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.

Tie-Ning Zhang,Xin-Yi Zhao,Ri Wen,Wei Wang,Xin-Mei Huang,Shan-Yan Gao,Jenny E Myers

doi:10.1371/journal.pmed.1003900

Tie-Ning Zhang, Xin-Yi Zhao + Show 5 more

Open Access

https://doi.org/10.1371/journal.pmed.1003900

Copy DOI

Journal: PLoS medicine	Publication Date: Feb 1, 2022
Citations: 30	License type: CC BY 4.0

Affiliation: China Medical University, Fudan University

Abstract

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. 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 < 0.001; for CHDs, RR = 3.46, 95% CI 2.77 to 4.32, P < 0.001) or GDM (for overall CAs, RR = 1.18, 95% CI 1.13 to 1.23, P < 0.001; for CHDs, RR = 1.50, 95% CI 1.38 to 1.64, P < 0.001). The results of the meta-regression analyses showed significant differences in RRs of CAs/CHDs in PGDM versus GDM (all P < 0.001). Of the 23 CA categories, excluding CHD-related categories, in offspring, maternal PGDM was associated with a significantly increased risk of CAs in 21 categories; the corresponding RRs ranged from 1.57 (for hypospadias, 95% CI 1.22 to 2.02) to 18.18 (for holoprosencephaly, 95% CI 4.03 to 82.06). Maternal GDM was associated with a small but significant increase in the risk of CAs in 9 categories; the corresponding RRs ranged from 1.14 (for limb reduction, 95% CI 1.06 to 1.23) to 5.70 (for heterotaxia, 95% CI 1.09 to 29.92). The main limitation of our analysis is that some high significant heterogeneity still persisted in both subgroup and sensitivity analyses. 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.

Highlights

The global prevalence of diabetes is increasing among women of reproductive age [1,2]
An additional 44 articles were excluded for the following reasons: 3 studies enrolled mothers with any type of diabetes and did not distinguish pre-gestational and gestational diabetes, 1 study did not have a comparison group that included mothers without diabetes, 4 studies were derived from the same dataset and reported the same associated outcome as another included study, 3 studies enrolled mothers with congenital anomaly (CA), 6 studies included data that could not be extracted or calculated, and 27 studies were not population-based (S2 Table)
Our results suggested that maternal Pre-gestational diabetes mellitus (PGDM) was associated with overall CAs in offspring (RR = 1.99, 95% confidence interval (CI) 1.82 to 2.17, I2 = 90.0%, P < 0.001; Fig 2), with no evidence of publication bias (Begg’s P = 0.88, Egger’s P = 0.30; Fig E in S1 Fig)

Summary

Introduction

The global prevalence of diabetes is increasing among women of reproductive age [1,2]. Pre-gestational diabetes mellitus (PGDM, which includes type 1 and 2 diabetes) has been known to be a risk factor for congenital heart defects (CHDs) for decades [3]. An increasing number of studies have concentrated on evaluating the risks of specific types of CAs in offspring born to women with GDM [4,5,10,11,12]. Pre-gestational diabetes mellitus (PGDM) has been known to be a risk factor for congenital heart defects (CHDs) for decades. 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

Objectives

Methods

Results

Conclusion