【作者】 陈璐；

【导师】 骆忠诚；

【作者基本信息】 上海交通大学 ， 儿科学， 2017， 硕士

【摘要】 背景:近20年来,由于肥胖和高龄孕妇增加等因素,妊娠期糖尿病(GDM)的发病率呈上升趋势。有研究表明,GDM可能增加子代发生近期及远期不良结局的风险。而对于一些糖尿病的高危人群而言,他们的子代发生近远期不良结局的风险更高。这些糖尿病的高危人群,是研究糖尿病(包括GDM在内)的不良影响及其机制的良好对象。为探索妊娠期糖尿病与子代出生结局的关系及其可能机制,我们依托加拿大出生队列和上海优生儿童队列平台展开研究。目的与方法:本研究从如下四个方面进行探索:(1).以加拿大土著人(GDM高危人群)为研究对象,以1996-2010年间加拿大魁北克的婴儿出生及死亡登记系统数据库为基础,建立回顾性出生队列(n=254,410),研究加拿大土著人和非土著人子代的不良出生结局、围产期和婴儿期死亡风险差异及近年来的变化趋势。(2).利用同一队列,在加拿大魁北克北美印第安人群(GDM高危人群,n=17090)和非土著人群(n=217760)中探究孕期糖尿病是否对印第安人及非土著人子代出生结局有不同影响。(3).利用加拿大前瞻性出生队列(n=275,单胎妊娠,其中26个GDM和248个非GDM),探究胎盘2型11β-羟基类固醇脱氢酶(11β-HSD2)蛋白表达水平和脐带血皮质醇浓度与子代婴儿代谢和心血管健康生物标记的相关性,并评估GDM的影响。(4).利用上海优生儿童队列和高危妊娠队列,筛选62例GDM和与之匹配的62例非GDM孕妇进行巢式病例对照研究,在中国汉族人中探索GDM孕妇脐带血皮质醇与11β-HSDs蛋白表达水平的变化及其与胎儿代谢健康生物标记的相关性。结果:研究结果表明:(1)近15年来,北美印第安人(GDM高危人群)子代的围产期死亡率和婴儿期死亡率分别是非土著人的1.47倍和1.80倍,因纽特人子代(GDM高危人群)的围产期死亡率和婴儿期死亡率分别是非土著人的2.37倍和4.46倍。此外在这15年中,魁北克因纽特人和非土著人之间的婴儿期死亡率差异变大(4.10倍增加到5.19倍),北美印第安人和非土著人(3.76倍增加到4.25倍)或因纽特人和非土著人(6.97倍增加到12.33倍)之间,后新生儿期婴儿死亡率的差异也增大。调整母亲的基线特征后,土著人子代死亡风险仍高于非土著人。(2)加拿大魁北克患孕前糖尿病(PGDM)的孕妇围产期子代死亡率比非糖尿病者高,且北美印第安孕妇组(RR 5.08(95%CI:2.99-8.62))此风险的升高大于非土著孕妇组(RR 1.76(1.17-2.66))。非土著PGDM孕妇子代后新生儿期婴儿死亡风险显著高于非土著的非糖尿病孕妇(RR 3.46(1.71-6.99)),但在北美印第安人中,未发现差异。妊娠糖尿病(GDM)与围产期死亡风险在非土著人中轻度负相关,而在印第安人中不相关。调整母亲的基线特征和其他孕期并发症或合并症后,结果发现相似。(3)GDM孕妇与非GDM孕妇的胎盘11β-HSD2水平以及子代一岁时代谢和心血管健康指标未发现显著差异。脐带血中皮质醇水平与胎儿出生时的β细胞功能指数呈负相关(偏相关系数r=-0.36,p<0.001)。胎盘11β-HSD2蛋白表达水平与婴儿一岁时胰岛素抵抗水平呈负相关(偏相关系数r=-0.17,p=0.02),与一岁时心脏收缩压有负相关的趋向(偏相关系数r=-0.16,p=0.057)。孕妇孕32-35周时循环血中的皮质醇水平与子代一岁时最大颈动脉内-中膜厚度呈正相关(偏相关系数r=0.2,p=0.02)。调整母亲和婴儿的特征后,这些相关趋势依旧存在。(4)妊娠期糖尿病孕妇的胎盘11β-HSD1表达水平明显低于正常对照孕妇(均数:0.61 vs.0.78,p<0.05),但11β-HSD2表达水平无差异。脐带血皮质醇水平与胎儿出生时胰岛素敏感性指标QUICKI呈负相关(偏相关系数r=-0.32,p=0.0027),与出生时胰岛素抵抗指数HOMA-IR呈显著正相关(偏相关系数r=0.30,p=0.0059)。胎盘11β-HSD2表达水平与胎儿出生时的胰岛素抵抗指数HOMA-IR呈显著正相关(偏相关系数r=0.35,p=0.0197)。调整母婴基线特征后,以上相关性仍然显著。结论:(1)近十余年间,加拿大魁北克土著人作为GDM的高危人群,其与非土著人之间子代不良出生结局、围产期和婴儿期死亡率的差异持续存在,且有逐渐增加的趋势。(2)孕期糖尿病(PGDM和GDM)在土著人(GDM的高危人群)和非土著人中与子代围产期和后新生儿期婴儿死亡率的相关性不同。这可能是由于人群血糖控制状况的不同以及对高血糖毒性的遗传敏感性的可能差异。(3)人胎盘11β-HSD2蛋白表达水平和母婴循环皮质醇水平与子代出生后早期心血管代谢健康有关。(4)妊娠期糖尿病(GDM)与胎盘11β-HSD1蛋白的表达密切相关,而脐带血皮质醇水平和胎盘11β-HSD2表达与胎儿胰岛素抵抗存在相关性。研究结果为GDM对子代影响与机制提供线索。更多还原

【Abstract】 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.更多还原