Summary: For women with epilepsy taking antiseizure medications (ASMs), the timing of vitamin supplementation can be a life-altering factor. A massive Nordic study reveals that starting high-dose folic acid before pregnancy reduces the risk of major congenital anomalies by approximately 45%.
Crucially, the study found that starting the supplement after becoming pregnant offered no protective effect, highlighting a strict “critical window” for intervention.
Key Findings
- Timing is Everything: The protective effect is entirely dependent on starting the supplement at least one month before conception. Once pregnancy begins, the “window” for preventing these specific anomalies appears to close.
- Clarifying the Evidence: While high-dose folic acid has been recommended for years, previous data was inconsistent. This study used target trial emulation to mimic a clinical trial, providing much-needed clarity on why previous studies may have failed (by not accounting for the exact start date).
- Planning is Paramount: Because many pregnancies are unplanned, this research underscores the need for women of childbearing age with epilepsy to maintain a constant dialogue with their neurologists regarding pregnancy planning.
- Observational Strength: While not a randomized controlled trial, the 20-year dataset across four countries makes this one of the most robust observational studies ever conducted on this topic.
Source: Aarhus University
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).
22 fewer cases per 1,000 pregnancies
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.
Funding: NordForsk, Trond Mohn Foundation, Research Council of Norway
Key Questions Answered:
A: You should always follow your doctor’s advice, but this study shows the preventative effect for major anomalies happens before conception. Folic acid is still important for other aspects of pregnancy, but the specific “shield” against medication-related defects is built in the weeks leading up to pregnancy.
A: Some epilepsy medications can interfere with how the body processes folate, which is essential for the early development of a baby’s neural tube and organs. High-dose folic acid helps “override” this interference, ensuring the embryo has the nutrients it needs during the first few days of life.
A: No. Standard prenatals usually contain about 400–800 micrograms. “High-dose” typically refers to 5 milligrams, which is only available by prescription. This study specifically looked at that higher therapeutic dose.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this neurology and neurodevelopment research news
Author: Jakob Christensen
Source: Aarhus University
Contact: Jakob Christensen – Aarhus University
Image: The image is credited to Neuroscience News
Original Research: Open access.
“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” by Yuelian Sun, Silje Alvestad, Jacqueline M. Cohen, Jannicke Igland, Nils Erik Gilhus, Håkon M. Vegrim, Torbjörn Tomson, Jakob Christensen, Maarit K. Leinonen, Mika Gissler, Helga Zoega, Neda Razaz, Julie Werenberg Dreier, and Marte-Helene Bjørk. Journal of Neurology, Neurosurgery, & Psychiatry
DOI:10.1136/jnnp-2025-337395
Abstract
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
Background
High-dose folic acid supplementation is recommended for women using antiseizure medication (ASMs) to reduce risk of major congenital anomalies (MCAs) in offspring, but evidence is lacking.
Methods
We conducted a sequential target trial emulation using nationwide register data from Denmark, Iceland, Norway, and Sweden (1997–2020). Eligible women using ASMs were included and classified as initiators or non-initiators based on whether they filled prescription for high-dose folic acid within one week of inclusion.
Risk difference (RD) and risk ratio (RR) for MCAs diagnosed before one year of age in offspring were estimated for initiators of high-dose folic acid (4 or 5 mg/day) supplementation in three periconceptional periods (13-52 weeks before, 1-12 weeks before, and 1-12 weeks after pregnancy onset) compared with non-initiators.
Results
We included 18 255, 13 619, and 12 365 eligible pregnancies and identified 1047 (5.7%), 521 (3.8%) and 1778 (14.4%) initiators of high-dose folic acid in the three periods, respectively. Initiation of high-dose folic acid 1–12 weeks before pregnancy was associated with a lower prevalence of MCA in offspring (2.6% vs 4.8% among non-initiators), corresponding to an absolute risk reduction of 2.2 percentage points (95% CI 0.5 to 3.5) and a 45% relative risk reduction (RR=0.55, 95% CI 0.25 to 0.91). No risk reduction was observed with initiation 1–12 weeks after (RR=1.27, 95% CI 0.94 to 1.64) or 13–52 weeks before (RR=0.99, 95% CI 0.65 to 1.36) pregnancy onset.
Conclusions
Initiation of high-dose folic acid in the 12 weeks before pregnancy was associated with a reduced risk of MCA in offspring of women using ASMs while initiation in the 12 weeks after pregnancy onset was not.
