Risks of Specific Congenital Anomalies in Offspring of Diabetic Mothers: A Systematic Review and Meta-Analysis of Population-Based Studies of More than 76 Million Births

Abstract

Background: Pregestational diabetes (PGDM) has been known to be a risk factor for congenital heart defects (CHD) for decades. However, the associations between maternal PGDM and gestational diabetes (GDM) and risk of specific types of CHD and other systems congenital anomalies (CAs) remains under debate. We investigated type-specific CAs in offspring of diabetic mothers and examined the extent to which different types of maternal diabetes increase CAs risks in offspring. Methods: For this systematic review and meta-analysis, we searched PubMed and Embase from inception to December 27, 2020, for population-based studies reporting on type-specific CAs in offspring of diabetic mothers. We assessed methodological quality using the Cochrane Risk of Bias Tool for Non-randomised Studies of Interventions. We calculated summary estimates for meta-analysis using random effects models. The primary outcomes were overall CAs and specific types of CHD. Findings: 56 studies (76,860,298 participants) were included. The meta-analyses showed increased risks of overall CAs/CHD, in offspring born to mothers with PGDM (for overall CAs, relative risks [RR] 1.99, 95% CI 1.82 to 2.17 and for CHD, 3.42, 95% CI 2.73 to 4.28) or GDM (for overall CAs, 1.18, 95% CI 1.13 to 1.23 and for CHD, 1.50, 95% CI 1.38 to 1.64). Results of meta-regression analyses showed significant differences in RRs of CAs/CHD in PGDM versus GDM (all P ˂ 0.001). Of 23 type-specific CAs of other systems in offspring, maternal PGDM was associated with a significantly increased risk of CAs in 21 categories, while maternal GDM had a small but significant increase in risk of CAs in 9 categories. Interpretation: The findings suggest that timely screening for diabetes in women who are pregnant or planning to be pregnant provides a window of opportunity to prevent congenital anomalies in offspring. Registration Information: This systematic review is registered with PROSPERO, number CRD42021229217. Funding Information: None. Declaration of Interests: We declare no competing interests.