By Erin C. Nacev, MD, MPH, and Maria I. Rodriguez, MD, MPH
Dr. Nacev is Resident Physician, Department of Obstetrics & Gynecology, Oregon Health & Science University, Portland.
Dr. Rodriguez is Professor, Obstetrics & Gynecology, Division of Complex Family Planning, Department of Obstetrics & Gynecology, Oregon Health & Science University, Portland.
In this large, retrospective cohort study of births covered by Medicaid from 2000-2018, the authors used linked Medicaid use data to compare 9,514 pregnancies with buprenorphine exposure and 3,846 with methadone exposure in the first trimester. After adjusting for relevant confounders, the risk of major congenital malformation was lower for buprenorphine-exposed infants compared to methadone-exposed infants (risk ratio, 0.82; 95% confidence interval, 0.69-0.97), although rates overall remained low (50.9 per 1,000 for buprenorphine and 60.6 per 1,000 for methadone).
Suarez EA, Bateman BT, Straub L, et al. First trimester use of buprenorphine or methadone and the risk of congenital malformations. JAMA Intern Med 2024;184:242-251.
Opioid use disorder (OUD) among people of reproductive age is increasing in the United States.1 Strong evidence supports medication for opioid use disorder (MOUD) during pregnancy with buprenorphine or methadone over untreated OUD or supervised withdrawal.2 Recent data suggest improved neonatal outcomes among those treated with buprenorphine compared to methadone, with lower rates of preterm birth, low birth weight, and neonatal abstinence syndrome.3 However, data regarding the risk of congenital malformations in pregnancies exposed to MOUD remain limited. One meta-analysis reported no statistical difference between methadone and buprenorphine, although it included only 14 cases of malformations among slightly more than 1,064 exposed pregnancies.4 Other studies have reported rates of congenital malformations among MOUD-exposed pregnancies but have been limited by small cohorts, lack of adjustment for confounders, and/or no formal comparison between groups.5,6 Thus, clinical guidance around this factor has been limited.
Buprenorphine is a partial mu-opioid receptor agonist that historically required a prescription waiver. However, this waiver was removed in January 2023, greatly improving access to the medication.7 Methadone, in contrast, is a full mu-opioid agonist that requires daily administration at an opioid treatment program (OTP). Benefits and drawbacks exist for both medications, and a decision about which is best for any patient must be individualized. In this study, the primary objective was to assess for a difference in the prevalence of major congenital malformations in pregnancies exposed to buprenorphine vs. methadone in the first trimester in a large population of births. The authors used linked Medicaid claims for the birthing parent and infant from 2000-2018. Dates of the last menstrual period were estimated as 245 days prior to a birth with a diagnosis code indicating preterm delivery and 270 days before a birth with a diagnosis code for all other pregnancies. The first trimester and timing of buprenorphine were estimated from this process.
Buprenorphine and methadone were identified in the pharmacy or medical claim files using National Drug Classification or Current Procedural Terminology codes. The primary outcome was a composite of any congenital malformation as well as specific malformations that have been associated with maternal opioid exposure during pregnancy, including cardiac defects, neural tube defects, cleft lip/palate, and clubfoot.
Their secondary analysis assessed for differences in other specific malformations. They included covariates associated with OUD during pregnancy. They used propensity scores to control for selection into treatment with cohorts matched on all relevant covariates. The authors found that buprenorphine was associated with a lower risk of any congenital malformation (50.9 per 1,000; 95% confidence interval [CI], 46.5-55.3) when compared to methadone (60.6 per 1,000; 95% CI, 53.0-68.1) with an adjusted relative risk of 0.82 (95% CI, 0.69-0.97).
The investigators adjusted for a wide range of potential confounders (n = 22), including different demographic, socioeconomic, and health history factors. The same was true for each specific malformation in their primary analysis. In their secondary analysis, the risk of each of the other malformations also was lower in the buprenorphine group, with the exception of gastrointestinal (GI) malformations. The majority of GI malformations were pyloric stenosis (74%). The adjusted relative risk for buprenorphine compared to methadone was 1.98 (95% CI, 1.15-3.39) for GI malformations.
The authors conducted several sensitivity analyses, including a negative cohort analysis of pregnancies in which MOUD was initiated in the second trimester (i.e., after organogenesis). As expected, they found no difference in the rates of congenital malformations between buprenorphine- and methadone-exposed pregnancies when initiated in the second trimester, suggesting that the difference seen in the primary analysis represents a true difference between groups.
COMMENTARY
Pregnant patients with OUD face barriers to MOUD despite consensus about its safety and status as the standard of care. The stigma around substance use persists, and the availability of MOUD is limited by provider comfort. Ultimately, treatment should be grounded in shared decision-making. Given longstanding safety data of both medications, the current study should not prompt switching or stopping MOUD during pregnancy. Generally, a patient who is stable on MOUD prior to pregnancy should be counseled that the medication is safe to continue during pregnancy. Significant morbidity and mortality is associated with untreated OUD or abrupt withdrawal from opioids during pregnancy.
In the current study, the rates of congenital malformations in both the buprenorphine and methadone groups were low, although the authors do not include a formal comparison to the population baseline risk of 3.0% quoted by the Centers for Disease Control and Prevention.8 The difference seen was statistically significant but small. Overall, these results should be considered among other factors relevant to patients receiving MOUD before and during pregnancy.
These data perhaps are most clinically relevant for counseling or guidance when initiating MOUD in the preconception and early pregnancy periods. The small increased risk of malformations seen in methadone-exposed pregnancies can be considered among other clinical and contextual factors and likely does not outweigh the benefits of methadone treatment for some patients.
Finally, exposure to medications in the first trimester often occurs before a pregnancy is recognized. Thus, these findings have relevance not only for the growing number of pregnancies per year affected by OUD but also for the growing number of people of reproductive age with OUD at risk for pregnancy.
REFERENCES
- Hirai AH, Ko JY, Owens PL, et al. Neonatal abstinence syndrome and maternal opioid-related diagnoses in the US, 2010-2017. JAMA 2021;325:146-155.
- Jones HE, Martin PR, Heil SH, et al. Treatment of opioid-dependent pregnant women: Clinical and research issues. J Subst Abuse Treat 2008;35:245-259.
- Suarez EA, Huybrechts KF, Straub L, et al. Buprenorphine versus methadone for opioid use disorder in pregnancy. N Engl J Med 2022;387:2033-2044.
- Zedler BK, Mann AL, Kim MM, et al. Buprenorphine compared with methadone to treat pregnant women with opioid use disorder: A systematic review and meta-analysis of safety in the mother, fetus and child. Addiction 2016;111:2115-2128.
- Nørgaard M, Nielsson MS, Heide-Jørgensen U. Birth and neonatal outcomes following opioid use in pregnancy: A Danish population-based study. Subst Abuse 2015;9(Suppl 2):5-11.
- Kelty E, Hulse G. A retrospective cohort study of birth outcomes in neonates exposed to naltrexone in utero: A comparison with methadone-, buprenorphine- and non-opioid-exposed neonates. Drugs 2017;77:1211-1219.
- Congress.gov. H.R.2617 – Consolidated Appropriations Act.; 2023. https://www.congress.gov/bill/ 117th-congress/house-bill/2617
- Centers for Disease Control and Prevention. Data and statistics on birth defects. https://www.cdc.gov/ncbddd/birthdefects/data.html
