Risks of specific congenital anomalies in offspring of women with diabetes: A systematic review and meta-analysis of population-based studies including over 80 million births

Abstract

Background Pre-gestational diabetes mellitus (PGDM) has been known to be a risk factor for congenital heart defects (CHDs) for decades. However, the associations between maternal PGDM and gestational diabetes mellitus (GDM) and the risk of specific types of CHDs and congenital anomalies (CAs) in other systems remain under debate. We aimed to investigate type-specific CAs in offspring of women with diabetes and to examine the extent to which types of maternal diabetes are associated with increased risk of CAs in offspring. Methods and findings We searched PubMed and Embase from database inception to 15 October 2021 for population-based studies reporting on type-specific CAs in offspring born to women with PGDM (combined type 1 and 2) or GDM, with no limitation on language. Reviewers extracted data for relevant outcomes and performed random effects meta-analyses, subgroup analyses, and multivariable meta-regression. Risk of bias appraisal was performed using the Cochrane Risk of Bias Tool. This study was registered in PROSPERO (CRD42021229217). Primary outcomes were overall CAs and CHDs. Secondary outcomes were type-specific CAs. Overall, 59 population-based studies published from 1990 to 2021 with 80,437,056 participants met the inclusion criteria. Of the participants, 2,407,862 (3.0%) women had PGDM and 2,353,205 (2.9%) women had GDM. The meta-analyses showed increased risks of overall CAs/CHDs in offspring born to women with PGDM (for overall CAs, relative risk [RR] = 1.99, 95% CI 1.82 to 2.17, P Conclusions In this study, we observed an increased rate of CAs in offspring of women with diabetes and noted the differences for PGDM versus GDM. The RRs of overall CAs and CHDs in offspring of women with PGDM were higher than those in offspring of women with GDM. Screening for diabetes in pregnant women may enable better glycemic control, and may enable identification of offspring at risk for CAs. In a systematic review and meta analysis, Tie-Ning Zhang and colleagues investigate the associations between maternal pre-gestational diabetes and gestational diabetes and congenital heart defects and other congenital anomalies in offspring. Author summary Why was this study done? It is controversial whether maternal pre-gestational or gestational diabetes affects specific types of congenital heart defects (CHDs) and congenital anomalies (CAs) in other systems. Comprehensive estimates of the risks of specific CAs for offspring of women with maternal diabetes are needed to counsel patients and for public health purposes. What did the researchers do and find? To the best of our knowledge, this is the first comprehensive systematic review and meta-analysis of population-based studies of over 80 million participants that demonstrates an increased risk of type-specific CAs, especially CHDs, in offspring born to women with pre-gestational or gestational diabetes. Our study shows that maternal pre-gestational diabetes is associated with a significant increase in the risk of 38 out of 45 categories of CAs in offspring, while maternal gestational diabetes is associated with a small but significant increase in the risk of 16 out of the 45 categories. The corresponding relative risks (RRs) of overall CAs/CHDs in offspring of women with pre-gestational diabetes are higher than those in offspring of women with gestational diabetes, with no overlap in the 95% CIs. What do these findings mean? In this study, we observed that there is an increased rate of CAs in offspring of women with maternal diabetes and noted the differences between pre-gestational and gestational diabetes. Considering the substantial rise in the prevalence of maternal diabetes over recent decades, the expectation that this prevalence will continue to increase, the number of pregnancies worldwide, and the significant individual and global burdens associated with CAs, it is crucial that healthcare providers are aware of this association and can identify women and offspring who are at risk.