Association and mediation pathways of maternal hyperglycaemia and liability to gestational diabetes with neonatal outcomes: A two-sample Mendelian randomization study.

IF 5.4 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM Diabetes, Obesity & Metabolism Pub Date : 2024-11-06 DOI:10.1111/dom.16045
Baoting He, Hugh Simon Lam, Xiu Qiu, Songying Shen, Shan Luo, Eric A W Slob, Shiu Lun Au Yeung
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Abstract

Aims: Maternal hyperglycemia is linked to adverse neonatal outcomes. However, current evidence was insufficient for mechanistic pathways. We aim to use two-sample Mendelian randomization (MR) to obtain a comprehensive understanding of the causal association and mediation pathways.

Materials and methods: Genetic variants of fasting glucose (FG), insulin sensitivity index (ISI), glycated haemoglobin (HbA1c), gestational diabetes mellitus (GDM) and type 2 diabetes (T2D) were used as instruments (N = 50 404-898 130). The associations with offspring birthweight, gestational duration, spontaneous preterm and post-term birth were assessed by the inverse-variance weighted method, using summary statistics of European genome-wide association studies (N = 131 279-210 248). Sensitivity analyses, including multivariable MR removing pleiotropic effect from maternal body mass index (BMI), assessed the robustness. Mediation via placental weight and maternal hypertension were assessed via a two-step MR design.

Results: FG (0.46 SD per mmol/L, 95% confidence interval [95% CI]: 0.32, 0.61) and GDM liability (0.18 SD per log odds, 95% CI: 0.08, 0.18) were positively associated with birthweight, with consistent findings for HbA1c, T2D liability and ISI. These associations were mediated by placental weight (proportion mediated: 32.8% to 77.7%). Higher HbA1c, GDM and T2D liability were associated with preterm birth (odds ratios for GDM: 1.07, 95% CI: 1.01, 1.14) and shorter gestational duration, whilst the association for T2D attenuated after adjusted for maternal BMI and gestational hypertension.

Conclusion: Maternal hyperglycemia is associated with higher birthweight (possibly indicating macrosomia), mediated via increased placental growth. GDM and T2D liability are related to preterm birth, whilst the association for T2D liability is driven by maternal adiposity.

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孕产妇高血糖和妊娠糖尿病与新生儿结局的关联和中介途径:双样本孟德尔随机研究。
目的:产妇高血糖与新生儿不良预后有关。然而,目前的证据不足以证明其机理途径。我们旨在利用双样本孟德尔随机化(MR)来全面了解其因果关系和中介途径:以空腹血糖(FG)、胰岛素敏感性指数(ISI)、糖化血红蛋白(HbA1c)、妊娠糖尿病(GDM)和 2 型糖尿病(T2D)的遗传变异为工具(N = 50 404-898 130)。利用欧洲全基因组关联研究的汇总统计数据(N = 131 279-210 248),采用逆方差加权法评估了与后代出生体重、妊娠期、自发性早产和过期产的关联。敏感性分析(包括去除母体体重指数(BMI)褶状效应的多变量 MR)评估了稳健性。通过两步MR设计评估了胎盘重量和母体高血压的中介作用:FG(0.46 SD/mmol/L,95% 置信区间 [95%CI]:0.32, 0.61)和 GDM 责任(0.18 SD/log odds,95% CI:0.08, 0.18)与出生体重呈正相关,HbA1c、T2D 责任和 ISI 的研究结果一致。这些关联受胎盘重量的影响(影响比例:32.8% 至 77.7%)。较高的 HbA1c、GDM 和 T2D 相关性与早产(GDM 的几率比:1.07,95% CI:1.01,1.14)和较短的妊娠期有关,而 T2D 的相关性在调整了产妇体重指数和妊娠高血压后有所减弱:结论:母体高血糖与较高的出生体重(可能表示巨大儿)有关,通过胎盘生长增加而介导。GDM 和 T2D 与早产有关,而 T2D 与早产的关联则是由孕产妇脂肪过多引起的。
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来源期刊
Diabetes, Obesity & Metabolism
Diabetes, Obesity & Metabolism 医学-内分泌学与代谢
CiteScore
10.90
自引率
6.90%
发文量
319
审稿时长
3-8 weeks
期刊介绍: Diabetes, Obesity and Metabolism is primarily a journal of clinical and experimental pharmacology and therapeutics covering the interrelated areas of diabetes, obesity and metabolism. The journal prioritises high-quality original research that reports on the effects of new or existing therapies, including dietary, exercise and lifestyle (non-pharmacological) interventions, in any aspect of metabolic and endocrine disease, either in humans or animal and cellular systems. ‘Metabolism’ may relate to lipids, bone and drug metabolism, or broader aspects of endocrine dysfunction. Preclinical pharmacology, pharmacokinetic studies, meta-analyses and those addressing drug safety and tolerability are also highly suitable for publication in this journal. Original research may be published as a main paper or as a research letter.
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