Metabolic phenotyping by treatment modality in obese women with gestational diabetes suggests diverse pathophysiology: An exploratory study

Background and purpose: Excess insulin resistance is considered the predominant pathophysiological mechanism in obese women who develop gestational diabetes (GDM). We hypothesised that obese women requiring differing treatment modalities for GDM may have diverse underlying metabolic pathways. Methods: In this secondary analysis of the UK pregnancies Better Eating and Activity Trial (UPBEAT) we studied women from the control arm with complete biochemical data at three gestational time points; at 15–18+6 and 27–28+6 weeks (before treatment), and 34–36+0 weeks (after treatment). A total of 89 analytes were measured (plasma/serum) using a targeted nuclear magnetic resonance (NMR) platform and conventional assays. We used linear regression with appropriate adjustment to model metabolite concentration, stratified by treatment group. Main findings: 300 women (median BMI 35kg/m2; inter quartile range 32.8–38.2) were studied. 71 developed GDM; 28 received dietary treatment only, 20 metformin, and 23 received insulin. Prior to the initiation of treatment, multiple metabolites differed (p<0.05) between the diet and insulin-treated groups, especially very large density lipoprotein (VLDL) and high density lipoprotein (HDL) subclasses and constituents, with some differences maintained at 34–36 weeks’ gestation despite treatment. Gestational lipid profiles of the diet treatment group were indicative of a lower insulin resistance profile, when compared to both insulin-treated women and those without GDM. At 28 weeks’ the diet treatment group had lower plasma fasting glucose and insulin than women treated with insulin, yet similar to those without GDM, consistent with a glycaemic mechanism independent of insulin resistance. Conclusions/Interpretation: This exploratory study suggests that GDM pathophysiological processes may differ amongst obese women who require different treatment modalities to achieve glucose control and can be revealed using metabolic profiling

Prediction of uncomplicated pregnancies in obese women: a prospective multicentre study.

BACKGROUND: All obese pregnant women are considered at equal high risk with respect to complications in pregnancy and birth, and are commonly managed through resource-intensive care pathways. However, the identification of maternal characteristics associated with normal pregnancy outcomes could assist in the management of these pregnancies. The present study aims to identify the factors associated with uncomplicated pregnancy and birth in obese women, and to assess their predictive performance. METHODS: Data form obese women (BMI ≥ 30 kg/m2) with singleton pregnancies included in the UPBEAT trial were used in this analysis. Multivariable logistic regression was used to identify sociodemographic, clinical and biochemical factors at 15+0 to 18+6 weeks' gestation associated with uncomplicated pregnancy and birth, defined as delivery of a term live-born infant without antenatal or labour complications. Predictive performance was assessed using area under the receiver operating characteristic curve (AUROC). Internal validation and calibration were also performed. Women were divided into fifths of risk and pregnancy outcomes were compared between groups. Sensitivity, specificity, and positive and negative predictive values were calculated using the upper fifth as the positive screening group. RESULTS: Amongst 1409 participants (BMI 36.4, SD 4.8 kg/m2), the prevalence of uncomplicated pregnancy and birth was 36% (505/1409). Multiparity and increased plasma adiponectin, maternal age, systolic blood pressure and HbA1c were independently associated with uncomplicated pregnancy and birth. These factors achieved an AUROC of 0.72 (0.68-0.76) and the model was well calibrated. Prevalence of gestational diabetes, preeclampsia and other hypertensive disorders, preterm birth, and postpartum haemorrhage decreased whereas spontaneous vaginal delivery increased across the fifths of increasing predicted risk of uncomplicated pregnancy and birth. Sensitivity, specificity, and positive and negative predictive values were 38%, 89%, 63% and 74%, respectively. A simpler model including clinical factors only (no biomarkers) achieved an AUROC of 0.68 (0.65-0.71), with sensitivity, specificity, and positive and negative predictive values of 31%, 86%, 56% and 69%, respectively. CONCLUSION: Clinical factors and biomarkers can be used to help stratify pregnancy and delivery risk amongst obese pregnant women. Further studies are needed to explore alternative pathways of care for obese women demonstrating different risk profiles for uncomplicated pregnancy and birth

Early Antenatal Prediction of Gestational Diabetes in Obese Women: Development of Prediction Tools for Targeted Intervention.

All obese women are categorised as being of equally high risk of gestational diabetes (GDM) whereas the majority do not develop the disorder. Lifestyle and pharmacological interventions in unselected obese pregnant women have been unsuccessful in preventing GDM. Our aim was to develop a prediction tool for early identification of obese women at high risk of GDM to facilitate targeted interventions in those most likely to benefit. Clinical and anthropometric data and non-fasting blood samples were obtained at 15+0-18+6 weeks' gestation in 1303 obese pregnant women from UPBEAT, a randomised controlled trial of a behavioural intervention. Twenty one candidate biomarkers associated with insulin resistance, and a targeted nuclear magnetic resonance (NMR) metabolome were measured. Prediction models were constructed using stepwise logistic regression. Twenty six percent of women (n = 337) developed GDM (International Association of Diabetes and Pregnancy Study Groups criteria). A model based on clinical and anthropometric variables (age, previous GDM, family history of type 2 diabetes, systolic blood pressure, sum of skinfold thicknesses, waist:height and neck:thigh ratios) provided an area under the curve of 0.71 (95%CI 0.68-0.74). This increased to 0.77 (95%CI 0.73-0.80) with addition of candidate biomarkers (random glucose, haemoglobin A1c (HbA1c), fructosamine, adiponectin, sex hormone binding globulin, triglycerides), but was not improved by addition of NMR metabolites (0.77; 95%CI 0.74-0.81). Clinically translatable models for GDM prediction including readily measurable variables e.g. mid-arm circumference, age, systolic blood pressure, HbA1c and adiponectin are described. Using a ≥35% risk threshold, all models identified a group of high risk obese women of whom approximately 50% (positive predictive value) later developed GDM, with a negative predictive value of 80%. Tools for early pregnancy identification of obese women at risk of GDM are described which could enable targeted interventions for GDM prevention in women who will benefit the most

Dietary patterns in obese pregnant women; influence of a behavioral intervention of diet and physical activity in the UPBEAT randomized controlled trial.

BACKGROUND: Understanding dietary patterns in obese pregnant women will inform future intervention strategies to improve pregnancy outcomes and the health of the child. The aim of this study was to investigate the effect of a behavioral intervention of diet and physical activity advice on dietary patterns in obese pregnant woman participating in the UPBEAT study, and to explore associations of dietary patterns with pregnancy outcomes. METHODS: In the UPBEAT randomized controlled trial, pregnant obese women from eight UK multi-ethnic, inner-city populations were randomly assigned to receive a diet/physical activity intervention or standard antenatal care. The dietary intervention aimed to reduce glycemic load and saturated fat intake. Diet was assessed using a food frequency questionnaire (FFQ) at baseline (15(+0)-18(+6) weeks' gestation), post intervention (27(+0)-28(+6) weeks) and in late pregnancy (34(+0)-36(+0) weeks). Dietary patterns were characterized using factor analysis of the baseline FFQ data, and changes compared in the control and intervention arms. Patterns were related to pregnancy outcomes in the combined control/intervention cohort (n = 1023). RESULTS: Four distinct baseline dietary patterns were defined; Fruit and vegetables, African/Caribbean, Processed, and Snacks, which were differently associated with social and demographic factors. The UPBEAT intervention significantly reduced the Processed (-0.14; 95% CI -0.19, -0.08, P <0.0001) and Snacks (-0.24; 95% CI -0.31, -0.17, P <0.0001) pattern scores. In the adjusted model, baseline scores for the African/Caribbean (quartile 4 compared with quartile 1: OR = 2.46; 95% CI 1.41, 4.30) and Processed (quartile 4 compared with quartile 1: OR = 2.05; 95% CI 1.23, 3.41) patterns in the entire cohort were associated with increased risk of gestational diabetes. CONCLUSIONS: In a diverse cohort of obese pregnant women an intensive dietary intervention improved Processed and Snack dietary pattern scores. African/Caribbean and Processed patterns were associated with an increased risk of gestational diabetes, and provide potential targets for future interventions. TRIAL REGISTRATION: Current controlled trials; ISRCTN89971375

Gestational diabetes in women with obesity; an analysis of clinical history and simple clinical/anthropometric measures.

AimWe assessed clinical risk factors, anthropometric measures of adiposity and weight gain to determine associations with development of GDM in a cohort of pregnant women with obesity.MethodsThis was a secondary analysis of the UPBEAT trial of a complex lifestyle intervention in pregnant women with obesity (ISRCTN89971375). Clinical risk factors, and measures of adiposity and weight were assessed in the early 2nd trimester (mean 17 +0 weeks), and adiposity and weight repeated in the early 3rd trimester (mean 27 +5 weeks').ResultsOf the 1117 women (median BMI 35.0 kg/m2) with complete data, 25.8% (n = 304) developed GDM (IADPSG criteria, OGTT 24-28weeks). Using multivariable analysis, early clinical risk factors associated with later development of GDM included age (adj OR 1.06 per year; 95% CI 1.04-1.09), previous GDM (3.27; 1.34-7.93) and systolic blood pressure (per 10mmHg, 1.34; 1.18-1.53). Anthropometric measures positively associated with GDM included second trimester (mean 17+0 weeks) subscapular skinfold thickness, (per 5mm, 1.12; 1.05-1.21), and neck circumference (per cm, 1.11; 1.05-1.18). GDM was not associated with gestational weight gain, or changes in skinfolds thicknesses or circumferences between visits.ConclusionsIn this cohort of women with obesity, we confirmed clinical risk factors for GDM, (age, systolic blood pressure) previously identified in heterogeneous weight women but add to these indices of adiposity which may provide a discriminatory approach to GDM risk assessment in this group. This study also underscores the need to focus on modifiable factors pre-pregnancy as an opportunity for GDM prevention, as targeting gestational weight gain and adiposity during pregnancy is likely to be less effective

Change in level of physical activity during pregnancy in obese women: findings from the UPBEAT pilot trial

Background: Maternal obesity is associated with an increased risk of pregnancy complications, including gestational diabetes. Physical activity (PA) might improve glucose metabolism and reduce the incidence of gestational diabetes. The purpose of this study was to explore patterns of PA and factors associated with change in PA in obese pregnant women.Methods: PA was assessed objectively by accelerometer at 16 -18 weeks\u27 (T0), 27 - 28 weeks\u27 (T1) and 35 - 36 weeks\u27 gestation (T2) in 183 obese pregnant women recruited to a pilot randomised trial of a combined diet and PA intervention (the UPBEAT study).Results: Valid PA data were available for 140 (77%), 76 (42%) and 54 (30%) women at T0, T1 and T2 respectively. Moderate and vigorous physical activity as a proportion of accelerometer wear time declined with gestation from a median of 4.8% at T0 to 3% at T2 (p &lt; 0.05). Total activity as a proportion of accelerometer wear time did not change. Being more active in early pregnancy was associated with a higher level of PA later in pregnancy. The intervention had no effect on PA.Conclusions: PA in early pregnancy was the factor most strongly associated with PA at later gestations. Women should be encouraged to participate in PA before becoming pregnant and to maintain their activity levels during pregnancy. There is a need for effective interventions, tailored to the needs of individuals and delivered early in pregnancy to support obese women to be sufficiently active during pregnancy

Association between Physical Activity in Obese Pregnant Women and Pregnancy Outcomes: The UPBEAT Pilot Study

Background: Obesity in pregnancy is associated with fetal macrosomia, a raised neonatal fat mass and an increased risk of obesity and poor metabolic health in childhood which persists into adulthood. The offspring of obese women are more likely to be obese than the offspring of lean women when they become pregnant themselves, perpetuating a cycle of obesity and its associated negative metabolic consequences. Increasing physical activity during pregnancy could improve insulin sensitivity and reduce the risk of maternal and offspring adverse outcomes. The UK Pregnancy Better Eating and Activity Trial (UPBEAT) is a trial of a complex intervention designed to improve pregnancy outcomes through dietary changes and physical activity. Data from the pilot trial of 183 women were available for analysis. The relationship between the time spent at different physical activity levels and maternal and infant pregnancy outcomes was examined. Key Messages: Strong evidence exists that physical activity improves insulin sensitivity in non-pregnant populations, and lifestyle interventions of proven effectiveness in non-pregnant populations have been developed. Women who are active in pregnancy demonstrate better glucose control and favourable pregnancy outcomes. There is a lack of effective interventions to support obese pregnant women to be physically active. Conclusions: No difference was detected in objectively measured physical activity between women randomised to the intervention and control arms of the UPBEAT pilot trial. Light-intensity physical activity was lower in early pregnancy in women who delivered macrosomic infants. Maternal sedentary time at 35-36 weeks\u27 gestation was positively associated and moderate-intensity physical activity was inversely associated with neonatal abdominal circumference. Maternal physical activity is associated with infant birth weight and abdominal circumference and is an appropriate target for intervention to improve infant outcomes. The challenge remains to develop an effective intervention to support obese pregnant women to be physically active. (C) 2014 S. Karger AG, Base

The Effects of the UK Pregnancies Better Eating and Activity Trial Intervention on Dietary Patterns in Obese Pregnant Women Participating in a Pilot Randomized Controlled Trial

Objective The objective of this study is to investigate the effects of the UK Pregnancies Better Eating and Activity Trial (UPBEAT) behavioral intervention on dietary patterns in obese pregnant women. Methods Dietary patterns were derived from Food Frequency Questionnaires using principal component analysis in 183 UPBEAT pilot study participants. Results Two unhealthy dietary patterns, processed and traditional , predominantly characterized by foods high in sugar and fat, improved [processed -0.54 (-0.92 to -0.16), P = 0.006 and traditional -0.83 (-1.20 to -0.45), P < 0.001] following the intervention, while a cultural pattern that was found to be associated with the Black African/Caribbean participants did not change [-0.10 (-0.46 to 0.26), P = 0.589]. Conclusion Unhealthy dietary patterns are evident in obese pregnant women. The UPBEAT intervention was effective in improving maternal dietary patterns; however, obese pregnant women from minority ethnic groups may be less receptive to intervention

Do elevated symptoms of depression predict adherence and outcomes in the UPBEAT randomised controlled trial of a lifestyle intervention for obese pregnant women?

Abstract Background Lifestyle interventions for obese pregnant women have been widely researched but little is known about predictors of low adherence or poor outcomes. This study evaluated the prospective associations between elevated symptoms of antenatal depression and gestational diabetes, adherence and gestational weight gain in a large RCT of a behavioural intervention for obese pregnant women. The effect of the intervention on symptoms of depression at follow-up was also examined. Methods The UPBEAT RCT randomised 1555 obese pregnant women to receive a dietary and physical activity lifestyle intervention or standard care. Symptoms of antenatal depression were assessed with the Edinburgh Postnatal Depression Scale at baseline (15+ 0–18+ 6 weeks’ gestation) and follow-up (27+ 0–28+ 6 weeks’ gestation). Gestational diabetes was assessed with an oral glucose tolerance test at 27+ 0–28+ 6 weeks’ gestation. Adherence was pre-defined as receiving at least 5 of 8 intervention sessions. Gestational weight gain was calculated as the difference between pre-pregnancy weight (estimated as measured baseline weight minus 1.25 kg) and last measured weight at 34+ 0–36+ 0 weeks’ gestation. Due to substantial missing data in certain variables, multiple imputation was used to impute missing data. Women who were no longer pregnant at 27+ 0–28+ 6 weeks’ gestation were excluded from the sample for these analyses. Results One thousand five-hundered twenty-six women were included in these analyses following multiple imputation; 797 (52.2%) had complete data. 13.4% had elevated symptoms of antenatal depression at baseline. There was no evidence for associations between antenatal depression status and gestational diabetes (adjusted OR 0.80, 95%CI 0.52 to 1.22, p = 0.30), adherence (adjusted OR 1.16, 95%CI 0.63 to 2.15, p = 0.63) or gestational weight gain (adjusted regression coefficient 0.52, 95%CI -0.26 to 1.29, p = 0.19). The intervention was not associated with change in depressive symptoms at follow-up (regression coefficient 0.003, 95%CI -0.49 to 0.49, p = 0.99). Similar results were obtained in complete case analyses. Conclusions Elevated symptoms of antenatal depression did not predict gestational diabetes, adherence or gestational weight gain in this large RCT of a lifestyle intervention for obese pregnant women. The intervention also did not influence symptoms of depression at follow-up. Obese pregnant women with elevated symptoms of depression should not be excluded from lifestyle interventions. Trial registration ISRCTN89971375. Registered 28 November 2008