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. RESEARCH PROTOCOL REGISTRATION: https://osf.io/vph2n/?view_only=c9361e4996eb4c4da32fc878f2fbf5b9.