Association between gestational diabetes mellitus and offspring health: a two-sample mendelian randomization study

Gestational diabetes mellitus (GDM) constitutes a significant contributor to maternal and fetal morbidity, which is observed to be associated with future risks of offspring health. Nevertheless, it is essential to acknowledge that observational findings may be susceptible to residual confounding and bias.

To investigate the association of GDM with offspring health, a genome-wide genetic association study employing Mendelian Randomization (MR) is conducted between May 31 and November 30, 2023. The inverse-variance-weighted (IVW) is utilized in the primary analysis stage. The study data of the majority patients are European ancestry, which are sourced from the IEU open genome-wide association study project.

Genetically predicted GDM is associated with an increased risk of various short- and long-term health problem in offspring. For fetal and neonatal conditions, GDM is linked to an elevated risk of preterm delivery [ odd ratio (OR) = 1.150, false discovery rate (FDR)-adjusted P_IVW = 0.009] and placental disorders (OR = 2.143, FDR-adjusted P_IVW = 0.028). In respiratory diseases, it is associated with a higher likelihood of influenza (OR = 1.175, FDR-adjusted P_IVW = 0.008), bacterial pneumonia (OR = 1.141, FDR-adjusted P_IVW = 0.008), congenital malformations of the respiratory system (OR = 1.673, FDR-adjusted P_IVW = 0.033), influenza with pneumonia (OR = 1.078, FDR-adjusted P_IVW = 0.008), and need for non-invasive ventilation (OR = 1.265, FDR-adjusted P_IVW = 0.028). In terms of neurodevelopmental and psychiatric outcomes, GDM is linked to a higher risk of cerebral palsy (OR = 1.721, FDR-adjusted P_IVW = 0.008). For urinary conditions, GDM increases the risk of acute tubulo-interstitial nephritis (OR = 1.098, FDR-adjusted P_IVW = 0.008). No association is identified between genetically predicted GDM and major digestive diseases, such as gastroesophageal reflux, or cardiovascular conditions in offspring.

The findings of this study provide genetic evidence supporting an association between GDM and higher risk of offspring diseases. This supports classification of GDM as risk factors for short- and long-term offspring health.