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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.
PLoS Med 2018; 15(10):e1002681PM

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.

Authors+Show Affiliations

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.Institute of Social Paediatrics and Adolescent Medicine, Division of Epidemiology, Faculty of Medicine, Ludwig-Maximilians-Universität München, Munich, Germany.Department of Obstetrics and Gynecology, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany.Institute for Medical Information Processing, Biometry, and Epidemiology (IBE), Faculty of Medicine, Ludwig-Maximilians-Universität München, Munich, Germany.Department of Obstetrics and Gynecology, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany. Division of Pediatric Cardiology and Intensive Care, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany.Department of Obstetrics and Gynecology, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany. Division of Pediatric Cardiology and Intensive Care, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany.Division of Pediatric Cardiology and Intensive Care, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany.Division of Pediatric Cardiology and Intensive Care, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany.Division of Pediatric Cardiology and Intensive Care, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany.Institute of Social Paediatrics and Adolescent Medicine, Division of Epidemiology, Faculty of Medicine, Ludwig-Maximilians-Universität München, Munich, Germany.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 Laboratory Medicine, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany.Institute of Laboratory Medicine, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany.Department of Obstetrics and Gynecology, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany.Department of Pediatrics, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany.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. Division of Pediatric Cardiology and Intensive Care, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30372451

Citation

Gomes, Delphina, et al. "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." PLoS Medicine, vol. 15, no. 10, 2018, pp. e1002681.
Gomes D, von Kries R, Delius M, et al. 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. PLoS Med. 2018;15(10):e1002681.
Gomes, D., von Kries, R., Delius, M., Mansmann, U., Nast, M., Stubert, M., ... Ensenauer, R. (2018). 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. PLoS Medicine, 15(10), pp. e1002681. doi:10.1371/journal.pmed.1002681.
Gomes D, et al. 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. PLoS Med. 2018;15(10):e1002681. PubMed PMID: 30372451.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Gomes,Delphina, AU - von Kries,Rüdiger, AU - Delius,Maria, AU - Mansmann,Ulrich, AU - Nast,Martha, AU - Stubert,Martina, AU - Langhammer,Lena, AU - Haas,Nikolaus A, AU - Netz,Heinrich, AU - Obermeier,Viola, AU - Kuhle,Stefan, AU - Holdt,Lesca M, AU - Teupser,Daniel, AU - Hasbargen,Uwe, AU - Roscher,Adelbert A, AU - Ensenauer,Regina, Y1 - 2018/10/29/ PY - 2018/02/04/received PY - 2018/09/25/accepted PY - 2018/10/30/entrez PY - 2018/10/30/pubmed PY - 2019/4/10/medline SP - e1002681 EP - e1002681 JF - PLoS medicine JO - PLoS Med. VL - 15 IS - 10 N2 - 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. SN - 1549-1676 UR - https://www.unboundmedicine.com/medline/citation/30372451/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_ L2 - http://dx.plos.org/10.1371/journal.pmed.1002681 DB - PRIME DP - Unbound Medicine ER -