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).

Influence of Prenatal Drug Exposure, Maternal Inflammation, and Parental Aging on the Development of Autism Spectrum Disorder

“…The risk of ASD appears to correlate with the severity of maternal infection, in which the risk was further elevated when mothers required hospitalization because of the infection ( 154 ). In another meta-analysis, maternal fever during pregnancy, regardless of whether it was caused by infection, increased the risk of neurodevelopmental disorders ( 156 ). The invasion of pathogens does not appear to be essential for the development of ASD in offspring; instead, the maternal inflammatory response itself seems sufficient.…”

Adherence to prescription medication during pregnancy: Do pregnant women use pharmacological treatment as prescribed?

“…Part of these lower levels of actual use for medication for occasional and short‐term use may be explained by forgetfulness when using interviews or questionnaires that cover a prolonged period of pregnancy, 22 but remained when using diaries as reference standard 21 . This disagreement may be worrisome for some maternal conditions, including infections (antibiotics) and fever (antipyretics), in which pharmacological treatment is often recommended to prevent maternal and infant morbidity and mortality 36–39 . In an Italian cross‐sectional study, 3.2% of women reported intentionally avoiding a prescribed antibiotic in pregnancy 40 …”

“…21 This disagreement may be worrisome for some maternal conditions, including infections (antibiotics) and fever (antipyretics), in which pharmacological treatment is often recommended to prevent maternal and infant morbidity and mortality. [36][37][38][39] In an Italian crosssectional study, 3.2% of women reported intentionally avoiding a prescribed antibiotic in pregnancy. 40 Although actual use among pregnant women seemed high compared to adherence estimates of 50-70% among adults with chronic conditions, 41,42 it does not assess whether medication is actually used as prescribed in terms of timing and dosage.…”

Do pregnant women use pharmacological treatment as prescribed?

“…Part of these lower levels of actual use for medication for occasional and short-term use may be explained by forgetfulness when using interviews or questionnaires that cover a prolonged period of pregnancy [22], but remained when using diaries as reference standard [21]. This disagreement may be worrisome for some maternal conditions, including infections (antibiotics) and fever (antipyretics), in which pharmacological treatment is often recommended to prevent maternal and infant morbidity and mortality [35][36][37][38]. In an Italian cross-sectional study, 3.2% of women reported intentionally avoiding a prescribed antibiotic in pregnancy [39].…”