Authors :
Presenting Author: Majed Alomar, MD – Neurological Institute, University Hospitals Cleveland Medical Center, Case Western Reserve University
Guadalupe Fernandez-Baca Vaca, MD – Epilepsy Center Director, Epilepsy Center, Neurological Institute, University Hospitals Cleveland Medical Center, Case Western Reserve University
Rationale:
Studies on folic acid (FA) supplementation for neural tube defects (NTDs) prevention in the general population showed risk reduction of 62% (95% confidence interval (CI): 49–71) for primary prevention and 70% (95% CI: 35-86) for recurrence prevention.1 Given the high risk of NTDs and congenital malformations (CMs) in pregnant patients taking anti-seizure medications (ASMs), several guidelines recommend high-dose FA supplementation for this group. Due to the benefits demonstrated in the general population in previous studies, there are no randomized trials that specifically examine the impact of FA supplementation on the risk of NTDs and CMs in patients on ASMs. This review study aims to assess and analyze the available evidence regarding the effects of FA supplementation on the risk of NTDs and CMs in patients taking ASMs.
Methods:
The primary literature search was conducted until May 31, 2023, utilizing Pubmed/MEDLINE and Embase databases. Studies were included if they assessed the association between FA supplementation before and/or during pregnancy and the risk of CMs or NTDs in the offspring of patients taking ASMs. Studies in languages other than English, case reports, case series, animal studies, or those that did not report primary clinical data were excluded. Fourteen studies met our criteria, all were observational studies.
Results:
Numerous studies have investigated the association between FA supplementation and the risk of CMs and NTDs in patients taking ASMs. The findings from these studies are mixed. Some studies suggest a potential association between lack of FA supplementation and an increased risk of CMs in offspring.2,3 A case-control study in 2007 showed a possible association between lower incidence of CMs and FA with OR 1.27 (95% CI: 0.85–1.89) and OR 1.47 (95% CI: 1.13–1.90) in the groups with and without FA supplementation, respectively. It also reported that in the ASMs polytherapy group, the odds ratio of CMs were 5.23 (95% CI: 1.42–19.33) for those not taking FA and 2.42 (95% CI: 0.54–10.83) for those taking FA. However, this possible effect was not statistically significant.4 On the contrary, a study of the Medical Birth Registry of Norway showed that for all ASMs groups there was a tendency toward a higher frequency of CMs in pregnancies with preconceptional FA supplementation compared to those without FA supplementation, this was statistically significant in the valproate group (13.2%, vs. 4.8%, p =0.049, OR = 2.9, 95% CI: 1.0-8.5).5 However, these results could be confounded by treatment-selection bias. Several other studies did not establish a clear association between FA supplementation and the risk of NTDs or CMs.6–15
Conclusions:
Although there is limited evidence regarding the impact of FA in patients taking ASMs, there is strong evidence that FA effectively reduces the risk of NTDs in the general population. Additional larger studies or meta-analyses of existing evidence are necessary to gain adequate statistical power and determine the influence of FA on the risk of NTDs and CMs in patients using ASMs. Furthermore, if a beneficial impact is identified, it is crucial to ascertain the minimum dosage required to achieve the desired outcomes.
Funding: None