Opioid use disorder during pregnancy: long‐term developmental outcomes

Widespread prescription and non-prescription opioid use has heightened concern regarding the potential effect of opioids on the developing fetus, as well as the optimal pharmacological management of opioid use disorder (OUD) during pregnancy. Questions also remain regarding the safety of neonatal opioid exposure, whether for analgesia or the treatment of neonatal opioid withdrawal syndrome. Levine et al. explored developmental outcomes associated with prenatal methadone exposure. They conducted a prospective, longitudinal cohort study of 100 infants born to opioid-dependent mothers maintained on methadone during pregnancy and 110 infants born to mothers who randomly gave birth at the same hospital during the same period. They focused on prenatal methadone exposure, and postnatal parental and family factors, and found higher rates of motor, cognitive, language, and emotional/behavioral dysregulation problems in methadone-exposed children, concluding that children exposed to methadone in utero have pervasive developmental difficulties by age 2 years, and arguing for the importance of specialist prenatal care and postnatal intervention support. Their analysis has strengths, including the multiple measures used to ascertain prenatal exposures of interest, the psychosocial measures of family environmental factors, and the long-term and multifaceted outcomes assessed. The key challenge in their analysis is the attribution of the differences in the observed outcomes between the OUD-exposed and OUD-unexposed infants to methadone itself, rather than the varied environmental, social, and clinical factors that may have affected outcomes. Of course, the group of infants exposed to methadone were also exposed to mothers with OUD, as well as differentially exposed to a number of other factors, such as poorer nutritional status in pregnancy, lower socioeconomic status, higher parental stress, and more depression/anxiety relative to the comparison group of infants. Half of the difference in the exposure–outcome association of interest was attenuated by the addition of postnatal family/environmental variables to their model. But it is unclear whether the remaining association, which ‘may reflect the direct effects of prenatal opioid exposure’, is causally related to such exposure or due to residual confounding from any number of measured or unmeasurable differences between the groups of interest. Due to the complexity of potential confounding risk factors and the inconsistent and highly varied results of published studies, the current body of literature has not demonstrated a significant negative association between prenatal opioid exposure (such as methadone) and long-term development. What is clear, however, is that treatment of OUD with methadone or buprenorphine during pregnancy vastly improves both maternal and obstetric outcomes, including reducing the risk of nonmedical opioid use and relapse, increasing OUD treatment retention and engagement in prenatal care, and reducing the risk of obstetric complications and preterm labor/birth. Gao et al. performed a systematic review of developmental outcomes in neonates treated with one opioid (morphine) for sedation or pain, finding that neonatal morphine administration had no negative long-term developmental outcomes in multiple domains assessed including cognitive, motor, and executive function development. Although the authors excluded studies examining the effects of morphine when used to manage neonatal opioid withdrawal syndrome, their findings may nevertheless be relevant to this setting, consistent with professional society clinical guidelines. Prescription opioids are not inherently good or bad, and their value depends crucially on how they are used in clinical practice. Because of the substantial risks of untreated OUD to both pregnant females and the developing fetus, and the maternal and obstetric benefits to treatment with medications for OUD (such as buprenorphine or methadone during pregnancy), professional society guidelines recommend their use as first-line treatment for OUD during pregnancy. Such medications represent just one important component of multidimensional approaches that provide mothers and newborn infants the best opportunity for successful recovery, growth, and development.