Abstract
BACKGROUND: Observational studies on the association between gestational diabetes mellitus (GDM) during pregnancy and pediatric neurological disorders (PNDs) such as cerebral palsy (CP), autism spectrum disorders (ASD), and epilepsy (EP) in offspring have yielded mixed findings, creating ambiguity in causal interpretations. The direct link between GDM and these PNDs remains unclear. Elucidating this connection is vital for developing effective early intervention strategies during pregnancy to mitigate the risk of PNDs in the offspring. This study utilizes a two-sample (2-sample) Mendelian randomization (MR) approach to investigate the causal relationship between GDM and its impact on CP, ASD, and EP in offspring. METHODS: We employed 2-sample MR using 6 single nucleotide polymorphisms (SNPs) strongly associated with GDM. Summary-level data for CP, ASD, and EP were obtained from the Integrative Epidemiology Unit (IEU) Open Genome-Wide Association Study (GWAS) project, encompassing sample sizes of 217,278, 46,351, and 463,010, respectively. The robustness of our findings was assessed using the inverse variance-weighted (IVW) method along with additional sensitivity analyses. RESULTS: The results demonstrate that GDM is associated with a higher risk of offspring CP as determined by the IVW method [odds ratio (OR): 1.74; 95% confidence interval (CI): 1.27-2.37; P<0.001]. In contrast, no association was observed between GDM and ASD or EP. Additionally, alternative methods for sensitivity analyses showed consistent results, and there was no pleiotropy detected using MR-Egger regression (P=0.48). CONCLUSIONS: This study provides strong evidence supporting a positive causal relationship between genetically predicted GDM and the increased risk of offspring CP, with no observed correlation found with ASD or EP.