Adverse Pregnancy Outcome Study Research Articles

Do variations in insulin sensitivity and insulin secretion in pregnancy predict differences in obstetric and neonatal outcomes?

Gestational diabetes mellitus (GDM) is generally defined based on glycaemia during an OGTT, but aetiologically includes women with defects in insulin secretion, insulin sensitivity or a combination of both. In this observational study, we aimed to determine if underlying pathophysiological defects evaluated as continuous variables predict the risk of important obstetric and neonatal outcomes better than the previously used dichotomised or categorical approaches. Using data from blinded OGTTs at mean gestational week 28 from five Hyperglycemia and Adverse Pregnancy Outcome study centres, we estimated insulin secretion (Stumvoll first phase) and sensitivity (Matsuda index) and their product (oral disposition index [DI]) in 6337 untreated women (1090 [17.2%] with GDM as defined by the International Association of Diabetes and Pregnancy Study Groups). Rather than dichotomising these variables (i.e. GDM yes/no) or subtyping by insulin impairment, we related insulin secretion and sensitivity as continuous variables, along with other maternal characteristics, to obstetric and neonatal outcomes using multiple regression and receiver operating characteristic curve analysis. Stratifying by GDM subtype offered superior prediction to GDM yes/no only for neonatal hyperinsulinaemia and pregnancy-related hypertension. Including the DI and the Matsuda score significantly increased the area under the receiver operating characteristic curve (AUROC) and improved prediction for multiple outcomes (large for gestational age [AUROC 0.632], neonatal adiposity [AUROC 0.630], pregnancy-related hypertension [AUROC 0.669] and neonatal hyperinsulinaemia [AUROC 0.688]). Neonatal hypoglycaemia was poorly predicted by all models. Combining the DI and the Matsuda score with maternal characteristics substantially improved the predictive power of the model for large for gestational age, neonatal adiposity and pregnancy-related hypertension. Continuous measurement of insulin secretion and insulin sensitivity combined with basic clinical variables appeared to be superior to GDM (yes/no) or subtyping by insulin secretion and/or sensitivity impairment in predicting obstetric and neonatal outcomes in a multi-ethnic cohort. Graphical abstract.

Real-world evaluation of adverse pregnancy outcomes in women with gestational diabetes mellitus in the German health care system

AimsThis study aims to estimate the incidence of adverse pregnancy outcomes in women with gestational diabetes mellitus (GDM) in Germany. MethodsPregnant women were identified from a health claims database for the year of 2016. Three groups were defined: general population without GDM, women with GDM without treatment and women with GDM and insulin treatment. Operationalisation of outcomes was aligned with the hyperglycaemia and adverse pregnancy outcomes (HAPO) study. ResultsThe cohort consisted of 58,297 mother-child pairs. Of those, 7245 had a GDM diagnosis and 1407 had a GDM diagnosis with a prescription of insulin. Adverse pregnancy outcomes were higher in both GDM groups compared to the control group. Birthweight (OR 2.08 [95% CI 1.50–2.90]), primary caesarean section (OR 1.70 [95% CI 1.48–1.95]), intensive neonatal care (OR 1.25 [95% CI 1.04–1.50]), preeclampsia (OR 1.51 [95% CI 1.23–1.85]), and clinical neonatal hypoglycaemia (OR 5.32 [95% CI 4.27–6.62]) were higher in the GDM+insulin group in comparison to a control group after adjustment for potential confounders. ConclusionMost of the adverse pregnancy outcomes were moderately higher in both identified GDM groups in comparison to women without GDM. Women receiving insulin treatment are at an increased risk of most of the defined adverse pregnancy outcomes.

The impact of revised diagnostic criteria on hospital trends in gestational diabetes mellitus rates in a high income country

ObjectiveIn 2010, national guidelines were published in Ireland recommending more sensitive criteria for the diagnosis of Gestational Diabetes Mellitus (GDM). The criteria were based on the 2008 Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) Study and were endorsed subsequently by the World Health Organization (WHO). Screening nationally is selective based on risk factors. We examined the impact of the new criteria on hospital trends nationally for GDM over the 10 years 2008–17.Research design and methodsData from three national databases, the Hospital Inpatient Enquiry System (HIPE), National Perinatal Reporting System (NPRS) and the Irish Maternity Indicator System (IMIS), were analyzed using descriptive statistics, analysis of variance, and Poisson loglinear modelling.ResultsThe overall incidence of GDM nationally increased almost five-fold from 3.1% in 2008 to 14.8% in 2017 (p ≤ 0.001). The incidence varied widely across maternity units. In 2008, the incidence varied from 0.4 to 5.9% and in 2017 it varied from 1.9 to 29.4%. There were increased obstetric interventions among women with GDM over the decade, specifically women with GDM having increased cesarean sections (CS) and induction of labor (IOL) (p ≤ 0.001). These trends were significant in large and mid-sized maternity hospitals (p ≤ 0.001). The increase in GDM diagnosis could not be explained by an increase in maternal age nationally over the decade. The data did not include information on other risk factors such as obesity. The increased incidence in GDM diagnosis was accompanied by a decrease in high birthweight ≥ 4.5 kg nationally.ConclusionsWe found adoption of the new criteria for diagnosis of GDM resulted in a major increase in the incidence of GDM rates. Inter-hospital variations increased over the decade, which may be explained by variations in the implementation of the new national guidelines in different maternity units. It is likely to escalate further as compliance with national guidelines improves at all maternity hospitals, with implications for provision and configuration of maternity services. We observed trends that may indicate improvements for women and their offspring, but more research is required to understand patterns of guideline implementation across hospitals and to demonstrate how increased GDM diagnosis will improve clinical outcomes.

Associations of gestational cardiovascular health with pregnancy outcomes: the Hyperglycemia and Adverse Pregnancy Outcome study

The American Heart Association's formal characterization of cardiovascular health combines several metrics in a health-oriented, rather than disease-oriented, framework. Although cardiovascular health assessment during pregnancy has been recommended, its significance for pregnancy outcomes is unknown. The purpose of this study was to examine the association of gestational cardiovascular health-formally characterized by a combination of 5 metrics-with adverse maternal and newborn outcomes. We analyzed data from the Hyperglycemia and Adverse Pregnancy Outcome study, including 2304 mother-newborn dyads from 6 countries. Maternal cardiovascular health was defined by the combination of the following 5 metrics measured at a mean of 28 (24-32) weeks' gestation: body mass index, blood pressure, lipids, glucose, and smoking. Levels of each metric were categorized using pregnancy guidelines, and the total cardiovascular health was scored (0-10 points, where 10 was the most favorable). Cord blood was collected at delivery, newborn anthropometrics were measured within 72 hours, and medical records were abstracted for obstetrical outcomes. Modified Poisson and multinomial logistic regression were used to test the associations of gestational cardiovascular health with pregnancy outcomes, adjusted for center and maternal and newborn characteristics. The average age of women at study exam was 29.6 years old, and they delivered at a mean gestational age of 39.8 weeks. The mean total gestational cardiovascular health score was 8.6 (of 10); 36.3% had all ideal metrics and 7.5% had 2+ poor metrics. In fully adjusted models, each 1 point higher (more favorable) cardiovascular health score was associated with lower risks for preeclampsia (relative risk, 0.67 [95% confidence interval, 0.61-0.73]), unplanned primary cesarean delivery (0.88 [0.82-0.95]), newborn birthweight >90th percentile (0.81 [0.75-0.87]), sum of skinfolds >90th percentile (0.84 [0.77-0.92]), and insulin sensitivity <10th percentile (0.83 [0.77-0.90]). Cardiovascular health categories demonstrated graded associations with outcomes; for example, relative risks (95% confidence intervals) for preeclampsia were 3.13 (1.39-7.06), 5.34 (2.44-11.70), and 9.30 (3.95-21.86) for women with ≥1 intermediate, 1 poor, or ≥2 poor (vs all ideal) metrics, respectively. More favorable cardiovascular health at 24 to 32 weeks' gestation was associated with lower risks for several adverse pregnancy outcomes in a multinational cohort.

Gestational Diabetes Mellitus and Long-Term Prognosis of the Offsprings

The hyperglycemia and adverse pregnancy outcomes (HAPO) study demonstrated a linear increase in the risk of adverse pregnancy outcomes with increasing maternal glycemia that can be less severe than overt diabetes and is often untreated. Recently, HAPO follow-up studies were published on long-term consequences on children of gestational diabetes mellitus (GDM) gravidas. Two articles examined the association of untreated maternal glycemia with markers of glucose metabolism in a total of 4,160 ethnically diverse children 10∼14 years of age. Children of mothers with GDM had higher prevalence of impaired glucose tolerance (IGT). Moreover, there were strong positive associations between maternal continuous and categorical glycemia status and child's 75-g glucose tolerance test, A1C, IGT, and impaired fasting glucose. Another two articles evaluated the risk of childhood adiposity of 4,832 children born from mothers with GDM. GDM was associated with childhood adiposity as evaluated by multiple methods. Additionally, maternal glucose level across a continuum was associated with childhood obesity, percentage body fat, and sum of skinfolds > 85th percentile after adjustment for maternal body mass index. These findings could have implications for glucose targets in mothers with GDM and indicate that even mild hyperglycemia can affect adversely glucose metabolism and obesity in the children of mothers with GDM. Keywords: Child; Gestational diabetes; Glucose intolerance; Glucose metabolism; Obesity

Metabolomic and genetic associations with insulin resistance in pregnancy.

Aims/hypothesisOur study aimed to integrate maternal metabolic and genetic data related to insulin sensitivity during pregnancy to provide novel insights into mechanisms underlying pregnancy-induced insulin resistance.MethodsFasting and 1 h serum samples were collected from women in the Hyperglycemia and Adverse Pregnancy Outcome Study who underwent an OGTT at ~28 weeks’ gestation. We obtained targeted and non-targeted metabolomics and genome-wide association data from 1600 and 4528 mothers, respectively, in four ancestry groups (Northern European, Afro-Caribbean, Mexican American and Thai); 1412 of the women had both metabolomics and genome-wide association data. Insulin sensitivity was calculated using a modified insulin sensitivity index that included fasting and 1 h glucose and C-peptide levels after a 75 g glucose load.ResultsPer-metabolite and network analyses across the four ancestries identified numerous metabolites associated with maternal insulin sensitivity before and 1 h after a glucose load, ranging from amino acids and carbohydrates to fatty acids and lipids. Genome-wide association analyses identified 12 genetic variants in the glucokinase regulatory protein gene locus that were significantly associated with maternal insulin sensitivity, including a common functional missense mutation, rs1260326 (β=−0.2004, p=4.67×10−12 in a meta-analysis across the four ancestries). This SNP was also significantly associated with multiple fasting and 1 h metabolites during pregnancy, including fasting and 1 h triacylglycerols and 2-hydroxybutyrate and 1 h lactate, 2-ketoleucine/ketoisoleucine and palmitoleic acid. Mediation analysis suggested that 1 h palmitoleic acid contributes, in part, to the association of rs1260326 with maternal insulin sensitivity, explaining 13.7% (95% CI 4.0%, 23.3%) of the total effect.Conclusions/interpretationThe present study demonstrates commonalities between metabolites and genetic variants associated with insulin sensitivity in the gravid and non-gravid states and provides insights into mechanisms underlying pregnancy-induced insulin resistance.

Gestational Diabetes Mellitus and Glucose Sample Handling.

Gestational diabetes mellitus (GDM) continues to provide challenges in terms of both diagnosis and management. Recent scientific discussions around the preanalytical processing of glucose samples from the glucose tolerance test (GTT) have generated considerable interest and debate (1,2). For most women, the diagnosis of GDM is based on the measurement of plasma glucose after the GTT. The observational Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study (3) and the consensus agreement about diagnostic criteria by the International Association of the Diabetes and Pregnancy Study Groups (IADPSG) (4) provided glucose thresholds for the diagnosis of GDM. The HAPO study was meticulous in the preanalytical and analytical processing of glucose samples (3). Given that our current diagnostic criteria are based on the findings of the HAPO study, if results are to be comparable, the same meticulous processing must also be applied to glucose samples processed in routine clinical care. A major source of preanalytical error in measuring glucose is loss of glucose from blood samples …

Maternal BMI at the time of birth and selected risk factors associated with severe neonatal outcomes: a secondary analysis of the WHO Better Outcomes in Labour Difficulty (BOLD) project.

The main objective of this secondary analysis was to describe the nutritional status of the Better Outcomes in Labour Difficulty (BOLD) project study population and determine possible associations between maternal nutritional status (as reflected by maternal BMI at the time of birth) and severe neonatal outcomes (SNO). We also analysed previous and index maternal pathologies to determine associations with neonatal outcomes. We used the classification designed by Atalah for maternal BMI and compared with the Hyperglycaemia and Adverse Pregnancy Outcome study one. To describe the nutritional status of this population, figures of distribution and test of normality related to weight and BMI were presented for the women and their babies. To explore the association between maternal BMI data and SNO, the χ2 test was performed. To identify a maternal characteristic or a group of characteristics that could predict SNO, we used Fisher's exact test using previous maternal pathology collected in the BOLD project as well as that in the index pregnancy. In this study, BMI at the time of birth was not associated with neonatal near miss or death. We found that previous maternal obesity, diabetes and chronic hypertension were associated with SNO. Maternal pathology in the index pregnancy such as other obstetric haemorrhage, pre-eclampsia, anaemia and gestational diabetes was associated with SNO.

1344-P: Metabolomics Reveals Broad Scale Metabolic Changes in Gestational Diabetes

Studies examining metabolites in GDM have been small with inconsistent results. To address this, we used targeted metabolomics to examine levels of 65 metabolites in a cohort of 3457 mothers from the Hyperglycemia and Adverse Pregnancy Outcome Study, of whom 547 were retrospectively diagnosed with GDM using IADPSG criteria. GDM was untreated. Metabolomics assays were performed on fasting and 1 hr serum samples collected during an oral glucose tolerance test (OGTT) at ∼28 weeks gestation. Differences in metabolite levels in women without and with GDM were determined using linear regression with adjustment for field center as well as maternal age, gestational age, height, mean arterial pressure, parity, smoking (yes/no), drinking (yes/no) and BMI at the OGTT and false discovery rate correction. Women with GDM had higher levels of a broad array of fasting metabolites, including branched chain amino acids (BCAA) and their metabolic byproducts, aromatic and other amino acids, triglycerides, non-esterified fatty acids and lipid byproducts, and medium- and long-chain acylcarnitines (ACs). Similar differences were seen 1 hr after a glucose load, except for higher levels of a broader array of ACs but lower levels of arachidonoyl carnitine in women with GDM. Prior studies categorizing women with GDM into those with normal and low insulin sensitivity demonstrated differences in maternal and newborn outcomes between groups. Compared to women with GDM and normal insulin sensitivity, women with GDM in the lowest quartile of insulin sensitivity had higher levels of BCAAs and their metabolic byproducts, aromatic amino acids, triglycerides, and lactate but lower levels of 3-hydroxybutyrate (3-HB) and multiple ACs. A generally a similar pattern was seen 1 hr after glucose except for no change in 3-HB. Together these data demonstrate broad scale perturbations in metabolites in women with GDM and differences across subgroups of women with GDM that may contribute to maternal and fetal complications related to GDM. Disclosure Y. Liu: None. A. Kuang: None. J.R. Bain: None. T. George: None. O. Ilkayeva: None. A. Mincey: None. M. Muehlbauer: None. L.P. Lowe: None. B.E. Metzger: None. C.B. Newgard: None. D. Scholtens: None. W. Lowe: None.

Paradigm Shifts in the Management of Diabetes in Pregnancy: The Importance of Type 2 Diabetes and Early Hyperglycemia in Pregnancy: The 2020 Norbert Freinkel Award Lecture.

For over 50 years, the diagnosis of gestational diabetes mellitus (GDM) has been based upon an oral glucose tolerance test at 24-28 weeks' gestation. This is the time during pregnancy when insulin resistance is increasing and hyperglycemia develops among those with insufficient insulin secretory capacity to maintain euglycemia. The Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study and the two major randomized controlled trials of treating GDM are based upon recruitment of women at this time during pregnancy. Meanwhile, the increasing prevalence of type 2 diabetes in pregnancy, with its significant risk of adverse pregnancy outcomes, has led to a need to identify undiagnosed diabetes as near to conception as possible. Screening for undiagnosed diabetes early in pregnancy also identifies women with hyperglycemia less than overt diabetes, yet at increased risk of adverse pregnancy outcomes. Such women are more insulin resistant-with higher blood pressure, triglycerides, perinatal mortality, and neonatal hypoglycemia with a greater need for insulin treatment-than those with GDM diagnosed at 24-28 weeks' gestation. Currently, there is uncertainty over how to diagnose GDM early in pregnancy and the benefits and harms from using the current management regimen. Randomized controlled trials testing the criteria for, and treatment of, GDM early in pregnancy are urgently needed to address this existing equipoise. In the meantime, the importance of early or "prevalent GDM" (i.e., mild hyperglycemia present from early [before] pregnancy) warrants interim criteria and thresholds for medication, which may differ from those in use for GDM diagnosed at 24-28 weeks' gestation.

The Joint Associations of Maternal BMI and Glycemia with Childhood Adiposity.

An obesogenic perinatal environment contributes to adverse offspring metabolic health. Previous studies have been limited by lack of direct adiposity measurements and failure to account for potential confounders. Examine the joint associations of maternal midpregnancy body mass index (BMI) and glycemia with direct adiposity measures in 10-14 year old offspring. International, epidemiological study: Hyperglycemia and Adverse Pregnancy Outcome (HAPO) and HAPO Follow-up Study, conducted between 2000-2006 and 2013-2016, respectively. In 4832 children, adiposity measures for body mass index (BMI), body fat with air displacement plethysmography, skinfold thickness, and waist circumference were obtained at mean age 11.4 years. Maternal BMI and glucose, as continuous and categorical variables, were the primary predictors. In fully adjusted models controlling for child age, sex, field center, and maternal characteristics, maternal BMI had significant, positive associations with all childhood adiposity outcomes, while maternal glycemia had significant, positive associations with childhood adiposity outcomes except BMI. In joint analyses, and compared with a nonobese, nongestational diabetes mellitus (GDM) reference group, maternal obesity and GDM were associated with higher odds (maternal obesity odds ratio; OR [95% confidence interval; CI], GDM OR [95% CI]; combined OR [95% CI]) of childhood overweight/obese BMI (3.00 [2.42-3.74], 1.39 [1.14-1.71], 3.55 [2.49-5.05]), obese BMI (3.54 [2.70-4.64], 1.73 [1.29-2.30], 6.10 [4.14-8.99]), percent body fat >85th percentile (2.15 [1.68-2.75], 1.33 [1.03-1.72], 3.88 [2.72-5.55]), sum of skinfolds >85th percentile (2.35 [1.83-3.00], 1.75 [1.37-2.24], 3.66 [2.55-5.27]), and waist circumference >85th percentile (2.52 [1.99-3.21], 1.39 [1.07-1.80], 4.18 [2.93-5.96]). Midpregnancy maternal BMI and glycemia are independently and additively associated with direct adiposity measures in 10-14 year old children. The combination of maternal obesity and GDM is associated with the highest odds of childhood adiposity.

Abstract 33: Associations of Gestational Cardiovascular Health With Pregnancy Outcomes: The Hyperglycemia and Adverse Pregnancy Outcome Study

Introduction: Combinations of risk factor levels typically contribute more to population burdens of disease than single adverse risk factors. CVH (as defined by the AHA) characterizes a range of health levels, but its significance in pregnancy for obstetric and neonatal outcomes is unknown. Methods: Data from the Hyperglycemia and Adverse Pregnancy Outcome Study were analyzed, including 1,754 mother-child dyads from 9 field centers in 6 countries: US (26%), Barbados (24%), UK (20%), China (15%), Thailand (8%), and Canada (7%). Maternal CVH was scored (0-10 points, with 10 most favorable) at a mean of 28 (range 23-34) weeks’ gestation using 5 metrics ( Table ). Cord blood was collected at delivery, neonatal anthropometrics were measured within 72 hours, and medical records were abstracted for obstetric outcomes. Logistic regression was utilized to test associations of gestational CVH with obstetric and neonatal outcomes, adjusted for center and maternal and infant characteristics ( Table footnote). Results: The mean gestational CVH score was 8.2 (SD 1.5) out of 10; 18% of mothers had all ideal, 37% had 1+ intermediate, 34% had 1 poor, and 9% had 2+ poor metrics. In fully adjusted models ( Table ), odds ratios per 1 point higher (better) CVH score were 0.65 (95% CI, 0.56-0.76) for preeclampsia, 0.89 (0.78-1.00) for unplanned primary cesarean section (among primiparous mothers), 0.84 (0.77-0.93) for large for gestational age infant, 0.87 (0.79-0.97) for infant sum of skinfolds &gt;90 th percentile, and 0.77 (0.69-0.86) for infant insulin sensitivity index (20/[C-peptide*glucose]) &lt;10 th percentile. CVH categories were also associated with outcomes; for example, compared with mothers with all metrics ideal, odds ratios for preeclampsia were 2.00 (0.71-7.14) for mothers with 1+ intermediate, 4.34 (1.63-15.09) for mothers with 1 poor, and 9.40 (3.22-34.52) for mothers with 2+ poor metrics. Conclusion: More favorable levels of gestational CVH were associated with healthier obstetric and neonatal outcomes in this multinational cohort.

Abstract P176: Associations of Gestational Lipids and Apolipoproteins With Pregnancy Outcomes: The Hyperglycemia and Adverse Pregnancy Outcome Study

Introduction: Gestational hyperlipidemia has traditionally been considered physiologic and benign, but the significance of inter-individual variation in lipid levels for maternal-fetal health are poorly understood. We examined associations of gestational lipids and apolipoproteins with adverse obstetric and neonatal outcomes. Methods: Data from the Hyperglycemia and Adverse Pregnancy Outcome Study were analyzed, including 1,813 mother-child dyads from 9 field centers in 6 countries: US (25%), Barbados (24%), UK (20%), China (16%), Thailand (8%), and Canada (7%). Fasting lipids and apolipoproteins were directly measured at a mean of 28 (range 23-34) weeks’ gestation. Cord blood was collected at delivery, neonatal anthropometrics were measured within 72 hours, and medical records were abstracted for obstetric outcomes. Logistic regression was utilized to test associations of lipids and apolipoproteins (per +1 SD; log-transformed if skewed) with pregnancy outcomes, adjusted for center, demographics, and maternal covariates such as BMI, blood pressure, and glycemia. Results: See Table for lipid and apolipoprotein levels in pregnant mothers. In fully adjusted models ( Table ), 1 SD higher log-triglycerides (i.e., ~2.7-fold higher triglyceride level) in late pregnancy was significantly associated with higher odds for preeclampsia (OR 1.53 [95% CI, 1.15-2.05]), large for gestational age infant (1.42 [1.21-1.67]), and infant insulin sensitivity &lt;10 th percentile (1.25 [1.03-1.50]), but not with unplanned primary cesarean section or infant sum of skinfolds &gt;90 th percentile. There were no significant associations of maternal HDL-C, LDL-C, or log-ApoB/A1 ratio with any outcome. Conclusion: Triglyceride levels in the latter half of pregnancy were uniquely associated with both maternal risks (preeclampsia) and neonatal risks (large for gestational age and insulin resistance), even after adjustment for maternal BMI, blood pressure, and glycemia.

Adverse Pregnancy Outcomes and Long-term Maternal Kidney Disease

Adverse pregnancy outcomes, such as hypertensive disorders of pregnancy, gestational diabetes, and preterm delivery, are associated with increased risk of maternal cardiovascular disease. Little is known about whether adverse pregnancy outcomes are associated with increased risk of maternal chronic kidney disease (CKD) and end-stage kidney disease (ESKD). To review and synthesize the published literature on adverse pregnancy outcomes (hypertensive disorders of pregnancy, gestational diabetes, and preterm delivery) and subsequent maternal CKD and ESKD. PubMed, Embase, and Web of Science were searched from inception to July 31, 2019, for cohort and case-control studies of adverse pregnancy outcomes and maternal CKD and ESKD. Selected studies included the following: a population of pregnant women, exposure to an adverse pregnancy outcome of interest, and at least 1 primary outcome (CKD or ESKD) or secondary outcome (hospitalization or death due to kidney disease). Adverse pregnancy outcomes included exposure to hypertensive disorders of pregnancy (preeclampsia, gestational hypertension, or chronic hypertension), preterm delivery (<37 weeks), and gestational diabetes. Three reviewers were involved in study selection. Of 5656 studies retrieved, 23 were eligible for inclusion. The Meta-analyses of Observational Studies in Epidemiology (MOOSE) guidelines were followed throughout. Three reviewers extracted data and appraised study quality. Random-effects meta-analyses were used to calculate overall pooled estimates using the generic inverse variance method. Primary outcomes included CKD and ESKD diagnosis, defined using established clinical criteria (estimated glomerular filtration rate or albuminuria values) or hospital records. The protocol for this systematic review was registered on PROSPERO (CRD42018110891). Of 23 studies included (5 769 891 participants), 5 studies reported effect estimates for more than 1 adverse pregnancy outcome. Preeclampsia was associated with significantly increased risk of CKD (pooled adjusted risk ratio [aRR], 2.11; 95% CI, 1.72-2.59), ESKD (aRR, 4.90; 95% CI, 3.56-6.74), and kidney-related hospitalization (aRR, 2.65; 95% CI, 1.03-6.77). Gestational hypertension was associated with increased risk of CKD (aRR, 1.49; 95% CI, 1.11-2.01) and ESKD (aRR, 3.64; 95% CI, 2.34-5.66). Preterm preeclampsia was associated with increased risk of ESKD (aRR, 5.66; 95% CI, 3.06-10.48); this association with ESKD persisted for women who had preterm deliveries without preeclampsia (aRR, 2.09; 95% CI, 1.64-2.66). Gestational diabetes was associated with increased risk of CKD among black women (aRR, 1.78; 95% CI, 1.18-2.70), but not white women (aRR, 0.81; 95% CI, 0.58-1.13). In this meta-analysis, exposure to adverse pregnancy outcomes, including hypertensive disorders of pregnancy, gestational diabetes, and preterm delivery, was associated with higher risk of long-term kidney disease. The risk of ESKD was highest among women who experienced preeclampsia. A systematic approach may be warranted to identify women at increased risk of kidney disease, particularly after hypertensive disorders of pregnancy, and to optimize their long-term follow-up.

Evaluation of the gestational diabetes mellitus diagnostic criteria recommended by the international association of diabetes and pregnancy study group for long-term maternal postpartum outcomes in mainland China.

The gestational diabetes mellitus (GDM) diagnostic criteria recommended by the International Association of Diabetes and Pregnancy Study Group (IADPSG) were established based on the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study and have been the most commonly used criteria for determining GDM worldwide. Although individuals from mainland China were not included in the HAPO study, the IADPSG criteria have been used in China since 2011. However, the appropriateness of the criteria for evaluating maternal postpartum outcomes in mainland China are unknown. We conducted this study to determine whether the IADPSG criteria are appropriate for Chinese patients for evaluating long-term maternal postpartum outcomes.Eighty-four patients who were diagnosed with hyperglycemia during pregnancy and had delivery in Peking University First Hospital from February 2007 to December 2009 were enrolled in the study. For patients in Group A, GDM was diagnosed using both the National Diabetes Data Group (NDDG) and the IADPSG criteria, while patients in Group B, gestational impaired glucose tolerance (GIGT) was diagnosed using the NDDG criteria while GDM was diagnosed based on the IADPSG criteria. Anthropometric data, glucose metabolism, lipid profiles, β cell function, and insulin resistance index were evaluated and compared to baseline after 5- to 6-year postpartum period.Patients in group A had significantly higher oral glucose tolerance test (OGTT) fasting, 2-hour and 3-hour plasma glucose levels compared to patients in group B at 24 to 28 weeks of gestation (P < .05). No significant differences were observed between the groups for anthropometric data, postpartum abnormal glucose metabolism (50.91% vs 44.83%, P = .596), type 2 diabetes mellitus (T2DM) (16.36% vs 3.45%, P = .167), lipid profiles, β cell function (homeostasis model assessment β-cell function index (HOMA-β) 1.04 vs 0.99, P = .935) and insulin resistance (homeostasis model assessment insulin resistance index (HOMA-IR) 2.01 vs 1.69, P = .583).Patients diagnosed with GDM using either the NDDG or IADPSG criteria had abnormal glucose levels and lipid metabolism after delivery. Patients with mild hyperglycemia had similar postpartum β-cell functional impairment and insulin resistance to those with moderate hyperglycemia during pregnancy. Hence, with respect to maternal long-term postpartum outcomes, the IADPSG diagnostic criteria for GDM could be appropriate for patients in mainland China.

Newborn Adiposity and Cord Blood C-Peptide as Mediators of the Maternal Metabolic Environment and Childhood Adiposity

Background: Excessive childhood adiposity is a risk factor for adverse metabolic health. We investigated associations of newborn body composition and fetal hyperinsulinemia with childhood anthropometrics and explored whether these newborn measures mediate associations of maternal mid-pregnancy glucose and BMI with childhood adiposity. Methods: Data on mother/offspring pairs (N=4832) from the epidemiological Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study and HAPO Follow Up Study (HAPO FUS) were analyzed. Linear regression was used to study associations between newborn and childhood anthropometrics. Structural equation modeling was used to explore newborn anthropometric measures as potential mediators of the associations of maternal BMI and glucose during pregnancy with childhood anthropometric outcomes. Findings: In models including maternal glucose and BMI adjustments, newborn adiposity (sum of skinfolds) was associated with child outcomes (adjusted mean difference, 95% CI, p-value) BMI(0·26,0·12-0·39,<0·001), BMI z-score(0·072,0·033-0·11,<0·001), fat mass (kg)(0·51,0·26-0·76,<0·001), percent bodyfat(0·61, 0·27-0·95,<0·001), and sum of skinfolds (mm)(1·14,0·43-1·86,0·0017). Structural equation models demonstrated significant mediation by newborn sum of skinfolds and cord C-peptide of maternal BMI effects on childhood BMI (proportion of total effect 2·5% and 1·0%, respectively), fat mass(3·1%,1·2%), percent bodyfat(3·6%,1·8%), and sum of skinfolds(2·9%,1·8%), and significant mediation by newborn sum of skinfolds and cord C-peptide of maternal glucose effects on child fat mass (proportion of total association 22·0% and 21·0%, respectively), percent bodyfat(15·0%,18·0%), and sum of skinfolds(15·0%,20·0%). Interpretation: Newborn adiposity is independently associated with childhood adiposity, and along with fetal hyperinsulinemia, mediate, in part, associations of maternal glucose and BMI with childhood adiposity. Funding Statement: United States National Institutes of Health Declaration of Interests: The authors do not have any conflicts of interest to disclose. Ethics Approval Statement: Institutional review boards at each field center approved both studies. Participants provided written informed consent and, where required, assent.

Maternal urinary levels of trichloroacetic acid and association with adverse pregnancy outcomes.

The current study aimed to determine the association between trichloroacetic acid (TCAA) levels and adverse pregnancy outcomes among third-trimester pregnant women who were exposed to chlorinated drinking water. A total of 205 pregnant women who participated in the disinfection by-products exposure and adverse pregnancy outcome study in South Africa were randomly asked to participate in this study by providing their morning urine sample voids. Samples were analysed for urinary creatinine and TCAA. Furthermore, participants gave individual data using a structured questionnaire. The mean (median) concentration of creatinine-adjusted urinary TCAA was 2.34 (1.95) μg/g creatinine. Elevated levels of creatinine-adjusted TCAA concentrations showed an increased risk of premature birth, small for gestational age (SGA) and low birth weight. There was no significant statistical correlation observed between creatinine-adjusted TCAA concentrations and the total volume of cold water ingested among the study population. No statistically significant association was observed between creatinine-adjusted urinary TCAA and premature birth, SGA and low birth weight newborns among the study subjects. However, the urinary TCAA concentrations identified in this study suggest potential health risks towards women and foetus. Therefore, further studies are warranted to prevent further adverse pregnancy outcomes.

Recommended pre-analytical plasma glucose sampling methodology may distort gestational diabetes mellitus prevalence: implications for diagnostic thresholds.

Current International Association of the Diabetes and Pregnancy Study Groups/World Health Organization gestational diabetes mellitus (GDM) diagnostic thresholds are based on a landmark study in which the pre-analytical plasma glucose sampling methodology is unclear. Worldwide, plasma glucose pre-analytical sampling methodology practices are divergent. We considered the effects of pre-analytical plasma glucose sampling methodology on GDM prevalence and gestational outcomes. This is a retrospective observational cohort study of 1178 pregnant women undergoing an oral glucose tolerance test (OGTT). Of the 1178 pregnant women, a subset of 892 non-GDM women with singleton births undergoing OGTT between 24 and 28 weeks' gestation were investigated for large for gestation age (LGA) outcomes. OGTT were determined using traditional methods (sodium fluoride tubes batched at roomed temperature). We modelled the potential effects of using a recommended pre-analytical plasma glucose methodology (lyophilized citrate tubes) on GDM prevalence. The GDM prevalence in our cohort was 13.5%. The incidence of LGA showed a linear association with maternal plasma glucose that was similar to the association observed in the Hyperglycemia and Adverse Pregnancy Outcome study. Frequency of LGA exceeded 10% at HAPO glucose category 4 (fasting, 4.8 to 4.9mmol/l; 1-h, 8.7 to 9.5 mmol/l) for fasting and 1-h plasma glucose. The use of a recommended pre-analytical method is projected to increase the prevalence of GDM to 39.2%. We challenge the consensus that recommended pre-analytical plasma glucose methodologies are optimal for the accurate diagnosis of GDM. Recommended pre-analytical plasma glucose methods may profoundly over-diagnose GDM. Centres using recommended pre-analytical plasma glucose methodologies may need to reappraise their diagnostic thresholds.

Cord Blood Metabolomics: Association With Newborn Anthropometrics and C-Peptide Across Ancestries.

Newborn adiposity is associated with childhood obesity. Cord blood metabolomics is one approach that can be used to understand early-life contributors to adiposity and insulin resistance. To determine the association of cord blood metabolites with newborn adiposity and hyperinsulinemia in a multiethnic cohort of newborns. Cross-sectional, observational study. Hyperglycemia and Adverse Pregnancy Outcome study. One thousand six hundred multiethnic mother-newborn pairs. Cord blood C-peptide, birthweight, and newborn sum of skinfolds. Meta-analyses across four ancestry groups (Afro-Caribbean, Northern European, Thai, and Mexican American) demonstrated significant associations of cord blood metabolites with cord blood C-peptide, birthweight, and newborn sum of skinfolds. Several metabolites, including branched-chain amino acids (BCAAs), medium- and long-chain acylcarnitines, nonesterified fatty acids, and triglycerides were negatively associated with cord C-peptide but positively associated with birthweight and/or sum of skinfolds. 1,5-Anhydroglucitol, an inverse marker of recent maternal glycemia, was significantly inversely associated with birthweight and sum of skinfolds. Network analyses revealed groups of interrelated amino acid, acylcarnitine, and fatty acid metabolites associated with all three newborn outcomes. Cord blood metabolites are associated with newborn size and cord blood C-peptide levels after adjustment for maternal body mass index and glucose during pregnancy. Negative associations of metabolites with C-peptide at birth were observed. 1,5-Anhydroglucitol appears to be a marker of adiposity in newborns. BCAAs were individually associated with birthweight and demonstrated possible associations with newborn adiposity in network analyses.

Diagnosis of Gestational Diabetes Mellitus in China: Perspective, Progress and Prospects

Abstract Gestational diabetes mellitus (GDM) is one of the most common complications during pregnancy. Despite extensive research in the past 50 years, the universal approach to diagnose GDM continues to be debated around the world and clinical practices vary from country to country and unit to unit within the same country. As new evidence emerges, the diagnostic criteria of GDM has continuously evolved since the 1990s. In 2011, after the announcement of the landmark International Association of Diabetes and Pregnancy Study Groups diagnostic criteria, many international organizations have accepted and advocated its use. However, there are differences in glucose metabolism among different ethnic groups, and the Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) Study lacked data from mainland China. Whether the criteria developed based on the HAPO study are applicable to China remains to be further validated. In this current review, we will discuss the evolution of GDM diagnostic criteria and guidelines in China, and compare them to that in western countries to figure out the proper recommendations on the diagnosis of GDM among Chinese women.