Summary: For women with epilepsy who take antiseizure medications (ASMs), the timing of folic acid supplementation is critically important. A large Nordic register-based study shows that initiating high-dose folic acid before pregnancy reduces the risk of major congenital anomalies by about 45% compared with not taking high-dose folic acid. Starting supplementation after pregnancy begins did not provide this protective effect, indicating a narrow periconceptional window for prevention.
This multicountry study emphasizes that prevention depends on starting high-dose folic acid at least one month before conception. The findings clarify earlier inconsistent results by focusing on precise timing and using a robust target trial emulation approach to approximate a randomized trial.
Key Findings
- Timing matters: The protective effect is confined to initiation of high-dose folic acid in the 1–12 weeks before pregnancy. Initiation after pregnancy onset showed no measurable reduction in risk.
- Clearer evidence with better methods: The study used target trial emulation to reduce biases common to observational research, especially those related to the exact timing of supplement initiation.
- Practical implications: Because many pregnancies are unplanned, women of childbearing potential who use ASMs should discuss preconception planning and folic acid strategies with their clinicians.
- Large and comprehensive dataset: The analysis spans more than 20 years of nationwide register data from Denmark, Norway, Sweden, and Iceland, making it one of the largest observational investigations on this topic.
Source: Aarhus University
Main conclusion: Women taking antiseizure medications who begin high-dose folic acid supplementation before conception have an approximately 45% lower risk of having a child with a major congenital anomaly compared with women on ASMs who do not start high-dose folic acid before pregnancy.
22 fewer cases per 1,000 pregnancies
The study analyzed more than 13,000 pregnancies among women treated with antiseizure medications across Denmark, Norway, Sweden, and Iceland. Researchers compared congenital anomaly rates between those who initiated high-dose folic acid in the periconceptional periods and those who did not.
Key numerical results:
- Among women on ASMs who did not take high-dose folic acid, the prevalence of major congenital anomalies was roughly 48 per 1,000 pregnancies.
- When high-dose folic acid was started 1–12 weeks before pregnancy, the prevalence was about 26 per 1,000 pregnancies.
This translates to an absolute reduction of 22 cases per 1,000 pregnancies and an approximate 45% relative risk reduction. No benefit was observed when supplementation began after pregnancy onset.
Stronger association with higher-risk antiseizure medications
The protective effect of preconception high-dose folic acid was more pronounced for women taking ASMs known to carry higher teratogenic risk, such as valproate. In subgroup analyses, the relative reduction in risk reached up to 86% for some high-risk medication groups, underscoring the importance of individualized preconception counseling for women on specific ASMs.
Clarifying years of uncertainty
High-dose folic acid has long been recommended for women with epilepsy, but prior studies produced mixed results—often because they did not accurately account for when supplementation began relative to conception. By applying target trial emulation and precise timing windows, this study provides stronger evidence that the protective effect is concentrated in the weeks immediately before conception.
Important: planning before pregnancy is essential
These findings do not mean women should change or stop medications without medical advice. Instead, the study highlights the critical need for preconception planning. Women using ASMs should consult their neurologist or prescriber about medication management and the need for prescription high-dose folic acid before attempting to conceive.
Robust method — still observational
The research is based on nationwide register data spanning 1997–2020 across four Nordic countries and uses an advanced target trial emulation approach to better emulate a randomized trial. Nonetheless, it is observational and cannot eliminate all possible unmeasured confounding, so conclusions should be interpreted with appropriate caution.
Funding: NordForsk, Trond Mohn Foundation, Research Council of Norway.
Key Questions Answered
A: Follow your doctor’s guidance. This study indicates that the specific preventive benefit against medication-related major anomalies occurs when high-dose folic acid is started before conception. However, folic acid remains important throughout pregnancy for other developmental reasons, so your clinician may still advise supplementation.
A: Some antiseizure medications can alter folate metabolism or otherwise interfere with early embryonic development. High-dose folic acid can help ensure adequate folate availability during the earliest stages of neural and organ development, reducing the risk of some major congenital anomalies.
A: No. Standard prenatal vitamins generally provide around 400–800 micrograms of folic acid. “High-dose” in this study refers to doses commonly around 4–5 milligrams (4,000–5,000 micrograms), which are typically prescription-strength and should be used under medical supervision.
Editorial Notes
- Edited by a Neuroscience News editor for clarity and context.
- Journal article reviewed in full by staff.
- Additional context added from the research team’s public report.
About this research news
Author: Jakob Christensen
Source: Aarhus University
Contact: Jakob Christensen, Aarhus University
Image: Image credit attributed to Neuroscience News
Original research: Open access. Title: “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.” Authors: Yuelian Sun et al. DOI: 10.1136/jnnp-2025-337395
Abstract (condensed)
Background: High-dose folic acid is commonly recommended for women using antiseizure medications to reduce the risk of major congenital anomalies, but evidence has been inconsistent.
Methods: A sequential target trial emulation used nationwide register data from Denmark, Iceland, Norway, and Sweden (1997–2020) to compare initiation of high-dose folic acid (4–5 mg/day) in defined periconceptional windows with non-initiation.
Results: Initiation 1–12 weeks before pregnancy was associated with a lower prevalence of major congenital anomalies (2.6% vs 4.8% among non-initiators), an absolute risk reduction of 2.2 percentage points and a 45% relative risk reduction. No risk reduction was observed when initiation occurred after pregnancy onset or in the 13–52 weeks before conception.
Conclusions: Starting high-dose folic acid in the 12 weeks before pregnancy was associated with reduced risk of major congenital anomalies among women using antiseizure medications, while initiation after pregnancy onset was not associated with such a reduction.