Summary: For women with epilepsy who take antiseizure medications (ASMs), the timing of high-dose folic acid supplementation can meaningfully reduce the risk of major congenital anomalies in their children. A large Nordic register-based study finds that initiating high-dose folic acid before pregnancy—specifically in the 12 weeks before conception—was associated with about a 45% relative reduction in major congenital anomalies. Starting supplementation after pregnancy onset showed no protective effect, highlighting a narrow periconceptional window for prevention.
This finding has important implications for preconception counseling, epilepsy management in women of childbearing age, and public health guidance on folic acid for those taking antiseizure medications.
Key Findings
- Timing matters: The study found that initiating high-dose folic acid at least one month—and particularly within 1–12 weeks—before conception is associated with the protective effect. Initiation after pregnancy onset did not reduce the risk of major congenital anomalies.
- Substantial risk reduction: Among pregnancies in women using ASMs, high-dose folic acid started 1–12 weeks before pregnancy reduced major congenital anomalies by about 45% relative to non-initiators.
- Absolute benefit: The observed difference corresponds to roughly 22 fewer cases of major congenital anomalies per 1,000 pregnancies when supplementation began in the critical periconceptional period.
- Greater benefit with higher-risk ASMs: The protective association was stronger for women taking ASMs known to carry higher teratogenic risk, including valproate, where subgroup analyses suggested an even larger relative reduction.
- Robust observational design: The study used nationwide register data from Denmark, Norway, Sweden, and Iceland collected over more than 20 years and applied a target trial emulation method to better approximate causal inference in an observational setting.
Source: Aarhus University
Study overview
The Nordic SCAN-AED register-based study analyzed more than 13,000 pregnancies in women treated with antiseizure medications across Denmark, Norway, Sweden, and Iceland. Researchers compared rates of major congenital anomalies (MCAs) among women who initiated high-dose folic acid at different periconceptional periods versus those who did not initiate supplementation.
22 fewer cases per 1,000 pregnancies
Results showed an MCA prevalence of approximately 48 per 1,000 pregnancies among women using ASMs without high-dose folic acid. When high-dose folic acid supplementation was initiated 1–12 weeks before pregnancy, MCA prevalence dropped to about 26 per 1,000 pregnancies. This corresponds to an absolute risk reduction of 22 cases per 1,000 pregnancies (about a 45% relative reduction).
No risk reduction was detected when initiation occurred after pregnancy onset, reinforcing the conclusion that the protective window is periconceptional rather than prenatal.
Stronger association for higher-risk antiseizure medications
The association between preconception high-dose folic acid and reduced risk was particularly pronounced for women taking antiseizure medications with higher known fetal risk, such as valproate. Subgroup analyses suggested up to an 86% relative reduction in some comparisons, underscoring the importance of targeted preconception care for women on these therapies.
Why this clarifies prior uncertainty
High-dose folic acid has been recommended for women with epilepsy for several years, but earlier studies produced inconsistent results. The new study used target trial emulation to account precisely for timing of supplementation and reduce bias that can arise when start dates are not clearly defined. By focusing on the periconceptional window, the research helps explain why earlier analyses may have failed to detect a clear protective effect.
Clinical implications: planning before pregnancy is essential
The researchers emphasize that these results do not mean women should change medications or start high-dose folic acid without medical advice. The key clinical message is the importance of preconception planning. Women of childbearing potential who take antiseizure medications should discuss pregnancy intentions, ASM choice, and folic acid dosing with their neurologist or treating physician to ensure optimal timing and safety.
Study design and limitations
The investigation used national registry data spanning more than two decades from four Nordic countries and applied sequential target trial emulation to emulate randomized comparisons. While this strengthens causal interpretation relative to simpler observational analyses, the study remains non-randomized. Results should be interpreted with caution because unmeasured confounding factors could still influence outcomes.
Funding: NordForsk, Trond Mohn Foundation, Research Council of Norway
Frequently asked questions
A: Follow your doctor’s guidance. This study indicates the specific preventive effect against medication-related major congenital anomalies occurs when high-dose folic acid is started before conception. Folic acid remains important during pregnancy for other reasons, but the “critical window” for preventing these particular defects is before pregnancy onset.
A: Certain antiseizure medications can interfere with folate metabolism or other developmental processes in early embryogenesis. High-dose folic acid can help compensate for impaired folate processing during the very early stages of development, particularly around neural tube formation.
A: No. Standard prenatal vitamins typically contain about 400–800 micrograms of folic acid. “High-dose” generally refers to 4–5 milligrams (4,000–5,000 micrograms) and is typically available by prescription; the study evaluated supplementation at these higher therapeutic doses.
Editorial notes
- This article was edited by a Neuroscience News editor.
- The journal paper was reviewed in full and additional context was added by editorial staff.
Research citation and contact
Author: Jakob Christensen
Source: Aarhus University
Contact: Jakob Christensen – Aarhus University
Image: The image is credited to Neuroscience News
Original research: 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. Published in Journal of Neurology, Neurosurgery & Psychiatry. DOI: 10.1136/jnnp-2025-337395. Open access.
Abstract (concise)
Background: High-dose folic acid supplementation is recommended for women using antiseizure medications to reduce risk of major congenital anomalies, but evidence has been inconsistent.
Methods: Using nationwide register data from Denmark, Iceland, Norway, and Sweden (1997–2020), the investigators performed a sequential target trial emulation. Eligible pregnancies were classified by whether high-dose folic acid (4–5 mg/day) was initiated in defined periconceptional windows (13–52 weeks before, 1–12 weeks before, or 1–12 weeks after pregnancy onset) and compared with non-initiators.
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 (95% CI 0.5 to 3.5) and a 45% relative risk reduction (RR=0.55, 95% CI 0.25 to 0.91). No reduction was observed for initiation 1–12 weeks after pregnancy onset or 13–52 weeks before.
Conclusions: Initiating high-dose folic acid in the 12 weeks before pregnancy was associated with reduced risk of major congenital anomalies in offspring of women using antiseizure medications; initiation after pregnancy onset was not associated with risk reduction.