Document Type


Publication Date



Maine Medical Center, Medical Education, Maine Medical Center Research Institute, Pediatrics, Neurology & Neuroscience

MeSH Headings

Pregnancy, Female, Infant, Newborn, Retrospective Studies, Parturition, Cephalometry


Purpose/Background: In Maine, one in 29 neonates is born following a pregnancy complicated by opioid use disorder. The standard of care treatment for pregnant women with opioid use disorder is medication assisted therapy with methadone or buprenorphine. Following birth, short-term symptoms of opioid withdrawal in the neonate are expected and well-studied, but less is known about the long term neurodevelopmental effects of antenatal opioid exposure on the developing child. In this study, we aimed to investigate the relationship between antenatal opioid exposure and small orbitofrontal head circumference (<3rd percentile), a commonly used proxy for increased risk of adverse neurodevelopmental outcome.

Methods/Approach: This retrospective cohort study of neonates born at a regional hospital in the Northeast US from 2013-2018 categorized 664 neonates with antenatal opioid exposure into three groups according to primary opioid taken during pregnancy (methadone, buprenorphine or “other opioid”). The frequency of head circumference <3rd percentile was calculated separately for males and females within each opioid exposure group and compared with 10,728 neonates without antenatal opioid exposure born during the same period. A linear regression analysis was performed on the three groups of neonates with antenatal opioid exposure to adjust for confounding by sex, gestational age, and co-exposures such as tobacco, marijuana and cocaine with the “other opioid” exposure group as the reference group.

Results: Among neonates exposed to antenatal opioids, primary exposures included: 152 (23%) methadone, 410 (62%) buprenorphine and 102 (15%) other opioids. Median maternal opioid dose was 90 mg daily among the methadone-exposed neonates and 16 mg daily among the buprenorphine-exposed neonates. Additional maternal medication or drug co-exposures including antidepressants, benzodiazepines, tobacco, marijuana and cocaine. Mean head circumference among neonates with antenatal methadone exposure was smaller in females by 0.8 cm (p=0.009) and in males by 0.7 cm (p=0.006) compared to neonates with primary exposures of both buprenorphine and other opioids. Head circumference < 3rd percentile was twice as prevalent among neonates with opioid exposures of any type as compared with neonates without opioid exposure; 12 (4.1%) female and 16 (4.5%) male opioid-exposed neonates vs. 91 (1.8%) female and 114 (2.1%) male unexposed. In regression analysis, antenatal exposure to methadone was associated with a 0.6 cm decrease in head circumference (-1.01, -0.22; p=0.002) and cocaine exposure with a 0.5 cm decrease (CI -0.91, -0.14; p=0.008) controlling for gestational age, infant sex, and co-exposures.

Conclusion: Neonates with antenatal opioid exposure were twice as likely to have head circumference < 3rd percentile at birth when compared with unexposed neonates. Primary methadone and cocaine antenatal exposures were associated with smaller head circumference at birth compared with other primary antenatal opioid exposure. Future research with neuroimaging and developmental testing is urgently needed to determine if the lower head circumference, particularly in the methadone exposed group, is associated with poorer neurodevelopmental outcomes.


2020 Costas T. Lambrew Research Retreat