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- Title
Prenatal Exposure to Valproic Acid Across Various Indications for Use.
- Authors
Smolinski, Nicole E.; Sarayani, Amir; Thai, Thuy N.; Jugl, Sebastian; Ewig, Celeste L. Y.; Winterstein, Almut G.
- Abstract
Key Points: Question: Are US Food and Drug Administration warnings to prevent prenatal exposure to valproic acid associated with changes in pregnancy risk and contraceptive use across indications? Findings: In this cohort study of 165 772 valproic acid treatment episodes among 69 390 women, pregnancy rates during treatment remained unchanged during the 15-year study and were more than doubled among users with mood disorder or migraine compared with epilepsy. Contraception use among users was uncommon, with only 22.3% of treatment episodes having a 1-day overlap of valproic acid and contraception use. Meaning: These findings suggest a need to review efforts to mitigate prenatal exposure to valproic acid, especially for clinical indications where risk of use during pregnancy outweighs therapeutic benefit and safer alternatives are available. This cohort study evaluates the risk for pregnancy onset during valproic acid treatment across indications and assesses the use of contraception during treatment among US women of childbearing age. Importance: Teratogenic outcomes associated with valproic acid use represent a substantial concern for persons of childbearing age. Regulatory agencies worldwide have enhanced warnings or implemented risk minimization programs to reduce exposure during pregnancy. Objectives: To determine pregnancy rates during valproic acid use and concomitant contraception use across indications. Design, Setting, and Participants: This retrospective cohort study used data from the Merative MarketScan commercial claims databases from January 1, 2005, to December 31, 2020, to identify female patients aged 12 to 44 years who initiated valproic acid treatment and had continuous insurance enrollment 6 months before initiation and 9 months after treatment end. A treatment episode included consecutive prescription fills that occurred within 7 days from the end of the days' supply of the previous dispensing. Data were analyzed from March 1 to September 10, 2023. Main Outcomes and Measures: Treatment episodes were categorized by inferred indication using diagnoses preceding treatment initiation, including epilepsy, migraine or headache, mood disorders, and unknown or off-label uses. Pregnancy incidence rate ratios (IRRs) were calculated and were adjusted for age and calendar year. Contraceptive use (prescription contraceptives, intrauterine devices, and implants) during treatment was examined. Results: The cohort included 165 772 valproic acid treatment episodes among 69 390 women (mean [SD] age, 29.8 [10.0] years). Mood disorders (42.5%) were the most common indication, followed by migraine or headache (20.1%), with epilepsy playing a minor role (14.9%). Pregnancy incidence rates during valproic acid use remained unchanged, with a rate of 1.74 (95% CI, 1.14-2.53) per 100 person-years in 2005 and a rate of 1.90 (95% CI, 1.16-3.12) per 100 person-years in 2019. Compared with epilepsy, pregnancy rates were more than double for mood disorder (IRR, 2.16 [95% CI, 1.93-2.42]) and migraine or headache (IRR, 2.01 [95% CI, 1.92-2.09]). Few treatment episodes coincided with contraceptive use (37 012 [22.3%]), and oral dosage forms were the most common (27 069 [73.1%]). Conclusions and Relevance: In this cohort study of patients of childbearing age who used valproic acid, pregnancy rates during valproic acid use did not decrease despite enhanced US Food and Drug Administration safety communications, and contraception use remained low. Patients with migraine and mood disorders accounted for the largest proportion of valproic acid use and had the highest pregnancy rates, while patients with epilepsy had the lowest. These findings suggest a need to enhance efforts to mitigate prenatal exposure to valproic acid, especially for indications where the risk of use during pregnancy outweighs the benefit.
- Subjects
POISSON distribution; PRENATAL exposure delayed effects; AFFECTIVE disorders; RETROSPECTIVE studies; DESCRIPTIVE statistics; LONGITUDINAL method; VALPROIC acid; EPILEPSY; CONTRACEPTION; CONFIDENCE intervals; COMPARATIVE studies; DATA analysis software; MIGRAINE; HOSPITAL pharmacies
- Publication
JAMA Network Open, 2024, Vol 7, Issue 5, pe2412680
- ISSN
2574-3805
- Publication type
Article
- DOI
10.1001/jamanetworkopen.2024.12680