Adverse Pregnancy Outcome Study Research Articles

Newborn adiposity is associated with cord blood DNA methylation at IGF1R and KLF7.

This study aimed to identify whether cord blood DNA methylation at specific loci is associated with neonatal adiposity, a key risk factor for childhood obesity. An epigenome-wide association study was conducted using the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study as a discovery sample. Linear regression models adjusted for maternal and offspring covariates and cell counts were used to analyze associations between neonatal adiposity as measured by sum of three skinfold thicknesses and cord blood DNA methylation. Assays were performed with Illumina EPIC arrays (791,359 CpG sites after quality control). Replication was performed in an independent cohort, Genetics of Glucose regulation in Gestation and Growth (Gen3G). In 2740 HAPO samples, significant associations were identified at 89 CpG sites after accounting for multiple testing (Bonferroni-adjusted p < 0.05). Replication analyses conducted in 139 Gen3G participants confirmed associations for seven CpG sites. These included IGF1R, which encodes a transmembrane receptor involved in cell growth and survival that binds insulin-like growth factor I and insulin, and KLF7, which encodes a regulator of cell proliferation and inhibitor of adipogenesis; both are key regulators of growth during fetal life. These findings support epigenetic mechanisms in the developmental origins of neonatal adiposity and as potential biomarkers of metabolic disease risk.

Genetics of glucose homeostasis in pregnancy and postpartum.

Pregnancy is accompanied by maternal metabolic adaptations to ensure fetal growth and development, including insulin resistance, which occurs primarily during the second and third trimesters of pregnancy, and a decrease in fasting blood sugar levels over the course of pregnancy. Glucose-related traits are regulated by genetic and environmental factors and modulated by physiological variations throughout the life course. We addressed the hypothesis that there are both overlaps and differences between genetic variants associated with glycaemia-related traits during and outside of pregnancy. Genome-wide SNP data were used to identify genetic variations associated with glycaemia-related traits measured during an OGTT performed at ~28 weeks' gestation in 8067 participants in the Hyperglycaemia and Adverse Pregnancy Outcome (HAPO) Study. Associations outside of pregnancy were determined in 3977 individuals who also participated in the HAPO Follow-Up Study at 11-14 years postpartum. A Bayesian classification algorithm was used to determine whether SNPs associated with fasting and 2 h glucose and fasting C-peptide during pregnancy had a pregnancy-predominant effect vs a similar effect during pregnancy and postpartum. SNPs in six loci (GCKR, G6PC2, GCK, PPP1R3B, PCSK1 and MTNR1B) were significantly associated with fasting glucose during pregnancy, while SNPs in CDKAL1 and MTNR1B were associated with 1 h glucose and SNPs in MTNR1B and HKDC1 were associated with 2 h glucose. Variants in CDKAL1 and MTNR1B were associated with insulin secretion during pregnancy. Variants in multiple loci were associated with fasting C-peptide during pregnancy, including GCKR, IQSEC1, PPP1R3B, IGF1 and BACE2. GCKR and BACE2 were associated with 1 h C-peptide and GCKR, IQSEC1 and BACE2 with insulin sensitivity during pregnancy. The associations of MTNR1B with 2 h glucose, BACE2 with fasting and 1 h C-peptide and insulin sensitivity, and IQSEC1 with fasting C-peptide and insulin sensitivity that we identified during pregnancy have not been previously reported in non-pregnancy cohorts. The Bayesian classification algorithm demonstrated that the magnitude of effect of the lead SNP was greater during pregnancy compared with 11-14 years postpartum in PCSK1 and PPP1R3B with fasting glucose, in three loci, including MTNR1B, with 2 h glucose, and in six loci, including IGF1, with fasting C-peptide. Our findings support the hypothesis that there are both overlaps and differences between the genetic architecture of glycaemia-related traits during and outside of pregnancy. Genetic variants at several loci, including PCSK1, PPP1R3B, MTNR1B and IGF1, appear to influence glycaemic regulation in a unique fashion during pregnancy. Future studies in larger cohorts will be needed to replicate the present findings, fully characterise the genetics of maternal glycaemia during pregnancy and determine similarities to and differences from the non-gravid state.

1215-P: Maternal Glycemia Associations with Cord Blood DNA Methylation in the Hyperglycemia and Adverse Pregnancy Outcome Study

1215-P: Maternal Glycemia Associations with Cord Blood DNA Methylation in the Hyperglycemia and Adverse Pregnancy Outcome Study

Impact of hypertensive disorders of pregnancy and gestational diabetes mellitus on offspring cardiovascular health in early adolescence

Adverse pregnancy outcomes, including hypertensive disorders of pregnancy (HDP) and gestational diabetes mellitus (GDM), influence maternal cardiovascular heath (CVH) long after pregnancy, but their relationship to offspring CVH following in utero exposure remains uncertain. To examine associations of HDP or GDM with offspring CVH in early adolescence. This analysis used data from the prospective Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study from 2000 to 2006 and the HAPO Follow-Up Study from 2013 to 2016. This analysis included 3,317 mother-child dyads from 10 field centers, comprising 70.8% of HAPO Follow-Up Study participants. Those with pregestational diabetes and chronic hypertension were excluded. The exposures were having any HDP or GDM compared with not having HDP or GDM, respectively (reference). The outcome was offspring CVH at ages 10 to 14 years, based on four metrics: body mass index, blood pressure, total cholesterol level, and glucose level. Each metric was categorized as ideal, intermediate, or poor using a framework provided by the American Heart Association. The outcome was primarily defined as having at least one CVH metric that was non-ideal versus all ideal (reference), and secondarily as the number of non-ideal CVH metrics: at least one intermediate metric, one poor metric, or at least two poor metrics versus all ideal (reference). Modified Poisson regression with robust error variance was used and adjusted for covariates at pregnancy enrollment, including field center, parity, age, gestational age, alcohol or tobacco use, child's assigned sex at birth, and child's age at follow-up. Among 3,317 maternal-child dyads, the median (IQR) ages were 30.4 (25.6, 33.9) years for pregnant individuals and 11.6 (10.9, 12.3) years for children. During pregnancy, 10.4% of individuals developed HDP and 14.6% developed GDM. At follow-up, 55.5% of offspring had at least one non-ideal CVH metric. In adjusted models, having HDP (aRR 1.14; 95% CI 1.04, 1.25) or having GDM (aRR 1.10; 95% CI 1.02, 1.19) was associated with greater risk that offspring developed less-than-ideal CVH at ages 10 to 14 years. The above associations strengthened in magnitude as the severity of adverse CVH metrics increased (i.e., with the outcome measured as >1 intermediate, 1 poor, and >2 poor adverse metrics), albeit the only statistically significant association was with the "1-poor-metric" exposure. In this multi-national prospective cohort, pregnant individuals who experienced either HDP and GDM were at significantly increased risk of having offspring with worse CVH in early adolescence. Reducing adverse pregnancy outcomes and increasing surveillance with targeted interventions after an adverse pregnancy outcome should be studied as potential avenues to enhance long-term cardiovascular health in the offspring exposed in utero.

Reflections on the Multicenter Randomized Trial of Treatment for Mild Gestational Diabetes.

After the 2006 hyperglycemia and adverse pregnancy outcomes study, which confirmed the relationship between maternal glycemia and pregnancy outcomes, the debate remained on whether treatment benefited gestational diabetes mellitus (GDM). Nonetheless, practitioners continued to universally screen for and treat women identified as GDM. To assess the benefits and harms of screening and treatment of GDM, the National Institute of Child Health and Human Development Maternal and Fetal Medicine Unit Network designed and conducted a well-designed randomized controlled trial in women with mild GDM. The trial established that treatment of GDM resulted in a significant reduction in several important perinatal and maternal outcomes.

Metabolomic and genetic architecture of gestational diabetes subtypes.

Physiological gestational diabetes mellitus (GDM) subtypes that may confer different risks for adverse pregnancy outcomes have been defined. The aim of this study was to characterise the metabolome and genetic architecture of GDM subtypes to address the hypothesis that they differ between GDM subtypes. This was a cross-sectional study of participants in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study who underwent an OGTT at approximately 28 weeks' gestation. GDM was defined retrospectively using International Association of Diabetes and Pregnancy Study Groups/WHO criteria, and classified as insulin-deficient GDM (insulin secretion <25th percentile with preserved insulin sensitivity) or insulin-resistant GDM (insulin sensitivity <25th percentile with preserved insulin secretion). Metabolomic analyses were performed on fasting and 1h serum samples in 3463 individuals (576 with GDM). Genome-wide genotype data were obtained for 8067 individuals (1323 with GDM). Regression analyses demonstrated striking differences between the metabolomes for insulin-deficient or insulin-resistant GDM compared to those with normal glucose tolerance. After adjustment for covariates, 33 fasting metabolites, including 22 medium- and long-chain acylcarnitines, were uniquely associated with insulin-deficient GDM; 23 metabolites, including the branched-chain amino acids and their metabolites, were uniquely associated with insulin-resistant GDM; two metabolites (glycerol and 2-hydroxybutyrate) were associated with the same direction of association with both subtypes. Subtype differences were also observed 1h after a glucose load. In genome-wide association studies, variants within MTNR1B (rs10830963, p=3.43×10-18, OR 1.55) and GCKR (rs1260326, p=5.17×10-13, OR 1.43) were associated with GDM. Variants in GCKR (rs1260326, p=1.36×10-13, OR 1.60) and MTNR1B (rs10830963, p=1.22×10-9, OR 1.49) demonstrated genome-wide significant association with insulin-resistant GDM; there were no significant associations with insulin-deficient GDM. The lead SNP in GCKR, rs1260326, was associated with the levels of eight of the 25 fasting metabolites that were associated with insulin-resistant GDM and ten of 41 1h metabolites that were associated with insulin-resistant GDM. This study demonstrates that physiological GDM subtypes differ in their metabolome and genetic architecture. These findings require replication in additional cohorts, but suggest that these differences may contribute to subtype-related adverse pregnancy outcomes.

The Association of Prenatal Vitamin D Status With Pregnancy and Neonatal Outcomes.

Vitamin D inadequacy is globally prevalent among pregnant women; however, its impact on pregnancy remains inconclusive. This study aims to explore the associations of maternal and umbilical cord serum 25-hydroxyvitamin D (25(OH)D) levels with pregnancy and neonatal outcomes. We used archived serum samples from the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study participants in the Hong Kong center and assayed maternal 25(OH)D levels at midgestation and umbilical cord 25(OH)D at birth using liquid chromatography-tandem mass spectroscopy. Data regarding pregnancy and perinatal outcomes were extracted from the HAPO study dataset and the hospital computerized medical system. Only 247 (16.4%) mothers and 66 (5.0%) neonates met the criteria for vitamin D sufficiency (ie, 25(OH)D ≥ 75 nmol/L). The ratio of umbilical cord to maternal vitamin D levels was positively associated with maternal age and ambient solar radiation at the month of delivery, while negatively associated with maternal serum total 25(OH)D at midgestation (all P < .001). Umbilical cord serum 25(OH)D was independently associated with a lower primary cesarean section rate (OR 0.990, 95% CI 0.982-0.999; P = .032). There were no associations of maternal and umbilical cord 25(OH)D levels with other adverse pregnancy and neonatal outcomes. Placental vitamin D transfer was found to be higher with a lower maternal vitamin D level, older maternal age, and higher ambient solar radiation at the time of the delivery. The protective effect of sufficient vitamin D in a cesarean section will require further studies.

OR18-06 Metabolomic And Genetic Architecture Of Gestational Diabetes Subtypes

Abstract Disclosure: K. Lee: None. A. Kuang: None. J. Bain: None. M.G. Hayes: None. M. Muehlbauer: None. O. Ilkayeva: None. C.B. Newgard: None. M. Hivert: None. D. Scholtens: None. W.L. Lowe: None. Gestational diabetes mellitus (GDM) is the most common complication of pregnancy. Recent studies defined physiological subtypes of GDM based on insulin sensitivity and secretion, i.e., GDM with a defect in insulin sensitivity and GDM with a defect in insulin secretion, which has been linked to different risks for adverse pregnancy outcomes. We hypothesized that the maternal metabolome and genetic architecture differed between GDM subtypes. This hypothesis was addressed using genetic and metabolomic analyses performed with fasting and 1-hr serum samples from a large multinational, multi-ancestry cohort of women enrolled in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study who underwent an oral glucose-tolerance test at ∼28 weeks’ gestation. GDM was defined retrospectively using IADPSG/WHO criteria and classified as GDM with insulin sensitivity defect (predominant sensitivity defect) or GDM with insulin secretion defect (predominant secretion defect). Targeted and non-targeted metabolomics analyses were performed on samples from 3463 mothers using tandem mass spectrometry and gas chromatography/mass spectrometry. Genome-wide genotyping was performed on 8067 mothers (1323 with GDM) from the multi-ancestry HAPO cohort. Per metabolite analyses were used to characterize GDM subtype metabolite profiles compared to no GDM.In a fully adjusted model that included adjustment for maternal BMI, 38 metabolites were associated with GDM with an insulin secretion defect (N=289) and 26 with GDM with an insulin sensitivity defect (N=742) (normoglycemic as reference group), only 3 of which (glycerol, palmitate, and 2-hydroxybutyrate) were common to the two subtypes. GDM with an insulin secretion defect was characterized by differences in 26 medium-and long-chain acylcarnitines in the fasting state, while GDM with an insulin sensitivity defect was associated with multiple amino acids, including the branched-chain amino acids and their metabolites in the fasting state. Differences in the maternal metabolome between the subtypes 1-hr after a glucose load were also observed, although the differences were not as evident compared to the fasting state. Genome-wide association analyses among all mothers with GDM demonstrated genome-wide significant association of SNPs within MTNR1B (most significant SNP rs1387153, p=1.05 x 10-10, OR = 1.038) and GCKR (most significant SNP rs397872078, p=9.85 x 10-10, OR = 1.037) with GDM (overall). GCKR variants demonstrated genome-wide association with GDM with an insulin-sensitivity defect (rs397872078, p=1.16 x 10-10, OR = 1.038), while no significant associations were observed for genetic variants with GDM with an insulin secretion defect. The present findings demonstrated differences in the maternal metabolome and underlying genetic architecture of GDM with an insulin secretion defect compared to GDM with an insulin sensitivity defect. Presentation: Saturday, June 17, 2023

45-OR: Newborn Adiposity and Cord Blood DNA Methylation—An Epigenome-Wide Association Study in HAPO with Validation in Gen3G

Differential cord blood DNA methylation (cb DNAm) in response to hyperglycemia in pregnancy may be associated with neonatal adiposity, a risk factor for childhood obesity. The Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study enrolled a multiethnic cohort to evaluate glycemia in pregnancy and newborn adiposity measured by skinfold thicknesses. We conducted an epigenome-wide association study using HAPO as a discovery sample and performed a replication study in an independent cohort, Gen3G. We analyzed cb DNAm with Illumina EPIC arrays (791,359 CpG sites after QC) on 2712 HAPO samples. We assessed the association between sum of 3 skinfolds and cb DNAm using linear regression models adjusted for maternal and offspring covariates and cell counts. We identified 90 CpG sites after accounting for multiple testing (Bonferroni-adjusted p&amp;lt;0.05). Using these sites identified in HAPO, we conducted similar regression analyses in 139 Gen3G cb DNAm samples to replicate findings. Similar associations at 7 CpG sites were identified including loci near KLF7, which encodes a regulator of cell proliferation and inhibitor of adipogenesis, and IGF1R, which encodes a transmembrane receptor involved in cell growth and survival that binds IGF1 and insulin, the latter especially during fetal life. These findings support epigenetic mechanisms in the developmental origins of neonatal adiposity. Disclosure J.L.Josefson: None. A.Kuang: None. D.Scholtens: None. C.Allard: None. W.Lowe: None. M.Hivert: None. Funding National Institutes of Health (R01HD034243, R01DK118403)

1419-P: Pandemic-Specific Associations of Maternal Exposure to Per- and Polyfluoroalkyl Substances and Glucose Metabolisms—A Cross-Sectional Analysis in Birth Cohort in Hong Kong

Introduction: Per- and polyfluoroalkyl substances (PFAS) have adverse cardiometabolic effects. Methods: We conducted a cross-sectional analysis in 1601 mothers who had joined the Hyperglycaemia and Adverse Pregnancy Outcome (HAPO) study in Hong Kong in 2001-2006. All mothers underwent a 75g-oral-glucose-tolerance test at 24-32 weeks of gestation. We measured serum concentrations of six PFAS biomarkers using high-performance LC-MS-MS. We fitted linear-regression, weighted-quantile-sum (WQS) regression, and quantile-g-computation (qgcomp) models to estimate the associations of individual PFAS and their mixture with levels of HbA1c and plasma-glucose (PG). Subgroup analyses were performed based on the enrollment period by the severe-acute-respiratory-syndrome (SARS) epidemic in Hong Kong between March 2003 and May 2004. Results: Maternal exposure to PFAS mixture was associated with increased HbA1c in both WQS (β=0.05, 95% CI: 0.02-0.07) and qgcomp models (β=0.04, 95% CI: 0.01-0.06). We did not observe significant associations of PFAS mixture with fasting PG, 1-h and 2-h PG in both models, except for 2-h PG in qgcmop model (β=0.074, 95% CI: 0.01-0.15). Pandemic-specific analyses showed a significant association of PFAS mixture with increased HbA1c in peri-SARS but not in pre-SARS and post-SARS epidemic period. Perfluorooctanoic-acid (PFOA) and perfluorooctane-sulfonic-acid (PFOS) were the main contributors to the overall positive effects on HbA1c. The level of PFOS was highest during the peri-SARS epidemic (median [IQR]: 24.7 [42.6-89.5] ng/mL) compared with pre-SARS (12.6 [20.0-49.8] ng/mL) and post-SARS (20.6 [27.8-46.4] ng/mL) epidemic. Conclusions: Maternal exposure to PFAS mixture is associated with glucose metabolisms during pregnancy. Pandemic-specific associations call for further studies on its adverse health effects during the COVID-19 pandemic. Disclosure A.Yang: None. C.H.Tam: None. R.Ozaki: None. W.L.Lowe: None. B.E.Metzger: None. W.H.Tam: None. C.K.Wong: None. R.C.Ma: Advisory Panel; AstraZeneca, Merck &amp; Co., Inc., Other Relationship; Bayer Inc., Boehringer-Ingelheim, Research Support; Tricida, Inc., Roche Diagnostics, Novo Nordisk. Funding Health and Medical Research Fund (13140761); Eunice Kennedy Shriver National Institute of Child Health and Human Development/National Institute of Diabetes and Digestive and Kidney Diseases (R01HD34242, R01HD34243); Research Grants Council of Hong Kong (473408, 471713)

Maternal and Cord Blood Serum Metabolite Associations with Childhood Adiposity and Body Composition Outcomes.

Maternal metabolites influence the size of newborns independently of maternal body mass index (BMI) and glycemia, highlighting the importance of maternal metabolism on offspring outcomes. This study examined associations of maternal metabolites during pregnancy with childhood adiposity, and cord blood metabolites with childhood adiposity using phenotype and metabolomic data from the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study and the HAPO Follow-Up Study. The maternal metabolites analyses included 2324 mother-offspring pairs, while the cord blood metabolites analyses included 937 offspring. Multiple logistic and linear regression were used to examine associations between primary predictors, maternal or cord blood metabolites, and childhood adiposity outcomes. Multiple maternal fasting and 1 hr metabolites were significantly associated with childhood adiposity outcomes in Model 1 but were no longer significant after adjusting for maternal BMI and/or maternal glycemia. In the fully adjusted model, fasting lactose levels were negatively associated with child BMI z-scores and waist circumference, while fasting urea levels were positively associated with waist circumference. One-hour methionine was positively associated with fat-free mass. There were no significant associations between cord blood metabolites and childhood adiposity outcomes. Few metabolites were associated with childhood adiposity outcomes after adjusting for maternal BMI and glucose, suggesting that maternal BMI accounts for the association between maternal metabolites and childhood adiposity.

Association of Maternal Metabolites and Metabolite Networks with Newborn Outcomes in a Multi-Ancestry Cohort.

The in utero environment is important for newborn size at birth, which is associated with childhood adiposity. We examined associations between maternal metabolite levels and newborn birthweight, sum of skinfolds (SSF), and cord C-peptide in a multinational and multi-ancestry cohort of 2337 mother-newborn dyads. Targeted and untargeted metabolomic assays were performed on fasting and 1 h maternal serum samples collected during an oral glucose tolerance test performed at 24-32 week gestation in women participating in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study. Anthropometric measurements were obtained on newborns at birth. Following adjustment for maternal BMI and glucose, per-metabolite analyses demonstrated significant associations between maternal metabolite levels and birthweight, SSF, and cord C-peptide. In the fasting state, triglycerides were positively associated and several long-chain acylcarnitines were inversely associated with birthweight and SSF. At 1 h, additional metabolites including branched-chain amino acids, proline, and alanine were positively associated with newborn outcomes. Network analyses demonstrated distinct clusters of inter-connected metabolites significantly associated with newborn phenotypes. In conclusion, numerous maternal metabolites during pregnancy are significantly associated with newborn birthweight, SSF, and cord C-peptide independent of maternal BMI and glucose, suggesting that metabolites in addition to glucose contribute to newborn size at birth and adiposity.

Gestational diabetes mellitus (Update 2023)

Gestational diabetes (GDM) is defined as any degree of glucose intolerance with onset during pregnancy and is associated with increased feto-maternal morbidity as well as long-term complications in mothers and the offspring. Women detected to have diabetes early in pregnancy receive the diagnosis of overt, non-gestational, diabetes (glucose: fasting ≥ 126 mg/dl, spontaneous ≥ 200 mg/dl or HbA1c ≥ 6.5% before 20weeks of gestation). GDM is diagnosed by an oral glucose tolerance test (oGTT) or increased fasting glucose (≥ 92 mg/dl). Screening for undiagnosed type2diabetes at the first prenatal visit is recommended in women at increased risk (history of GDM/pre-diabetes; malformation, stillbirth, successive abortions or birth weight > 4500 g previously; obesity, metabolic syndrome, age > 35years, vascular disease; clinical symptoms of diabetes (e.g. glucosuria) or ethnic origin with increased risk for GDM/T2DM (Arab, South- and Southeast Asian, Latin American)) using standard diagnostic criteria. Performance of the oGTT (120 min; 75 g glucose) may already be indicated in the first trimester in high-risk women but is mandatory between gestational week 24-28 in all pregnant women with previous non-pathological glucose metabolism. Following WHO recommendations, which are based on the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study, GDM is defined, if fasting venous plasma glucose is ≥ 92 mg/dl or 1 h ≥ 180 mg/dl or 2 h ≥ 153 mg/dl after glucose loading (international consensus criteria). In case of one pathological value astrict metabolic control is mandatory. After bariatric surgery we do not recommend to perform an oGTT due to risk of postprandial hypoglycemia. All women with GDM should receive nutritional counseling, be instructed in blood glucose self-monitoring and motivated to increase physical activity to moderate intensity levels-if not contraindicated (Evidence levelA). If blood glucose levels cannot be maintained in the therapeutic range (fasting < 95 mg/dl and 1 h after meals < 140 mg/dl, Evidence levelB) insulin therapy should be initiated as first choice (Evidence levelA). Maternal and fetal monitoring is required in order to minimize maternal and fetal/neonatal morbidity and perinatal mortality. Regular obstetric examinations including ultrasound examinations are recommended (Evidence levelA). Neonatal care of GDM offspring at high risk for hypoglycaemia includes blood glucose measurements after birth and if necessary appropriate intervention. Monitoring the development of the children and recommendation of healthy lifestyle are important issues to be tackled for the whole family. After delivery all women with GDM have to be reevaluated as to their glucose tolerance by a75 g oGTT (WHO criteria) 4-12weeks postpartum. Assessment of glucose parameters (fasting glucose, random glucose, HbA1c or optimally oGTT) are recommended every 2-3years in case of normal glucose tolerance. All women have to be instructed about their increased risk of type2diabetes and cardiovascular disease at follow-up. Possible preventive meassures, in particular lifestyle changes as weight management and maintenance/increase of physical activity should be discussed (evidence levelA).

Exploring the Optimal Diagnostic Thresholds of Hyperglycemia During Pregnancy

Exploring the Optimal Diagnostic Thresholds of Hyperglycemia During Pregnancy

The roles of newborn anthropometrics in the association between maternal weight gain and childhood cardiovascular risks.

The aim was to study the association between newborn anthropometrics and childhood cardiovascular risks and whether newborn anthropometrics mediate the effect of maternal gestational weight gain (GWG) on childhood risks. Data of 926 mother-child dyads from the Hyperglycemia and Adverse Pregnancy Outcomes study were analyzed. Newborn anthropometrics were treated as predictors and mediators by using a regression model and causal mediation model, respectively. Newborn sum of skinfolds (SSF) was associated with childhood diastolic blood pressure (DBP) and pulse wave velocity (coefficients [95% CI]: 0.13 [0.06 to 0.20]; 0.08 [0.004 to 0.15]), whereas newborn ponderal index (PI) was inversely associated with childhood systolic blood pressure (SBP), DBP, and pulse wave velocity (-0.08 [-0.15 to -0.01]; -0.08 [-0.14 to -0.008]; -0.09 [-0.16 to -0.03]). Newborn SSF mediated the effects of maternal excessive GWG on childhood SSF and DBP (proportion of total effect 9% and 8%, respectively). In contrast, a significant negative mediation through newborn PI was found for the effect of maternal excessive GWG on childhood DBP (-8%) and its effect on childhood SBP through birth weight (-27%). Childhood cardiovascular risks are positively associated with newborn SSF but inversely associated with newborn PI. Newborn SSF mediates the impact of excessive maternal GWG on childhood BP, but birth weight and newborn PI negatively mediate it.

Oral glucose tolerance test to diagnose gestational diabetes mellitus: Impact of variations in specimen handling

To improve birth outcomes, all pregnant women without known diabetes are recommended for an oral glucose tolerance test (OGTT) to screen for hyperglycaemia in pregnancy (diabetes in pregnancy or gestational diabetes mellitus (GDM)). This narrative review presents contemporary approaches to minimise preanalytical glycolysis in OGTT samples with a focus on GDM diagnosis using criteria derived from the Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study. The challenges of implementing each approach across a diverse Australian healthcare setting were explored. Many Australian sites currently collect and transport OGTT samples at ambient temperature in sodium fluoride (NaF) tubes which is likely to lead to missed diagnosis of GDM in a significant proportion of cases. Alternative preanalytical solutions should be pragmatic and tailored to individual settings and as close as possible to the preanalytical conditions of the HAPO study for correct interpretation of OGTT results. Rapid centrifugation of barrier tubes to separate plasma could be suitable in urban settings provided time to centrifugation is strictly controlled. Tubes containing NaF and citrate could be useful for remote or resource poor settings with long delays to analysis but the impact on the interpretation of OGTT results should be carefully considered. Testing venous blood glucose at the point-of-care bypasses the need for glycolytic inhibition but requires careful selection of devices with robust analytical performance. Studies to evaluate the potential error of each solution compared to the HAPO protocol are required to assess the magnitude of misdiagnosis and inform clinicians regarding the potential impact on patient safety and healthcare costs.

Is there a residual risk of large-for-gestational-age infant related to gestational diabetes mellitus when it is treated?

ObjectiveThe hyperglycaemia and adverse pregnancy outcomes (HAPO) study, where hyperglycaemia was untreated, showed a continuous association between large-for-gestational-age (LGA) infant and seven increasing categories of fasting plasma glucose (PG), 1-hour and 2-hour PG values after a 75 g oral glucose tolerance test at 24–32 gestational weeks. We evaluated whether the excess risk persisted in the 6th and 7th glucose categories - corresponding to women treated for gestational diabetes mellitus (GDM). Patients and methodsWe included 7,190 women meeting the HAPO criteria, of whom 655 (9.2%) were treated for GDM (dietary education in all; insulin therapy in 150 (20.3%)). We evaluated the adjusted odds ratio (aOR) for each glucose category (reference 1st category) for LGA infant. ResultsThe aOR for LGA linearly increased from the 1st to 5th categories of fasting, 1-hour and 2-hour PG. Specifically, the aORs for the 5th category were 2.20 (95% confidence interval 1.41–3.44), 2.25 (1.11–4.59), and 2.51 (1.63–3.85), respectively. The aORs for the 6th category were globally stable at 2.52 (1.46–4.36), 2.87 (1.48–5.54), and 2.47 (1.46–4.16), respectively. The same was true for the 7th category: 1.41 (0.56–3.55), 2.84 (1.03–7.86), and 3.53 (1.77–7.06), respectively. ConclusionWe confirmed the association between increasing PG category and LGA infant in women without GDM. We did not observe a residual risk of LGA infant in women treated for GDM in our hospital, irrespective of elevated fasting, 1-hour, or 2-hour PG diagnosis. The risk of LGA infant was globally similar to that in women with high normal glucose values.

Comparing IADPSG and NICE Diagnostic Criteria for GDM in Predicting Adverse Pregnancy Outcomes.

OBJECTIVETo compare the performance of diagnostic criteria for gestational diabetes mellitus (GDM) proposed by the International Association of the Diabetes and Pregnancy Study Groups (IADPSG) with those endorsed by the National Institute for Health and Care Excellence (NICE) in predicting adverse pregnancy outcomes.RESEARCH DESIGN AND METHODSWe performed a secondary data analysis of the Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study participants in five study centers. Logistic regression analyses were performed, and Akaike information criterion were applied for the comparison of different statistical prediction models. We further analyzed the performance by four racial/ethnic subgroups, namely, Whites, Hispanics, Asians, and Blacks.RESULTSAmong all, IADPSG criteria diagnosed 267 (4.1%) more women with GDM, but predicted primary caesarean section (CS) and large for gestational age (LGA) and neonatal adiposity better than did NICE criteria after adjustment for potential confounders. Among Whites, IADPSG criteria diagnosed 65 (2.5%) more subjects with GDM and predicted LGA and neonatal adiposity better, but predicted hypertensive disorders, primary CS and clinical neonatal hypoglycemia worse. Among Hispanics, the IADPSG criteria diagnosed 203 (12.1%) more with GDM but performed better in predicting hypertensive disorders, LGA, neonatal adiposity, and hyperinsulinemia. Among Asians, the IADPSG criteria diagnosed 34 (2.0%) fewer subjects with GDM but predicted hypertensive disorders better in the unadjusted model. In Blacks, IADPSG criteria diagnosed 34 (10.5%) more women with GDM.CONCLUSIONSIADPSG criteria appear to be more favorable than NICE for identification of adverse pregnancy outcomes among Hispanic and Asian women, while they are comparable to NICE among White women.

Network Approaches to Integrate Analyses of Genetics and Metabolomics Data with Applications to Fetal Programming Studies

The integration of genetics and metabolomics data demands careful accounting of complex dependencies, particularly when modelling familial omics data, e.g., to study fetal programming of related maternal–offspring phenotypes. Efforts to identify genetically determined metabotypes using classic genome wide association approaches have proven useful for characterizing complex disease, but conclusions are often limited to a series of variant–metabolite associations. We adapt Bayesian network models to integrate metabotypes with maternal–offspring genetic dependencies and metabolic profile correlations in order to investigate mechanisms underlying maternal–offspring phenotypic associations. Using data from the multiethnic Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study, we demonstrate that the strategic specification of ordered dependencies, pre-filtering of candidate metabotypes, incorporation of metabolite dependencies, and penalized network estimation methods clarify potential mechanisms for fetal programming of newborn adiposity and metabolic outcomes. The exploration of Bayesian network growth over a range of penalty parameters, coupled with interactive plotting, facilitate the interpretation of network edges. These methods are broadly applicable to integration of diverse omics data for related individuals.

106-OR: Fetal Sex Influences Maternal Insulin and Glucose Metabolism in Pregnancy

Aims and Hypothesis: Women carrying a male fetus are suggested to have altered maternal glucose and insulin dynamics and increased rates of GDM, but current literature remains inconclusive. We aimed to determine the relationship between fetal sex and maternal glucose and insulin metabolism and assess whether inclusion of fetal sex improves prediction of IADPSG GDM. Methods: Using blinded data from five Hyperglycaemia and Adverse Pregnancy Outcome study centres, we examined maternal metabolic data at mean gestational week 28 in 6337 untreated women. Stratifying women by either male (n = 3273) or female fetus (n = 3064) we analysed data from the 75g OGTT, estimates of insulin secretion (Stumvoll first phase) and sensitivity (Matsuda index) and their product (oral Disposition index) using multiple linear regression analysis. To assess the relationship and predictive ability of fetal sex and GDM we utilised multiple logistic regression and receiver operating characteristic curve analysis. Results: Women carrying a male fetus were found to have a modest increase in fasting plasma glucose (4.52 vs. 4.44 mmol/L; P=0.008) and 1 h glucose (7.57 vs. 7.46 mmol/L; P=0.015) during OGTT which translated into an overall increase in the OGTT z score (0.vs. 0.02; P=0.005) . The Matsuda (β: -0.06; 95% CI [-0.10, -0.02]; P=0.008) and oral Disposition index (β: -0.07; 95% CI [-0.11, -0.02]; P=0.005) were significantly reduced in women carrying a male fetus after correction for established maternal clinical risk factors. Women carrying a male fetus were not at higher odds of developing GDM in adjusted (aOR: 1.04; 95% CI [0.9, 1.19]; P=0.6) or unadjusted (OR: 1.09; 95% CI [0.96, 1.25]; P=0.16) models. Conclusion/interpretation: The male fetus is associated with increased maternal fasting and postprandial glucose with concomitant decreased insulin sensitivity and β-cell compensation. The alterations in maternal glucose and insulin dynamics associated with having a male fetus does not translate into a clinical diagnosis of GDM. Disclosure T.P.Mullins: None. K.S.Gibbons: None. L.R.Madsen: None. R.C.Ma: Other Relationship; Bayer AG, Boehringer Ingelheim International GmbH, Research Support; AstraZeneca, Bayer AG, Novo Nordisk A/S, Pfizer Inc., Tricida, Inc. W.H.Tam: None. P.Catalano: None. D.A.Sacks: None. H.L.Barrett: None. D.Mcintyre: None.