Secular trend for increasing birthweight in offspring of pregnant women with type 1 diabetes: is improved placentation the reason?

Despite enormous progress in managing blood glucose levels, pregnancy in women with type 1 diabetes still carries risks for the growing fetus. While, previously, fetal undergrowth was not uncommon in these women, with improved maternal glycaemic control we now see an increased prevalence of fetal overgrowth. Besides short-term implications, offspring of women with type 1 diabetes are more likely to become obese and to develop diabetes and features of the metabolic syndrome. Here, we argue that the increase in birthweight is paradoxically related to improved glycaemic control in the pre- and periconceptional periods. Good glycaemic control reduces the prevalence of microangiopathy and improves placentation in early pregnancy, which may lead to unimpeded fetal nutrition. Even mild maternal hyperglycaemia may then later result in fetal overnutrition. This notion is supported by circumstantial evidence that lower HbA1c levels as well as increases in markers of placental size and function in early pregnancy are associated with large-for-gestational age neonates. We also emphasise that neonates with normal birthweight can have excessive fat deposition. This may occur when poor placentation leads to initial fetal undergrowth, followed by fetal overnutrition due to maternal hyperglycaemia. Thus, the complex interaction of glucose levels during different periods of pregnancy ultimately determines the risk of adiposity, which can occur in fetuses with both normal and elevated birthweight. Prevention of fetal adiposity calls for revised goal setting to enable pregnant women to maintain blood glucose levels that are closer to normal. This could be supported by continuous glucose monitoring throughout pregnancy and appropriate maternal gestational weight gain. Future research should consider the measurement of adiposity in neonates.

Ultrasonographic Assessment of Body Fat Index for Prediction of Gestational Diabetes Mellitus and Neonatal Complications.

OBJECTIVES: To assess maternal pre-peritoneal fat and subcutaneous fat at 16-20 weeks gestation by ultrasound. Thus, calculate body fat index (BFI) and determine its cut-off value for prediction of gestational diabetes mellitus (GDM) and neonatal subcutaneous adiposity. METHODS: A cohort study was conducted in 200 pregnant women with singleton fetus during anomaly scan using BFI where they were screened for GDM at 24-28 weeks gestation by oral glucose tolerance test. Labour and neonatal outcomes were recorded. The receiver operating characteristic curve was used to determine the cut-offs for BFI, pre-peritoneal fat thickness, and subcutaneous fat thickness in order to predict GDM. RESULTS: The area under receiver operating characteristic curve for BFI was 0.967 (95% CI 0.932-0.987) with a sensitivity of 97.3%, specificity of 89.57%, negative predictive value of 99.3%, and diagnostic accuracy of 91% at a BFI cut-off of 0.88. The study analysis demonstrated BFI to be statistically superior to BMI > 22.9 kg/m2 for prediction of GDM. BFI > 0.88 was a risk factor for developing neonatal subcutaneous adiposity. CONCLUSIONS: BFI is a practical and convenient non-invasive screening tool to predict GDM and neonatal subcutaneous adiposity.

Metabolomic signatures of low- and high-adiposity neonates differ based on maternal BMI.

Maternal obesity [body mass index (BMI) > 30 kg/m2] is associated with greater neonatal adiposity, cord blood (CB) insulin levels, and a proinflammatory phenotype at birth, contributing to risk of future cardiometabolic disease in the offspring. Variation in neonatal adiposity within maternal BMI groups is underappreciated, and it remains unclear whether the metabolic impairments at birth are an outcome of maternal obesity or excess fetal fat accrual. We examined the hypothesis that CB metabolites associated with fetal fat accrual differ between offspring of normal-weight and obese women. Umbilical venous blood was collected at the time of scheduled cesarean delivery from 50 normal-weight women (LE; pregravid BMI = 22.3 ± 1.7 kg/m2) and 50 obese women (OB; BMI = 34.5 ± 3.0 kg/m2). Neonatal adiposity was estimated from flank skinfold thickness. The first (low adiposity, LA) and third (high adiposity, HA) tertiles of neonatal %body fat were used to create four groups: OBLA, OBHA, LELA, and LEHA. CB metabolites were measured via untargeted metabolomics. Broadly, the LA offspring of OB women (OBLA) metabolite signature differed from other groups. Lauric acid (C12:0) was 82-118% higher in OBLA vs. all other groups [false discovery rate (FDR) < 0.01]. Several other fatty acids, including palmitate, stearate, and linoleate, were higher in OBLA vs. OBHA groups. CB metabolites, such as lauric acid, a medium-chain fatty acid that may improve insulin sensitivity, were associated with neonatal adiposity differently between offspring of women with and without obesity. Changes in metabolically active lipids at birth may have long-term consequences for offspring metabolism.NEW & NOTEWORTHY Using untargeted metabolomics in 100 newborns, we found that cord blood metabolite signatures associated with neonatal adiposity differed between offspring of women with and without obesity.

Percent Body Fat Content Measured by Plethysmography in Infants Randomized to High- or Usual-Volume Feeding after Very Preterm Birth.

We measured percent body fat by air-displacement plethysmography in 86 infants born at <32 weeks of gestation randomized to receive either high-volume (180-200 mL/kg/day) or usual volume feeding (140-160 mL/kg/day). High-volume feeding increased percent body fat by ≤2% at 36 weeks of postmenstrual age (within a predefined range of equivalence). TRIAL REGISTRATION: ClincialTrials.gov: NCT02377050.

Prediction of Birth Weight and Neonatal Adiposity Using Ultrasound Assessment of Soft Tissue Parameters in Addition to Two-Dimensional Conventional Biometry.

INTRODUCTION: We aim to evaluate the supplementary predictive value of soft tissue markers, including fetal limb volumes, for fetal birth weight and fat tissue weight. METHODS: This is a prospective study of 60 patients undergoing term induction of labor. Ultrasound was performed 48 h before birth, and 2D sonographic measurements, subcutaneous tissue thickness, and 3D fetal limb volumes were taken. Birth weight and neonatal fat weight were assessed by plethysmography. Clinical data were collected. The relation between ultrasound and neonatal outcomes was assessed by univariate and multivariate predictive models. The estimated and actual birth weights were compared applying different published formulas, and systematic and random error were collected and compared. RESULTS: 3D fetal limb volumes showed a strong relation to birth weight, absolute weight, and relative fat weight. The Lee 6 formula performed better than either Hadlock 3 or Lee 3 with the lowest random error. Fractional limb volumes involve a highly reproducible technique, with excellent correlation (intra-class coefficient >0.90) for both inter- and intra-observer reliability. The prevalence of estimated EFW measures within 10% error from the actual birth weight was 71.7% with the Hadlock 3 model and 95.0% with the Lee 6 model (p = 0.09). CONCLUSION: Late assessment of 3D fetal limb volume in upper and lower extremities is not only useful for accurately predicting birth weight but is a useful marker for prediction of birth fat tissue weight.

Cord blood metabolic markers are strong mediators of the effect of maternal adiposity on fetal growth in pregnancies across the glucose tolerance spectrum: the PANDORA study.

AIMS/HYPOTHESIS: We aimed to assess associations between cord blood metabolic markers and fetal overgrowth, and whether cord markers mediated the impact of maternal adiposity on neonatal anthropometric outcomes among children born to Indigenous and Non-Indigenous Australian women with normal glucose tolerance (NGT), gestational diabetes mellitus (GDM) and pregestational type 2 diabetes mellitus. METHODS: From the Pregnancy and Neonatal Outcomes in Remote Australia (PANDORA) study, an observational cohort of 1135 mother-baby pairs, venous cord blood was available for 645 singleton babies (49% Indigenous Australian) of women with NGT (n = 129), GDM (n = 419) and type 2 diabetes (n = 97). Cord glucose, triacylglycerol, HDL-cholesterol, C-reactive protein (CRP) and C-peptide were measured. Multivariable logistic and linear regression were used to assess the associations between cord blood metabolic markers and the outcomes of birthweight z score, sum of skinfold thickness (SSF), being large for gestational age (LGA) and percentage of body fat. Pathway analysis assessed whether cord markers mediated the associations between maternal and neonatal adiposity. RESULTS: Elevated cord C-peptide was significantly associated with increasing birthweight z score (ß 0.57 [95% CI 0.42, 0.71]), SSF (ß 0.83 [95% CI 0.41, 1.25]), percentage of body fat (ß 1.20 [95% CI 0.69, 1.71]) and risk for LGA [OR 3.14 [95% CI 2.11, 4.68]), after adjusting for age, ethnicity and diabetes type. Cord triacylglycerol was negatively associated with birthweight z score for Indigenous Australian women only. No associations between cord glucose, HDL-cholesterol and CRP >0.3 mg/l (2.9 nmol/l) with neonatal outcomes were observed. C-peptide mediated 18% (95% CI 13, 36) of the association of maternal BMI with LGA and 11% (95% CI 8, 17) of the association with per cent neonatal fat. CONCLUSIONS/INTERPRETATION: Cord blood C-peptide is an important mediator of the association between maternal and infant adiposity, across the spectrum of maternal glucose tolerance.

Maternal lipids are associated with newborn adiposity, independent of GDM status, obesity and insulin resistance: a prospective observational cohort study.

OBJECTIVE: To determine the association between maternal lipaemia and neonatal anthropometrics in Malaysian mother-offspring pairs. DESIGN: Prospective observational cohort study. SETTING: Single tertiary multidisciplinary antenatal clinic in Malaysia. POPULATION: A total of 507 mothers: 145 with gestational diabetes mellitus (GDM); 94 who were obese with normal glucose tolerance (NGT) (pre-gravid body mass index, BMI ≥ 27.5 kg/m2 ), and 268 who were not obese with NGT. METHODS: Maternal demographic, anthropometric, and clinical data were collected during an interview/examination using a structured questionnaire. Blood was drawn for insulin, C-peptide, triglyceride (Tg), and non-esterified fatty acid (NEFA) during the 75-g 2-hour oral glucose tolerance test (OGTT) screening, and again at 36 weeks of gestation. At birth, neonatal anthropometrics were assessed and data such as gestational weight gain (GWG) were extracted from the records. MAIN OUTCOME MEASURES: Macrosomia, large-for-gestational-age (LGA) status, cohort-specific birthweight (BW), neonatal fat mass (NFM), and sum of skinfold thickness (SSFT) > 90th centile. RESULTS: Fasting Tg > 95th centile (3.6 mmol/L) at screening for OGTT was independently associated with LGA (adjusted odds ratio, aOR 10.82, 95% CI 1.26-93.37) after adjustment for maternal glucose, pre-gravid BMI, and insulin sensitivity. Fasting glucose was independently associated with a birthweight ratio (BWR) of >90th centile (aOR 2.06, 95% CI 1.17-3.64), but not with LGA status, in this well-treated GDM cohort with pre-delivery HbA1c of 5.27%. In all, 45% of mothers had a pre-gravid BMI of <23 kg/m2 and 61% had a pre-gravid BMI of ≤ 25 kg/m2 , yet a GWG of >10 kg was associated with a 4.25-fold risk (95% CI 1.71-10.53) of BWR > 90th centile. CONCLUSION: Maternal lipaemia and GWG at a low threshold (>10 kg) adversely impact neonatal adiposity in Asian offspring, independent of glucose, insulin resistance and pre-gravid BMI. These may therefore be important modifiable metabolic targets in pregnancy. TWEETABLE ABSTRACT: Maternal lipids are associated with adiposity in Asian babies independently of pre-gravid BMI, GDM status, and insulin resistance.

A reduction in sedentary behaviour in obese women during pregnancy reduces neonatal adiposity: the DALI randomised controlled trial.

AIMS/HYPOTHESIS: Offspring of obese women are at increased risk of features of the metabolic syndrome, including obesity and diabetes. Lifestyle intervention in pregnancy might reduce adverse effects of maternal obesity on neonatal adiposity. METHODS: In the Vitamin D And Lifestyle Intervention for Gestational Diabetes Mellitus (GDM) Prevention (DALI) lifestyle trial, 436 women with a BMI ≥29 kg/m2 were randomly assigned to counselling on healthy eating (HE), physical activity (PA) or HE&PA, or to usual care (UC). In secondary analyses of the lifestyle trial, intervention effects on neonatal outcomes (head, abdominal, arm and leg circumferences and skinfold thicknesses, estimated fat mass, fat percentage, fat-free mass and cord blood leptin) were assessed using multilevel regression analyses. Mediation of intervention effects by lifestyle and gestational weight gain was assessed. RESULTS: Outcomes were available from 334 neonates. A reduction in sum of skinfolds (-1.8 mm; 95% CI -3.5, -0.2; p = 0.03), fat mass (-63 g; 95% CI -124, -2; p = 0.04), fat percentage (-1.2%; 95% CI -2.4%, -0.04%; p = 0.04) and leptin (-3.80 µg/l; 95% CI -7.15, -0.45; p = 0.03) was found in the HE&PA group, and reduced leptin in female neonates in the PA group (-5.79 µg/l; 95% CI -11.43, -0.14; p = 0.05) compared with UC. Reduced sedentary time, but not gestational weight gain, mediated intervention effects on leptin in both the HE&PA and PA groups. CONCLUSIONS/INTERPRETATION: The HE&PA intervention resulted in reduced adiposity in neonates. Reduced sedentary time seemed to drive the intervention effect on cord blood leptin. Implications for future adiposity and diabetes risk of the offspring need to be elucidated. TRIAL REGISTRATION: ISRCTN70595832.

Fat mass estimation in neonates: anthropometric models compared with air displacement plethysmography.

Newborn adiposity, a nutritional measure of the maternal-fetal intra-uterine environment, is representative of future metabolic health. An anthropometric model using weight, length and flank skinfold to estimate neonatal fat mass has been used in numerous epidemiological studies. Air displacement plethysmography (ADP), a non-invasive technology to measure body composition, is impractical for large epidemiological studies. The study objective was to determine the consistency of the original anthropometric fat mass estimation equation with ADP. Full-term neonates were studied at 12-72 h of life with weight, length, head circumference, flank skinfold thickness and ADP measurements. Statistical analyses evaluated three models to predict neonatal fat mass. Lin's concordance correlation coefficient, mean prediction error and root mean squared error between the predicted and observed ADP fat mass values were used to evaluate the models, where ADP was considered the gold standard. A multi-ethnic cohort of 468 neonates were studied. Models (M) for predicting fat mass were developed using 349 neonates from site 1, then independently evaluated in 119 neonates from site 2. M0 was the original anthropometric model, M1 used the same variables as M0 but with updated parameters and M2 additionally included head circumference. In the independent validation cohort, Lin's concordance correlation estimates demonstrated reasonable accuracy (model 0: 0·843, 1: 0·732, 2: 0·747). Mean prediction error and root mean squared error in the independent validation was much smaller for M0 compared with M1 and M2. The original anthropometric model to estimate neonatal fat mass is reasonable for predicting ADP, thus we advocate its continued use in epidemiological studies.

Maternal traditional dietary pattern and antiretroviral treatment exposure are associated with neonatal size and adiposity in urban, black South Africans.

This study examines the associations between maternal Traditional dietary pattern adherence and HIV/treatment with neonatal size and adiposity in urban, black South Africans, as well as how specific maternal factors - that is BMI and gestational weight gain (GWG) - may influence these associations. Multiple linear regression models were used to examine associations among maternal Traditional diet pattern adherence (pattern score), HIV/treatment status (three groups: HIV negative, HIV positive (antenatal antiretroviral treatment (ART) initiation), HIV positive (pre-pregnancy ART initiation)), BMI and GWG (kg/week), and newborn (1) weight:length ratio (WLR, kg/m) in 393 mother-neonate pairs, and (2) Peapod estimated fat mass index (FMI, kg/m3) in a 171-pair subsample. In fully adjusted models, maternal obesity and GWG were associated with 0·25 kg/m (P=0·008) and 0·48 kg/m (P=0·002) higher newborn WLR, whereas Traditional diet pattern score was associated with lower newborn WLR (-0·04 kg/m per +1 sd; P=0·033). In addition, Traditional diet pattern score was associated with 0·13 kg/m3 (P=0·027) and 0·32 kg/m3 (P=0·005) lower FMI in the total sample and in newborns of normal-weight women, respectively. HIV-positive (pre-pregnancy ART) v. HIV-negative (ref) status was associated with 1·11 kg/m3 (P=0·002) higher newborn FMI. Promotion of a Traditional dietary pattern, alongside a healthy maternal pre-conception weight, in South African women may reduce newborn adiposity and metabolic risk profiles. In HIV-positive women, targeted monitoring and management strategies are necessary to limit treatment-associated effects on in utero fat deposition.

Comparison of 2- and 3-Dimensional Sonography for Estimation of Birth Weight and Neonatal Adiposity in the Setting of Suspected Fetal Macrosomia.

OBJECTIVES: To compare the accuracy of 2-dimensional (2D) and 3-dimensional (3D) fetal measurements for prediction of birth weight Z score and neonatal adiposity (percent body fat) in the setting of suspected fetal macrosomia. METHODS: We conducted a prospective observational study of term singleton pregnancies with suspected macrosomia. Patients were enrolled on admission to labor and delivery and underwent sonographic examinations. Within 48 hours of delivery, neonatal anthropometric measurements were obtained. RESULTS: Thirty-four neonates were included in the analysis. Mothers were very obese (mean body mass index ± SD, 39.1 ± 7.8 kg/m(2)); 56.5% were white; and 39.1% had diabetes. Neonates were 38% female and had a mean birth weight of 3940.0 ± 496.8 g, percent body fat of 18.5% ± 4.0%, and Ponderal index of 2.8 ± 0.3 g/cm(3). Mean 2D estimated fetal weight was 3973 ± 443 g; mean 3D estimated fetal weight was 3803 ± 528 g; and mean thigh volume was 102.5 ± 19.6 cm(3). Both 2D and 3D measurements accounted for about half the variance in predicted birth weight (R(2) for 2D = 0.53, 71% within 10% of birth weight; R(2) for 3D = 0.47, 65% within 10% of birth weight). Thigh volume Z score was the prenatal parameter most highly correlated with both birth weight Z score (R(2) = 0.52; r = 0.72; 95% confidence interval, 0.54-0.84; P < .001) and percent body fat (R(2) = 0.22; r = 0.47; 95% confidence interval, 0.17-0.69; P = .04). CONCLUSIONS: In our population of fetuses with suspected macrosomia, fractional thigh volume was the best sonographic estimate of neonatal percent body fat and birth weight Z score. Future research on prediction of neonatal weight and adiposity in macrosomic fetuses should include an estimate of fetal soft tissue given the generalized increase in body fat of these fetuses.

Neonatal adiposity is associated with microRNAs in adipocyte-derived extracellular vesicles in maternal and cord blood.

Background: Maternal body size, nutrition, and hyperglycemia contribute to neonatal body size and composition. There is little information on maternal-fetal transmission of messages which influence fetal growth. We analyzed adipocyte-derived small extracellular vesicular (ADsEV) microRNAs in maternal and cord blood to explore their adipogenic potential. Methods: We studied 127 mother-neonate pairs (51 lean and 76 adipose neonates, in 68 NGT and 59 GDM pregnancies). Adiposity refers to the highest tertile (T3) of sum of skinfolds in neonates of normal glucose tolerant (NGT) mothers, lean to the to lowest tertile (T1). ADsEV miRNAs from maternal and cord blood samples were profiled on Agilent 8*60K microarray. Differential expression (DE) of ADsEV miRNAs in adipose vs. lean neonates was studied before and after adjustment for maternal gestational diabetes mellitus (GDM), adiposity, and vitamin B12-folate status. Results: Multiple miRNAs were common in maternal and cord blood and positively correlated. We identified 24 maternal and 5 cord blood miRNAs differentially expressed (p ≤ 0.1) in the adipose neonate group, and 19 and 26 respectively, in the adjusted analyses. Even though DE miRNAs were different in maternal and cord blood, they targeted similar adipogenic pathways (e.g., the forkhead box O (FOXO) family of transcription factors, mitogen-activated protein kinase (MAPK) pathway, transforming growth factor beta (TGF-ß) pathway). Maternal GDM and adiposity were associated with many DE ADsEV miRNAs. Conclusion: Our results suggest that the ADsEV miRNAs in mothers are potential regulators of fetal adiposity. The expression and functionality of miRNAs appears to be influenced by maternal adiposity, hyperglycemia, and micronutrient status during pregnancy.

Physical Activity during Pregnancy and Newborn Body Composition: A Systematic Review.

The current literature demonstrates that not only is exercise during pregnancy safe, but it has substantial maternal and infant benefits and appears to influence infant growth/size throughout pregnancy and at birth. However, many existing studies have investigated only the effects of prenatal exercise on birth weight. The purpose of this review was to determine the impact or association of maternal physical activity during pregnancy on neonatal body composition assessed between birth and two weeks of age. Electronic database searches were conducted on 29 July 2019 for randomized control trials and cohort studies, with an updated search completed on 8 January 2021. A total of 32 articles that met eligibility criteria were selected for review. Overall, prenatal exercise was not associated with infant body composition at birth. Yet, five of the studies identified suggest that infant body composition could be influenced by higher volumes of mid-to-late term prenatal physical activity. This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and registered in PROSPERO (Registration No. CRD42020160138).

Maternal Lipid Metabolism Is Associated With Neonatal Adiposity: A Longitudinal Study.

CONTEXT: Pregnancy is characterized by progressive decreases in glucose insulin sensitivity. Low insulin sensitivity resulting in hyperglycemia is associated with higher neonatal adiposity. However, less is known regarding lipid metabolism, particularly lipid insulin sensitivity in pregnancy and neonatal adiposity. OBJECTIVE: Because higher maternal prepregnancy body mass index is strongly associated with both hyperlipidemia and neonatal adiposity, we aimed to examine the longitudinal changes in basal and clamp maternal lipid metabolism as contributors to neonatal adiposity. METHODS: Twelve women planning a pregnancy were evaluated before pregnancy, in early (12-14 weeks), and late (34-36 weeks) gestation. Body composition was estimated using hydrodensitometry. Basal and hyperinsulinemic-euglycemic clamp glucose and glycerol turnover (GLYTO) were measured using 2H2-glucose and 2H5-glycerol and substrate oxidative/nonoxidative metabolism with indirect calorimetry. Total body electrical conductivity was used to estimate neonatal body composition. RESULTS: Basal free-fatty acids decreased with advancing gestation (P = 0.0210); however, basal GLYTO and nonoxidative lipid metabolism increased over time (P = 0.0046 and P = 0.0052, respectively). Further, clamp GLYTO and lipid oxidation increased longitudinally over time (P = 0.0004 and P = 0.0238, respectively). There was a median 50% increase and significant positive correlation during both basal and clamp GLYTO from prepregnancy through late gestation. Neonatal adiposity correlated with late pregnancy basal and clamp GLYTO (r = 0.6515, P = 0.0217; and r = 0.6051, P = 0.0371). CONCLUSIONS: Maternal prepregnancy and late pregnancy measures of basal and clamp lipid metabolism are highly correlated. Late pregnancy basal and clamp GLYTO are significantly associated with neonatal adiposity and account for ~40% of the variance in neonatal adiposity. These data emphasize the importance of maternal lipid metabolism relating to fetal fat accrual.

Prenatal exposure to tobacco and adverse birth outcomes: effect modification by folate intake during pregnancy.

BACKGROUND: Fetal exposure to tobacco increases the risk for many adverse birth outcomes, but whether diet mitigates these risks has yet to be explored. Here, we examined whether maternal folate intake (from foods and supplements) during pregnancy modified the association between prenatal exposure to tobacco and with preterm delivery, small-for-gestational age (SGA) births, or neonatal adiposity. METHODS: Mother-child pairs (n = 701) from Healthy Start were included in this analysis. Urinary cotinine was measured at ~ 27 weeks gestation. Diet was assessed using repeated 24-h dietary recalls. Neonatal adiposity (fat mass percentage) was measured via air displacement plethysmography. Interaction was assessed by including a product term between cotinine (< / ≥ limit of detection [LOD]) and folate (< / ≥ 25th percentile [1077 µg/day]) in separate logistic or linear regression models, adjusting for maternal age, race, ethnicity, education, pre-pregnancy body mass index, and infant sex. RESULTS: Approximately 26% of women had detectable levels of cotinine. Folate intake was significantly lower among women with cotinine ≥ LOD as compared to those with cotinine < LOD (1293 µg/day vs. 1418 µg/day; p = 0.01). Folate modified the association between fetal exposure to tobacco with neonatal adiposity (p for interaction = 0.07) and SGA (p for interaction = 0.07). Among those with lower folate intake, fetal exposure to tobacco was associated with lower neonatal adiposity (mean difference: -2.09%; 95% CI: -3.44, -0.74) and increased SGA risk (OR: 4.99; 95% CI: 1.55, 16.14). Conversely, among those with higher folate intake, there was no difference in neonatal adiposity (mean difference: -0.17%; 95% CI: -1.13, 0.79) or SGA risk (OR: 1.15; 95% CI: 0.57, 2.31). CONCLUSIONS: Increased folate intake during pregnancy (from foods and/or supplements) may mitigate the risk of fetal growth restriction among those who are unable to quit smoking or cannot avoid secondhand smoke during pregnancy.

Predictors of neonatal adiposity and associations by fetal sex in women with gestational diabetes mellitus and normal glucose-tolerant women.

AIMS: To determine predictors of neonatal adiposity and differences in associations by fetal sex in women with gestational diabetes mellitus (GDM), normal-weight and overweight (BMI ≥ 25 kg/m2) normal glucose-tolerant women (NGT). METHODS: Skinfold thickness was measured in 576 newborns, and cord blood leptin, c-peptide and lipids in 327 newborns in a multi-centric prospective cohort study. RESULTS: Compared to neonates of normal-weight NGT women (327), neonates of women with GDM (97) were more often large-for-gestational age (LGA) (16.5% vs 8.6%, p = 0.024) ,but the macrosomia rate (8.2% vs 5.8%, p = 0.388), sum of skinfolds (13.9 mm ± 2.9 vs 13.3 mm ± 2.6, p = 0.067), neonatal fat mass (1333.0 g ± 166.8 vs 1307.3 g ± 160.9, p = 0.356), and cord blood biomarkers were not significantly different. Compared to neonates of normal-weight NGT women, neonates of overweight NGT women (152) had higher rates of macrosomia (12.5% vs 5.8%, p = 0.012), LGA (17.1% vs 8.6%, p = 0.006), higher sum of skinfolds (14.3 mm ± 2.6 vs 13.2 mm ± 2.6, p < 0.001), neonatal fat mass (1386.0 g ± 168.6 vs 1307.3 g ± 160.9, p < 0.001), % neonatal fat mass > 90th percentile (15.2% vs 7.1%, p < 0.001), without significant differences in cord blood biomarkers. Maternal BMI, fasting glycemia, triglycerides, gestational weight gain, cord blood leptin ,and cord blood triglycerides were independent predictors for neonatal adiposity. Gestational weight gain was positively associated with adiposity in boys only. CONCLUSION: Compared to neonates of normal-weight NGT women, neonates of GDM women have higher LGA rates but similar adiposity, while neonates of overweight NGT women have increased adiposity. Limiting gestational weight gain might be especially important in the male fetus to reduce neonatal adiposity.

The angiogenic properties of human amniotic membrane stem cells are enhanced in gestational diabetes and associate with fetal adiposity.

BACKGROUND: An environment of gestational diabetes mellitus (GDM) can modify the phenotype of stem cell populations differentially according to their placental localization, which can be useful to study the consequences for the fetus. We sought to explore the effect of intrauterine GDM exposure on the angiogenic properties of human amniotic membrane stem cells (hAMSCs). METHODS: We comprehensively characterized the angiogenic phenotype of hAMSCs isolated from 14 patients with GDM and 14 controls with normal glucose tolerance (NGT). Maternal and fetal parameters were also recorded. Hyperglycemia, hyperinsulinemia and palmitic acid were used to in vitro mimic a GDM-like pathology. Pharmacological and genetic inhibition of protein function was used to investigate the molecular pathways underlying the angiogenic properties of hAMSCs isolated from women with GDM. RESULTS: Capillary tube formation assays revealed that GDM-hAMSCs produced a significantly higher number of nodes (P = 0.004), junctions (P = 0.002) and meshes (P < 0.001) than equivalent NGT-hAMSCs, concomitant with an increase in the gene/protein expression of FGFR2, TGFBR1, SERPINE1 and VEGFA. These latter changes were recapitulated in NGT-hAMSCs exposed to GDM-like conditions. Inhibition of the protein product of SERPINE1 (plasminogen activator inhibitor 1, PAI-1) suppressed the angiogenic properties of GDM-hAMSCs. Correlation analyses revealed that cord blood insulin levels in offspring strongly correlated with the number of nodes (r = 0.860; P = 0.001), junctions (r = 0.853; P = 0.002) and meshes (r = 0.816; P = 0.004) in tube formation assays. Finally, FGFR2 levels correlated positively with placental weight (r = 0.586; P = 0.028) and neonatal adiposity (r = 0.496; P = 0.014). CONCLUSIONS: GDM exposure contributes to the angiogenic abilities of hAMSCs, which are further related to increased cord blood insulin and fetal adiposity. PAI-1 emerges as a potential key player of GDM-induced angiogenesis.

Optimal gestational weight gain for Chinese women - analysis from a longitudinal cohort with childhood follow-up.

BACKGROUND: Maternal gestational weight gain (GWG) influences not only on pregnancy outcome but also impacts on mothers' and children's long-term health. However, there is no consensus on recommendations of optimal GWG in Asians or the Chinese population. METHODS: We performed a secondary analysis of the birth outcome of Chinese women who had joined the "Hyperglycemia and Adverse Pregnancy Outcome" study in Hong Kong and their children's cardiometabolic risk at 7-year of age. Optimal ranges of GWG were derived from models based on the probabilities of small for gestational age and large for gestational age (model 1), lean and fat infants (model 2) and the integration of model 1 and 2 (model 3), and were compared with that recommended by the Institute of Medicine (IOM) on children's cardiometabolic risk. FINDINGS: GWG range derived from model 2 is associated with 8 cardiometabolic risk factors, while that from models 1 and 3 are associated with 1 and 7 of them respectively. Mothers whose GWG lie within the recommended range increases from 40.8% according to the IOM recommendation to 50.2% according to that derived from model 2. INTERPRETATION: Optimal GWG derived from model 2 (i.e. 14.0-18.5 kg, 9.0-16.5 kg and 5.0-11.0 kg for underweight, normal weight and overweight Chinese women, respectively) appeared to be associated with the lowest cardiometabolic risk in the offspring. FUNDING: General Research Fund of the Research Grants Council of the Hong Kong SAR, China (grants CUHK 473408 and, in part, CUHK 471713).

Social and economic factors, maternal behaviours in pregnancy and neonatal adiposity in the PANDORA cohort.

BACKGROUND: Australian Indigenous women experience high rates of social disadvantage and type 2 diabetes (T2D) in pregnancy, but it is not known how social factors and maternal behaviours impact neonatal adiposity in offspring of women with hyperglycaemia in pregnancy. METHODS: Participants were Indigenous (n = 404) and Europid (n = 240) women with gestational diabetes mellitus (GDM) or T2D in pregnancy and their offspring in the Pregnancy and Neonatal Diabetes Outcomes in Remote Australia (PANDORA) study. Social, economic factors, and maternal behaviours were measured in pregnancy and six neonatal anthropometric outcomes were examined after birth. RESULTS: On univariate analysis, maternal education < 12 years (p = 0.03), unemployment (p = 0.001), welfare income vs no welfare income (p = 0.001), lower area based socio-economic score (p < 0.001), and fast food intake > 2 times/week (p = 0.002) were associated with increased sum of skinfolds (SSF) in offspring. Smoking was significantly associated with a reduction in anthropometric measures, except SSF. In multivariable models adjusted for ethnicity, BMI and hyperglycaemia, social and economic factors were no longer significant predictors of neonatal outcomes. Smoking was independently associated with a reduction in length, head circumference and fat free mass. Frequent fast food intake remained independently associated with SSF (ß-coefficient 1.08 mm, p = 0.02). CONCLUSION: In women with hyperglycaemia in pregnancy, social factors were associated with neonatal adiposity, particularly skinfold measures. Promoting smoking cessation and limited intake of energy-dense, nutrient-poor foods in pregnancy are important to improve neonatal adiposity and lean mass outcomes. Addressing inequities in social and economic factors are likely to be important, particularly for Indigenous women or women experiencing social disadvantage.

Maternal pre-pregnancy BMI downregulates neonatal cord blood LEP methylation.

BACKGROUND: Neonatal adiposity has many determinants and may be a risk factor for future obesity. Epigenetic regulation of metabolically important genes is a potential contributor. OBJECTIVES: The objective of the study is to determine whether methylation changes in the LEP gene in cord blood DNA are impacted by the maternal environment or affect neonatal adiposity measures. METHODS: A cross-sectional study of 114 full-term neonates born to healthy mothers with normal glucose tolerance was performed. Cord blood was assayed for leptin and genome-wide DNA methylation profiles via the Illumina 450K platform. Neonatal body composition was measured by air displacement plethysmography. Multivariate linear regression models and semi-partial correlation coefficients were used to analyze associations. False discovery rate was estimated to account for multiple comparisons. RESULTS: Maternal pre-pregnancy BMI was associated with decreased methylation at five CpG sites near the LEP transcription start site in an adjusted model (false discovery rate <0.022 for each site). The association between maternal BMI and cord blood leptin approached significance (r = 0.18, p = 0.054). Cord blood leptin was positively correlated with neonatal adiposity measures including birth weight (r = 0.45, p < 0.001), fat mass (r = 0.47, p < 0.001) and percent body fat (r = 0.44, p < 0.001). CONCLUSIONS: Maternal pre-pregnancy BMI is strongly associated with decreased cord blood LEP gene methylation and may mediate the well-known association between maternal pre-pregnancy BMI and neonatal adiposity.