(096) Medications considered to have substantial teratogenic risk commonly used in US pregnant population – quality of evidence and magnitude of risk

Publication Number: 1091

Background: Exposure to teratogenic medications during pregnancy can cause significant harm for both mother and infant, but most known teratogens are approved without risk mitigation programs that could help prevent prenatal exposure. To appropriately weigh risk-benefit of risk mitigation programs, high-quality evidence supporting teratogenicity and precise estimates of the magnitude of risk are needed.

Objectives: To evaluate the available evidence on teratogenic risk of teratogens with high prenatal exposure prevalence and without risk mitigation programs in the US.

Methods: We conducted a literature search in PubMed on the most commonly used teratogens during pregnancy from inception to December 2022. Included teratogens were sulfamethoxazole/trimethoprim (SMX/TMP), fluconazole, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEis/ARBs), carbamazepine (CBZ), warfarin, and vedolizumab. We used a broad search strategy to identify studies that were conducted among pregnant populations with reported fetal and/or infant outcomes resulting from the use of these medications. We excluded animal studies and uncontrolled human studies (e.g., case series). Among included studies, we extracted data on all fetal and infant-related outcomes including outcome types and magnitude of risk. Two independent reviewers conducted risk of bias evaluations using ROBINS-1 for all included observational studies.

Results: All study drugs had evidence from controlled studies, although few were assessed as having low/moderate risk of bias: 11 (7 with low/moderate risk of bias) for fluconazole, 13 (6) ACEis/ARBs, and 6 (0) vedolizumab. Evaluation of warfarin (30) and CBZ (107) is in progress. SMP/TMX had 14 studies, 11 (4) were observational and 3 were clinical trials in HIV pregnant patients. Evaluated outcomes varied across drugs: each had studies that evaluated risk of pregnancy loss and congenital malformations. Other outcomes included developmental disorders (CBZ, TMP/SMX), APGAR (CBZ), prematurity (CBZ, warfarin, vedolizumab, TMP/SMX), and small for gestational age (CBZ, TMP/SMX).

Conclusions: The quality of evidence and types of evaluated outcomes detailing the magnitude of teratogen risk varied across selected drugs. Addressing this inconsistency can help inform regulatory and clinical decision-making on the need for risk mitigation strategies to prevent prenatal exposure and evaluate the risk-benefit of treatment during pregnancy. A critical review of existing evidence, or lack thereof, could provide the necessary direction for future research.