中华流行病学杂志  2021, Vol. 42 Issue (5): 903-908   PDF    
http://dx.doi.org/10.3760/cma.j.cn112338-20200804-01015
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文章信息

陈逍天, 叶莹, 张羿, 姜袁, 王胤, 陈红燕, 窦亚兰, 李梦茹, 孙绪鹏, 严卫丽.
Chen Xiaotian, Ye Ying, Zhang Yi, Jiang Yuan, Wang Yin, Chen Hongyan, Dou Yalan, Li Mengru, Sun Xupeng, Yan Weili
孕早期脂蛋白a水平与妊娠期糖尿病的前瞻性队列研究
Association of lipoprotein a in early pregnancy with gestational diabetes mellitus: a prospective cohort study
中华流行病学杂志, 2021, 42(5): 903-908
Chinese Journal of Epidemiology, 2021, 42(5): 903-908
http://dx.doi.org/10.3760/cma.j.cn112338-20200804-01015

文章历史

收稿日期: 2020-08-04
孕早期脂蛋白a水平与妊娠期糖尿病的前瞻性队列研究
陈逍天1 , 叶莹2 , 张羿1 , 姜袁1 , 王胤3 , 陈红燕1 , 窦亚兰3 , 李梦茹1 , 孙绪鹏1 , 严卫丽1,3     
1. 复旦大学附属儿科医院临床流行病学研究室, 上海 201102;
2. 复旦大学附属儿科医院皮肤科, 上海 201102;
3. 复旦大学附属儿科医院临床试验中心, 上海 201102
摘要: 目的 探讨孕早期脂蛋白a(Lpa)水平与妊娠期糖尿病(GDM)的关系。方法 以“母体关键营养素与子代特应性皮炎”队列中的445名孕12~14周孕妇为研究对象,通过问卷调查收集一般人口学特征,检测孕早期空腹糖脂代谢指标,随访孕24~28周口服糖耐量试验(OGTT)结果。应用多因素logistic回归分析Lpa水平与GDM的关系,计算OR值及其95%CI结果 孕中期GDM发病人数为78人(17.5%)。GDM孕妇孕早期Lpa水平[105.5(92.0,122.0)mg/L]高于非GDM孕妇[97.0(87.0,109.0)mg/L],差异有统计学意义(P < 0.05)。Lpa每升高10 mg/L,GDM发生风险增加21%,OR值(95%CI)为1.21(1.08~1.36),P < 0.05;校正年龄、孕周等协变量后,关联仍有统计学意义,校正OR值(95%CI)为1.14(1.01~1.30),P=0.03。结论 孕早期Lpa水平升高可能是GDM发生的危险因素之一,维持正常Lpa水平可能有助于GDM早期预防、提高子代健康水平。
关键词: 妊娠期糖尿病    脂蛋白a    孕早期    队列研究    
Association of lipoprotein a in early pregnancy with gestational diabetes mellitus: a prospective cohort study
Chen Xiaotian1 , Ye Ying2 , Zhang Yi1 , Jiang Yuan1 , Wang Yin3 , Chen Hongyan1 , Dou Yalan3 , Li Mengru1 , Sun Xupeng1 , Yan Weili1,3     
1. Department of Clinical Epidemiology, Children's Hospital of Fudan University, Shanghai 201102, China;
2. Department of Dermatology, Children's Hospital of Fudan University, Shanghai 201102, China;
3. Department of Clinical Trial Unit, Children's Hospital of Fudan University, Shanghai 201102, China
Abstract: Objective To investigate the association of lipoprotein a (Lpa) in early pregnancy with gestational diabetes mellitus (GDM) risk. Methods A total of 445 pregnant women in 12-14 gestational weeks from " Maternal Key Nutritional Factors and Offspring's Atopic Dermatitis" cohort were included in this study. The demographic characteristics of participants were collected by using questionnaires, and the fasting glucose and lipids levels in early pregnancy were measured. The results of oral glucose tolerance test (OGTT) between 24-28 gestational weeks were recorded. Multivariate logistic regression model was applied to analyze the association of Lpa with GDM by calculating the OR and 95%CI after adjustment for covariates. Results The incidence number of GDM was 78 (17.5%). The Lpa level in pregnant women with GDM was significantly higher than that in pregnant women without GDM[105.5 (92.0, 122.0) vs. 97.0 (87.0, 109.0) mg/L], P < 0.05. Lpa was significantly associated with GDM risk[OR (95%CI)=1.21(1.08-1.36) per 10 mg/L], P < 0.05. The association was still significant after adjustment for covariates including age, gestational weeks et al, the adjusted OR was 1.14 (95%CI: 1.01-1.30), P=0.03. Conclusions The elevation of Lpa in early pregnancy is one of risk factor for GDM. Maintaining normal Lpa level during early pregnancy can benefit early prevention of GDM and offspring health.
Key words: Gestational diabetes mellitus    Lipoprotein a    Early pregnancy    Cohort study    

妊娠期糖尿病(gestational diabetes mellitus,GDM)是孕产妇最常见的慢性代谢性疾病之一,已成为我国妇幼健康领域面临的巨大挑战[1]。流行病学调查研究显示,我国GDM发病率约为17.5%[2-3]。GDM不仅能显著增加早产、难产、巨大儿等不良妊娠结局的发生风险[4],也可显著增加孕妇远期罹患2型糖尿病、心脏病等心血管疾病的风险,对母子健康均有严重不良影响[5-6]。GDM受个体长期环境因素和遗传因素及两者交互作用共同影响[7],具体发病机制仍然不清。围孕期血脂代谢紊乱是GDM及其他不良妊娠结局发生的重要危险因素[8-9]。脂蛋白a [lipoprotein(a),Lpa]作为反映血脂水平的指标之一,是心血管疾病发生的重要危险因素[10-11]。近年来,研究Lpa与GDM的关系已逐渐成为热点。Lpa包括脂质和蛋白质两部分,由TG、胆固醇、载脂蛋白B-100和载脂蛋白a分子组成[12],可促进炎症反应、平滑肌细胞增殖[13]。研究发现,Lpa水平在糖尿病对象中显著高于正常人[(47.65±6.22)mg/dl vs.(20.80±3.54)mg/dl][14];Lpa升高能够增加糖尿病患者发生冠心病的风险(OR=1.56),加重冠心病的严重程度[15]。病例-对照研究显示,母亲Lpa水平升高导致先兆子痫和子代低出生体重发生[16-17]。然而,关于Lpa与糖尿病关系的研究结果却并不完全一致[18-19]。本研究基于前瞻性队列探讨孕早期Lpa暴露水平与GDM的关系,为GDM的早期预防和干预、改善妊娠结局、提高子代健康水平提供科学依据。

对象与方法

1. 研究对象:来自复旦大学附属儿科医院“母体关键营养素与子代特应性皮炎”队列(NCT02889081)。2016年6-9月在上海市某区妇幼保健院早孕门诊纳入计划在该院完成产检、分娩并接受产后儿保随访者共487名孕妇。本研究根据问卷信息和孕期档案,排除既往有糖尿病病史或围孕期服用降糖药者;排除因人口流动或孕早期胎停、人工流产等因素导致孕中期口服糖耐量试验(oral glucose tolerance test,OGTT)信息缺失的对象,最终445名孕妇纳入分析。所有纳入对象均签署知情同意书,研究方案通过复旦大学附属儿科医院伦理委员会审查(批准文号:2016-34)。

2. 研究方法:

(1)基线调查:现场问卷调查人员经统一培训后,负责收集孕妇基本信息,包括年龄、文化程度、身高、孕前体重、妊娠次数、孕周等;收集孕妇疾病史、糖尿病或高血压家族史、围孕期烟草暴露、饮酒等情况。糖尿病或高血压家族史定义为直系亲属患有糖尿病或高血压疾病;烟草暴露定义为在妊娠期间,孕妇本人吸烟或在家里、公共场所及工作单位暴露于他人烟草烟雾;饮酒情况定义为孕前3个月至今饮用过任何含有酒精的饮料。根据孕24~28周产检信息,计算孕早期增重(OGTT检测时体重-孕早期纳入时体重)。

(2)OGTT临床诊断:根据《中国妊娠合并糖尿病防治指南》(2014年)诊断标准[20]:孕妇于孕24~28周进行OGTT筛查,将75 g葡萄糖溶于250 ml水中,受试者5 min内喝完,分别测定空腹、服糖后1 h、2 h静脉血糖值。FPG≥5.1 mmol/L,或餐后1 h血糖≥10.0 mmol/L,或2 h血糖≥8.5 mmol/L,符合上述任一指标者即诊断为GDM。

(3)孕早期血样检测:根据早孕门诊常规流程,每位纳入对象均完成基线FPG和血脂检测。血脂指标包括Lpa、HDL-C、LDL-C、TG和TC,所有指标的检测均血样采集后的0.5 h内完成。检测仪器型号为Roche C501全自动生化分析仪。

(4)统计学分析:符合正态分布的连续性数据用x±s表示,偏态分布数据用MP25P75)表示。应用秩和检验方法,比较糖尿病孕妇和非糖尿病孕妇孕早期Lpa水平。计算BMI=体重(kg)/身高(m)2,根据中国肥胖工作组的分类标准进行分类[21],以BMI < 18.5、18.5~和 > 24.0 kg/m2分为低体重、正常体重、超重/肥胖3组。应用Spearman秩相关方法分析Lpa与OGTT血糖水平的关系。应用logistic回归方法,将Lpa检测值除以10后,以连续变量纳入回归模型作为自变量,分析与GDM的关系并报告OR值及其95%CI。根据既往研究发现的GDM危险因素[22],本研究考虑的协变量包括年龄、孕周、孕早期增重、基线FPG、孕前BMI(连续变量)以及饮酒史、烟草暴露史和糖尿病或高血压家族史(二分类变量)。基于本研究GDM的发病率(78/445),当连续变量Lpa每变化10 mg/L的关联结果OR值达1.42时,本研究在双侧α=0.05水平上有80%的把握度检验出该效应值。统计学分析软件采用Stata16.0(Stata Corp,Texas,USA),以双侧检验P < 0.05为差异有统计学意义。

结果

1. 基线信息:研究对象平均年龄、孕周、孕期增重和孕前BMI分别为29.5岁、13.5周、6.2 kg和20.6 kg/m2,其中孕前低体重和超重/肥胖者分别占18.6%和10.6%。有糖尿病或高血压家族史者、烟草暴露和饮酒史为182人(40.9%)、77人(17.3%)和73人(16.4%)。孕早期FPG、HDL-C、LDL-C、TG、TC和Lpa检测水平的M分别为4.1 mmol/L、1.8 mmol/L、2.3 mmol/L、1.3 mmol/L、4.3 mmol/L和98 mg/L。见表 1

表 1 纳入对象基线人口学特征(n=445)

2. 孕早期Lpa水平与GDM的关联分析:GDM随访发病人数为78人(17.5%)。GDM孕妇孕早期Lpa水平[105.5(92.0,122.0)mg/L]高于非GDM孕妇[97.0(87.0,109.0)mg/L],差异有统计学意义(P < 0.05);GDM组LDL-C、TG和TC水平也高于非GDM组(图 1)。logistic回归分析结果显示,Lpa每升高10 mg/L,GDM发生风险增加21%,OR值(95%CI)为1.21(1.08~1.36),P < 0.05;校正年龄、孕周、孕期增重、HDL-C、孕前BMI、饮酒史、烟草暴露史和糖尿病或高血压家族史协变量后,关联仍有统计学意义,调整OR值(95%CI)为1.15(1.02~1.30),P=0.02。进一步校正基线血糖后,Lpa与GDM的发生风险仍有统计学意义,调整OR值(95%CI)分别为1.14(1.01~1.30),P=0.03。此外,单因素分析模型显示TG和TC与GDM的发生显著相关,OR值(95%CI)分别为2.61(1.62~4.20)和1.51(1.13~2.02),P < 0.05。校正基线血糖后,TG与GDM的发生风险仍有统计学意义,调整OR值(95%CI)为1.93(1.08~3.44),P=0.02。见表 2

图 1 GDM和非GDM组孕早期脂蛋白a、HDL-C、LDL-C、TG和TC水平比较
表 2 孕早期脂蛋白a、HDL-C、LDL-C、TG和TC与GDM的关联分析

3. 孕早期Lpa和TG与OGTT血糖水平相关性分析:多因素回归分析显示,Lpa和TG与GDM显著关联,进一步分析显示,Lpa和TG与2 h血糖水平变化呈正相关,相关系数rho值分别为0.16和0.22,P < 0.05。见图 2

图 2 孕早期脂蛋白a和TG与口服糖耐量试验FPG、1 h血糖和2 h血糖相关性分析
讨论

GDM是影响孕妇自身和子代健康最常见的妊娠并发症之一。根据国际标准,GDM的诊断在孕24~28周,此时对孕妇和胎儿造成的危害已不可逆,研究围孕期血脂暴露水平与GDM的关系将为GDM早期预防提供可干预的研究证据。本研究基于前瞻性队列,首次探讨孕早期Lpa水平与GDM的关系。结果显示,GDM孕妇孕早期Lpa水平显著高于正常孕妇,Lpa水平升高能显著增加GDM的发生风险,且与OGTT血糖水平呈正相关,孕早期Lpa水平升高可能是GDM发生的一个危险因素。

孕早期是GDM发生和进展的关键窗口期,随着孕周增加,孕妇血脂水平会轻度升高以满足胎儿生长和发育需要,孕早期各类营养素(如脂质)摄入过多易导致血脂代谢紊乱,进而影响妊娠结局[23]。近年关于Lpa与心血管疾病的研究已经证实,Lpa是冠心病、脑卒中等心血管事件发生的重要生物标志物[24-25],但与糖尿病的关系研究结果并不一致。在正常妊娠情况下,有研究显示Lpa从围孕期开始到孕35周左右水平一直持续升高,在分娩后逐渐降低于孕早期水平[26]。既往研究关于Lpa与子痫的关系已有文献报道,而Lpa水平升高是否与参与GDM的发生有待进一步探讨。本研究结果显示,Lpa水平升高能显著增加GDM发生风险,推测孕早期Lpa升高可能是GDM发病的独立危险因素。GDM孕妇孕早期Lpa水平显著高于非GDM孕妇,与国内一项孕中期开展的病例-对照研究结果一致[27]。本研究进一步发现Lpa水平与OGTT血糖水平呈正相关,提示孕早期Lpa可能与孕中期血糖控制有关。

Lpa参与GDM的发病机制目前仍不清楚。Habib等[28]及Rainwater和Haffner[29]的研究显示,胰岛素具有降低Lpa水平的作用;动物研究也证实肝脏细胞合成的Lpa水平和LPA基因转录水平受胰岛素调控[30]。国外一项横断面研究显示,Lpa水平与胰岛素抵抗指数呈正相关[31],由于胰岛素抵抗是GDM发生的重要因素之一,推测Lpa升高参与GDM的发病机制可能是通过增加胰岛素抵抗所致,具体生物学机制有待于进一步功能研究进行探讨。Lpa水平基本不受性别、体重和大多数降胆固醇类药物影响,筛选显著影响Lpa水平的LPA基因遗传变异位点有助于早期筛查GDM高危对象、构建GDM风险预测模型。

本研究结果显示,在校正了孕前BMI和基线血糖等协变量后,TG与GDM的关联仍然显著,提示TG可能对GDM具有独立的危险作用,这与Bao等[32]的研究结果一致。TG是胰岛素抵抗的预测指标,与胰岛素抵抗的发生密切相关[33]。在胰岛素作用的靶器官中,TG水平过高会导致沉积、抑制胰岛素的输送,降低外周葡萄糖的利用,从而促进胰岛素抵抗[34]。基于全基因组关联研究筛选出的影响TG表型的候选基因单核苷酸多态性与胰岛素抵抗有显著的交互作用,这提示基于TG相关的遗传标志位点可作为孕中期胰岛素抵抗程度及GDM发病的预测依据。

本研究存在局限性。首先,与Lpa水平有关的膳食、体力活动、基因遗传等混杂因素未予以考虑;其次,研究对象均来自上海地区的孕妇,经济和医疗条件相对较好,可能存在选择偏倚,结果是否能外推至全国其他地区有一定局限性,有待于大样本多中心队列研究进行验证。

综上所述,GDM孕妇孕早期Lpa的水平显著高于非GDM孕妇,Lpa水平升高能显著增加GDM的发生风险。本研究结果将为临床GDM孕妇早期筛查、干预和治疗提供新思路,孕早期血脂水平与GDM关系应值得进一步关注。

利益冲突  所有作者均声明不存在利益冲突

志谢 感谢所有队列参与者;感谢参与队列现场实施、质控的成员;感谢复旦大学附属儿科医院领导对课题项目的支持

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