Background: Valproic acid (VA) has multiple neurologic and psychiatric indications. Given its known teratogenic effect, the risk-benefit of VA use among persons of childbearing age may vary by indication. To prevent prenatal exposure, regulatory agencies worldwide have issued warnings or implemented risk minimization programs.
Objectives: To determine the rate of pregnancy onset during VA use and the extent of contraception use across different indications.
Methods: We conducted a retrospective cohort study using Merative Marketscan Research Databases (2005-2020) of female patients 12-55 years old who had VA treatment episodes (defined as continuous exposure with ≤7-day gap in days’ supply). We required continuous insurance enrollment 6 months before treatment initiation to 9 months after treatment end. We identified VA related indications (epilepsy, migraine, and mood disorders) based on outpatient diagnoses in the 6 months before treatment initiation and used a previously validated pregnancy identification algorithm to identify pregnancy episodes. We calculated unadjusted and age-standardized (using 2015 US Census data) pregnancy incidence rates during VA use, stratified by indication. Exposure periods to hormonal contraceptives (any dosage form) and intrauterine devices (hormonal or copper) were ascertained from pharmacy fills and outpatient procedure codes. Contraception use was defined as having ≥1-day overlap with VA treatment episodes.
Results: Our cohort included 268,623 VA episodes among women with a median age of 40. Mood disorders (41.9%) were the most common indication, followed by migraine/headache (20.5%) and epilepsy (12.9%). We identified 733 pregnancies during VA use. Patients with epilepsy had the lowest age-standardized pregnancy incidence rate (1.29 per 100 person-years, 95% CI 0.88-1.69), while those with mood disorders had the highest rate (2.30, 95% CI 2.20-2.39), followed by migraine/headache (2.22, 95% CI 1.89-2.55). Only 15.2% of treatment episodes coincided with contraceptive use with oral hormonal contraceptives used most frequently (80.1%).
Conclusions: Pregnancy incidence rates during treatment with VA varied by clinical indications, and concomitant contraception use was uncommon. Our study suggests that additional risk mitigation efforts are warranted, especially for patients with higher pregnancy rates and higher potential for unfavorable risk-benefit of VA use during pregnancy, such as those with migraine/headaches or mood disorders.
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