#93092: Management of Opioid Dependency During Pregnancy

Because many oral prescription opioids have half-lives of 24 to 36 hours, users often use at least daily to avoid withdrawal symptoms. Early symptoms and signs experienced during withdrawal include:

Late symptoms of withdrawal include:

The most common symptoms are vomiting, diarrhea, profuse sweating, and tremor/shakiness [13,14]. Withdrawal from opioids requires monitoring and medical management at a facility qualified to provide sensitive and intense care [15]. The facility may be a hospital or an agency structured to specifically care for patients undergoing opioid detoxification. Medical management of detoxification and withdrawal in a specialty facility decreases the risk of injury or death from the withdrawal syndrome [16]. With this approach, methadone or buprenorphine is given for approximately five days at slowly decreasing doses while the vital signs are monitored very closely. Although this method of detoxification is highly recommended for many patients, it is not recommended for pregnant women because of the harmful effects detoxification can have on the fetus [15,17]. During pregnancy, dependent patients are often maintained on specific opioids and dosages in order to avoid withdrawal.

Methadone has been the gold standard for opioid maintenance and avoidance of withdrawal during medically managed detoxification since the 1960s, and it remains the preferred option for the management of pregnant women dependent on opioids [17]. As noted, methadone has been classified as pregnancy category C by the FDA because there is a lack of human studies. Although the FDA has concerns, mothers who have been administered methadone properly, under medical supervision, have been found less likely to use other illicit drugs that could harm the fetus [21].

Methadone maintenance therapy consists of an induction phase and a stabilization phase. The induction phase either continues the current methadone dose, if the patient was already using methadone pre-pregnancy, or starts an initial dose (based on weight, height, gestational age, and presence of withdrawal symptoms) if the patient has never taken methadone. If treatment is being initiated for the first time, it may be preferable for the patient to be admitted to an inpatient opioid treatment program for approximately 72 hours of observation. During the inpatient stay, the opioid levels and the physical status of the mother and the pregnancy are assessed [17,23]. However, methadone induction is most often initiated in a licensed outpatient opioid treatment program, because inpatient care is not always available [22].

The average dose of methadone for pregnant women is 20–40 mg in the first trimester [24]. As the fetus and placenta increase in size, a medical review is necessary to determine whether an increase of the dose of methadone is needed to avoid potentially harmful withdrawal symptoms. The dose is increased by 10 mg at each stage of significant growth; at the end of the 36 weeks, the average dose is 70 mg. Immediately prior to delivery (38 to 40 weeks), the usual dose is 80 mg [17]. After the birth, additional titration will be necessary, but the medication should be continued and not significantly reduced—the mother should be closely monitored during the postpartum period to avoid over-sedation [22]. An aftercare plan should also be in place for the safety of the mother and the child [23].

Methadone can be administered once per day in early pregnancy; however, as the pregnancy progresses, split dosing is recommended [17]. However, there has been a lack of empirical investigation of the effects on fetal and maternal plasma levels. As the dose increases, adverse effects are also more common, including sleep disturbances, excess weight gain, fluid retention, and intolerance to pain during delivery [26]. Any medications typically used for pain management during childbirth should be used with caution.

There are medical risks associated with methadone maintenance during pregnancy. One main concern is exposure of infants to the opioid in utero, resulting in withdrawal symptoms manifesting minutes to days later. Most symptoms develop within 72 hours after birth. This acute withdrawal is referred to as neonatal abstinence syndrome (NAS), and it is an expected and treatable outcome in infants born following methadone maintenance [25]. Despite the risks, the benefits of methadone generally outweigh the negatives. Infants born to mothers on methadone maintenance are more likely to be born within the 36- to 38-week period and tend to be of average weight than children born to mothers with uncontrolled opioid use [17].

Another pharmacologic option for opioid maintenance during pregnancy is oral buprenorphine [22]. Clinical trials have determined that the efficacy of buprenorphine is comparable to methadone. This medication is prescribed for women who are unable to take methadone, or who were previously taking buprenorphine/naloxone, or who need an immediate change from another opioid [27].

Buprenorphine is usually self-administered on an outpatient basis, but it is also used in inpatient treatment programs [22,28]. Various studies have found that administration of buprenorphine lowers the use of other drugs, increases the rate of treatment completion, and improves the likelihood of giving birth at term (between 38 and 40 weeks) [27]. However, careful patient selection is critical, as this option has a higher potential for misuse than methadone [22].

Unlike methadone doses, which can increase up to 80 mg, the dosage for buprenorphine is one 4–16 mg tablet per day in the induction period, with a maximum of 24–32 mg per day by the end of the pregnancy. The lower dosage results from the longer half-life (24 to 60 hours, compared to 24 to 36 hours for methadone) [29].

The birth outcomes with buprenorphine are the same as those outlined for methadone maintenance. However, compared with methadone exposure, infants exposed to buprenorphine in utero have less opioid in their system at birth as measured by urine, umbilical cord, and meconium drug testing and they display less severe NAS symptoms [29,30].

Patients on buprenorphine maintenance take one tablet per day for the duration of the pregnancy, making compliance easier than with the split doses of methadone. The FDA has also approved a buprenorphine implant, but there is no safety data on its use during pregnancy [22].

Even in a supervised environment, opioid use during pregnancy can have negative effects on the fetus, and there is a significant risk of congenital birth defects. Infants born to mothers who used opioids during pregnancy may develop [31,48]:

The heart and eyes appear to be most severely impacted, particularly in the first three weeks of pregnancy [18]. Long-term effects to offspring include language and cognitive deficits as well as behavior problems and issues with social acceptance by school-age peers [23].

All healthcare professionals caring for a woman during labor and delivery should be aware that she is undergoing MAT [23]. As discussed, additional medications for pain relief may be necessary, as the maintenance dose of methadone or buprenorphine will not offer analgesia. The American College of Obstetricians and Gynecologists (ACOG) recommends offering epidural or spinal anesthesia for the management of pain in labor or delivery (when appropriate) and avoidance of narcotic agonist-antagonist drugs, such as butorphanol, nalbuphine, and pentazocine, as they may precipitate acute withdrawal [22].

Infants who have been exposed to opioids run a higher risk (30% to 80%) of developing NAS, which can appear within 72 hours to 14 days after birth for methadone (resolving in several days to weeks) and within 12 to 48 hours after birth for buprenorphine (peak: 72 to 96 hours; resolving in seven days) [22,25]. NAS can also occur or be exacerbated in infants exposed or co-exposed to nicotine, benzodiazepines, and/or selective serotonin reuptake inhibitors in utero [22,25,33].

After delivery, the neonate should be assessed immediately for NAS, the signs of which are generally apparent with routine newborn assessment and Apgar scores. Apgar scores are based on assessment of five categories (heart rate, respiratory effort, muscle tone, reflex irritability, and color) and are administered to all infants regardless of opioid exposure; however, special attention should be paid to possible signs of withdrawal in exposed infants [18]. The scores in each Apgar domain range from 0 to 2, with a maximum possible score of 10. The average score is 8 to 10, which indicates the infant does not need immediate attention. If the score is less than 8, the system affected is identified and appropriate medical procedures are initiated. If a third assessment at 10 minutes after birth does not show improvement, transfer to the NICU is warranted. Infants with acute NAS usually have an Apgar score less than 8; however, there have been instances in which an infant's Apgar score is within normal range at birth but then deteriorates and begins to show signs of NAS within 3 to 12 hours [18]. Comparison studies have found no significant differences in Apgar scores at birth of infants exposed to buprenorphine compared to those exposed to methadone [34].

The signs of NAS are a result of the effects of opioid withdrawal on the infant's neurologic, gastrointestinal, and autonomic systems [19]. Neurologically, the clinical signs of NAS include irritability; staying awake for long periods of time/sleeping in short intervals; high-pitched crying and inconsolability; seizures; sneezing; stiff arms, legs, and back; and body tremors with or without a Moro reflex [20]. NAS may also compromise the infant's gastrointestinal system, resulting in vomiting, diarrhea, dehydration, and inadequate weight gain. High fever is common, and regulating the body temperature can be difficult. Elevations in respiration and blood pressure can occur [20]. Infants often appear uncomfortable and restless, even after being fed or swaddled.

If signs of NAS are present, the infant should be taken to the NICU for further assessment and to determine the amount of opioid replacement (e.g., morphine) necessary to stabilize the patient, reverse the syndrome, and reduce the complications of withdrawal, if indicated. Additional medications (e.g., phenobarbital for seizures) may be required to control symptoms.

Several assessment tools are available and recommended to help determine the severity of NAS, including the Finnegan Neonatal Abstinence Scoring System, the Lipsitz Neonatal Drug-Withdrawal Scoring System, the Neonatal Withdrawal Inventory, the Neonatal Narcotic Withdrawal Index, and the Withdrawal Assessment Tool–Version 1 (WAT-1) [20,22,39]. The Finnegan Neonatal Abstinence Scoring System is a 31-item scale that will quantify the severity of NAS in order to help guide treatment decisions. The tool may be administered every four hours, and if an infant receives a score of 8 or more points, or the total for three consecutive scores is greater than 23, pharmacotherapy is indicated. In response to the complexity of the Finnegan tool, a shorter modified version is available (the Finnegan Neonatal Abstinence Syndrome Scale—Short Form) and is recommended by the American Academy of Pediatrics [37]. The Lipsitz Neonatal Drug-Withdrawal Scoring System consists of 11 items, and a score of 4 or greater is an indication that opioid therapy should be started. The Neonatal Withdrawal Inventory is an 8-point checklist of NAS symptoms, with a 4-point behavioral distress scale [20]. The Neonatal Narcotic Withdrawal Index is comprised of six items, for a possible maximum score of 12 points. A score of 5 or more on this index should prompt pharmacologic intervention [20]. Finally, the WAT-1 is administered to infants experiencing NAS who have been exposed to opioids and benzodiazepines for an extended period (including throughout a pregnancy) [25]. With this tool, pharmacotherapy is recommended for patients who score 10 or more points. However, the relative efficacy of these scores has not been definitively proven [35].

If indicated, opioid treatment should be initiated and the infant should be reassessed every three hours. Treatment with other sedatives (e.g., benzodiazepines, clonidine) has been effective, but 83% of physicians in the United States use an opioid (morphine or methadone) to treat NAS [35]. The dose of replacement opioid varies according to the severity of symptoms and degree of exposure; the average initial dose of morphine sulfate is 0.05 mg/kg every three hours [36]. If there is no improvement after three hours, the dose may be increased to 0.08 mg/kg, then again to a maximum of 0.1 mg/kg every four hours if necessary. Stabilization may take up to 48 hours. After 24 to 48 hours of a constant morphine dose, a gradual weaning can begin. Even after morphine is discontinued, the infant should be monitored hourly for 48 hours. If signs of NAS reappear, the original dose should be restarted and the same procedure followed until successful. After this, discharge plans may be implemented [37].

After NAS has resolved and the infant is stabilized, the interdisciplinary team, together with the mother or caregiver, should work to create a discharge plan that will be conducive to the health and safety of the infant and the mother. It is important that infants continue to be physically supported and monitored for any signs of digression.