Multi-ancestry genome-wide association study of gestational diabetes mellitus highlights genetic links with type 2 diabetes.

Gestational diabetes mellitus (GDM) is associated with increased risk of pregnancy complications and adverse perinatal outcomes. GDM often reoccurs and is associated with increased risk of subsequent diagnosis of type 2 diabetes (T2D). To improve our understanding of the aetiological factors and molecular processes driving the occurrence of GDM, including the extent to which these overlap with T2D pathophysiology, the GENetics of Diabetes In Pregnancy Consortium assembled genome-wide association studies of diverse ancestry in a total of 5485 women with GDM and 347 856 without GDM. Through multi-ancestry meta-analysis, we identified five loci with genome-wide significant association (P < 5 × 10-8) with GDM, mapping to/near MTNR1B (P = 4.3 × 10-54), TCF7L2 (P = 4.0 × 10-16), CDKAL1 (P = 1.6 × 10-14), CDKN2A-CDKN2B (P = 4.1 × 10-9) and HKDC1 (P = 2.9 × 10-8). Multiple lines of evidence pointed to the shared pathophysiology of GDM and T2D: (i) four of the five GDM loci (not HKDC1) have been previously reported at genome-wide significance for T2D; (ii) significant enrichment for associations with GDM at previously reported T2D loci; (iii) strong genetic correlation between GDM and T2D and (iv) enrichment of GDM associations mapping to genomic annotations in diabetes-relevant tissues and transcription factor binding sites. Mendelian randomization analyses demonstrated significant causal association (5% false discovery rate) of higher body mass index on increased GDM risk. Our results provide support for the hypothesis that GDM and T2D are part of the same underlying pathology but that, as exemplified by the HKDC1 locus, there are genetic determinants of GDM that are specific to glucose regulation in pregnancy.

Human milk oligosaccharides in Chinese lactating mothers and relationship with allergy development in offspring.

BACKGROUND: The health benefits of breastfeeding are partly contributed by human milk oligosaccharides (HMOs), but there is limited data on breast milk (BM) HMO composition in Chinese. OBJECTIVE: This study investigated the association between early-life HMO intake and allergy occurrence in Chinese children. METHODS: 103 healthy Chinese pregnant women regardless of allergy history were recruited into this birth cohort. Their babies were followed until 24 months old. Concentrations of 2'-fucosyllactose (2'-FL), lacto-N-neotetraose (LNnT), -sialyllactose (3'-SL) and 6'-sialyllactose (6'-SL) in BM collected at 1-month postpartum were measured by liquid chromatography-mass spectrometry. The associations between these HMOs and allergy occurrence by 24 months were analyzed by multivariate regression analyses. RESULTS: Twenty-nine percent and 19% of participants had eczema at 12 and 24 months old respectively. Eighty BM samples were analyzed, with 2'-FL being the most abundant HMO (median 1447 ppm, interquartile range [IQR] 291-1906 ppm), and median (IQR) levels of LNnT, 6'-SL and 3'-SL in ppm were 738 (580-950), 20.5 (12.7-38.8) and 23.0 (17.8-27.6) respectively. Participants with eczema by 24 months consumed BM with higher 2'-FL concentration at 1-month (P = 0.008), and also lower 6'-SL concentration in exclusively breastfed infants (P = 0.012) but higher 6'-SL concentration for those with mixed feeding at 1 month (P = 0.043). Food allergic children at 12 months consumed BM with higher 2'-FL concentrations at 1 month (P = 0.048). CONCLUSIONS: BM 2'-FL concentration is higher in children who develops eczema by 24 months and food allergy during infancy. The relationship for 6'-SL is divergent depending on mode of feeding in infants.

Early emergence of sexual dimorphism in offspring leukocyte telomere length was associated with maternal and children's glucose metabolism-a longitudinal study.

BACKGROUND: Leukocyte telomere length (LTL) is suggested to be a biomarker of biological age and reported to be associated with metabolic diseases such as type 2 diabetes. Glucose metabolic traits including glucose and insulin levels have been reported to be associated with LTL in adulthood. However, there is relatively little research focusing on children's LTL and the association with prenatal exposures. This study investigates the relationship between maternal and offspring glucose metabolism with offspring LTL in early life. METHODS: This study included 882 mother-child pairs from the HAPO Hong Kong Field Centre, with children evaluated at age 7.0 ± 0.4 (mean ± SD) years. Glucose metabolic traits including maternal post-load glucose during pregnancy, children's glucose and insulin levels, and their derived indices at follow-up were measured or calculated. Offspring LTL was assessed using real-time polymerase chain reaction. RESULTS: Sex- and age-adjusted children's LTL was found to be associated with children's HOMA-IR (ß=-0.046 ± 0.016, p=0.005). Interestingly, both children's and maternal post-load glucose levels were positively associated with children's LTL. However, negative associations were observed between children's LTL and children's OGTT insulin levels. In addition, the LTL in females was more strongly associated with pancreatic beta-cell function whilst LTL in males was more strongly associated with OGTT glucose levels. CONCLUSIONS: Our findings suggest a close association between maternal and offspring glucose metabolic traits with early life LTL, with the offspring sex as an important modifier of the disparate relationships in insulin production and response.

Iron status of full-term infants in early infancy is not associated with maternal ferritin levels nor infant feeding practice.

Iron deficiency (ID) in early life is associated with morbidities. Most fetal iron required for infant growth is acquired in the third trimester from maternal iron store. However, how prenatal iron level affects ferritin level in early infancy remains controversial. This study aimed to examine the associations between maternal ferritin levels and cord blood serum ferritin (CBSF) and to compare the ferritin levels between different feeding practices in early infancy. Healthy Chinese mothers with uncomplicated pregnancy and their infants were followed up at 3 months post-delivery for questionnaire completion and infant blood collection. Infants who were predominantly breastfed and those who were predominantly formula fed were included in this analysis. Serum ferritin levels were measured in maternal blood samples collected upon delivery, cord blood and infant blood samples at 3 months of age. Ninety-seven mother-baby dyads were included. Maternal ID is common (56 %) while the CBSF levels were significantly higher than maternal ferritin levels. Only three infants (3 %) had ID at 3 months of age. There were no significant correlations between maternal ferritin levels with CBSF (r 0·168, P = 0·108) nor with infant ferritin levels at 3 months of age (r 0·023, P = 0·828). Infant ferritin levels at 3 months were significantly and independently associated with CBSF (P = 0·007) and birth weight (P < 0·001) after adjusting for maternal age, parity, maternal education, infant sex and feeding practice. In conclusion, maternal ID was common upon delivery. However, maternal ferritin levels were not significantly associated with CBSF concentrations nor infant ferritin concentrations at 3 months of age.

Genome-wide associations for birth weight and correlations with adult disease.

Birth weight (BW) has been shown to be influenced by both fetal and maternal factors and in observational studies is reproducibly associated with future risk of adult metabolic diseases including type 2 diabetes (T2D) and cardiovascular disease. These life-course associations have often been attributed to the impact of an adverse early life environment. Here, we performed a multi-ancestry genome-wide association study (GWAS) meta-analysis of BW in 153,781 individuals, identifying 60 loci where fetal genotype was associated with BW (P < 5 × 10-8). Overall, approximately 15% of variance in BW was captured by assays of fetal genetic variation. Using genetic association alone, we found strong inverse genetic correlations between BW and systolic blood pressure (Rg = -0.22, P = 5.5 × 10-13), T2D (Rg = -0.27, P = 1.1 × 10-6) and coronary artery disease (Rg = -0.30, P = 6.5 × 10-9). In addition, using large -cohort datasets, we demonstrated that genetic factors were the major contributor to the negative covariance between BW and future cardiometabolic risk. Pathway analyses indicated that the protein products of genes within BW-associated regions were enriched for diverse processes including insulin signalling, glucose homeostasis, glycogen biosynthesis and chromatin remodelling. There was also enrichment of associations with BW in known imprinted regions (P = 1.9 × 10-4). We demonstrate that life-course associations between early growth phenotypes and adult cardiometabolic disease are in part the result of shared genetic effects and identify some of the pathways through which these causal genetic effects are mediated.

Gestational weight gain rates in the first and second trimesters are associated with small for gestational age among underweight women: a prospective birth cohort study.

BACKGROUND: Despite the well-studied effects of gestational weight gain (GWG) on offspring health, little is known about the association of trimester-specific GWG with offspring birth weight among underweight pregnant women. This study aimed to explore the association of trimester-specific GWG rate with small for gestational age (SGA) in underweight women. METHODS: The GWG rate of underweight pregnant women (pre-pregnancy body mass index [BMI] lower than 18.5 kg/m2) of the Born in Guangzhou Cohort Study was calculated as the weight gain during a specific trimester divided by the corresponding duration of week. Total GWG was calculated as the weight difference between pre-pregnancy and delivery, and was categorized into inadequate, adequate, and excessive weight gain based on the 2009 Institute of Medicine (IOM) weight gain recommendation. The INTERGROWTH-21st standards were used to define SGA. Logistic regression models were used to examine the associations of total GWG and trimester-specific GWG rates with SGA. Associations between trimester-specific GWG rates and SGA were also analyzed separately based on different total GWG categories (i.e. inadequate and adequate/excessive GWG). RESULTS: Of the 3839 participants, SGA births occurred in 397 (10.3%), and mean GWG was 14.9 kg (SD 3.9). A lower risk of SGA was observed among women with higher GWG rate (per 0.5 kg/week increase) during the first (adjusted OR [aOR] 0.74, 95%CI 0.57, 0.96) and second (adjusted OR [aOR] 0.40, 95%CI 0.30, 0.55) but not third trimester. Similar association between higher GWG rate during the second trimester and a decreased risk of SGA were observed among women with inadequate (< 12.5 kg) and adequate/excessive (≥12.5 kg) total GWG, respectively. Compared to women with adequate GWG rate, women with inadequate GWG rate during the second trimester had a significantly increased risk of SGA (aOR 1.58, 95% CI 1.14, 2.20). CONCLUSIONS: Second-trimester GWG might be the key driver for the association between inadequate GWG and increased risk of SGA births in underweight women.

Dietary patterns of Chinese pregnant women in Hong Kong.

BACKGROUND AND OBJECTIVES: Maternal nutrition is important for healthy pregnancy, but it has not been well studied among pregnant women in Hong Kong. This study aims to examine the dietary pattern and nutritional intake of women in early pregnancy, and the associations between dietary patterns, dietary quality, and other health parameters. METHODS AND STUDY DESIGN: This is a prospective cohort study of healthy Chinese pregnant women, recruited at their first antenatal appointment. Dietary intakes were assessed by a locally validated food frequency questionnaire (FFQ) and dietary patterns were derived by principal component analysis. RESULTS: Of 160 women recruited, the mean age was 32.7±3.9 years and body mass index (BMI) before pregnancy was 22.6±3.8 kg/m2. The dietary analyses were restricted to 156 women who had completed the FFQ. 99% of women had excessive sodium intake and only 2.6% of women met the recommended fibre intake. Three dietary patterns identified were 'sweet and fast-food pattern', 'prudent pattern' and 'meat pattern', which altogether accounted for 23.5% of the total variation. The 'prudent pattern' was positively associated with dietary quality indices [Dietary Approaches to Stop Hypertension score, ρ=0.323, p<0.01; Dietary Quality Index-International, ρ=0.400, p<0.01; Mediterranean Diet Score, ρ=0.243, p=0.02]; and was inversely associated systolic (B=-3.71, 95% CI -7.06, -0.36) and diastolic blood pressure (B=-2.69, 95% CI -5.12, -0.26), suggesting this pattern represented a relatively healthier dietary option. CONCLUSIONS: Suboptimal dietary intake is a common issue among pregnant women in Hong Kong. Early dietary assessment and attention are warranted in this population.

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

AIMS/HYPOTHESIS: 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. METHODS: 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. RESULTS: 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. CONCLUSION/INTERPRETATION: 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.

A polysaccharide extract from the medicinal plant Maidong inhibits the IKK-NF-κB pathway and IL-1ß-induced islet inflammation and increases insulin secretion.

The herb dwarf lilyturf tuber (Maidong, Ophiopogonis Radix) is widely used in Chinese traditional medicine to manage diabetes and its complications. However, the role of Maidong polysaccharide extract (MPE) in pancreatic ß-cell function is unclear. Here, we investigated whether MPE protects ß-cell function and studied the underlying mechanisms. We treated db/db and high-fat diet (HFD)-induced obese mice with 800 or 400 mg/kg MPE or water for 4 weeks, followed by an oral glucose tolerance test. Pancreas and blood were collected for molecular analyses, and clonal MIN6 ß-cells and primary islets from HFD-induced obese mice and normal chow diet-fed mice were used in additional analyses. In vivo, MPE both increased insulin secretion and reduced blood glucose in the db/db mice but increased only insulin secretion in the HFD-induced obese mice. MPE substantially increased the ß-cell area in both models (3-fold and 2-fold, p < 0.01, for db/db and HFD mice, respectively). We observed reduced nuclear translocation of the p65 subunit of NF-κB in islets of MPE-treated db/db mice, coinciding with enhanced glucose-stimulated insulin secretion (GSIS). In vitro, MPE potentiated GSIS and decreased interleukin 1ß (IL-1ß) secretion in MIN6 ß-cells. Incubation of MIN6 cells with tumor necrosis factor α (TNFα), interferon-γ, and IL-1ß amplified IL-1ß secretion and inhibited GSIS. These effects were partially reversed with MPE or the IκB kinase ß inhibitor PS1145, coinciding with reduced activation of p65 and p-IκB in the NF-κB pathway. We conclude that MPE may have potential for therapeutic development for ß-cell protection.

Role of maternal glucose metabolism in the association between maternal BMI and neonatal size and adiposity.

BACKGROUND/OBJECTIVE: One potential mechanism by which maternal obesity impacts fetal growth is through hyperglycemia below the threshold for gestational diabetes. Data regarding which measures of maternal glucose metabolism mediate this association is sparse. The objectives of this study were to (i) quantify the associations of maternal pre-pregnancy body mass index (BMI) with neonatal size and adiposity and (ii) examine the role of markers of maternal glucose metabolism as mediators in these associations. SUBJECTS/METHODS: This is a secondary analysis of 6,379 mother-infant dyads from the Hyperglycemia and Adverse Pregnancy Outcome cohort. Markers of glucose metabolism, including plasma glucose and c-peptide values, Stumvoll first-phase estimate, modified Matsuda index, and oral disposition index were measured and calculated from an oral glucose tolerance test (OGTT) between 24- and 32-weeks' gestation. We calculated the direct effect of maternal BMI category, measured at the time of the OGTT and regressed to estimate pre-pregnancy BMI, on neonatal (1) birth weight (BW), (2) fat mass (FM), (3) % body fat (BF%), and (4) sum of skinfold thickness (sSFT). We then calculated the indirect effect of BMI category on these measures through markers of glucose metabolism. RESULTS: Maternal BMI category was positively associated with neonatal BW, FM, BF%, and sSFT. Additionally, mothers who were overweight or obese had higher odds of delivering an infant with BW, FM, BF%, or sSFT >90th percentile. Fasting glucose and c-peptide values were the strongest mediators in the linear associations between maternal BMI category and neonatal size and adiposity. CONCLUSIONS: Maternal overweight and obesity were associated with higher odds of neonatal BW and adiposity >90th percentile. Fasting measures of glucose metabolism were the strongest mediators of these associations, suggesting that future studies should investigate whether incorporation of these markers in pregnant women with obesity may improve prediction of neonatal size and adiposity.

Maternal glucose levels during pregnancy and childhood adiposity in the Hyperglycemia and Adverse Pregnancy Outcome Follow-up Study.

AIMS/HYPOTHESIS: Maternal type 2 diabetes during pregnancy and gestational diabetes are associated with childhood adiposity; however, associations of lower maternal glucose levels during pregnancy with childhood adiposity, independent of maternal BMI, remain less clear. The objective was to examine associations of maternal glucose levels during pregnancy with childhood adiposity in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) cohort. METHODS: The HAPO Study was an observational epidemiological international multi-ethnic investigation that established strong associations of glucose levels during pregnancy with multiple adverse perinatal outcomes. The HAPO Follow-up Study (HAPO FUS) included 4832 children from ten HAPO centres whose mothers had a 75 g OGTT at ~28 weeks gestation 10-14 years earlier, with glucose values blinded to participants and clinical caregivers. The primary outcome was child adiposity, including: (1) being overweight/obese according to sex- and age-specific cut-offs based on the International Obesity Task Force (IOTF) criteria; (2) IOTF-defined obesity only; and (3) measurements >85th percentile for sum of skinfolds, waist circumference and per cent body fat. Primary predictors were maternal OGTT and HbA1c values during pregnancy. RESULTS: Fully adjusted models that included maternal BMI at pregnancy OGTT indicated positive associations between maternal glucose predictors and child adiposity outcomes. For one SD difference in pregnancy glucose and HbA1c measures, ORs for each child adiposity outcome were in the range of 1.05-1.16 for maternal fasting glucose, 1.11-1.19 for 1 h glucose, 1.09-1.21 for 2 h glucose and 1.12-1.21 for HbA1c. Associations were significant, except for associations of maternal fasting glucose with offspring being overweight/obese or having waist circumference >85th percentile. Linearity was confirmed in all adjusted models. Exploratory sex-specific analyses indicated generally consistent associations for boys and girls. CONCLUSIONS/INTERPRETATION: Exposure to higher levels of glucose in utero is independently associated with childhood adiposity, including being overweight/obese, obesity, skinfold thickness, per cent body fat and waist circumference. Glucose levels less than those diagnostic of diabetes are associated with greater childhood adiposity; this may have implications for long-term metabolic health.

Progression of glucose intolerance and cardiometabolic risk factors over a decade in Chinese women with polycystic ovary syndrome: A case-control study.

BACKGROUND: Polycystic ovary syndrome (PCOS) is associated with increased metabolic risk, though data on long-term follow-up of cardiometabolic traits are limited. We postulated that Chinese women with PCOS would have higher risk of incident diabetes and cardiometabolic abnormalities than those without PCOS during long-term follow-up. METHODS AND FINDINGS: One hundred ninety-nine Chinese women with PCOS diagnosed by the Rotterdam criteria and with a mean age of 41.2 years (SD = 6.4) completed a follow-up evaluation after an average of 10.6 ± 1.3 years. Two hundred twenty-five women without PCOS (mean age: 54.1 ± 6.7 years) who underwent baseline and follow-up evaluation over the same period were used for comparison. Progression of glycaemic status of women both with and without PCOS was assessed by using 75-g oral glucose tolerance test (OGTT) screening with the adoption of 2009 American Diabetes Association diagnostic criteria. The frequency of impaired glucose regulation, hypertension, and hyperlipidaemia of women with PCOS at follow-up has increased from 31.7% (95% CI 25.2%-38.1%) to 47.2% (95% CI 40.3%-54.2%), 16.1% (95% CI 11.0%-21.2%) to 34.7% (95% CI 28.1%-41.3%), and 52.3% (95% CI 45.3%-59.2%) to 64.3% (95% CI 57.7%-71.0%), respectively. The cumulative incidence of diabetes mellitus (DM) in follow-up women with PCOS is 26.1% (95% CI 20.0%-32.2%), almost double that in the cohort of women without PCOS (p < 0.001). Age-standardised incidence of diabetes among women with PCOS was 22.12 per 1,000 person-years (95% CI 10.86-33.37) compared with the local female population incidence rate of 8.76 per 1,000 person-years (95% CI 8.72-8.80) and 10.09 per 1,000 person-years (95% CI 4.92-15.26, p < 0.001) for women without PCOS in our study. Incidence rate for women with PCOS aged 30-39 years was 20.56 per 1,000 person-years (95% CI 12.57-31.87), which is approximately 10-fold higher than that of the age-matched general female population in Hong Kong (1.88 per 1,000 person-years, [95% CI 1.85-1.92]). The incidence rate of type 2 DM (T2DM) of both normal-weight and overweight women with PCOS was around double that of corresponding control groups (normal weight: 8.96 [95% CI 3.92-17.72] versus 4.86 per 1,000 person-years [95% CI 2.13-9.62], p > 0.05; overweight/obese: 28.64 [95% CI 19.55-40.60] versus 14.1 per 1,000 person-years [95% CI 8.20-22.76], p < 0.05). Logistic regression analysis identified that baseline waist-to-hip ratio (odds ratio [OR] = 1.71 [95% CI 1.08-2.69], p < 0.05) and elevated triglyceride (OR = 6.63 [95% CI 1.23-35.69], p < 0.05) are associated with the progression to T2DM in PCOS. Limitations of this study include moderate sample size with limited number of incident diabetes during follow-up period and potential selection bias. CONCLUSIONS: High risk of diabetes and increased cardiovascular disease risk factors among Chinese women with PCOS are highlighted in this long-term follow-up study. Diabetes onset was, on average, 10 years earlier among women with PCOS than in women without PCOS.

Birth ball for pregnant women in labour research protocol: a multi-centre randomised controlled trial.

BACKGROUND: Birth ball is one of the non-pharmacologic pain relief methods to help mothers cope with the labouring process. A randomised controlled trial (RCT) is conducted to evaluate the effectiveness, safety and harm of birth ball use by pregnant women in labour compared to treatment as usual group. METHODS: A prospective multi-centre randomised controlled trial (RCT) will be conducted in Obstetrics and Gynaecological units of five public hospitals in Hong Kong, China. Data will be collected from March 2016 onward for 2 years. The target population is Chinese women with an uncomplicated singleton pregnancy at gestational age of 37 to 42 weeks. Participants are randomised based on parity (nulliparous and multiparous) and type of labour onset (spontaneous and induced). Women in the intervention group are actively offered and taught how to use a birth ball; those in the control group receive the usual midwifery care. The target sample size is 512. The primary outcome measures are maternal pain intensity, satisfaction with pain relief, sense of control in labour, assisted delivery and satisfaction with childbirth experience. Labour pain relief is measured by visual analogue scale (VAS). Other outcomes will be measured through four different validated questionnaires. To control for potential cluster effects, a linear mixed model will be used. An intention-to-treat analysis is adopted and performed by researchers unknown to subjects' group allocation. DISCUSSION: Results will provide rigorous scientific evidence for policy development and practice. We are using stratified randomisation according to potential confounders of parity and type of labour onset to give four possible combinations. If the results are favourable, it will facilitate systematic implementation to promote birth ball use for women in labour. TRIAL REGISTRATION: Chinese Clinical Trial Register (ChiCTR), Registration number: ChiCTR-IIC-16008275 , Date of registration 12 April 2016 (retrospectively registered), Date of enrolment of the first participant to the trial 1 March 2016.

The impact of maternal gestational weight gain on cardiometabolic risk factors in children.

AIMS/HYPOTHESIS: Accumulating evidence suggests an impact of gestational weight gain (GWG) on pregnancy outcomes; however, data on cardiometabolic risk factors later in life have not been comprehensively studied. This study aimed to evaluate the relationship between GWG and cardiometabolic risk in offspring aged 7 years. METHODS: We included a total of 905 mother-child pairs who enrolled in the follow-up visit of the multicentre Hyperglycemia and Adverse Pregnancy Outcome study, at the Hong Kong Centre. Women were classified as having gained weight below, within or exceeding the 2009 Institute of Medicine (IOM) guidelines. A standardised GWG according to pre-pregnancy BMI categories was calculated to explore for any quadratic relationship. RESULTS: Independent of pre-pregnancy BMI, gestational hyperglycaemia and other confounders, women who gained more weight than the IOM recommendations had offspring with a larger body size and increased odds of adiposity, hypertension and insulin resistance (range of p values of all the traits: 4.6 × 10-9 < p < 0.0390) than women who were within the recommended range of weight gain during pregnancy. Meanwhile, women who gained less weight than outlined in the recommendations had offspring with increased risks of hypertension and insulin resistance, compared with those who gained weight within the recommended range (7.9 × 10-3 < p < 0.0477). Quadratic relationships for diastolic blood pressure, AUC for insulin, pancreatic beta cell function and insulin sensitivity index were confirmed in the analysis of standardised GWG (1.4 × 10-3 < pquadratic < 0.0282). Further adjustment for current BMI noticeably attenuated the observed associations. CONCLUSIONS/INTERPRETATION: Both excessive and inadequate GWG have independent and significant impacts on childhood adiposity, hypertension and insulin resistance. Our findings support the notion that adverse intrauterine exposures are associated with persistent cardiometabolic risk in the offspring.

Association of Gestational Diabetes With Maternal Disorders of Glucose Metabolism and Childhood Adiposity.

Importance: The sequelae of gestational diabetes (GD) by contemporary criteria that diagnose approximately twice as many women as previously used criteria are unclear. Objective: To examine associations of GD with maternal glucose metabolism and childhood adiposity 10 to 14 years' postpartum. Design, Setting, and Participants: The Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study established associations of glucose levels during pregnancy with perinatal outcomes and the follow-up study evaluated the long-term outcomes (4697 mothers and 4832 children; study visits occurred between February 13, 2013, and December 13, 2016). Exposures: Gestational diabetes was defined post hoc using criteria from the International Association of Diabetes and Pregnancy Study Groups consisting of 1 or more of the following 75-g oral glucose tolerance test results (fasting plasma glucose ≥92 mg/dL; 1-hour plasma glucose level ≥180 mg/dL; 2-hour plasma glucose level ≥153 mg/dL). Main Outcomes and Measures: Primary maternal outcome: a disorder of glucose metabolism (composite of type 2 diabetes or prediabetes). Primary outcome for children: being overweight or obese; secondary outcomes: obesity, body fat percentage, waist circumference, and sum of skinfolds (>85th percentile for latter 3 outcomes). Results: The analytic cohort included 4697 mothers (mean [SD] age, 41.7 [5.7] years) and 4832 children (mean [SD] age, 11.4 [1.2] years; 51.0% male). The median duration of follow-up was 11.4 years. The criteria for GD were met by 14.3% (672/4697) of mothers overall and by 14.1% (683/4832) of mothers of participating children. Among mothers with GD, 52.2% (346/663) developed a disorder of glucose metabolism vs 20.1% (791/3946) of mothers without GD (odds ratio [OR], 3.44 [95% CI, 2.85 to 4.14]; risk difference [RD], 25.7% [95% CI, 21.7% to 29.7%]). Among children of mothers with GD, 39.5% (269/681) were overweight or obese and 19.1% (130/681) were obese vs 28.6% (1172/4094) and 9.9% (405/4094), respectively, for children of mothers without GD. Adjusted for maternal body mass index during pregnancy, the OR was 1.21 (95% CI, 1.00 to 1.46) for children who were overweight or obese and the RD was 3.7% (95% CI, -0.16% to 7.5%); the OR was 1.58 (95% CI, 1.24 to 2.01) for children who were obese and the RD was 5.0% (95% CI, 2.0% to 8.0%); the OR was 1.35 (95% CI, 1.08 to 1.68) for body fat percentage and the RD was 4.2% (95% CI, 0.9% to 7.4%); the OR was 1.34 (95% CI, 1.08 to 1.67) for waist circumference and the RD was 4.1% (95% CI, 0.8% to 7.3%); and the OR was 1.57 (95% CI, 1.27 to 1.95) for sum of skinfolds and the RD was 6.5% (95% CI, 3.1% to 9.9%). Conclusions and Relevance: Among women with GD identified by contemporary criteria compared with those without it, GD was significantly associated with a higher maternal risk for a disorder of glucose metabolism during long-term follow-up after pregnancy. Among children of mothers with GD vs those without it, the difference in childhood overweight or obesity defined by body mass index cutoffs was not statistically significant; however, additional measures of childhood adiposity may be relevant in interpreting the study findings.

Evaluation of an in-house real-time polymerase chain reaction method to identify group B streptococcus colonization in pregnancy.

AIM: The aim of this study was to evaluate the performance of in-house real-time polymerase chain reaction (qPCR) in detecting group B streptococcus (GBS) colonization compared with the standard culture method in a cohort of pregnant women. MATERIAL AND METHODS: A total of 134 rectovaginal swabs were collected from 125 pregnant women, of whom 108 were known carriers or presented with preterm prelabor rupture of membranes. The swabs were placed in Standard Methods Broth (Todd-Hewitt broth supplemented with 6 µg/mL gentamicin and 15 µg/mL nalidixic acid) for culture identification of GBS. An in-house qPCR was also performed from the broth and after overnight incubation of the broth. RESULTS: The detection rate of GBS in this cohort was 30.6% and 50.7% using standard culture method and qPCR, respectively. GBS-specific qPCR assay gave sensitivities of 97.6% and 100%, specificities of 73.1% and 71.0%, and negative predictive values of 98.6% and 100% from direct specimen and from broth after overnight incubation, respectively. CONCLUSIONS: The in-house qPCR test has high sensitivity in detecting GBS colonization. The high negative predictive value helps to avoid unnecessary use of antibiotics in uncolonized women.

A randomized controlled trial to evaluate the effects of an early postnatal lifestyle modification program on diet, adiposity and metabolic outcome in mothers with gestational diabetes mellitus.

OBJECTIVE: The aim of the present study was to evaluate the effectiveness of a 12-month early postnatal lifestyle intervention program in women with gestational diabetes in a recent pregnancy. METHODS: This study was a prospective randomized intervention study conducted at a diabetes center in Hong Kong. Chinese women aged 18-45 years, who developed gestational diabetes mellitus (GDM) in their most recent pregnancy, were invited. Eligible women were randomized in 1:1 ratio at baseline (6-12 weeks postpartum), to standard care or lifestyle intervention (diet and physical activity) groups for 12 months. A standardized biochemistry assessment including oral glucose tolerance test, blood lipids, complete blood count, renal and liver functions, were measured at baseline and at 12-month. Anthropometry assessment and lifestyle questionnaire were performed at various timepoints. RESULTS: A total of 103 women were randomized at baseline and a total of 79 women (standard care, n = 39, intervention, n = 40) completed the assessment. After the 12-month study period, women in the intervention group had significantly lower energy intake (intervention, -497.6 ± 488.3 kcal; standard, -222.0 ± 390.0 kcal, P < 0.01) compared to the standard care group, and a trend towards greater weight reduction (intervention, -0.93 ± 4.68 kg; standard, -0.01 ± 3.12 kg, P = 0.36). CONCLUSION: The lifestyle intervention implemented within 3 months postpartum appeared to promote postpartum weight loss. The early postnatal lifestyle intervention program may provide an opportunity to reduce the long-term risk of diabetes in this high-risk population.

Gestational age-specific reference intervals for androgens in pregnancy.

BACKGROUND: Androgen could impact cervical remodelling during pregnancy, and a higher level is associated with adverse pregnancy outcomes. A population-based gestation age-specific reference interval (RI) of total testosterone (TT), androstenedione (A4), and 17-hydroxyprogesterone (17-OHP) can help to diagnose maternal hyperandrogenism. METHODS: We enrolled 600 healthy Chinese women to obtain longitudinal serum samples across gestation. The serum androgen profile was measured by liquid chromatography-tandem mass spectrometry. The equations for medians of TT, A4, and 17-OHP were generated by MedCal, and the variances adjusted for 2-level modeling were generated by MLwiN, a system for the specification and analysis of a range of multilevel models. RESULTS: A4 and TT levels increased across the gestation, and they closely correlated with each other (R = 0.90, P=<0.001), whereas 17-OHP level decreased from 5th gestational week to 16th gestational week and then increased afterward towards the end of pregnancy. Women diagnosed with preeclampsia (PE) were found to have a significantly higher level of A4, TT, and 17-OHP when compared with non-PE cases with p ≤0.01, whereas mothers carrying male versus female fetuses have comparable levels of A4, TT, and 17-OHP. CONCLUSION: The study highlights a methodology for constructing gestational age-specific TT, A4, and 17-OHP levels to provide a better interpretation of results in a cohort of healthy Chinese women. The observation in PE supports previous findings, and the higher levels of TT, A4, and 17-OHP were observed before the onset of PE.

Epidemic-specific association of maternal exposure to per- and polyfluoroalkyl substances (PFAS) and their components with maternal glucose metabolism: A cross-sectional analysis in a birth cohort from Hong Kong.

Per- and polyfluoroalkyl substances (PFAS) are persistent chemicals that have been linked to increased risk of gestational diabetes mellitus (GDM) and may affect glucose metabolisms during pregnancy. We examined the associations between maternal PFAS exposure and maternal glucose metabolisms and GDM risk among 1601 mothers who joined the Hyperglycaemia-and-Adverse-Pregnancy-Outcome (HAPO) Study in Hong Kong in 2001-2006. All mothers underwent a 75 g-oral-glucose-tolerance test at 24-32 weeks of gestation. We measured serum concentrations of six PFAS biomarkers using high-performance liquid-chromatography-coupled-with-tandem-mass-spectrometry (LC-MS-MS). We fitted conventional and advanced models (quantile-g-computation [qgcomp] and Bayesian-kernel machine regression [BKMR]) to assess the associations of individual and a mixture of PFAS with glycaemic traits. Subgroup analyses were performed based on the enrollment period by the severe-acute-respiratory-syndrome (SARS) epidemic periods in Hong Kong between March 2003 and May 2004. PFOS and PFOA were the main components of PFAS mixture among 1601 pregnant women in the Hong Kong HAPO study, with significantly higher median PFOS concentrations (19.09 ng/mL), compared to Chinese pregnant women (9.40 ng/mL) and US women (5.27 ng/mL). Maternal exposure to PFAS mixture was associated with higher HbA1c in the qgcomp (ß = 0.04, 95 % CI: 0.01-0.06) model. We did not observe significant associations of PFAS mixture with fasting plasma glucose (PG), 1-h and 2-h PG in either model, except for 2-h PG in the qgcmop model (ß = 0.074, 95 % CI: 0.01-0.15). PFOS was the primary contributor to the overall positive effects on HbA1c. Epidemic-specific analyses showed specific associations between PFAS exposure and the odds of GDM in the pre-SARS epidemic period. The median concentration of PFOS was highest during the peri-SARS epidemic (21.2 [14.5-43.6] ng/mL) compared with the pre-SARS (12.3 [9.2-19.9] ng/mL) and post-SARS (20.3 [14.2-46.3] ng/mL) epidemic periods. Potential interactions and exposure-response relationships between PFOA and PFNA with elevated HbA1c were observed in the peri-SARS period in BKMR model. Maternal exposure to PFAS mixture was associated with altered glucose metabolism during pregnancy. SARS epidemic-specific associations call for further studies on its long-term adverse health effects, especially potential modified associations by lifestyle changes during the COVID-19 pandemic.

Health impacts of new-onset diabetes in women post-gestational diabetes mellitus: Insights from Hong Kong's territory-wide data.

AIMS/INTRODUCTION: To determine the population health burden attributable to the development of diabetes among women with a history of gestational diabetes mellitus (GDM). MATERIALS AND METHODS: We conducted a retrospective analysis of women with a history of GDM attending the Hong Kong Hospital Authority between 2000 and 2019. The time-varying population attributable fraction was calculated. RESULTS: A total of 76,181 women with a history of gestational diabetes mellitus were included, 6,606 of them developed diabetes during a median follow-up of 8.6 years. The respective hazard ratios (95% confidence interval) among women with GDM who developed diabetes vs those with GDM only were 2.8 (2.2, 3.7) for cardiovascular disease (CVD), 4.8 (3.0, 7.7) for end-stage kidney disease (ESKD), 2.2 (1.9, 2.6) for infection-related hospitalization, and 1.8 (1.3, 2.4) for all-cause mortality. The development of diabetes was associated with 1.3 (0.8, 1.7), 0.6 (0.3, 0.8), 3.2 (2.4, 4.0), and 0.5 (0.2, 0.9) additional incident cases per 1,000 person-years, accounting for 24.0% (13.2%, 35.9%), 42.0% (22.5%, 58.8%), 10.8% (7.1%, 14.9%), and 6.0% (-3.1%, 16.1%) of absolute number of CVD, ESKD, infection-related hospitalization, and all-cause mortality over 20 years after GDM, respectively. CONCLUSIONS: Diabetes is a significant contributor to the population health burden of some clinical outcomes in women with a history of gestational diabetes mellitus, but other risk factors need to be considered.