Folic Acid Supplementation and Risk of Neurodevelopmental Disorders in Children Prenatally Exposed to Anti-Seizure Medication. SCAN-AED: A Nordic Population-based Cohort Study

Abstract number : 2.127
Submission category : 4. Clinical Epilepsy / 4E. Women's Issues
Year : 2021
Submission ID : 1826546
Source : www.aesnet.org
Presentation date : 12/5/2021 12:00:00 PM
Published date : Nov 22, 2021, 06:55 AM

Authors :
Silje Alvestad, MD, PhD - National Centre for Epilepsy, Oslo University Hospital, and University of Bergen, Norway; Jacqueline Mallory Cohen, PhD - Researcher, Department of Chronic Diseases and Ageing, and Centre for Fertility and Health, Norwegian Institute of Public Health, Oslo, Norway; Julie Werenberg Dreier, PhD - University of Bergen, Norway, and Aarhus University, Denmark; Jakob Christensen, MD, DrMedSci - Department of Neurology - Aarhus University Hospital, Denmark; Nils Erik Gilhus, MD PhD - Professor, University of Bergen and Haukeland University Hospital, Bergen, Norway; Mika Gissler, PhD - Finnish Institute for Health and Welfare, Helsinki, Finland, and Karolinska Institute, Stockholm, Sweden; Jannicke Igland, PhD - University of Bergen, Norway; Maarit K. Leinonen, MD PhD - Finnish Institute for Health and Welfare, Helsinki, Finland; Yuelian Sun, PhD - Aarhus University, and Aarhus University Hospital, Denmark; Helga Zoega, PhD - University of Iceland, Reykjavik, Iceland, and University of New South Wales, Sydney, Australia; Torbjörn Tomson, MD PhD - Professor, Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden; Marte-Helene Bjørk, MD PhD - University of Bergen, and Haukeland University Hospital, Norway

Rationale: Prenatal exposure to valproate is associated with an increased risk of neurodevelopmental deficits in children, and folic acid supplementation has been suggested as a method to mitigate such adverse effects. The objective of this study was to investigate whether high-dose periconceptional folic acid supplementation is associated with a reduced risk of neurodevelopmental disorders among children exposed to ASM prenatally.

Methods: This was a prospective population-based cohort study based on health and social register data within the Nordic population-based study of prenatal exposure to anti-seizure medication (ASM) (the SCAN-AED project (www.scanaed.org)). Singleton children born in Denmark, Iceland, Norway, and Sweden between 1997 and 2017 were included. We defined maternal use of periconceptional high-dose folic acid supplement as any redeemed prescription for folic acid at a dose ≥ 1 mg/day, between 90 days before the last menstrual period (LMP) and 60 days after LMP. Prenatal exposure to ASM was defined as at least one redeemed prescription for any substance with ATC class N03, code N05BA09 or code S01EC01, between LMP and birth. The main outcome was neurodevelopmental disorders (NDD), defined as any diagnosis (ICD-10 code) of autism spectrum disorder or intellectual disability from specialist care. Cox proportional hazard regression provided adjusted hazard ratios (HR) and 95% confidence intervals (CIs). The primary analysis was among all children prenatally exposed to ASM. Secondary analyses were restricted to i) children whose mothers had epilepsy, or ii) ASM exposure throughout pregnancy (redeemed prescriptions both in the first trimester and in the second or third trimester).

Results: We identified 15,627 children prenatally exposed to ASM, of whom 4,701 (30%) were also exposed to high-dose periconceptional folic acid. The risk of NDD did not differ between children who were exposed to high-dose periconceptional folic acid and those who were not (HR 0.95, 95% CI 0.75-1.21). The risk was similar when restricting the analysis to children born to mothers with epilepsy (HR 0.89, 95% CI 0.67-1.18). Among children exposed to lamotrigine monotherapy, the HR (95% CI) was 0.73 (0.41-1.31), for carbamazepine monotherapy 0.78 (0.39-1.58), and for valproate monotherapy 0.82 (0.45-1.50). When the analyses were restricted to children with ASM exposure throughout pregnancy, the HRs for NDD associated with high-dose folic acid were lower for lamotrigine (HR 0.56, 95% CI: 0.27-1.15) and for valproate (HR 0.59, 95% CI: 0.30-1.16).

Conclusions: Overall, maternal high-dose folic acid use was not associated with a reduced risk of NDDs for children with any prenatal exposure to ASM. The results were suggestive of a protective effect of high-dose folic acid use for children prenatally exposed to lamotrigine and valproate but did not reach statistical significance.

Funding: Please list any funding that was received in support of this abstract.: Supported by NordForsk.

Clinical Epilepsy