Date Published: October 29, 2018
Publisher: Public Library of Science
Author(s): Delphina Gomes, Rüdiger von Kries, Maria Delius, Ulrich Mansmann, Martha Nast, Martina Stubert, Lena Langhammer, Nikolaus A. Haas, Heinrich Netz, Viola Obermeier, Stefan Kuhle, Lesca M. Holdt, Daniel Teupser, Uwe Hasbargen, Adelbert A. Roscher, Regina Ensenauer, Jenny E. Myers
Abstract: BackgroundMaternal 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.Methods and findingsThe 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.ConclusionsFindings 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.
Partial Text: Since up to two-thirds of women of reproductive age are now overweight or obese in European countries and the US [1,2], obesity in pregnancy and its consequences represent a major public health challenge . In Germany, the prevalence of overweight and obesity is 38.1% (obesity: 15.4%) among women of childbearing age  and 35.8% (obesity: 14.2%) among pregnant women . Obese women are 3 to 5.5 times more likely to develop gestational diabetes mellitus (GDM) than normal weight women , leading to an approximately 3- to 10-fold increased risk of developing type 2 diabetes mellitus (T2DM) later in life [7,8]. In addition, in offspring of obese women, the risk of adverse health outcomes such as the development of adiposity, T2DM, cardiovascular disease, and asthma is higher [9,10].
Identifying crucial periods of developmental programming is important for designing effective interventions , considering that obesity and diabetes in pregnancy are the major transgenerational health burden to date [35,36]. As yet, to our knowledge, the occurrence of dysglycemia in the last trimester of pregnancy despite prior negative testing for GDM has not been considered a problem for long-term health outcomes of obese pregnancies and thus has not been included in respective clinical care guidelines as part of routine monitoring . Our data suggest that late-pregnancy dysglycemia predisposes the offspring of obese, GDM-negative mothers to alterations in weight development during early childhood. Moreover, offspring of obese mothers treated and monitored 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 an abnormal glucose metabolism.