Maternal fever during preconception and conception is associated with congenital heart diseases in offspring: An updated meta-analysis of observational studies.

Backgrounds: Many studies have evaluated the effect of maternal fever on the development risk of congenital heart diseases (CHDs) in offspring, but the findings were inconsistent. Furthermore, a complete overview of the existing data was also missing. Therefore, we intend to provide updated epidemiologic evidence to estimate the association between maternal fever and the risk of overall CHDs and specific CHD phenotypes in offspring.

Methods: Pubmed, Embase, and Web of Science were searched through March 2020 to identify eligible studies that assessed the association between maternal fever and CHDs risk in offspring. The summary risk estimates were calculated using random-effects models. Potential heterogeneity source was explored by subgroup analyses and potential publication bias was assessed by Begg funnel plots and Begg rank correlation test.

Results: Sixteen studies involving 31,922 CHDs cases among 183,563 participants were included in this meta-analysis. Overall, mothers who had a fever experience during preconception and conception periods had a significantly higher risk of overall CHDs in offspring (odds ratio [OR] = 1.45, 95% confidence interval [CI]: 1.21-1.73) when compared with those who did not have a fever experience. For specific CHD phenotypes in offspring, a statistically significant association was found between maternal fever and risk of conotruncal defects (CTD) (OR = 1.38, 95%CI: 1.01-1.89), atrial septal defects (ASD) (OR = 1.48, 95% CI: 1.01-2.17), transposition of the great vessels (TGA) (OR = 1.81, 95% CI: 1.14-2.88), and right ventricular outflow tract obstruction (RVOTO) (OR = 1.66, 95% CI: 1.04-2.65). Relevant heterogeneity moderators have been identified by subgroup analyses, and sensitivity analyses yielded consistent results.

Conclusions: Although the role of potential bias and evidence of heterogeneity should be carefully evaluated, our review indicates that maternal fever is significantly associated with the risk of CHDs in offspring, which highlights that preventing maternal fever during the preconception and conception periods play an important role in decreasing the risk of CHDs in offspring. However, given the limited number of current case-control studies, larger-sample prospective studies are required to further confirm our results. Besides, due to the underlying mechanisms between maternal fever and the risk of specific CHD phenotypes in offspring are still unreported, more research is needed to explore the possible mechanisms.