From Pages to Practice

By Clement Lee, MD, MSc

Published February 28, 2023


Opioid use disorder (OUD) continues to be a national crisis in the United States. President Biden has identified battling the opioid crisis as a top priority and the U.S. Department of Health and Human Services (HHS) has awarded $1.6 billion to various communities for ongoing addiction evaluation and management.

In addition to the inherent complications of OUD, including drug overdose, withdrawal, multiple organ toxicities (e.g., constipation, endocrinopathy, obstructive sleep apnea, infections related to intravenous drug use), certain sequelae are unique to pregnancy. Adverse obstetric outcomes related to OUD include maternal death, cardiac arrest, placental abruption, preterm labor, oligohydramnios, and premature rupture of membranes. Adverse neonatal outcomes include fetal demise, neonatal abstinence syndrome (NAS), intrauterine growth restriction, gastroschisis, and neurodevelopmental disorders.

Methadone and buprenorphine are the two evidenced-based options for medication-assisted treatment in pregnant patients with OUD. Differences between the two agents include regulatory restrictions (e.g., methadone is dispensed in federally certified clinics), pharmacodynamics (e.g., methadone prolongs the QT interval), and adverse effects (e.g., buprenorphine lowers the seizure threshold). Because buprenorphine acts as a partial opioid agonist, it is thought to be associated with less respiratory depression and lower risk of overdose than the full agonist methadone, and it is postulated to lead to shorter duration of NAS. But buprenorphine may be less potent than methadone, given its shorter half-life. Results of a 2020 Cochrane systematic review suggest that the two drugs are equal in efficacy and safety in mothers and their infants, and both drugs are recommended by the American College of Gynecology and the Substance Abuse and Mental Health Services Administration for treatment of OUD in pregnant women.

Given the relative equipoise of these two opioids, a large cohort study by Suarez et al. published in NEJM is a welcome addition to the literature. The researchers compared pregnancy and neonatal outcomes among more than 2 million pregnancies that resulted in live births in Medicaid-insured women who received buprenorphine or methadone during pregnancy. They used propensity matching to adjust for potential confounding factors. Maternal outcomes, including cesarian section and a composite of life-threatening conditions, were similar in the two groups. However, buprenorphine was associated with lower risk of adverse neonatal outcomes, including NAS (adjusted relative risk, 0.73; 95% CI, 0.71-0.75), preterm birth (ARR, 0.58; 95% CI 0.53-0.62), small for gestational age (ARR, 0.72; 95% CI 0.66-0.80), and low birth weight (ARR, 0.56; 95% CI 0.50-0.63).

The authors concluded that these data reinforce prior evidence (including the 2010 MOTHER trial) indicating that buprenorphine is superior to methadone for treatment of OUD during pregnancy and reduces the risk for adverse neonatal outcomes. However, limitations of the study include the primarily white population and use of dispensing records for buprenorphine treatment. Further, concurrent use of specific selective serotonin reuptake and serotonin and norepinephrine reuptake inhibitors (SSRIs and SNRIs) was not detailed. SSRIs or SNRIs (especially duloxetine) are known to compound the risk of NAS. Finally, neonatal and childhood outcomes associated with in utero opiate exposure (e.g., gastroschisis and childhood conduct disorders) were not assessed.

Given these caveats, the results of this study may not be applicable to a broader population and should not be extrapolated to the treatment of NAS. Some evidence from small studies suggest that buprenorphine treatment is associated with shorter hospital stay and less respiratory depression requiring ICU transfer than methadone. Further, direct comparisons of buprenorphine and methadone for management of NAS are lacking. Nonetheless, the evidence to date seem to point to buprenorphine as the preferred agent for treatment of OUD in pregnancy. Patient preferences, rising rates of fentanyl use, and medication availability are factors to consider in treatment decisions.

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Clement Lee, MD, MSc, was a 2021–2022 NEJM Editorial Fellow and is a 2022-2023 Senior Editorial Fellow. He is currently an internal medicine hospitalist at Newton-Wellesley Hospital and a pediatric hospitalist at Boston Children's Hospital. He completed his internal medicine-pediatrics residency at Penn-CHOP.