Fever during pregnancy as a risk factor for neurodevelopmental disorders: results from a systematic review and meta-analysis

Stephanie Antoun,Pierre Gressens,Michelle Rosenzwajg,Hugo Peyre,Richard Delorme,Pierre Ellul,David Klatzmann

doi:10.1186/s13229-021-00464-4

Abstract

BackgroundFever during pregnancy is a relatively common and most often trivial event. However, under specific conditions, it could affect significantly fetal brain development. Few studies, with inconsistent results, investigated whether fever, regardless the pathogen, could represent a risk factor for neurodevelopmental disorders (NDD) in the offspring. We aimed to explore further this question by performing a systematic review and meta-analysis.MethodsPeer-reviewed studies exploring the occurrence of NDD in offspring after a fetal exposure to maternal fever were included. We specifically considered the impact of fever severity and duration, taking into consideration some confounding variables such as the use of antipyretic during pregnancy, the trimester in which the fever arose, the maternal age or smoking at time of gestation. MEDLINE, EMBASE, PsycINFO, Cochrane and Web of Science were searched without language restriction. PRISMA recommendations were followed. Odds ratio (OR) were pooled using random-effects meta-analysis. Heterogeneity in effect size across studies was studied using random-effects meta-regression analysis. (PROSPERO CRD42020182801).ResultsWe finally considered ten studies gathering a total of 10,304 children with NDD. Among them, 1394 were exposed to fever during pregnancy. The selected studies were divided into 5 case–control studies and 5 cohort studies. Maternal exposure to fever during pregnancy increased the risk of NDD in offspring with an OR of 1.24 [95% CI: 1.12–1.38]. Secondary analysis revealed an increased risk for NDD when fever occurred during the first trimester of gestation [OR 1.13–95% CI: 1.02–1.26].LimitationsWe excluded studies that considered infections with no evidence of fever. Another potential limitation may be the possible heterogeneity between study designs (cohorts and case–control).ConclusionAdditional evidence supported the association between fever during pregnancy and increased risk for NDD in offspring. Careful monitoring should be considered for children born from mothers with a febrile episode during pregnancy (specifically during the first trimester).

Highlights

Fever during pregnancy is a relatively common and most often trivial event
Additional evidence supported the association between fever during pregnancy and increased risk for neurodevelopmental disorders (NDD) in offspring
Careful monitoring should be considered for children born from mothers with a febrile episode during pregnancy

Summary

Introduction

Fever during pregnancy is a relatively common and most often trivial event. under specific conditions, it could affect significantly fetal brain development. The determinism of NDD remains unclear but depends on Antoun et al Molecular Autism (2021) 12:60 the interaction of genetic vulnerability and environmental insults [2, 3] Twin studies upheld this gene-environment interaction model reporting up to 90% concordance rate in monozygotic twins and 50% in dizygotic [1, 4]. The effect of maternal fever during pregnancy may explain by itself the increased prevalence of NDD observed in the offspring [3, 13, 14] This association was suggested to occur secondarily to maternal immune activation (MIA), rather than the direct effect of the pathogen on the fetal brain [14, 15]. While current evidence did not bring out a direct causal link, genetic susceptibility probably intervened in the subsequent NDD-related symptoms [3]

Objectives

Methods

Results

Discussion

Conclusion