Pregnant patients with opioid use disorder (OUD) are strongly encouraged to receive medication treatment with either buprenorphine or methadone. Medications for OUD (MOUD) reduce the risks associated with untreated OUD during pregnancy, including adverse outcomes due to withdrawal, return to opioid use, overdose, intravenous drug use, and inadequacy of prenatal care. Thus far, there has been very sparse data on the reproductive safety of buprenorphine and methadone. 

A recent study from Suarez and colleagues compares the risk of congenital malformations following first trimester exposure to buprenorphine and methadone. The researchers analyzed data from publicly insured Medicaid beneficiaries in the US between 2000 and 2018. In this cohort, a total of 13,360 pregnancies with first trimester use of either buprenorphine or methadone were identified and linked to infant medical records. Rates of major malformations overall and specific malformations previously associated with opioid exposure (cardiac malformations, neural tube defects, clubfoot, and oral clefts) were assessed. 

The cohort included 9,514 pregnancies with first-trimester buprenorphine exposure (mean [SD] maternal age, 28.4 [4.6] years) and 3,846 with methadone exposure (mean [SD] maternal age, 28.8 [4.7] years). The risk of malformations overall was 50.9 per 1000 pregnancies for buprenorphine and 60.6 per 1,000 pregnancies for methadone. After adjusting for confounding factors, buprenorphine was associated with a lower risk of malformations compared with methadone (RR, 0.82; 95% CI, 0.69-0.97). With regard to specific malformations, risk was lower with buprenorphine for 

  • Cardiac malformations (RR, 0.63; 95% CI, 0.47-0.85), 
  • Oral clefts (RR, 0.65; 95% CI, 0.35-1.19), and 
  • Clubfoot (RR, 0.55; 95% CI, 0.32-0.94).

In secondary analyses, buprenorphine was associated with a lower risk of central nervous system, urinary, and limb malformations but a greater risk of gastrointestinal malformations compared to methadone. 

Clinical Implications

In this large cohort study analyzing data from publicly insured Medicaid beneficiaries, the overall risk of malformations was lower with buprenorphine than with methadone. Moreover, the risk of most malformations previously associated with opioid exposure, including cardiac defects, oral clefts, and clubfoot, was lower in buprenorphine-exposed infants compared to those exposed to methadone. This study is the largest to date examining the reproductive safety of buprenorphine and methadone and provides important information to patients and their providers.

While risk of malformation is one important factor informing decisions regarding the use of medications for opioid use disorder during pregnancy, it is not the only factor. Whatever treatment is selected, it is important to emphasize that the “best” treatment is the one that reduces the risk of opioid use during pregnancy. 

Although this study indicates that buprenorphine may have a lower risk of malformations than methadone, this finding does not preclude the use of methadone during pregnancy. For some pregnant patients, particularly those on stable treatment with methadone prior to pregnancy or patients who do not respond well to buprenorphine, methadone may be the best treatment choice.

The ultimate goal is to ensure continued access to effective MOUD during pregnancy and the postpartum period. One must consider information regarding reproductive safety, as well as other factors including access to a particular treatment, patient preference, treatment response, and the likelihood of retention in treatment.

Ruta Nonacs, MD PhD


Suarez EA, Bateman BT, Straub L, Hernández-Díaz S, Jones HE, Gray KJ, Connery HS, Davis JM, Lester B, Terplan M, Zhu Y, Vine SM, Mogun H, Huybrechts KF. First Trimester Use of Buprenorphine or Methadone and the Risk of Congenital Malformations. JAMA Intern Med. 2024 Jan 22: e236986.

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