Gestational Diabetes Mellitus And Early Offspring Neurodevelopment: A Prospective Birth Cohort Study

Background and Objectives The association of maternal gestational diabetes mellitus（GDM）with neurodevelopmental outcomes remains controversial and evidence that maternal increasing levels of glucose during pregnancy associated with the risk for impaired neurodevelopment were limited.Our aims were to identify the continuous association of increasing maternal glucose levels with neurodevelopmental disorders in offspring and explore the potential contribution of cord metabolites to this association.Methods This study was based on the Hefei Maternal and Infant health cohort study.From March 2015 to April 2019,the final analysis sample was 1036 mother-infant pairs.The prospective birth cohort study included 1036 mother-child pairs.Primary predictors were maternal exposure GDM and maternal glucose values at a 75-g oralglucose-tolerance test at 24 to 28 weeks during pregnancy.Primary neurodevelopmental outcomes at 12 months in offspring were assessed by the Ages and Stages Questionnaires,Third Edition（ASQ-3）.Based on maternal GDM status during pregnancy and failure to ASQ-3 domains in offspring,participants were randomly divided into four groups: GDM-negative ASQ-negative group,GDM-negative ASQpositive group,GDM-positive ASQ-negative and GDM-positive ASQ-positive group.,and maternal plasma metabolomics analysis was performed.Cord blood samples from were collected for the detection of glycolipid metabolite levels including C-peptide,high-density lipoprotein,low-density lipoprotein,total cholesterol and total triglycerides.Results Of 1036 enrolled participants,228（22.0%）mothers were diagnosed with GDM.There was no significant difference in the distribution of pregnancy age at least30 years（44.9% vs 42.1%）and education level less than 12 years（69.3% vs 70.3%）between non-GDM and GDM pregnant women.Pre-pregnancy overweight/obesity was higher in pregnant women with GDM than in women without GDM（36.8% vs 13.5%,P<0.001）.GDM women had significantly higher systolic blood pressure levels in the second trimester than non-GDM women（70±7.7 vs 68±7.4,mm Hg;P = 0.001）.In terms of characteristics of infants,there were no significant differences in the proportion of cesarean section,preterm birth,gender,and proportion of 6-month-old offspring receiving partial breastfeeding and formula feeding between GDM and nonGDM pregnant women.However,GDM-exposed infants had shorter gestational age（38.9 ± 1.3 vs 39.1 ± 1.2,weeks;P = 0.032）and greater birth weight（3484 ± 486 vs3414 ± 438,grams;P = 0.039）compared with non-GDM).On the level of cord blood metabolic markers,compared with non-GDM women,GDM women had higher cord blood C-peptide levels（median: 0.55 vs 0.46,nmol/L,P<0.001）.Maternal GDM was associated with failing the communication domain in offspring in the adjusted models [relative risk（RR）with 95% CI: 1.97（1.11,3.52）].Increasing levels of fasting plasma glucose（FPG）,1-h plasma glucose（1-h PG）and 2-h plasma glucose（2-h PG）with 1 SD change were at higher risks in failing the personal social domain of ASQ-3 [RRs with 95% CI for FPG: 1.49（1.09,2.04）;for 1-h PG: 1.70（1.27,2.29）;for 2-h PG: 1.36（1.01,1.84）].The linear association was also demonstrated.Compared with girls,boys exposed to higher maternal glucose levels were inclined to the failure of the personal social domain.Mediation analysis showed the contribution of maternal GDM to failure of communication domain mediated by Cpeptide.There were significant differences of levels of plasma 2’-Deoxyinosine,Rhapontigenin,caffeic acid,cis-aconitic acid,（R）-（E）-Sulforaphene,hypoxanthine,adenosine,choline,Erythrono-1,4-lactone,Flavidulol Cand and fermentone acid among 4 groups [GDM-negative ASQ-negative group,GDM-negative ASQ-positive group,GDM-positive ASQ-negative and GDM-positive ASQ-positive group]Conclusion Maternal glucose levels below those diagnostic of diabetes are continuously associated with impaired neurodevelopment in offspring at 12 months.Maternal purine metabolism,amino acid metabolism（glutamate,alanine,and aspartate）and glycerophospholipid metabolism pathways during pregnancy were involved in neurodevelopmental disorders caused by maternal hyperglycemia.