Adverse Birth Outcomes In High-risk Population,the Impact Of Gestational Diabetes Mellitus On Birth Outcomes And The Mechanisms

Background: The incidence of gestational diabetes mellitus(GDM)has been on the rise over the last two decades in both developing and developed counties,partly due to increasing frequency of obese and elderly pregnant women.Studies have shown that GDM may increase the risks of short-term and long-term adverse health outcomes in the offspring.The offspring born to pregnant women at high-risk of GDM may be at increased risks for adverse birth outcomes.The high-risk population for GDM is a good target poplation for exploring the adverse impacts of diabetes in pregnancy(including GDM)on the offspring and the possible mechanism.The present study is based on Canadian and Shanghai birth cohorts,exploring the impacts of diabetes in pregnancy on birth outcomes,metabolic health in the offspring and the possible mechanisms.Objectives and Methods: Our study includes four parts:(1)We conducted a population-based retrospective cohort study(n=254,410)using the linked vital events registry databases for singleton births in Quebec 1996-2010.The aim was to explore the disparities and trends in birth outcomes,perinatal and infant mortality in Aboriginal(a high-risk population for GDM)vs.non-Aboriginal populations.(2)We conducted a retrospective birth cohort study of 17090 First Nations(high-risk population for GDM)and 217760 non-Indigenous singleton infants in Quebec1996-2010.This part aimed to evaluate whether pre-gestational or gestational diabetes mellitus(PGDM,GDM)may have differential impacts on offspring’s survival in First Nations versus non-Indigenous populations.(3)We conducted a prospective birth cohort study of 275 mother-infant pairs(26 GDM and 248 Control mother-infant pairs).The aim was to explore the correlations between placental 11-beta hydroxysteroid dehydrogenase type 2(11β-HSD2)and cord blood cortisol levels and glucose metabolic health and cardiometabolic health biomarkers in infants at 1 year of age,and assess the impacts of gestational diabetes mellitus.(4)We conducted a nested case-control study(62 GDM,62 Control)using the Shanghai Birth Cohort and the High-risk Pregnancy Cohort.aim was to explore cord blood cortisol concentrations and placental 11β-HSDs levels in GDM pregnant women in relation to fetal metabolic health biomarkers.Results: The results showed that(1)Perinatal and infant mortality rates were 1.47 and1.80 times higher in First Nations(10.1 and 7.3 per 1000,respectively),and 2.37 and4.46 times higher in Inuit(16.3 and 18.1 per 1000,respectively)relative to non-Aboriginal(6.9 and 4.1 per 1000,respectively)births(all p<0.001).In the recent15 years(1996-2010),as compared to non-Aboriginal infants,the relative risk disparities increased for infant mortality(from 4.10 to 5.19 times)in Inuit,and for postneonatal mortality in Inuit(from 6.97 to 12.33 times)or First Nations(from 3.76 to 4.25 times)infants.Adjusting for maternal characteristics attenuated the risk differences,but significantly elevated risks remained in Aboriginal populations.(2)PGDM was more strongly associated with an increased risk of perinatal death in First Nations [relative risk(RR)5.08(95% confidence interval: 2.99,8.62)] versus non-Indigenous [RR 1.76(1.17-2.66)] infants.PGDM was associated with an increased risk of postneonatal death in non-Indigenous infants [RR 3.46(1.71-6.99)]only.GDM was associated with a marginally lower risk of perinatal death in non-Indigenous infants [RR 0.72(0.53-0.98)] only.Adjusting for maternal characteristics and other pregnancy complications,the associations were similar.(3)There were no significant differences in placental 11β-HSD2 levels and cardiometabolic outcomes comparing 1-y old infants of GDM(n=26)versus non-diabetic mothers.Cord blood cortisol levels were negatively correlated with beta-cell function indices at birth(r=-0.36,p<0.01),but not at 1-y of age.Higher placental 11β-HSD2 levels were correlated with lower insulin resistance(r=-0.17,p<0.01),and lower systolic blood pressure(r=-0.16,p=0.057)in 1-y old infants.Similar findings were observed after adjusting for maternal and infant characteristics.(4)Placenta 11β-HSD1 levels were significant lower in GDM versus healthy pregnant women(means: 0.61 vs.0.78,p < 0.05),while placenta 11β-HSD2 levels were not significantly different between the two groups(means: 0.63 vs.0.57,p = 0.3625).Cord blood cortisol was negatively correlated with insulin sensitivity index(QUICKI)(r=-0.32,p=0.0027),and positively correlated with insulin resistant index(HOMA-IR)(r=0.30,p=0.0059)in newborns.Placenta 11β-HSD2 level was positively correlated with insulin resistant index(HOMA-IR)(r=0.35,p=0.0197)in newborns..Similar associations were observed after adjusting for maternal and infant characteristics.Conclusions: Our study reveals that:(1)Aboriginal vs.non-Aboriginal disparities in adverse birth outcomes,perinatal and infant mortality are persistent or worsening over the recent decade in Quebec.(2)There were differential associations of PGDM and GDM with perinatal and postneonatal mortality in Indigenous versus non-Indigenous populations.This could be due to population differences in the quality of glycemic control and/or genetic vulnerability to hyperglycemic toxicity.(3)Circulating cortisol and placental 11β-HSD2 levels are associated with cardiometabolic health in early postnatal life in humans.(4)GDM was associated with lower levels of placental11β-HSD2.Cord blood cortisol and placental 11β-HSD2 levels were correlated with insulin resistance.Our studies have shed new light on the impacts of GDM on the offspring and the possible mechanisms.