Late-pregnancy dysglycemia in obese pregnancies after negative testing for gestational diabetes and risk of future childhood overweight: An interim analysis from a longitudinal mother – child cohort study
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, Regina Ensenauer
Source: PLOS Medicine
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.
Pre-conception obesity is associated with an increased risk of pregnancy complications and adverse long-term health outcomes for the mother and her child.
Obese pregnant women can develop impairments in glucose metabolism in late pregnancy despite prior negative testing for gestational diabetes mellitus (GDM).
Yet, to date, guidelines on obesity in pregnancy and GDM have focused only on early glucose screening rather than targeting factors relevant to the last trimester of pregnancy.
To evaluate whether recommendations on management of obese pregnancies require optimization, additional evidence is needed on the consequences of late-pregnancy dysglycemia for long-term childhood and maternal outcomes.
We performed an interim analysis of 898 obese and normal weight mothers and their offspring from the Programming of Enhanced Adiposity Risk in Childhood–Early Screening (PEACHES) cohort study (total n = 1,671) that recruited pregnant women in Germany from 2010 to 2015.
Late-pregnancy dysglycemia predisposed the offspring of obese, GDM-negative mothers to higher weight gain in early childhood and a higher body mass index at age 4 years.
Children of obese mothers treated because of a diagnosis of GDM appeared to have a better weight outcome than those of obese mothers who remained untreated following a negative GDM test and developed late-pregnancy dysglycemia.
Obese, GDM-negative women with late-pregnancy dysglycemia also had a 4-fold higher risk of prediabetes or diabetes several years after delivery compared to those with normal glucometabolic status in late pregnancy.
We suggest that a negative GDM test at the end of the second trimester should not be understood as an “all-clear signal” and should not result in reduced attention of caregivers and a false sense of security in the mothers.
Guidelines to manage and maintain third-trimester glycemic and weight gain control are needed for “high risk” obese women.
Further analyses and studies should validate the findings and investigate the possible role of third-trimester factors for future mother–child health.