Reducing Exposure Before Birth: An Interrupted Time Series Study of Prenatal Exposure to Fetotoxic Medications Under Risk Management Plans in Canada

Canada's 2009 risk management plan (RMP) framework has not been evaluated for prenatal exposure impact. Conversely, widely used drugs such as nonsteroidal anti-inflammatory drugs (NSAIDs) lack RMPs. We assessed first-trimester exposure to RMP-regulated medications following regulatory interventions and to NSAIDs following safety publications. We conducted interrupted time series analyses using data from the Québec Pregnancy Cohort (1998-2022), including pregnancies among individuals aged 15-45 years with continuous public prescription drug insurance. First-trimester exposure was defined as dispensed prescriptions overlapping or initiated during gestational weeks 0-14. Exposures included RMP-regulated medications (overall, retinoids, and valproic acid) and prescription NSAIDs. RMP dates served as interruption points. Monthly incidence rates were analyzed using segmented Poisson regression to estimate incidence rate ratios (IRRs) with 95% confidence intervals (CIs). Among 559,215 eligible pregnancies, 6,215 and 87,820 involved first-trimester exposure to RMP-regulated medications and NSAIDs, respectively. The Canadian RMP framework was associated with an immediate 45.3% reduction (IRR: 0.547, 95% CI: 0.403-0.743) and a sustained 1.3% monthly decline (IRR: 0.987, 95% CI: 0.981-0.994). Retinoid exposure declined by 12.5% per month post-SMART RMP (IRR: 0.875, 95% CI: 0.772-0.993), with reductions post-iPLEDGE RMP (IRR: 0.949, 95% CI: 0.932-0.966). Valproic acid exposure declined after the strengthened FDA boxed warning (IRR: 0.869, 95% CI: 0.836-0.903) and migraine prophylaxis contraindication (IRR: 0.754, 95% CI: 0.543-1.046). NSAID publications yielded transient effects. RMPs were associated with sustained prenatal exposure reductions, whereas safety publications were associated with transient effects, highlighting the need for reinforced risk-management strategies.