Prenatal exposure to teratogenic medications in the era of Risk Evaluation and Mitigation Strategies.

Background: Prevention of prenatal exposures to teratogenic drugs is a significant clinical and public health concern. With the enactment of the US Food and Drug Administration Amendments Act in 2007, the US Food and Drug Administration has begun to require manufacturers to implement Risk Evaluation and Mitigation Strategies to prevent prenatal exposures. Among 12 risk evaluation and mitigation strategy drugs, several had predecessor risk mitigation plans (eg, isotretinoin) and some were newly required (eg, mycophenolate). Only a small proportion of teratogenic drugs are currently subject to Risk Evaluation and Mitigation Strategies, and the extent of prenatal exposure to the universe of teratogenic drugs compared with drugs subject to Risk Evaluation and Mitigation Strategies is unknown. Moreover, the effectiveness of such advanced risk mitigation programs in preventing prenatal exposure is not clear.

Objective: This study aimed to characterize the epidemiology of prenatal exposures to definite and potential teratogens during the risk evaluation and mitigation strategy era.

Study Design: We constructed a time-series of pregnancies identified from a national private insurance claims database (IBM MarketScan) to estimate prenatal exposures to teratogenic drugs (2006-2017). Pregnancy outcomes, gestational age, and the onset of pregnancy were determined with previously validated algorithms. The Teratology Information Service and Clinical Pharmacology databases were used to identify drugs with definite (n=141) or potential (n=65) teratogenic effects, and drugs with debatable risks such as benzodiazepines, statins, tetracyclines, sex hormones, infertility treatments, and gonadotropin-releasing hormone analogs were excluded. We defined prenatal exposure as ≥1 prescription fill or medical encounter involving administration of drugs with a definite teratogenic risk (including 12 for which there is a "current or discontinued" risk evaluation and mitigation strategy) or a potential teratogenic risk. We evaluated secular trends and modeled the effects of age, preconception exposure, and state healthcare quality rankings on prenatal exposure, adjusting for demographic factors and clinical conditions.

Results: The cohort included 3,445,612 pregnancies (2,532,444 live deliveries). Prenatal exposures to definite teratogens decreased slightly during the study years from 1.86 to 1.24 per 100 pregnancies between 2006 and 2017, whereas exposure increased for potential teratogens from 3.40% to 5.33%. Prenatal exposure prevalences were higher during the first trimester and for pregnancies that ended in nonlive outcomes. Drugs subject to Risk Evaluation and Mitigation Strategies had low background utilization and contributed to a small proportion of prenatal exposures (15.1 per 100,000 pregnancies). We also observed fewer prenatal exposures to risk evaluation and mitigation strategy drugs among women of childbearing age who used these treatments (0.14% vs 0.36% for any definite teratogen). Age extremes and low state-level healthcare quality rankings were independent predictors of prenatal exposure.

Conclusion: Fetuses in more than 1 in 16 pregnancies continued to be exposed to teratogenic drugs during the past decade. Drugs with Risk Evaluation and Mitigation Strategies imposed a small burden of prenatal exposure because of the low background utilization rates and lower pregnancy prevalence among women of childbearing age who used these drugs. Although the declining exposure rates to teratogenic drugs with definite risk are encouraging, the rising prenatal exposure to drugs with potential risk calls for more assessments. Future research is needed to elucidate the health outcomes of fetuses exposed to potential risk drugs, understand the effectiveness of risk evaluation and mitigation strategy programs, and prioritize teratogenic drugs for advanced risk mitigation.