Buprenorphine versus Methadone for Opioid Use Disorder in Pregnancy

Abstract

Background: Opioid agonist therapy is strongly recommended for pregnant persons with opioid use disorder. Buprenorphine may be associated with more favorable neonatal and maternal outcomes than methadone, but existing data are limited.

Methods: We conducted a cohort study involving pregnant persons who were enrolled in public insurance programs in the United States during the period from 2000 through 2018 in which we examined outcomes among those who received buprenorphine as compared with those who received methadone. Exposure to the two medications was assessed in early pregnancy (through gestational week 19), late pregnancy (gestational week 20 through the day before delivery), and the 30 days before delivery. Risk ratios for neonatal and maternal outcomes were adjusted for confounders with the use of propensity-score overlap weights.

Results: The data source for the study consisted of 2,548,372 pregnancies that ended in live births. In early pregnancy, 10,704 pregnant persons were exposed to buprenorphine and 4387 to methadone. In late pregnancy, 11,272 were exposed to buprenorphine and 5056 to methadone (9976 and 4597, respectively, in the 30 days before delivery). Neonatal abstinence syndrome occurred in 52.0% of the infants who were exposed to buprenorphine in the 30 days before delivery as compared with 69.2% of those exposed to methadone (adjusted relative risk, 0.73; 95% confidence interval [CI], 0.71 to 0.75). Preterm birth occurred in 14.4% of infants exposed to buprenorphine in early pregnancy and in 24.9% of those exposed to methadone (adjusted relative risk, 0.58; 95% CI, 0.53 to 0.62); small size for gestational age in 12.1% and 15.3%, respectively (adjusted relative risk, 0.72; 95% CI, 0.66 to 0.80); and low birth weight in 8.3% and 14.9% (adjusted relative risk, 0.56; 95% CI, 0.50 to 0.63). Delivery by cesarean section occurred in 33.6% of pregnant persons exposed to buprenorphine in early pregnancy and 33.1% of those exposed to methadone (adjusted relative risk, 1.02; 95% CI, 0.97 to 1.08), and severe maternal complications developed in 3.3% and 3.5%, respectively (adjusted relative risk, 0.91; 95% CI, 0.74 to 1.13). Results of exposure in late pregnancy were consistent with results of exposure in early pregnancy.

Conclusions: The use of buprenorphine in pregnancy was associated with a lower risk of adverse neonatal outcomes than methadone use; however, the risk of adverse maternal outcomes was similar among persons who received buprenorphine and those who received methadone. (Funded by the National Institute on Drug Abuse.).

Figure 1.. Characteristics of Pregnant Persons and Infants Included in the Study Population.

Receipt of any methadone as an exclusion criterion for persons in the buprenorphine exposure group was defined according to procedure codes for methadone administration and methadone dispensings for indications unrelated to opioid use disorder. Receipt of any buprenorphine as an exclusion criterion for persons in the methadone group was defined as dispensings of buprenorphine of any formulation (not limited to formulations indicated for opioid use disorder). Adjusted analyses were further restricted to pregnant persons with complete ZIP Code data to enable calculation of the socioeconomic status proxies (missing for <1%). This restriction resulted in 10,635 persons in the buprenorphine group and 4332 in the methadone group being included in the analysis during early exposure (from the last menstrual period to gestational week 19), 11,200 in the buprenorphine group and 5001 in the methadone group being included in the analysis during late exposure (gestational week 20 through the day before delivery), and 9908 in the buprenorphine group and 4545 in the methadone group being included in the analysis for exposure in the 30 days before delivery.

Figure 2.. Adverse Outcomes at Birth with Buprenorphine as Compared with Methadone in Pregnancy.

The adjusted analysis was adjusted for all defined covariates, including markers of a history of opioid use disorder and severity, nonopioid substance use or dependence, medical conditions associated with opioid use disorder, mental health conditions, chronic coexisting conditions, other medication use, health care utilization metrics, proxies for social issues, demographic characteristics, and proxies for socioeconomic status. The high-dimensional propensity-score analysis empirically selected 200 variables from all available diagnosis codes, procedure codes, and medication dispensings on the basis of the strength of their relationship to the exposure status for inclusion in the propensity score along with all prespecified covariates. Confidence intervals have not been adjusted for multiple testing and therefore should not be used in place of a hypothesis test.

Figure 3.. Sensitivity Analyses of Adverse Outcomes at Birth with Exposure to Buprenorphine as Compared with Methadone during Pregnancy.

For the early and late exposure, the definition of two or more fills of buprenorphine was two or more dispensings during the exposure windows. For the exposure window of 30 days before delivery, the definition of two or more fills of buprenorphine was two or more dispensings during the 30-day window or at least one dispensing in the 30-day window and one dispensing that was filled before the 30-day window but overlapped with the 30-day window based on the number of days supplied by that dispensing (e.g. a 30-day supply). The subgroup regarding documented opioid use disorder was restricted to persons with a diagnosis code for opioid use disorder from 90 days before the last menstrual period to 1 day before delivery. Coverage of both medications was an analysis cohort restricted to persons who received buprenorphine or methadone when both were covered by the state Medicaid program. The subgroup regarding highest prenatal care was restricted to persons with the highest level of prenatal care as measured with the Adequacy of Prenatal Care Utilization Index (consisting of four categories ranging from inadequate [the lowest rating] to adequate plus [the highest] that rank the adequacy of when prenatal care began and the number of prenatal care visits received). Confidence intervals have not been adjusted for multiple testing and therefore should not be used in place of a hypothesis test.