(268) Comparative safety of prenatal exposure to buprenorphine versus methadone with regards to adverse neurodevelopmental outcomes

Background: Buprenorphine and methadone are both recommended for opioid agonist treatment during pregnancy. Evidence on their comparative safety with regards to long-term neurodevelopment of the child is scarce.

Objectives: To compare the incidence of neurodevelopmental disorders (NDD) among children with prenatal exposure to buprenorphine versus methadone

Methods: This cohort study utilized US nationwide Medicaid data on > 2.5 million live births from 2000 to 2018. Included were mother-child dyads with any exposure to either buprenorphine or methadone during pregnancy. The primary outcome was any of the following NDDs, which were individually examined as secondary outcomes: autism spectrum disorder, attention deficit hyperactivity disorder, developmental speech or language disorder, developmental coordination disorder, behavioral disorder, learning difficulty, and intellectual disability.
Cumulative incidences were obtained using Kaplan-Meier analyses and Cox proportional hazards regression was used to estimate hazard ratios (HR). Propensity score overlap weighting was applied for confounding adjustment including a wide range of covariates: demographics, proxies for severity of opioid use disorder, nonopioid substance use, pain conditions, mental health conditions, other comorbidities, proxies for severity of mental health conditions, concomitant medications, healthcare utilization, and adequacy of prenatal care utilization.

Results: A total of 12,635 and 5390 children were prenatally exposed to buprenorphine and methadone, respectively. The crude cumulative incidence of NDDs was 34% (95% CI: 30-38%) at age 8 years among those exposed to buprenorphine and 33% (95% CI: 29-37%) among those exposed to methadone, corresponding to a crude HR of 0.94 (95% CI: 0.83-1.07).
Adjusted analyses suggested slightly lower hazards of any NDD with prenatal buprenorphine exposure compared to methadone: HR 0.81 (95% CI: 0.70-0.94). Similar findings were observed, however, when using a negative control exposure comparing buprenorphine to methadone exposure (1) within one year prior to pregnancy (adj. HR: 0.84 [95% CI 0.50-1.41]) and (2) within nine months after delivery (adj. HR: 0.83 [95% CI: 0.64-1.07]) without exposure of the fetus during pregnancy.
Secondary analyses indicated a direction in findings consistent with the primary results across individual NDDs.

Conclusions: These findings suggest that the slightly lower hazards of neurodevelopmental disorders among children with in utero exposure to buprenorphine compared with methadone are likely due to unmeasured differences between the two groups rather than a biological effect.