Maternal virus infections in pregnancy and type 1 diabetes in their offspring: Systematic review and meta-analysis of observational studies

Virus infections are implicated in the development of type 1 diabetes based on epidemiological, clinical, in vitro cell-based and molecular studies, and animal models. We reviewed the association between virus infections in pregnant women and development of islet autoimmunity or type 1 diabetes in their offspring. We performed a systematic review and meta-analysis, analysed using random effects models, of human studies from Medline and EMBASE without language restriction. Inclusion criteria were as follows: cohort and case-control studies measuring viral nucleic acid in blood, stool, urine, or tissue, or serological tests for viruses, in pregnant women whose offspring developed islet autoimmunity and/or type 1 diabetes. All studies required sufficient data to calculate odds ratios and 95% confidence intervals. The 10 studies (4 case control, 6 nested-case control) that met the eligibility criteria included 2992 participants (953 offspring, 2039 mothers), with varying study design. The 2 outcomes examined were islet autoimmunity (n=466) and type 1 diabetes (n=2526). Meta-analysis showed a significant association between virus infection during pregnancy and clinical type 1 diabetes during childhood (odds ratio 2.16, 95% CI 1.22-3.80; P=0.008; heterogeneity X-2=1.65, I-2=40%), but no association with islet autoimmunity (1.45, 0.63-3.31; P=0.38; X-2=1.34, I-2=25%). The increased risk of type 1 diabetes following maternal virus infection is consistent with viraemia involving the fetus during pregnancy and suggests a potential causative link between antenatal infection and type 1 diabetes. Larger prospective birth studies with more frequent sampling, and pathogenesis studies, are required to more clearly establish an aetiological link.