranium, or thorax [4]. However, other investigators found no difference in the prevalence of overweight and obesity among survivors and the general population [557]. In this latter study, an age of younger than 6 years and overweight and obesity at the time of diagnosis were stronger factors than cranial radiation for overweight and obesity in adulthood [557]. Data from a longitudinal analysis of a multiethnic cohort of pediatric ALL survivors suggest that weight gain within the first year after diagnosis is more strongly associated with long-term increased BMI than early (within 30 days) weight gain [558].

Childhood cancer survivors should be weighed yearly at the time of routine history and physical examination and a body mass index should be determined. The patient's height should be considered when reviewing the body mass index, as a high body mass index may be the result of normal weight gain but relative loss of height. Primary care practitioners should emphasize the importance of weight control through healthy eating habits and exercise in preventing the development of such chronic conditions as diabetes, hypertension, dyslipidemia, and cardiovascular disease [313,520,526].

Gonadal Dysfunction

Gonadal dysfunction can occur in both boys and girls as a result of alkylating agents or radiation therapy [266,520,526]. In boys, testicular dysfunction may include delayed or arrested puberty, oligospermia, azoospermia, or infertility. In girls, ovarian dysfunction may include delayed or arrested puberty, premature menopause, or infertility [209,266,313,520,526]. The risk is dose-dependent and is increased when an alkylating agent is used in combination with radiation or an anthracycline [209,526]. The majority of these late effects arise from radiation-induced uterine injury. Such injuries are reported at higher incidence in adult survivors of childhood cancers who were exposed to uterine radiation (i.e., pelvic, spinal, or total-body) during childhood. Findings from long-term follow-up studies of the reproductive performance of female survivors provides some reassurance to them by documenting that pregnancy and live birth rates were not significantly compromised in survivors, including those who had been treated with alkylating agents and had not received pelvic, cranial, and total-body irradiation [559]. The relative risk for male infertility has been reported to be 9.03 in association with use of an alkylating agent and 10.6 in association with both an alkylating agent and an anthracycline [4]. Cranial radiation is correlated with an increased risk for premature puberty, especially for girls treated before 8 years of age [266]. The risk of infertility is low and is directly related to gonadal exposure to radiation and age at the time of treatment [560,561]. The possibility of maintaining gonadal function in the presence of higher cumulative doses of alkylating agents is greater in girls than for boys [526].

The annual history and physical for survivors at high risk for gonadal dysfunction should include evaluation of the puberty stage and pace, sexual function, and Tanner assessment [526]. Baseline levels of follicle-stimulating hormone, luteinizing hormone, and estradiol (girls) or testosterone (boys) should be determined at 13 years of age for girls or 14 years of age for boys and as clinically indicated [526].

Neurocognitive Impairment

Neurocognitive impairment is among the most common and distressing late effect of pediatric cancer treatment [4,313,451,520,562,563,564]. In one study, the relative risk of severe cognitive dysfunction among more than 10,000 survivors was 10.5 compared with sibling controls [3]. In another study, cognitive or psychosocial disorders represented approximately 8% of all severe, life-threatening, or disabling events [4]. A cancer experience alone increases the risk for neurocognitive impairment, and the interruption of regular schooling during treatment can have serious effects on academic performance [526]. Cranial radiation is the greatest contributor to the risk for neurocognitive deficits. The highest risk is associated with cranial radiation in combination with an age of younger than 3 years at the time of treatment or female sex [526]. The intensity of treatment and the time since treatment are also factors [526]. The replacement of prophylactic cranial radiation with intrathecal chemotherapy has led to a decrease in neurocognitive toxicity, but intrathecal chemotherapy (primarily methotrexate) is associated with some level of deficit in approximately 30% of survivors [562,563,564].

A variety of impairments have been reported, and the most common deficits are related to [52,313,465,526,563]:

- Attention

- Memory

- Mathematic reasoning

- Reading comprehension

- Executive function (planning and organization)

- Visual-motor coordination

- Written expression

- Delays in academic achievement

The deficits in survivors of leukemia and lymphoma are more often related to information processing [526].

The findings of studies on the academic status of survivors support the high reported rate of neurocognitive impairment. In a Childhood Cancer Survivor Study involving 12,430 survivors and 3,410 siblings, significantly more survivors used special education services (23% compared with 8% for siblings) [564]. The results indicated that the greatest differences were found for survivors who were younger than 6 years of age at the time of treatment or who had a diagnosis of CNS tumors, leukemia, or Hodgkin lymphoma [564]. Survivors of leukemia and non-Hodgkin lymphoma were among those who were least likely to finish high school [564]. In addition, a Canadian survey of parents of childhood cancer survivors showed that significantly more survivors than controls had educational or other school problems (46% compared with 23%), had repeated a grade (21% compared with 9%), had attended a learning disability program (19% compared with 7%), or had participated in a special education program (20% compared with 8%) [451]. Leukemia survivors were among the subgroups that were more likely to have educational problems. While there is longstanding recognition that these effects span the whole illness trajectory and continue beyond treatment completion, further clarity is needed on the specific barriers and facilitators to education during cancer treatment and beyond, as well as on the experiences of children and adolescents across the full range of education settings (e.g., hospital, home, virtual, original school of enrollment), in order to determine which interventions are successful in improving access and experience from their perspective [565].

The COG long-term follow-up guidelines recommend that the annual examination for all childhood cancer survivors include an assessment of educational and/or vocational progress [526]. A baseline formal neuropsychologic evaluation is recommended, with follow-up testing for survivors who demonstrate evidence of impaired progress. Primary care practitioners should alert parents to signs of neurocognitive impairment, emphasizing the importance of evaluating any learning-related problems [52]. In addition, primary care practitioners should refer patients with neurocognitive deficits to a school liaison or community service to facilitate access to educational services or vocational rehabilitation.

Dental Problems

Dental abnormalities have been associated primarily with radiation to the head and neck area or brain and also with chemotherapy. Abnormalities include tooth agenesis, enamel dysplasia, blunting of roots, incomplete calcification, high plaque index, arrested tooth development, and tooth discoloration [209,266,313,520]. The maturity of the teeth appear to be a substantial factor, as the most severe abnormalities have been found in children who are younger than 5 years of age at the time of treatment [266]. Dental caries and periodontal disease are also associated with bone marrow transplantation with chronic graft-versus-host disease [526].

Despite the prevalence of dental abnormalities, the rate of routine dentist visits among survivors of childhood cancer is lower than that recommended for the general population [566]. Primary care practitioners should encourage patients and parents to maintain regularly scheduled dentist visits, with dental cleaning every six months and an oral examination yearly [526].

Psychosocial Disorders

Psychosocial disorders are thought to be related to physical function, well-being, and anxiety related to future health needs [438]. As such, survivors of childhood cancers would be vulnerable to such disorders. However, long-term studies have shown contrasting results with respect to the psychologic health of childhood cancer survivors. In general, the psychologic health of survivors is similar to that of the general population, but a small percentage of survivors and family members have difficulty with coping and with personal and social skills [454].

A meta-analysis of 20 studies showed no deficits in measures of anxiety, depression, and self-esteem when results for survivors were compared with those for population norms or matched controls [438]. Following that study, the CCSS reported on the psychologic outcomes for survivors of pediatric leukemia and lymphoma [439]. That study indicated that survivors were approximately 1.7 times more likely to report symptomatic levels of depression or somatic distress compared with sibling controls, but the rate of depression and distress were similar to those among the general population [439,567].

In another Childhood Cancer Survivor Study, the percentage of leukemia and lymphoma survivors who reported an adverse effect on mental health or anxiety was similar to the overall population of survivors. One exception was a greater likelihood for Hodgkin lymphoma survivors to report cancer-related anxiety [529]. The authors of the report suggested that the older age at the time of Hodgkin lymphoma diagnosis may account for this difference, as the patient is better able to understand the seriousness of the cancer diagnosis [529]. This rationale supports the finding of post-traumatic stress disorder symptoms in approximately 20% of adolescent survivors [568].

Age and time since diagnosis may be factors in reported levels of post-traumatic stress disorder [569]. In one study, 255 children with cancer, stratified by time since diagnosis, and 101 demographically matched peers were assessed for post-traumatic stress disorder using structured interviews by both child and parent reports and survey measures of post-traumatic stress symptoms by child report. Cancer was identified as a traumatic event by 52.6% of children with cancer, declining to 23.8% in those who were five years or more from diagnosis [569].

The authors of one study sought to estimate the prevalence of emotional distress in a large cohort of adult survivors of childhood cancer and to evaluate the inter-relationship of risk factors, including cancer-related late effects. A total of 1,863 adult survivors of childhood cancer (median age at follow-up: 32 years) completed comprehensive medical evaluations. Elevated global distress was reported by 15.1% of survivors, and childhood cancer-related morbidities, including pain and learning or memory problems, appear to be directly and indirectly associated with elevated distress symptoms decades after treatment [570].

Sociodemographic factors related to psychosocial disorders among childhood cancer survivors are similar to those of the general population, with higher rates associated with female sex, lower level of educational attainment, and lower socioeconomic status [439,529]. One systematic review assessed unemployment in adult childhood cancer survivors compared with the general population, and its predictors [571]. Overall, approximately one in six survivors was unemployed and survivors were more likely to be unemployed than controls. Survivors of brain tumors were more likely to be unemployed. Younger age, female sex, radiotherapy, and physical late effects were predictors of unemployment [571]. Because the effects of prolonged psychologic distress can be severe, assessment for depression, anxiety, post-traumatic stress, and social withdrawal should be carried out annually [526]. Special attention should be directed toward female survivors, Hispanic survivors, and survivors with low socioeconomic status. Primary care practitioners should refer patients with emotional difficulties for psychologic consultation.

Other Late Effects

The CCSS cohort was used to compare the incidence rates of infections among five-year survivors of pediatric cancer with the rates of siblings [572]. Compared with that of the U.S. population, survivors were at an increased risk of death from infectious causes, with girls/women and those exposed to total body radiation being at greatest risk. Survivors also reported higher rates of overall infectious complications than siblings [572]. As part of the Swiss CCSS, a questionnaire was sent to all registered survivors (20 to 40 years of age), all aged younger than 16 years at diagnosis who had survived five or more years [573]. Fewer survivors than siblings had life partners, and fewer survivors were married than siblings and participants in the Swiss Health Survey. Older and female survivors were more likely to have life partners. Survivors who had undergone radiotherapy, bone marrow transplants, or who had a CNS diagnosis were less likely to have life partners [573].

HEALTH PROMOTION AND EDUCATION

Surveys of childhood cancer survivors have shown knowledge deficits regarding the late effects of cancer and cancer treatment [574,575]. More than half of the participants in a Childhood Cancer Survivor Study survey could not accurately report their anthracycline exposure or site of radiation therapy, information that is essential for appropriate long-term follow-up care [575]. In addition, 46% of respondents said that previous treatment did not pose a serious health issue, and 19% did not know that previous treatment was related to adverse events [575].

Given the lack of knowledge about the risk for adverse effects and the need for long-term follow-up care, education is essential and should focus on the importance of:

- Obtaining documentation of cancer type and treatment

- Understanding the risk of specific late effects according to a specific cancer diagnosis and specific therapies

- Engaging in healthy lifestyle behaviors to reduce the risk of treatment-related morbidity

- Seeking routine follow-up care and recommended screening

When developing or recommending educational resources for patients and family members, clinicians should consider the native language and literacy level, as appropriate materials will facilitate comprehension.

Documentation of Cancer Type and Treatment

It is imperative that every childhood cancer survivor have written documentation of his or her specific diagnosis and all diagnostic and treatment details. The concept of survivorship care plans has been developed as a way to facilitate better follow-up care for all survivors [576,577]. Among the basic elements of a survivorship care plan are [577]:

- Diagnostic tests performed and results

- Disease characteristics (e.g., histologic type, stage, grade, site)

- Start and end dates of treatment

- Type of treatment (chemotherapy and radiation therapy regimens, including doses and schedules)

- Indicators of treatment response

- Treatment-related toxicities

- Psychosocial and other supportive services provided

- Information on possible late and long-term effects of treatment and symptoms of such effects

- Information on possible signs of recurrence

- Description of recommended cancer screening and other periodic testing and examinations, their performance schedule, and which provider should perform them

- Specific recommendations for healthy behaviors (e.g., diet, exercise, healthy weight, sunscreen use, immunizations, smoking avoidance/cessation, osteoporosis prevention)

- List of cancer-related resources and information (e.g., web-based sources and telephone listings for major cancer support organizations)

- Identifying number and title of clinical trial (if applicable)

- Full contact information on treating institutions and key individual practitioners

- Identification of a key contact and a coordinator of continuing care

One study suggests, however, that a majority of cancer survivors and their physicians have not yet embraced survivor care plans [578]. From April to July 2012, researchers conducted in-depth telephone interviews with 53 adult survivors (average age: 39.1 years) recruited from the Utah Cancer SEER Registry. Participants were randomly selected from sex, age, and rural/urban strata and were younger than 21 years of age at the time of diagnosis. Participants were asked if they had a primary care physician, if they discussed their cancer history with their physician, and if they had interest in a survivor care plan. Most (83%) survivors had a current primary care physician; nearly 50% were not concerned about their health despite having had cancer; and few had a follow-up care plan, although more than half felt that a survivor care plan could empower their medical decision making. However, more than 30% of survivors were skeptical about the usefulness of a survivor care plan and some expressed concern about healthcare costs [578].

The National Children's Cancer Society has introduced a new online Late Effects After Treatment Tool (LEATT), which is available online at https://leatt.thenccs.org. The tool was designed to help survivors learn about potential late effects of childhood cancer. The LEATT provides personalized results, based on the information that the survivor enters, and it takes less than 10 minutes to complete. The results describe potential late effects and symptoms to look for, provide recommendations for follow-up care, and offer preventive tips to help reduce the risk of further health issues [579].

Understanding Risks of Late Effects

A valuable resource for patient and family education is Health Links, a series of educational handouts based on the COG guidelines for long-term care of childhood cancer survivors. The handouts address more than 40 topics within the guidelines, and each handout contains a brief overall description of a specific late effect, as well as [525,526]:

- Explanation of risk factors

- Description of common symptoms

- Explanation of exacerbating conditions

- Recommended screening

- Next steps after positive screening

- Brief explanation of the treatment

- Health-promoting behaviors and interventions

Healthy Lifestyle Behaviors

The health behaviors of childhood cancer survivors have not been well-studied, but overall, young cancer survivors report lifestyle behaviors that are at least as healthy as the age-matched population [52,524]. Behaviors have been shown to vary according to race/ethnicity; overall, black survivors have reported better preventive practices and have been less likely to engage in risky behaviors such as smoking and alcohol consumption [580]. In one study, 40% of survivors reported eating a nutritious diet, 64% said they practiced sun protection, and 94% said they did not smoke [581]. In a later and much larger study, the rate of physical inactivity was high (52% to 72%), with the lowest rate for Hispanic male survivors and the highest rate for black female survivors [580]. In that same study, the rates of smoking among black and Hispanic survivors were lower than the rates among their peers in the general population [580].

In a case-control study published in 2014, researchers sought to identify factors other than cancer-related treatment and presence/severity of chronic health conditions that might be associated with late mortality risk among adult survivors of pediatric cancer [582]. A total of 445 participants who died from causes other than cancer recurrence/progression or non-health-related events were compared with 7,162 surviving participants matched for primary diagnosis, age at baseline questionnaire, time from diagnosis to baseline questionnaire, and time at risk. Exercising fewer than three days per week, being underweight, increased medical care use, and self-reported fair-to-poor health were associated with an increased risk for all-cause mortality [582]. A report from the Childhood Cancer Survivor Study found that poor physical activity during adolescence, parents with less than a college education, previous treatment with cranial radiation, limitations of activity due to health or mobility restriction, and low self-esteem were associated with level of psychosocial functioning among childhood and young adult cancer survivors [583].

Primary care practitioners should make sure that childhood cancer survivors understand that the risks associated with unhealthy lifestyle behaviors may be increased because of their previous cancer treatment. In addition, clinicians should ensure that survivors know the importance of a healthy diet, regular exercise, routine sun protection, avoidance of tobacco, and moderation in alcohol consumption. Survivors should also be educated about the signs and symptoms of depression and of ways to alleviate stress and anxiety.

Routine Follow-Up Care and Recommended Screening

The cancer screening practices and compliance with healthcare recommendations have been less than optimal among childhood cancer survivors, and most survivors have contact with primary care practitioners rather than oncology specialists or follow-up clinics [524,542,561,576]. These findings indicate the importance of primary care practitioners assuming responsibility for the long-term follow-up care of childhood cancer survivors; however, barriers to doing so remain. In one study, a minority of primary care physicians perceived that their medical training was adequate to recognize late effects of chemotherapy (27.6%), cancer surgery (36.6%), and radiation therapy (38.1%). Most (93%) had never used the COG guidelines, but 86% would follow their recommendations. Most (84% to 86%) stated that they had never received a cancer treatment summary or survivorship care plan, but more than 90% thought these documents would be useful [584]. Although most general internists report involvement in the care of pediatric cancer survivors, many are unfamiliar with surveillance guidelines and uncomfortable caring for survivors, citing access to guidelines and treatment summaries as the most useful resources in caring for survivors and preferring to care for survivors in collaboration with a cancer care center [585]. A survey of U.S. and Canadian family physicians involved in the care of pediatric cancer survivors revealed similar attitudes. Clinicians also cited surveillance recommendations and clinical care guidelines as being the most useful in assisting them with survivor care and were willing to care for survivors in consultation with a cancer care center [586].

Due to their heightened risk of developing late-occurring adverse outcomes, pediatric cancer survivors are advised to receive follow-up care in specialized survivor clinics. Research indicates that most survivors (71%) who do not attend a specialized clinic were "not aware" of their availability [587]. Clinicians should use every opportunity (e.g., acute care visits, parental or sibling visits, annual examinations) to emphasize the importance of long-term follow-up care in a survivor care clinic and adherence to recommended screening guidelines for survivors.

CHALLENGES IN PROVIDING HEALTH CARE

Approximately one in every 640 young adults (20 to 39 years of age) in the United States is a childhood cancer survivor [520]. This large and increasing population, with its increased risk of adverse events, creates a substantial healthcare burden. As such, there are several challenges to providing long-term care for childhood cancer survivors.

The first challenge is related to the overall age of childhood cancer survivors. Because survival rates have improved over the years, the population of survivors is young and will require close follow-up for several years. The primary responsibility for follow-up care has typically been assigned to oncologists, but many have suggested that primary care practitioners are best equipped to provide the full spectrum of health care to cancer survivors [52,314,520,576,588]. This shift in responsibility may be especially important given the predicted shortage of oncologists by the year 2020, as well as the predisposition of survivors to seek care with primary practitioners [589].

The increasing age of childhood cancer survivors also creates many challenges to maintaining long-term follow-up care. First, over the course of childhood, adolescence, and young adulthood, individuals are more likely to be mobile, which makes continuity of long-term follow-up difficult. Second, as children/adolescents mature, the primary responsibility for their care shifts from their parents to themselves and they begin to make their own decisions. Third, most pediatric cancer centers do not have programs for follow-up into adulthood, which means that when survivors become adults, they must seek follow-up care elsewhere [588]. Lastly, long-term follow-up centers that are in existence are confronted with many barriers, including inadequate funding, lack of capacity of the growing population of survivors, and lack of awareness or interest among survivors [520].

Models of care that take into account the transition of care into the adult setting are needed. Until such programs are available, it becomes incumbent on pediatric oncologists to share treatment plans with pediatricians and family practitioners and for oncologists and primary care practitioners to collaborate on survivorship care plans. With emerging technology, the use of electronic media to store health information will facilitate maintenance of important documentation in a portable format.

Lack of awareness of diagnosis, treatments, and potential late effects among childhood cancer survivors also presents a challenge. Such information is essential for appropriate long-term care, and primary care practitioners have an important role in providing educational resources to help survivors better understand their health and receive optimal long-term care.

14. CASE STUDIES

CASE STUDY 1

Patient A, a bright, energetic boy, 8 years of age, had shown less enthusiasm for his normal activities for a few days. He told his mother he felt tired and was sometimes nauseated, and his mother found that he had a low-grade fever (37.8 degrees Centigrade). Mrs. T, the patient's mother, took Patient A to his pediatrician, who noted no abnormalities on physical examination. He told Mrs. T that the patient probably had a virus. A week later, Patient A was still not feeling better, and Mrs. T took him to the pediatrician again. On physical examination, the pediatrician noted that the patient appeared pale and had slight lymphadenopathy. Suspecting infection, the pediatrician prescribed a 10-day course of an antibiotic. After completing the course of antibiotics, Patient A still did not feel better and continued to have a low-grade fever. At that time, the pediatrician noted ecchymoses of the skin and slight splenomegaly, findings that had not been previously evident. He ordered laboratory and imaging studies to rule out leukemia. The complete blood count demonstrated slight anemia and leukopenia; the chest x-ray was normal, and computerized tomography confirmed splenomegaly.

The signs and symptoms of pediatric leukemia are often insidious and persistent. The most common symptom associated with ALL is a low-grade fever of unknown etiology. Many symptoms related to leukemia are associated with other diseases and conditions, and care is needed in making a differential diagnosis. Reactive lymphadenopathy is common in children and adolescents, and clinicians should first rule out infectious or inflammatory conditions. Because of this, symptoms of ALL are present for an average of four to six weeks before the diagnosis is made. Further evaluation for leukemia is warranted when fever persists for more than two weeks and when findings on physical examination include pallor, petechiae, ecchymoses of the skin or mucous membranes, or lymphadenopathy. Splenomegaly (or hepatomegaly) at the time of diagnosis of ALL is common. Imaging studies should be carried out to determine the presence of leukemic involvement.

The pediatrician talked with Mr. and Mrs. T privately (without Patient A present) and carefully explained that their son may have leukemia and that he was referring Patient A to a pediatric cancer care center in a neighboring city. Patient A's parents were both devastated by the news. The pediatrician encouraged them to express their emotions and to ask questions. He patiently answered all questions, checking often to make sure they understood. He also reassured Mr. and Mrs. T that he would be available to talk with them or their son at any time. Mr. and Mrs. T told the pediatrician that they did not want Patient A to know about the diagnosis until it was confirmed. The pediatrician tried to persuade them to carefully consider this decision.

A cancer diagnosis is overwhelming for parents, and clinicians discussing the diagnosis should use clear language, encourage questions, check often for understanding, and offer reassurance and support. In addition, clinicians should elicit and validate parents' and patients' emotions. The American Academy of Pediatrics recommends that clinicians refer children to pediatric cancer centers for diagnostic testing for leukemia (and lymphoma), where the availability of appropriate technology and subspecialists helps to ensure an accurate diagnosis. Many parents wish to protect their child by withholding information about the diagnosis, but clinicians should encourage parents to share information with their child, as studies have shown that children often recognize the severity of their illness and wish to be included in discussions about diagnosis and treatment. Open discussion can help a child feel less fear about the unknown and feel trust for their family and caregivers.

After much discussion, Mr. and Mrs. T decided not to tell Patient A the suspected diagnosis, but they did tell him he would need to see another physician and possibly have more tests. Patient A was concerned about the tests and wanted to know if they would be painful. The patient and his parents met with the pediatric oncologist, who performed a bone marrow aspiration, ensuring that Patient A was comfortable during the procedure. Examination of the bone marrow sample showed the presence of leukemic blast cells consistent with ALL. A lumbar puncture was performed, again ensuring that the patient was comfortable, and there was no evidence of leukemic involvement of the CNS. Cytogenetic examination of bone marrow cells demonstrated hyperploidy.

Pain interventions during diagnostic procedures are important, and the goal is to achieve unconsciousness, amnesia, and analgesia to ensure optimum comfort and cooperation. Preventing pain during diagnostic procedures is also important to avoid a child's fear of future diagnostic testing and to avoid post-traumatic stress years later. The sample obtained during bone marrow aspiration should be enough for both cytogenetic examination and immunophenotyping.

The pediatric oncologist met with Patient A and his parents to discuss the findings. Before the oncologist could discuss the diagnosis, Patient A's mother requested that the oncologist speak with only her and her husband before telling the patient. Both Mr. and Mrs. T seemed to be masking their emotions. The oncologist noted that Patient A should be included in the conversation, but Mr. and Mrs. T were adamant. Reluctantly, the oncologist discussed the diagnosis and prognostic factors with the parents only; he told them that the prognostic factors were favorable and noted that a clinical trial would be the best option. Mr. and Mrs. T began to express strong emotions, with Mrs. T crying and Mr. T becoming angry. They did not ask any questions, and Mr. T said he did not want his son to be a "guinea pig" in a clinical trial. The oncologist encouraged them to consider the decision carefully and to talk about the diagnosis with Patient A. When the oncologist suggested that Patient A be involved in the decision about participating in a clinical trial, both parents argued that he was too young to make such a decision. The oncologist provided Mr. and Mrs. T with educational resources and the names of some parents who had agreed to talk with parents of children with newly diagnosed leukemia. He also told them that a decision would need to be made quickly, as treatment should begin as soon as possible.

The emotional behavior of Mr. and Mrs. T indicates that they are having a difficult time dealing with their son's diagnosis. It is important for the clinician to be empathic and to encourage them to express their emotions. The clinician should also reiterate the importance of Patient A being involved with discussions about the diagnosis and treatment. Among the favorable prognostic factors are Patient A's age; age at the time of diagnosis is a strong prognostic factor, and disease-free survival is better for children 1 to 9 years of age than for other age groups. In addition, hyperploidy is associated with a highly favorable prognosis. These factors will allow treatment with a standard-risk protocol. Clinical trial participation should always be encouraged, as it provides the maximum opportunity for cure and long-term survival. The age threshold for a child participating in a discussion about a clinical trial has been debated, but most agree that individual decisions should be made on the basis of the child's level of maturity and physiologic and psychologic state. The Children's Oncology Group recommends that the clinician and parents seek the child's perspective and that the clinician should encourage the parents and patient to make the decision jointly as a family. During the clinical trial discussion, the clinician should discuss all facets of the clinical trial, emphasizing that a trial involves several possible treatment options, one of which is the treatment their child would receive outside of the clinical trial. Parents of children with cancer have suggested that providing educational resources and arranging for discussions with other parents are helpful for making decisions about a clinical trial.

Mr. and Mrs. T met with other parents and gained support for their emotional reactions. They also decided that Patient A should know about the diagnosis. He had many questions, and they arranged a meeting with the oncologist. The oncologist also discussed the possibility of a clinical trial, and Patient A said he wanted to participate; his parents supported his decision.

Patient A received induction therapy, CNS prophylaxis, consolidation therapy, and three years of maintenance therapy. Throughout his treatment, the patient received support from his extended family, friends, and classmates. He was tutored at home and managed to keep up with his school work. Four years after diagnosis, Patient A has no evidence of disease and he has returned to a "normal" life of school and activities. The pediatric oncologist documented the patient's complete diagnosis and a comprehensive account of treatment in a survivorship care plan, which he forwarded to the patient's pediatrician.

As Patient A continues routine health care, the survivorship care plan will provide the information his pediatrician and subsequent physicians need to understand his health risks according to his cancer type and its treatment. His physicians should also consult the Children's Oncology Group's evidence-based guidelines for the long-term follow-up care of childhood cancer survivor to provide individualized follow-up care and screening. Lastly, Patient A's physicians should use every healthcare visit as an opportunity to educate Patient A (and his parents) about his specific health risks and the importance of appropriate prevention measures, engaging in healthy lifestyle behaviors, and avoiding risky behaviors.

CASE STUDY 2

E is a Puerto Rican girl, 10 years of age, whose brother, Patient M, 5 years of age, is in the second year of his three-year course of chemotherapy for ALL. Before Patient M was diagnosed with cancer, E enjoyed helping her mother with his care and teaching him how to count and to say the alphabet. E also enjoyed taking dance classes, and she and her classmates would visit each other's homes to practice. E's mother, Mrs. P, does not work outside the home and had been very involved in E's activities before the diagnosis. E's father, Mr. P, works full-time on the weekdays and paints houses on the weekends to ensure that the family can live in a nice neighborhood outside of the city. Several Puerto Rican families live in the neighborhood, and the P family enjoys close ties within this community. Both Mr. and Mrs. P speak Spanish as a first language and use English sparingly.

Because of the financial strain and the long drive to the hospital, the family moved into a two-bedroom condominium closer to the hospital. E's family is the only Hispanic family in the complex, and E spends much time at home alone, as Mr. P continues to work two jobs and Mrs. P spends most of each day at the hospital. E's grades begin to drop, and she does not complete assignments or closely follow directions. E's teacher feels that she is disinterested in academics and her classmates. At home and at the hospital, E argues frequently with Mrs. P and cries often, saying that she wants to live with her friends in her former neighborhood because she feels "bored." In general, Mrs. P is embarrassed and frustrated by E's behavior. She often physically handles E following outbursts, resulting in E's crying and embarrassment. Conversely, Mrs. P is very kind to the staff and her son. If E is not present, Mrs. P does not exhibit signs of emotional distress.

E has lost many things that were important to her: dance lessons, familiar school, and friends, and her behavior and outbursts may be indicative of loneliness as well as jealously and resentment she feels against the time and attention Mrs. P provides Patient M. Cancer-free siblings are often reactive to the loss of day-to-day family routine, restrictions on their social activities, and inability to help their siblings with cancer. In addition, cancer-free siblings receive the least attention in the family, and their parents often overlook or underestimate their emotional and health-related responses [489]. E's feelings and behaviors increase the risk of unhealthy psychosocial adjustment and lower educational achievements.

Noting the emotional behaviors of E and her mother, Patient M's healthcare team seeks to provide psychosocial support for the family. A female member of the medical team who has been involved with Patient M's treatment and a professional interpreter arrange to talk with Mr. and Mrs. P and E independently so that they can share their concerns and express their emotions openly. The team member reassures the parents that E is expressing feelings and behaviors typical of cancer-free siblings. She acknowledges that the move has been difficult for the entire family, and points out that it is particularly so for E because of the social support she lost in addition to the time lost with her family. In the discussion with E, the team member acknowledges how difficult the adjustment is for E and emphasizes that her parents love her. E says that she misses being with her mother and brother and wishes she could be more involved. She also misses her father and wishes he could spend more time with the family. On the basis of the discussions with the family, the team member recommends several interventions, including a problem-solving skills training program for Mrs. P, family therapy, and a sibling program for E. The team member also encourages Mrs. P to involve E in Patient M's care and helps Mr. and Mrs. P seek additional practical resources to help them meet the challenges associated with Patient M's illness.

Family-centered care is essential in pediatric cancer, and the healthcare team must emphasize the importance of family cohesion and communication [498,499,500]. Helping Mr. and Mrs. P understand the reasons for E's behavior enhances the likelihood that they will agree to have her participate in a psychosocial intervention [503]. The use of a professional interpreter helps to make Mr. and Mrs. P more comfortable and provides for better comprehension [163]. The recommendation for a problem-solving program for Mrs. P is especially appropriate as such training has been shown to have increased effectiveness for Spanish-speaking mothers [515]. Family therapy will help Mr. and Mrs. P and E communicate more openly with each other, and the therapeutic peer support group can help E with psychosocial adjustment.

Four months after the intervention, E says that she feels she has more of an active role in Patient M's treatment and that she is helping him with pain and emotional management. E is able to speak with her mother and father about problems at school and emotional aspects related to Patient M's cancer and the move. Mrs. P is noticeably affectionate with E. The family has received financial assistance with help from a cancer society, and Mr. P has negotiated with his employer to be off on every Friday and has quit his second job, allowing him to spend more time with his family. The family also makes arrangements to see friends in their former neighborhood occasionally. E is interacting with schoolmates again and is also performing better academically.

15. CONCLUSION

The diagnosis, treatment, and follow-up care for children and adolescents with leukemia and lymphoma are complex. Although pediatric oncologists and a host of oncology specialists will provide treatment, primary care practitioners should be familiar with the signs and symptoms indicative of the most common types of hematologic cancers to ensure timely detection and early treatment, when the chances for cure are best. The types of leukemia and lymphoma differ from each other according to patient factors (age, sex, and race/ethnicity), clinical features, cancer biology and histology, approaches to treatment, late effects, and rates of overall and disease-free survival.

Diagnosing childhood leukemia and lymphoma is challenging because of the similarity between their symptoms and the symptoms of other common childhood conditions, especially infection. Careful history and physical examination targeted to suspicious symptoms is the first step of testing to confirm the diagnosis and determine the biology and histology of the cancer.

The diagnosis of cancer in a young person is devastating for patients and families. Therefore, clinicians should follow the tenets of "breaking bad news" and use clear, simple language, show empathy, and allow the patient and family to express concerns and emotion. As in all healthcare encounters, communicating the diagnosis should be done with consideration of the family's cultural context, with a professional interpreter used if English is not the family's native language.

Children and adolescents with leukemia or lymphoma should be treated in a pediatric cancer center and should be encouraged to participate in a clinical trial, which provides the opportunity for the most advanced care. The discussion of clinical trial participation should include all the pertinent information necessary for decision making. When possible, the family should make a decision together, with involvement of the patient. Treatment for leukemia and lymphoma is centered on chemotherapy, and several regimens have been evaluated for each type of disease. Radiation therapy is also a cornerstone of treatment, especially for lymphoma. The underlying principle of treatment is to maximize the potential for cure while minimizing the toxic effects of chemotherapy and/or radiation therapy. As such, treatment is risk-adapted according to prognostic variables. Research focused on adverse events related to chemotherapy and radiation therapy has demonstrated a variety of acute and late effects of treatment, and investigators continue to modify treatment regimens to avoid toxicity.

Disease-directed treatment is only one component of the overall treatment of children and adolescents with pediatric leukemia or lymphoma. Treatment also includes supportive, palliative, and psychosocial care. Supportive care involves the evaluation and treatment of potential complications of both the disease and treatment. The most common complications are infection, neutropenia, anemia, and thrombocytopenia. Palliative care focuses on the careful assessment and treatment of symptoms to enhance the quality of life. The prevalence of such symptoms as pain, fatigue, gastrointestinal disturbances, mucositis, and pruritus are high among children/adolescents with leukemia or lymphoma, and clinicians should implement both pharmacologic and nonpharmacologic interventions to relieve discomfort.

As a result of advances in treatment, the five-year overall survival for a child/adolescent with leukemia or lymphoma is approximately 80% [4]. Despite this high rate of success, some children and adolescents will die of the disease or complications. Pediatric end-of-life care is a challenge for several reasons and does not need to exclude curative therapy. Parents often have unrealistic expectations or optimism about cure, and clinicians should talk openly with the family to ensure that the priority in decision making is the patient's quality of life. Throughout all treatment, children and adolescents with cancer should be allowed to express opinions about the direction of care in a way that is appropriate for their developmental age.

Addressing the psychosocial and spiritual needs of children and adolescents with cancer is an integral component of comprehensive care. Evaluating these needs and providing referrals for interventions help patients and their families cope with the diagnosis and treatment of cancer and help to avoid later psychosocial distress. By definition, pediatric health care is family-centered, and it is important for clinicians to ensure that the psychosocial and spiritual needs of parents, siblings, and other family members are also met.

The advances in treatment for children/adolescents with pediatric leukemia or lymphoma have led to a substantial number of childhood cancer survivors, and the health burden caused by the late effects of treatment is substantial for this growing population. Close follow-up care is essential to ensure the early detection and/or prevention of such late effects as second cancers, cardiac abnormalities, abnormal growth and development, gonadal dysfunction, neurocognitive impairment, and psychosocial disorders. Follow-up care should be individualized according to treatment exposure and risk, and evidence-based guidelines are now available for care.

There are many challenges inherent in providing long-term follow-up care to childhood cancer survivors. Patient and family education is necessary to heighten awareness of the importance of follow-up care and the potential late effects. Primary care practitioners are uniquely poised to provide the full spectrum of care for childhood cancer survivors and can play a pivotal role in ensuring the long-term health of this growing population.

16. RESOURCES FOR FAMILIES WITH A CHILD OR ADOLESCENT WITH LEUKEMIA OR LYMPHOMA

GENERAL EDUCATION AND ADVOCACY

American Cancer Society

https://www.cancer.org

American Childhood Cancer Organization

https://www.acco.org

The Leukemia and Lymphoma Society

https://www.lls.org

The National Children's Cancer Society

https://www.thenccs.org

13Thirty Cancer Connect

http://13thirty.org

The Ulman Cancer Fund for Young Adults

https://ulmanfoundation.org

SURVIVORSHIP

Cancervive

https://cancervive.ca

Children's Oncology Group

http://www.survivorshipguidelines.org

Stupid Cancer

https://stupidcancer.org

National Coalition for Cancer Survivorship

https://canceradvocacy.org

Office of Cancer Survivorship (of the National Cancer Institute)

https://cancercontrol.cancer.gov/ocs

INSURANCE, LEGAL, AND EDUCATIONAL ISSUES

International Center for Disability Resources on the Internet

http://www.icdri.org

Patient Advocate Foundation

https://www.patientadvocate.org

FREE WEEKLONG AND WEEKEND CAMPS

Big Sky Kids

https://eaglemount.org/camp/big-sky-kids

Camp Mak-A-Dream

https://www.campdream.org

Camp Sunshine

https://www.campsunshine.org

First Descents

https://firstdescents.org

Special Love for Children with Cancer Camp Fantastic

https://specialove.org/event/camp-fantastic

Works Cited

1. Noone AM, Howlader N, Krapcho M, et al. (eds). SEER Cancer Statistics Review, 1975–2018. Bethesda, MD: National Cancer Institute; 2018.

2. National Cancer Institute. Cancer in Children and Adolescents. Available at https://www.cancer.gov/types/childhood-cancers/child-adolescent-cancers-fact-sheet. Last accessed July 26, 2021.

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583. Devine KA, Mertens AC, Whitton JA, et al. Factors associated with physical activity among adolescent and young adult survivors of early childhood cancer: a report from the Childhood Cancer Survivor Study (CCSS). Psychooncology. 2018;27(2):613-619.

584. Sima JL, Perkins SM, Haggstrom DA. Primary care physician perceptions of adult survivors of childhood cancer. J Pediatric Hematol Oncol. 2014;36(2):118-124.

585. Suh E, Daugherty CK, Wroblewski K, et al. General internists' preferences and knowledge about the care of adult survivors of childhood cancer: a cross-sectional survey. Ann Intern Med. 2014;160(1):11-17.

586. Nathan PC, Daugherty CK, Wroblewski, et al. Family physician preferences and knowledge gaps regarding the care of adolescent and young adult survivors of childhood cancer. J Cancer Surviv. 2013;7(3):275-282.

587. Ford JS, Chou JF, Sklar CA. Attendance at a survivorship clinic: impact on knowledge and psychosocial adjustment. J Cancer Surviv. 2013;7(4):535-543.

588. Meadows A. Pediatric cancer survivorship: research and clinical care. J Clin Oncol. 2006;24(32):5160-5165.

589. Erikson C, Salsberg E, Forte G, Bruinooge S, Goldstein M. Future supply and demand for oncologists: challenges to assuring access to oncology services. J Oncol Pract. 2007;3(2):79-86.

Evidence-Based Practice Recommendations Citations

1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Pediatric Hodgkin Lymphoma. Version 3.2021. Available at https://www.nccn.org/professionals/physician_gls/pdf/ped_hodgkin.pdf. Last accessed August 5, 2021.

2. Centers for Disease Control and Prevention. Epidemiology and Prevention of Vaccine-Preventable Diseases. Atlanta, GA: Centers for Disease Control and Prevention; 2020. Available at https://www.cdc.gov/vaccines/pubs/pinkbook/meas.html. Last accessed August 5, 2021.

3. Lehrnbecher T, Robinson P, Fisher B, et al. Guideline for the management of fever and neutropenia in children with cancer and/or undergoing hematopoietic stem cell transplantation: 2017 update. J Clin Oncol. 2017;35(18):2082-2094. Available at https://childrensoncologygroup.org/downloads/COG_SC_FN_Guideline_Document.pdf. Last accessed August 5, 2021.

4. Barnard D, Portwine C, Members of the C17 Standards and Guidelines Group. Guideline for Platelet Transfusion Thresholds for Pediatric Hematology/Oncology Patients. Edmonton: C17 Council, Children's Cancer & Blood Disorders; 2011. Available at https://www.c17.ca/application/files/2916/2006/0821/C17_Platelet_Guideline_English_Summary_2011.pdf. Last accessed August 5, 2021.

5. Wiener L, Kazak AE, Noll RB, Patenaude AF, Kupst MJ. Standards for the psychosocial care of children with cancer and their families: an introduction to the special issue. Pediatr Blood Cancer. 2015;62(Suppl 5):S419-S424. Available at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6397048. Last accessed August 5, 2021.