Prenatal and perinatal factors associated with developing multiple sclerosis later in life: A systematic review and meta-analysis

Objective: Both genetic and environmental factors play roles in Multiple Sclerosis (MS) etiopathogenesis. The relationship between prenatal/perinatal factors/exposures and future MS occurrence in the offspring remains controversial. Here, we aimed to review the available evidence on prenatal/perinatal factors associated with later MS occurrence. Method: We performed systematic search of PubMed, Web of Science, and Scopus from inception to October 2020. We included original observational studies conducted on human participants addressing the association between prenatal/perinatal factors and MS occurrence. Data were extracted according to the PRISMA guideline. The adjusted odds ratio (OR) with 95% confidence interval (CI) was considered as the desired effect size. The heterogeneity was evaluated by Cochran's Q and I2 and the publication bias was assessed. We excluded gestational/neonatal vitamin D level, season of birth, and latitude because of recently published systematic reviews/ meta-analyses on these subjects. Results: Overall, 2306 records were identified in the primary search. After excluding irrelevant studies, we evaluated 34 studies with contributing data on 100 prenatal/perinatal factors associated with an increased or decreased risk of MS occurrence. In the meta-analyses, we found no statistically significant associations between later MS occurrence in offspring and prenatal smoking exposure (OR = 1.01, 95% CI = 0.77-1.34), mode of delivery (OR = 0.90, 95% CI = 0.52-1.56), birth order (OR = 0.85, 95% CI = 0.72-1.00), and maternal age (OR = 1.34, 95% CI = 0.88-2.04). Paternal age and parents' marital status at the time of childbirth, maternal preeclampsia/ toxemia, forceps use, birth weight, plurality, and preterm birth were the other most studied factors, and none reported to affect MS risk. Conclusion: We found that prenatal smoking exposure, mode of delivery, birth order, and maternal age do not affect risk of future MS development. Moreover, most of the other investigated factors were reported not to affect MS risk in the offspring.