Department of General Pediatrics, Neonatology and Pediatric Cardiology, Division of Experimental Pediatrics and Metabolism, University Children's Hospital, Faculty of Medicine, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
Institute of Social Paediatrics and Adolescent Medicine, Division of Epidemiology, Faculty of Medicine, Ludwig-Maximilians-Universität München, Munich, Germany.
PLoS Med. 2018 Oct 29;15(10):e1002681. doi: 10.1371/journal.pmed.1002681. eCollection 2018 Oct.
Maternal pre-conception obesity is a strong risk factor for childhood overweight. However, prenatal mechanisms and their effects in susceptible gestational periods that contribute to this risk are not well understood. We aimed to assess the impact of late-pregnancy dysglycemia in obese pregnancies with negative testing for gestational diabetes mellitus (GDM) on long-term mother-child outcomes.
The prospective cohort study Programming of Enhanced Adiposity Risk in Childhood-Early Screening (PEACHES) (n = 1,671) enrolled obese and normal weight mothers from August 2010 to December 2015 with trimester-specific data on glucose metabolism including GDM status at the end of the second trimester and maternal glycated hemoglobin (HbA1c) at delivery as a marker for late-pregnancy dysglycemia (HbA1c ≥ 5.7% [39 mmol/mol]). We assessed offspring short- and long-term outcomes up to 4 years, and maternal glucose metabolism 3.5 years postpartum. Multivariable linear and log-binomial regression with effects presented as mean increments (Δ) or relative risks (RRs) with 95% confidence intervals (CIs) were used to examine the association between late-pregnancy dysglycemia and outcomes. Linear mixed-effects models were used to study the longitudinal development of offspring body mass index (BMI) z-scores. The contribution of late-pregnancy dysglycemia to the association between maternal pre-conception obesity and offspring BMI was estimated using mediation analysis. In all, 898 mother-child pairs were included in this unplanned interim analysis. Among obese mothers with negative testing for GDM (n = 448), those with late-pregnancy dysglycemia (n = 135, 30.1%) had higher proportions of excessive total gestational weight gain (GWG), excessive third-trimester GWG, and offspring with large-for-gestational-age birth weight than those without. Besides higher birth weight (Δ 192 g, 95% CI 100-284) and cord-blood C-peptide concentration (Δ 0.10 ng/ml, 95% CI 0.02-0.17), offspring of these women had greater weight gain during early childhood (Δ BMI z-score per year 0.18, 95% CI 0.06-0.30, n = 262) and higher BMI z-score at 4 years (Δ 0.58, 95% CI 0.18-0.99, n = 43) than offspring of the obese, GDM-negative mothers with normal HbA1c values at delivery. Late-pregnancy dysglycemia in GDM-negative mothers accounted for about one-quarter of the association of maternal obesity with offspring BMI at age 4 years (n = 151). In contrast, childhood BMI z-scores were not affected by a diagnosis of GDM in obese pregnancies (GDM-positive: 0.58, 95% CI 0.36-0.79, versus GDM-negative: 0.62, 95% CI 0.44-0.79). One mechanism triggering late-pregnancy dysglycemia in obese, GDM-negative mothers was related to excessive third-trimester weight gain (RR 1.72, 95% CI 1.12-2.65). Furthermore, in the maternal population, we found a 4-fold (RR 4.01, 95% CI 1.97-8.17) increased risk of future prediabetes or diabetes if obese, GDM-negative women had a high versus normal HbA1c at delivery (absolute risk: 43.2% versus 10.5%). There is a potential for misclassification bias as the predominantly used GDM test procedure changed over the enrollment period. Further studies are required to validate the findings and elucidate the possible third-trimester factors contributing to future mother-child health status.
Findings from this interim analysis suggest that offspring of obese mothers treated because of a diagnosis of GDM appeared to have a better BMI outcome in childhood than those of obese mothers who-following negative GDM testing-remained untreated in the last trimester and developed dysglycemia. Late-pregnancy dysglycemia related to uncontrolled weight gain may contribute to the development of child overweight and maternal diabetes. Our data suggest that negative GDM testing in obese pregnancies is not an "all-clear signal" and should not lead to reduced attention and risk awareness of physicians and obese women. Effective strategies are needed to maintain third-trimester glycemic and weight gain control among otherwise healthy obese pregnant women.
母体孕前肥胖是儿童超重的一个强烈危险因素。然而，导致这种风险的易感性妊娠期间的产前机制及其影响尚未得到很好的理解。我们旨在评估肥胖妊娠中晚期妊娠糖代谢异常（即妊娠糖尿病检测结果为阴性）对母子长期结局的影响。
前瞻性队列研究 Programing of Enhanced Adiposity Risk in Childhood-Early Screening（PEACHES）（n = 1671）纳入了 2010 年 8 月至 2015 年 12 月期间肥胖和正常体重的母亲，在妊娠中期有关于葡萄糖代谢的具体数据，包括妊娠中期末的妊娠糖尿病检测结果和分娩时的糖化血红蛋白（HbA1c）作为晚期妊娠糖代谢异常（HbA1c≥5.7%[39mmol/mol]）的标志物。我们评估了后代长达 4 年的短期和长期结局，以及母亲产后 3.5 年的葡萄糖代谢情况。使用多元线性和二项式回归，以平均增量（Δ）或相对风险（RR）和 95%置信区间（CI）表示，检查晚期妊娠糖代谢异常与结局之间的关系。使用线性混合效应模型研究后代体重指数（BMI）z 分数的纵向发展。使用中介分析估计晚期妊娠糖代谢异常对母体孕前肥胖与后代 BMI 之间关联的贡献。共有 898 对母子对纳入了此次无计划的中期分析。在肥胖且妊娠糖尿病检测结果为阴性的母亲中（n = 448），有晚期妊娠糖代谢异常的（n = 135，占 30.1%）比没有的有更高比例的总妊娠期体重过度增加、妊娠晚期体重过度增加和巨大儿出生体重。除了出生体重较高（增加 192g，95%CI 100-284）和脐带血 C 肽浓度较高（增加 0.10ng/ml，95%CI 0.02-0.17）外，这些女性的后代在幼儿期体重增长更快（每年 BMI z 分数增加 0.18，95%CI 0.06-0.30，n = 262），4 岁时 BMI z 分数更高（增加 0.58，95%CI 0.18-0.99，n = 43），高于肥胖且妊娠糖尿病检测结果为阴性但分娩时 HbA1c 值正常的母亲的后代。肥胖且妊娠糖尿病检测结果为阴性的母亲中晚期妊娠糖代谢异常占母亲肥胖与 4 岁时后代 BMI 之间关联的约四分之一（n = 151）。相比之下，肥胖妊娠中妊娠糖尿病的诊断对后代的 BMI 没有影响（阳性：0.58，95%CI 0.36-0.79，与阴性：0.62，95%CI 0.44-0.79）。触发肥胖、妊娠糖尿病检测结果为阴性的母亲晚期妊娠糖代谢异常的一个机制与妊娠晚期体重过度增加有关（RR 1.72，95%CI 1.12-2.65）。此外，在母亲人群中，如果肥胖、妊娠糖尿病检测结果为阴性的女性分娩时 HbA1c 值较高，那么她们未来患糖尿病前期或糖尿病的风险会增加 4 倍（RR 4.01，95%CI 1.97-8.17）（绝对风险：43.2%比 10.5%）。由于主要使用的妊娠糖尿病检测程序在招募期间发生了变化，因此存在潜在的分类偏倚。需要进一步的研究来验证这些发现，并阐明可能导致母婴健康状况未来发展的第三个因素。
此次中期分析的结果表明，与肥胖母亲因为妊娠糖尿病的诊断而接受治疗的后代相比，那些肥胖但妊娠糖尿病检测结果为阴性的母亲在分娩后未接受治疗，且在妊娠晚期出现糖代谢异常，这些母亲的后代在儿童时期的 BMI 结局更好。与不受控制的体重增加相关的晚期妊娠糖代谢异常可能导致儿童超重和母亲糖尿病的发展。我们的数据表明，肥胖妊娠中的妊娠糖尿病检测结果为阴性并不是一个“安全信号”，不应该导致医生和肥胖女性降低对其的关注和风险意识。需要有效的策略来维持其他方面健康的肥胖孕妇在妊娠晚期的血糖和体重控制。
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