Early folic acid supplementation may halve risk of birth defects, finds research

Women taking antiseizure medication for epilepsy, have around a 45% reduced risk of major congenital anomalies in their children-if they initiate high-dose folic acid before pregnancy.

This is the finding of a large Nordic register-based study (SCAN-AED) involving Aarhus University Hospital. The study also finds that starting folic acid supplementation after pregnancy onset is not associated with any protective effect.

– We observe a clear association between the timing of initiation of high dose folic acid supplementation and the risk of congenital anomalies. The critical window of starting high-dose folic acid supplementation appears to be before pregnancy, says Jakob Christensen, consultant neurologist at Aarhus University Hospital and professor at Aarhus University.

The paper has been published in the scientific journal JNNP (Journal of Neurology, Neurosurgery & Psychiatry). 

The study includes data from more than 13,000 pregnancies among women treated with antiseizure medications in Denmark, Norway, Sweden, and Iceland.

The results show that:

• The risk of congenital anomalies was approximately 48 per 1000 pregnancies among women using antiseizure medication without high-dose folic acid
• The risk of congenital anomalies was approximately 26 per 1000 pregnancies when supplementation with high dose folic acid is initiated 1–12 weeks before pregnancy

This corresponds to an absolute risk reduction of 22 cases per 1000 pregnancies and a relative reduction of 45%.

No reduction in risk of congenital anomalies was observed when folic acid supplementation was initiated after pregnancy onset.

Stronger association with high-risk medications

The association was even stronger among women taking medications associated with a higher risk of fetal harm, including valproate, where subgroup analyses showed up to an 86% relative reduction in risk.

Clarifies years of uncertainty

High-dose folic acid has been recommended for pregnant women with epilepsy for many years, but the evidence has been limited and inconsistent.

– Previous studies of folic acid have not adequately accounted for timing of the treatment. Our study shows that this is a crucial factor, says Dr. Yuelian Sun, who is the first author on the paper and Senior researcher at Aarhus University Hospital and the University of Bergen in Norway.

Important: Requires planning before pregnancy

The researchers emphasize that the findings do not mean women should change treatment on their own.

– The key message is that planning before pregnancy is essential. Women should always discuss both medication and folic acid supplementation with their doctor, says Julie Werenberg Dreier, Professor at the Department of Public Health at Aarhus University.

Robust method - but not a randomized trial

The study is based on nationwide register data from four Nordic countries over more than 20 years and uses an advanced method known as target trial emulation, which mimics a clinical trial.

However, it remains an observational study, and the findings should be interpreted with caution due to the possibility of unmeasured confounding factors with potential impact on child outcome.

Reference:

Sun Y, Alvestad S, Cohen JM, et al. Timing of high-dose folic acid supplementation in the periconceptional period among women taking antiseizure medications and risk of major congenital anomalies: a target trial emulation Journal of Neurology, Neurosurgery & Psychiatry, 2026 DOI: 10.1136/jnnp-2025-337395