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

Abstract

Background: Fever 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.

Methods: Peer-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).

Results: We 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].

Limitations: We 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).

Conclusion: Additional 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).

Keywords: Autism; Children; Immunology; Maternal immune activation.

Fig. 1

Flowchart of the study inclusion and exclusion process

Fig. 2

Forest plot relative to maternal fever during pregnancy

Fig. 3

Forest plot relative to fever occurring in the first trimester

Fig. 4

Forest plot relative to fever occurring in the second trimester

Fig. 5

Forest plot relative to fever occurring in the third trimester

Fig. 6

Forest plot relative to fever duration longer than three days

Fig. 7

Forest plot relative to fever duration shorter than three days

Fig. 8

Forest plot relative to fever medication use

Fig. 9

Meta-regression relative to fever medication use

Fig. 10

Meta-regression relative to maternal age