The effect of antiseizure medications on the exposure to combined oral contraceptives: A systematic review and network meta‐analysis

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OBJECTIVE: Current recommendations for prescribing combined oral contraceptives (COCs) to people with epilepsy are often conflicting, particularly for weak inducers of cytochrome P450 3A4. We aimed to critically review the literature and compare the antiseizure medication (ASM)-induced changes in exposure to COC components. METHODS: In this systematic review and network meta-analysis (PROSPERO: CRD42024513792), in accordance with PRISMA 2015/2020, we searched PubMed, EMBASE, Cochrane, and FDA documents up to January 2026. Eligible studies were clinical trials assessing induction (≥ 5 days) of ethinylestradiol combined with progestins by ASMs. The areas under the concentration-time curve (AUC) of individual hormones with/without the ASM were indirectly compared. The point estimate was the standardized mean difference (SMD; significant when the 95% confidence interval does not encompass zero). Bias risk was assessed using the PKclin tool. RESULTS: The 17 studies (16 reports) involving 399 individuals and 15 ASMs were all conducted with COCs containing the two progestins least sensitive to enzyme induction and ≥ 30 μg ethinylestradiol. Nine ASMs were studied at doses 13-75% lower than the recommended maximum (median 50%). Brivaracetam (100 mg/day) reduced the exposure to ethinylestradiol more than 1000 mg/day levetiracetam (SMD -10; 95% confidence interval - 0.20-0). The effects of 300 mg/day lamotrigine on ethinylestradiol and levonorgestrel were greater than those of 400 mg/day lacosamide (0.18; 0.11-0.25, 0.28; 0.20-0.37). Low-dose (50 mg/day) and high-dose (200 mg/day) topiramate were comparable in their effects on ethinylestradiol and norethindrone, and the low dose did not differ from weak inducers in altering ethinylestradiol exposure. SIGNIFICANCE: Current recommendations may underestimate ASM effects on exposure to COC components, especially those in newer COCs. Greater caution is recommended with low-dose topiramate. For individuals treated with weak COC inducers without additional contraceptive means, COCs containing levonorgestrel or norethindrone might be preferable given their lower vulnerability to induction.