First trimester maternal infections and offspring congenital heart defects: a systematic review and meta-analysis
Authors: Su H , Guo E , Woodward M , He J R , Dwyer T , Rahimi K , Budts W , Conrad N 
Published: October 2024

Abstract

Background
Maternal infections early in pregnancy have been proposed as playing a role in the development of congenital heart defects. We aimed to summarise contemporary evidence regarding the association between first-trimester maternal infection and risk of offspring congenital heart defects.

Methods
For this systematic review and meta-analysis, we searched Medline and Embase for studies reporting associations of at least one measure of maternal infection during pregnancy and offspring congenital heart disease in humans and published in English between January 1, 1990 and February 13, 2024. Studies were eligible for inclusion if they reported rates of offspring congenital heart defects among both infected and non-infected mothers, and included a minimum of 50 offspring with congenital heart defects. We stratified associations by type of infection and type of heart defect when data from at least two studies were available. We used inverse variance weighted random-effect meta-analyses to pool the estimates. In main analyses, we pooled crude estimates from studies reporting maternal infections during the first trimester of pregnancy. We performed sensitivity analyses to include studies that i) investigated infections later in pregnancy or at unspecified time-points, and ii) adjusted for potential confounders such as maternal age, socioeconomic status, or ethnicity.
Findings: We identified 11 studies (7 case control studies, 4 cohort studies) with data from 1,805,115 pregnancies. Nine of these studies assessed maternal infectious status through self-reported questionnaires or medical records, two used laboratory antibody testing and three reported on specific infectious pathogens. Studies reported on various types of bacterial and viral infections, including influenza, urinary tract infections, cytomegalovirus, herpes simplex virus, or chlamydia, with varying effect sizes. Ten studies reported a positive association between maternal infection variables and offspring congenital heart defects, with a pooled odds ratio (OR) and 95% confidence interval of 1.56 (1.27, 1.91) across all types of infections. Associations differed by individual subtype of congenital heart defects, with ORs ranging from 1.28 (0.89, 1.85) for pulmonary atresia to 1.75 (1.23, 2.49) for ventricular septal defects. Sensitivity analyses that included infections measured later in pregnancy, or adjusted rates for potential confounders, showed broadly similar trends but attenuated effect sizes.
Interpretation: First trimester maternal infections are associated with increased risk of congenital heart defects. Associations appear to vary by type of infection and type of congenital heart defect, and to extend beyond infections commonly tested for during routine pregnancy screening. Larger-scale studies are warranted to confirm these findings using laboratory antibody testing and investigating how these associations vary by specific pathogens and subtypes of congenital heart defects.