(A-021) Risk Minimization Strategies for Preventing Prenatal Exposure to Teratogenic Medications: Evaluating the Evidence

Background: Risk minimization measures (RMM) measures such as Risk Evaluation and Mitigation Strategies in the US, can be required by health regulatory authorities to prevent prenatal exposure to teratogenic medications. Evidence regarding the impact of RM in achieving the intended goals remains limited.

Objectives: To summarize the current literature on the impact of various RMMs for teratogenic medications on process measures and safety outcomes.

Methods: We conducted a literature review in MEDLINE and EMBASE for studies published from 2000 to 2024. Relevant search terms (e.g. REMS, risk minimization, pregnancy) were used to identify candidate articles. We excluded studies that were (1) qualitative, (2) surveys, or (3) had outcomes not directly assessing the intended impact of the RMM (e.g. effects on other medications with similar indications). We conducted summative analysis of the study designs, outcomes, elements of RMMs, and measures of effectiveness.

Results: Our search yielded 2,105 articles; 13 met our inclusion criteria, 3 of which included studies from multiple countries resulting in 25 unique studies for analysis. RMM for valproate (n=10, 40%) and oral retinoids (n=11, 44%) were the most prevalent target for evaluation. Evaluated RMMs had 4-7 components to minimize prenatal exposure risk, most commonly safe use conditions (e.g. contraception during treatment) and patient/prescriber education. Study designs used were interrupted time series (n=11, 44%), retrospective cohort (i.e. pre- vs post- RMM period (n=9, 36%) and population/therapeutic comparator (n=4, 16%)). Prenatal exposure, defined as conception during treatment (n=8, 33.3%) or pregnancy at treatment initiation (n=13, 52%), was a frequently evaluated safety outcome. Common process measures were proportion of patients with contraception use (n=8, 33.3%) and medication utilization in the target population (n=8, 32%). Among the 17 studies that evaluated prenatal exposure, 10 reported a difference in the incidence of pregnancy during treatment (-0.57 to 0.1 per 100 exposures) compared to a benchmark; 5 of which were statistically significant. Studies on contraceptive use (n=8) reported a 0.34% to 30% increase in this safe use behavior under RMM programs.

Conclusions: Although most studies reported an overall reduction in prenatal exposure, few met the threshold for statistical significance under RMM for teratogenic medications. Heterogeneity in measurement of outcomes and variability of components within each RMM pose challenges in summarizing or comparing effectiveness. Standardization of RMM evaluation metrics and reporting would facilitate evidence synthesis