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

Abstract

Background: 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.

Methods and findings: 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.

Conclusions: 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.

Fig 1. PEACHES study population and follow-up investigations of children.

^aDid not meet inclusion criteria for analysis including pre-conception obesity or normal weight, singleton live birth, and absence of type 1 diabetes and type 2 diabetes. ^bMissing information for at least 1 of the following variables: pre-conception body mass index group (normal weight or obese), GDM status (GDM-negative or GDM-positive), maternal HbA_1c at delivery (<5.7% [39 mmol/mol] or ≥5.7%), or confounding variables. ^c“Healthy” defined as GDM-negative and HbA_1c < 5.7% at delivery. ^dOffspring too young at the time of data retrieval from the PEACHES database. ^eLoss to follow-up or withdrawal from participation. GDM, gestational diabetes mellitus; HbA_1c, glycated hemoglobin; PEACHES, Programming of Enhanced Adiposity Risk in Childhood–Early Screening.

Fig 2. Offspring 4-year BMI z-score by maternal pre-conception weight status and glucometabolic status in pregnancy and at delivery.

Stratification of maternal groups was performed in enrolled mother–child pairs with offspring 4-year BMI z-scores according to the (A) pre-conception BMI group of 352 mothers, (B) positive or negative testing for GDM in 246 obese women, and (C) HbA_1c at delivery in 151 obese, GDM-negative women. Data are shown as median (horizontal lines within the boxes), 25th and 75th centile (lower and upper boundaries of the boxes), 1.5 times the interquartile range (whisker ends), and outliers (circles). Numerical values and dots within the boxes represent unadjusted mean 4-year BMI z-score of offspring. Differences between groups were tested using Student’s t test. ^aAccording to the International Association of Diabetes and Pregnancy Study Groups criteria [18]. ^bDichotomized based on a predefined cutoff value of ≥5.7% (39 mmol/mol) [17]. BMI, body mass index; GDM, gestational diabetes mellitus; HbA_1c, glycated hemoglobin.

Fig 3. Contribution of late-pregnancy dysglycemia to the effect of maternal obesity on increased weight status in 4-year-old children.

Mediation analysis was performed to study the total effect of pre-conception obesity in GDM-negative mothers on offspring BMI z-score at age 4 years, comprising the direct effect of maternal obesity and the indirect effect of late-pregnancy dysglycemia (as indicated by a high maternal HbA_1c [≥5.7%] at delivery). Data are coefficients derived from linear regression models, adjusted for maternal smoking at any time during pregnancy, total GWG, and exclusive breastfeeding ≥1 month. ^aEstimated as β₁ from: BMIz_{4 years} = β₀ + β₁ * maternal obesity_yes/no + β₂ * maternal smoking_yes/no + β₃ * total GWG + β₄ * breastfeeding_yes/no ^bEstimated as γ₁ from: BMIz_{4 years} = γ₀ + γ₁ * maternal obesity_yes/no + γ₂ * maternal smoking_yes/no + γ₃ * total GWG + γ₄ * breastfeeding_yes/no + γ₅ * HbA_{1c≥5.7% or <5.7%}. ^cCalculated as β₁−γ₁ BMI, body mass index; GDM, gestational diabetes mellitus; GWG, gestational weight gain; HbA_1c, glycated hemoglobin.