Association of GDF15 levels with body mass index and endocrine status in ß-thalassaemia.

OBJECTIVE: GDF15 has emerged as a stress-induced hormone, acting on the brain to reduce food intake and body weight while affecting neuroendocrine function. Very high GDF15 levels are found in thalassaemia, where growth, energy balance and neuroendocrine function are impaired. We examined the relationships between GDF15 and anthropometric measures and endocrine status in ß-thalassaemia. DESIGN: Cross sectional study. PATIENTS: All ß-thalassaemia patients attending the thalassaemia unit of Colombo North Teaching Hospital for blood transfusions. MEASUREMENTS: Anthropometric data, appetite scores, circulating GDF15, IGF, thyroid and reproductive hormone levels in 103 ß-thalassaemia patients were obtained. RESULTS: GDF15 levels were markedly elevated in thalassaemia patients (24.2-fold with ß-thalassaemia major compared with healthy controls). Among patients with ß-thalassaemia major, the relationship between GDF15 and body mass index (BMI) was curvilinear with all individuals with GDF15 levels above 24,000 pg/mL having a BMI below 20 kg/m2 . After adjustment for BMI, age and Tanner stage, serum IGF1 concentrations correlated negatively with GDF15 in all thalassaemia patients (ß = -.027, p = .02). We found a significant positive relationship between GDF15 and gonadotropin (in both sexes) and testosterone (in males). CONCLUSIONS: GDF15 levels were markedly elevated in patients with ß-thalassaemia and its association with BMI is consistent with the known effect of GDF15 to reduce body weight. The inverse association between GDF15 with IGF1 levels may reflect a neuroendocrine impact of GDF15 or an indirect effect via impaired nutritional state. The positive association with testosterone in males and gonadotropins in both sexes, was surprising and should prompt further GDF15 studies on the hypothalamic pituitary gonadal axis.

Associations between breast milk intake volume, macronutrient intake and infant growth in a longitudinal birth cohort: the Cambridge Baby Growth and Breastfeeding Study (CBGS-BF).

Growth patterns of breastfed infants show substantial inter-individual differences, partly influenced by breast milk (BM) nutritional composition. However, BM nutritional composition does not accurately indicate BM nutrient intakes. This study aimed to examine the associations between both BM intake volumes and macronutrient intakes with infant growth. Mother-infant dyads (n 94) were recruited into the Cambridge Baby Growth and Breastfeeding Study (CBGS-BF) from a single maternity hospital at birth; all infants received exclusive breast-feeding (EBF) for at least 6 weeks. Infant weight, length and skinfolds thicknesses (adiposity) were repeatedly measured from birth to 12 months. Post-feed BM samples were collected at 6 weeks to measure TAG (fat), lactose (carbohydrate) (both by 1H-NMR) and protein concentrations (Dumas method). BM intake volume was estimated from seventy infants between 4 and 6 weeks using dose-to-the-mother deuterium oxide (2H2O) turnover. In the full cohort and among sixty infants who received EBF for 3+ months, higher BM intake at 6 weeks was associated with initial faster growth between 0 and 6 weeks (ß + se 3·58 + 0·47 for weight and 4·53 + 0·6 for adiposity gains, both P < 0·0001) but subsequent slower growth between 3 and 12 months (ß + se - 2·27 + 0·7 for weight and -2·65 + 0·69 for adiposity gains, both P < 0·005). BM carbohydrate and protein intakes at 4-6 weeks were positively associated with early (0-6 weeks) but tended to be negatively related with later (3-12 months) adiposity gains, while BM fat intake showed no association, suggesting that carbohydrate and protein intakes may have more functional relevance to later infant growth and adiposity.

Methylation of the C19MC microRNA locus in the placenta: association with maternal and chilhood body size.

OBJECTIVES: To study DNA methylation at the C19MC locus in the placenta and its association with (1) parental body size, (2) transmission of haplotypes for the C19MC rs55765443 SNP, and (3) offspring's body size and/or body composition at birth and in childhood. SUBJECTS AND METHODS: Seventy-two pregnant women-infant pairs and 63 fathers were included in the study. Weight and height of mothers, fathers and newborns were registered during pregnancy or at birth (n = 72). Placental DNA methylation at the C19MC imprinting control region (ICR) was quantified by bisulfite pyrosequencing. Genotyping of the SNP was performed using restriction fragment length polymorphisms. The children's body size and composition were reassessed at age 6 years (n = 32). RESULTS: Lower levels of placental C19MC methylation were associated with increased body size of mother, specifically with higher pregestational and predelivery weights and height of the mother (ß from -0.294 to -0.371; R2 from 0.04 to 0.10 and all p < 0.019), and with higher weight, height, waist and hip circumferences, and fat mass of the child (ß from -0.428 to -0.552; R2 from 0.33 to 0.56 and all p < 0.009). Parental transmission of the SNP did not correlate with an altered placental methylation status at the C19MC ICR. CONCLUSIONS: Increased maternal size is associated with reduced placental C19MC methylation, which, in turn, relate to larger body size of the child.

Reduced size at birth and persisting reductions in adiposity in recent, compared with earlier, cohorts of infants born to mothers with gestational diabetes mellitus.

AIMS/HYPOTHESIS: This study aimed to explore the infancy growth trajectories of 'recent' and 'earlier' offspring of mothers with gestational diabetes mellitus (OGDM), each compared with the same control infants, and investigate whether 'recent' OGDM still exhibit a classical phenotype, with macrosomia and increased adiposity. METHODS: Within a prospective observational birth cohort, 98 'earlier' OGDM born between 2001 and 2009 were identified using 75 g oral glucose tolerance testing at 28 weeks gestation, 122 recent OGDM born between 2011 and 2013 were recruited postnatally through antenatal diabetes clinics, and 876 normal birthweight infants of mothers with no history of diabetes were recruited across the full study period as the control group. All infants followed the same study protocol (measurements at birth, 3, 12 and 24 months, including weight, length and skinfold thickness indicating adiposity, and detailed demographic data). In all cases, GDM was defined using the International Association of Diabetes and Pregnancy Study Group criteria. RESULTS: Earlier OGDM had higher birthweight SD scores (SDS) than control infants. Conversely, recent OGDM had similar birthweight- and length SDS to control infants (mean ± SD, 0.1 ± 1.0 and- 0.1 ± 0.9, respectively), but lower mean skinfold thickness SDS (-0.4 ± 0.6 vs 0.0 ± 0.9; p < 0.001). After birth, earlier OGDM showed reduced gains in weight and length between 3 and 12 months. In contrast, recent OGDM had increased weight and skinfold thickness gains until 3 months, followed by reduced gains in those variables from 3 to 12 months, compared with control infants. At 24 months, recent OGDM had lower adiposity than control infants (mean skinfold thickness SDS -0.3 ± 0.7 vs 0.0 ± 0.8; p < 0.001). At all time points recent OGDM had lower growth measurements than earlier OGDM. CONCLUSIONS/INTERPRETATION: Recent OGDM showed different growth trajectories to the earlier group, namely normalisation of birthweight and reduced adiposity at birth, followed by initial rapid weight gain but subsequent reduced adiposity postnatally. While avoidance of macrosomia at birth may be advantageous, the longer-term health implications of these changing growth trajectories are uncertain.

Human Milk Short-Chain Fatty Acid Composition is Associated with Adiposity Outcomes in Infants.

BACKGROUND: Presumed benefits of human milk (HM) in avoiding rapid infancy weight gain and later obesity could relate to its nutrient composition. However, data on breast milk composition and its relation with growth are sparse. OBJECTIVE: We investigated whether short-chain fatty acids (SCFAs), known to be present in HM and linked to energy metabolism, are associated with infancy anthropometrics. METHODS: In a prospective birth cohort, HM hindmilk samples were collected from 619 lactating mothers at 4-8 wk postnatally [median (IQR) age: 33.9 (31.3-36.5) y, body mass index (BMI) (kg/m2): 22.8 (20.9-25.2)]. Their offspring, born at 40.1 (39.1-41.0) wk gestation with weight 3.56 (3.22-3.87) kg and 51% male, were assessed with measurement of weight, length, and skinfold thickness at ages 3, 12, and 24 mo, and transformed to age- and sex-adjusted z scores. HM SCFAs were measured by 1H-nuclear magnetic resonance spectroscopy (NMR) and GC-MS. Multivariable linear regression models were conducted to analyze the relations between NMR HM SCFAs and infancy growth parameters with adjustment for potential confounders. RESULTS: NMR peaks for HM butyrate, acetate, and formic acid, but not propionate, were detected. Butyrate peaks were 17.8% higher in HM from exclusively breastfeeding mothers than mixed-feeding mothers (P = 0.003). HM butyrate peak values were negatively associated with changes in infant weight (standardized B  = -0.10, P = 0.019) and BMI (B = -0.10, P = 0.018) between 3 and 12 mo, and negatively associated with BMI (B = -0.10, P = 0.018) and mean skinfold thickness (B = -0.10, P = 0.049) at age 12 mo. HM formic acid peak values showed a consistent negative association with infant BMI at all time points (B < = -0.10, P < = 0.014), whereas HM acetate was negatively associated with skinfold thickness at 3 mo (B = -0.10, P = 0.028) and 24 mo (B = -0.10, P = 0.036). CONCLUSIONS: These results suggest that HM SCFAs play a beneficial role in weight gain and adiposity during infancy. Further knowledge of HM SCFA function may inform future strategies to support healthy growth.

Associations between the maternal circulating lipid profile in pregnancy and fetal imprinted gene alleles: a cohort study.

BACKGROUND: Imprinted genes, which are expressed in a parent of origin-specific manner, are thought to mediate the genetic priorities of each parent in pregnancy. Recently we reported that some fetal imprinted gene variants are associated with maternal glucose concentrations and blood pressures in pregnancy. We suggest that the conflict between the effects of paternal and maternal transmitted genes starts at conception and may already be evident in measures of maternal metabolism in early pregnancy, before gestational diabetes is manifest. METHODS: Lipid fractions in maternal non-fasting serum collected around week 15 of pregnancy were profiled using direct infusion mass spectrometry in a subset Discovery Cohort (n = 200) of women from the Cambridge Baby Growth Study using direct infusion mass spectrometry. Associations between 151 haplotype-tag fetal polymorphisms in 16 imprinted genes and lipids were determined using partial least squares discriminant analysis. Variable importance in projection scores were used to identify those lipid species that contribute most to the underlying variation in the lipid profile and the concentrations of these species tested for associations with fetal imprinted gene alleles using linear regression. In an internal Validation Cohort (n = 567 women from the same cohort) the lipid fraction was profiled using liquid chromatography-mass spectrometry and tested for associations with the same fetal imprinted gene variants as above, followed by meta-analysis of associations from the Discovery and Validation Cohorts. RESULTS: The most significant associations were between a monounsaturated triglyceride (44:1) and both paternally-transmitted fetal H19 rs7950932 (R = 0.14, p = 2.9 × 10- 3, n = 386) and maternally-transmitted fetal FAM99A rs7131362 (R = 0.18, p = 6.2 × 10- 3, n = 351; association with maternal-untransmitted allele R = 0.08, p = 0.07, n = 328). This same triglyceride isoform was also associated with subsequent week 28 fasting glucose concentrations (R = 0.09, p = 9.9 × 10- 3, n = 673) and homeostasis model assessment of insulin resistance (R = 0.09, p = 0.01, n = 664). CONCLUSIONS: Fetal imprinted genes may influence maternal circulating clinically relevant triglyceride concentrations early in pregnancy.

Vomiting in pregnancy is associated with a higher risk of low birth weight: a cohort study.

BACKGROUND: Low birth weight has important short- and long-term health implications. Previously it has been shown that pregnancies affected by hyperemesis gravidarum in the mother are at higher risk of having low birth weight offspring. In this study we tested whether such risks are also evident with less severe nausea and vomiting in pregnancy. METHODS: One thousand two hundred thirty-eight women in the prospective Cambridge Baby Growth Study filled in pregnancy questionnaires which included questions relating to adverse effects of pregnancy and drugs taken during that time. Ordinal logistic regression models, adjusted for parity, ethnicity, marital and smoking status were used to relate the risk of giving birth to low birth weight (< 2.5 kg) babies to nausea and/or vomiting in pregnancy that were not treated with anti-emetics and did not report suffering from hyperemesis gravidarum. RESULTS: Only three women in the cohort reported having had hyperemesis gravidarum although a further 17 women reported taking anti-emetics during pregnancy. Of those 1218 women who did not take anti-emetics 286 (23.5%) did not experience nausea or vomiting, 467 (38.3%) experienced nausea but not vomiting and 465 experienced vomiting (38.2%). Vomiting during pregnancy was associated with higher risk of having a low birth weight baby (odds ratio 3.5 (1.2, 10.8), p = 0.03). The risk associated with vomiting was found in the first (p = 0.01) and second (p = 0.01) trimesters but not the third (p = 1.0). The higher risk was not evident in those women who only experienced nausea (odds ratio 1.0 (0.3, 4.0), p = 1.0). CONCLUSIONS: Vomiting in early pregnancy, even when not perceived to be sufficiently severe to merit treatment, is associated with a higher risk of delivering a low birth weight baby. Early pregnancy vomiting might therefore be usable as a marker of higher risk of low birth weight in pregnancy. This may be of benefit in situations where routine ultrasound is not available to distinguish prematurity from fetal growth restriction, so low birth weight is used as an alternative.

Nutrients as Risk Factors and Treatments for Gestational Diabetes.

Gestational diabetes (GDM), traditionally defined as any form of glucose intolerance first detected in pregnancy [...].

Leptin and IGF-1 in Infancy Are Associated With Variants in DHCR7 and CYP2R1 That Relate With Type 1 Diabetes and 25OHD.

CONTEXT: Vitamin D has been variably implicated in risk of developing type 1 diabetes based on cohorts of at-risk individuals. Emergent type 1 diabetes in childhood is putatively preceded by altered growth. OBJECTIVE: We explored whether polymorphisms in vitamin D metabolism genes modify risk of type 1 diabetes via effects on growth in a prospective, population-based cohort of infants. METHODS: The Cambridge Baby Growth Study enrolled newborns from Cambridgeshire, UK, for follow-up in infancy. In 612 infants, we genotyped single nucleotide polymorphisms in vitamin D metabolism genes that relate with type 1 diabetes: rs10741657 and rs12794714 in CYP2R1, rs12785878 in DHCR7, and rs10877012 in CYP27B1. Multivariate linear regression analyses tested associations between genotypes and anthropometric indices (weight, length, and skinfold thickness) or growth-related hormones (C-peptide, IGF-1, and leptin) in infancy. RESULTS: Birth weight showed borderline associations with the diabetes risk-increasing alleles in CYP2R1, rs10741657 (ß = -.11, P = .02) and rs12794714 (ß = -.09, P = .04). The risk-increasing allele rs12794714 was also associated with higher IGF-1 levels at age 24 months (ß = .30, P = .01). At age 3 months, the risk-increasing allele rs12785878 in DHCR7, known to negatively associate with 25-hydroxyvitamin D levels, showed a positive association with leptin levels (ß = .23, P = .009), which was pronounced in girls (P = .004) vs boys (P = .7). CONCLUSION: The vitamin D metabolism genes DHCR7 and CYP2R1 might influence infancy leptin and IGF-1 levels respectively. These findings open the possibility for a developmental role of vitamin D that is mediated by growth-related hormones with implications for the onset of type 1 diabetes autoimmunity.

Pregnancy glucagon-like peptide 1 predicts insulin but not glucose concentrations.

AIMS: Incretin hormones glucagon-like peptide 1 (GLP-1) and gastric inhibitory peptide (GIP) cause increased insulin secretion in non-pregnant adults, but their role in pregnancy, where there are additional metabolically-active hormones from the placenta, is less clear. The aim of the present study was to assess if fasting and post-load incretin concentrations were predictive of pregnancy insulin and glucose concentrations. METHODS: Pregnant women (n = 394) with one or more risk factors for gestational diabetes were recruited at 28 weeks for a 75 g oral glucose tolerance test (OGTT). Glucose, insulin, GLP-1 and GIP were measured in the fasting state and 120 min after glucose ingestion. RESULTS: Fasting plasma GLP-1 concentrations were associated with plasma insulin (standardised ß' 0.393 (0.289-0.498), p = 1.3 × 10-12; n = 306), but not with glucose concentrations (p = 0.3). The association with insulin was still evident when adjusting for BMI (ß' 0.271 (0.180-0.362), p = 1.1 × 10-8; n = 297). Likewise, at 120 min the OGTT GLP-1 concentrations were associated with plasma insulin concentrations (ß' 0.216 (0.100-0.331), p = 2.7 × 10-4; n = 306) even after adjusting for BMI (ß' 0.178 (0.061-0.294), p = 2.9 × 10-3; n = 296), but not with glucose (p = 0.9). GIP concentrations were not associated with insulin or glucose concentrations at either time point (all p > 0.2). In pregnancy plasma GLP-1, but not GIP, concentrations appear to be predictive of circulating insulin concentrations, independently of associations with BMIs. CONCLUSIONS: These results suggest that the relationship between insulin and incretins is preserved in pregnancy, but that other factors, such as placental hormones or counter-regulatory hormones, may be more important determinants of glycaemia and gestational diabetes aetiology.

Associations of appetitive traits with growth velocities from infancy to childhood.

Several studies have reported associations between appetitive traits and weight gain during infancy or childhood, but none have directly compared these associations across both age periods. Here, we tested the associations between appetitive traits and growth velocities from birth to childhood. Appetitive trait data were collected using the Children's Eating Behaviour Questionnaire (CEBQ) in 149 children from the Cambridge Baby Growth Study at age 9-17 years. These participants also provided anthropometric measurements during infancy (birth, 3, 12, 18, and 24 months) and childhood (5 to 11 years). Standardized growth velocities (in weight, length/height, BMI, and body fat percentage) for 0-3 months, 3-24 months, and 24 months to childhood were estimated using individual linear-spline models. Associations between each of the eight CEBQ traits and each growth velocity were tested in separate multilevel linear regression models, adjusted for sex, age at CEBQ completion, and the corresponding birth measurement (weight, length, BMI, or body fat percentage). The three food-approach traits (food responsiveness, enjoyment of food and emotional overeating) were positively associated with infancy and childhood growth velocities in weight, BMI, and body fat percentage. By contrast, only one of the food-avoidant traits, satiety responsiveness, was negatively associated with all growth velocities. Significant associations were mostly of similar magnitude across all age periods. These findings reveal a broadly consistent relationship between appetitive traits with gains in weight and adiposity throughout infancy and childhood. Future interventions and strategies to prevent obesity may benefit from measuring appetitive traits in infants and children and targeting these as part of their programs.

Butyrate in Human Milk: Associations with Milk Microbiota, Milk Intake Volume, and Infant Growth.

Butyrate in human milk (HM) has been suggested to reduce excessive weight and adipo-sity gains during infancy. However, HM butyrate's origins, determinants, and its influencing mechanism on weight gain are not completely understood. These were studied in the prospective longitudinal Cambridge Baby Growth and Breastfeeding Study (CBGS-BF), in which infants (n = 59) were exclusively breastfed for at least 6 weeks. Infant growth (birth, 2 weeks, 6 weeks, 3 months, 6 months, and 12 months) and HM butyrate concentrations (2 weeks, 6 weeks, 3 months, and 6 months) were measured. At age 6 weeks, HM intake volume was measured by deuterium-labelled water technique and HM microbiota by 16S sequencing. Cross-sectionally at 6 weeks, HM butyrate was associated with HM microbiota composition (p = 0.036) although no association with the abundance of typical butyrate producers was detected. In longitudinal analyses across all time points, HM butyrate concentrations were overall negatively associated with infant weight and adiposity, and associations were stronger at younger infant ages. HM butyrate concentration was also inversely correlated with HM intake volume, supporting a possible mechanism whereby butyrate might reduce infant growth via appetite regulation and modulation of HM intake.

Iron Supplementation in Pregnancy and Risk of Gestational Diabetes: A Narrative Review.

Pregnant women frequently supplement their diets with iron to treat any cryptic anemia, on the assumption that if anemia is not present, there will be no negative consequences. However, in women who are already iron-replete, it has been suggested that this can lead to iron overload and an increased risk of certain pregnancy complications. One such complication is gestational diabetes. Fourteen clinical trials, case-control or cohort studies (found using Pubmed/Scopus/Web of Science) have investigated links between iron supplementation in pregnancy and risk of gestational diabetes, several of them finding significant associations with increased risk. Potential mechanisms include increased oxidative stress leading to insulin resistance and inadequate compensatory insulin secretion. Current evidence suggests that dietary supplementation with iron in pregnancy may increase a pregnant woman's chance of developing gestational diabetes, although available evidence is somewhat contradictory, and the magnitude of any increased risk appears relatively small. Meta-analyses have suggested the presence of significant heterogeneity in results between studies, urging a degree of caution in interpreting these results. It is currently suggested that advice to pregnant women about whether to supplement their diets with iron or not should consider both their current iron status and their other established risk factors for gestational diabetes.

Increased basal insulin sensitivity in late pregnancy in women carrying a male fetus: a cohort study.

BACKGROUND: It has been suggested that fetal sex may be able to modify maternal metabolism and physiology during pregnancy. Recently pregnant women carrying a male fetus were reported to be more insulin sensitive than those carrying females, although related evidence is inconsistent. METHODS: In this study we administered a 75 g oral glucose tolerance test at around week 28 of pregnancy in 813 pregnant women from a contemporary birth cohort (the Cambridge Baby Growth Study), derived surrogate indices of insulin secretion and sensitivity, and related them to the fetal sex. RESULTS: Carrying a male fetus was associated with lower fasting glucose (difference in mean concentrations ≈ 0.1 mmol/L; ß' = 0.063; p = 0.02) and insulin (≈ 1.1 pmol/L; ß' = 0.075; p = 0.01) concentrations but not with post-load glucose or insulin concentrations. Male fetal sex was also associated with lower HOMA IR (≈ 1.08 units; ß' = 0.071; p = 0.02) and higher QUICKI (≈ 1.06 units; ß' = 0.080; p = 0.007) values suggesting increased basal insulin sensitivity. There were no differences in indices of insulin secretion, except for the insulin disposition index which was higher in women carrying a male fetus (≈ 1.15 units; ß' = 0.090; p = 0.007). Birth weights were higher in male offspring. CONCLUSIONS: Women carrying a male fetus were relatively more insulin sensitive in the fasting state and secreted more insulin relative to this degree of insulin sensitivity. These results are consistent with the idea that the fetal sex may be able to modify the maternal glucose-insulin axis.

Associations between maternal iron supplementation in pregnancy and offspring growth and cardiometabolic risk outcomes in infancy and childhood.

It was previously observed that maternal iron supplementation in pregnancy was associated with increased offspring size and adiposity at birth, possibly mediated through increased risk of gestational diabetes. In this study we investigated potential long-term associations of maternal iron supplementation in pregnancy with offspring growth in infancy, and growth and cardiometabolic risk factors in mid-childhood to seek evidence of nutritional programming. Using a nested case-control format, markers of growth and adiposity were measured at 3, 12 and 24 months of age in 341 infants from the Cambridge Baby Growth Study whose mothers supplemented with iron in pregnancy and 222 infants whose mothers did not. Measures of growth, glucose tolerance (using a 30 minute 1.75 g glucose/kg body weight oral glucose tolerance test), insulin sensitivity (HOMA IR) and blood pressure were collected in 122 and 79 of these children, respectively, at around 9.5 years of age. In infancy adiposity-promoting associations with maternal iron supplementation in pregnancy were evident at 3 months of age (e.g. mean difference in skinfold thickness: ß = +0.15 mm, p = 0.02, in n = 341 whose mothers supplemented versus 222 that did not; waist circumference: ß = +0.7 cm, p = 0.04, in n = 159 and 78, respectively) but differences lessened after this time (e.g. 3-12 month change in mean difference in skinfold thickness: ß = -0.2 mm, p = 0.03, in n = 272 and 178, respectively). At ~9.5 years of age children whose mothers supplemented with iron in pregnancy had lower mean arterial blood pressures (ß = -1.0 mmHg, p = 0.03, in n = 119 and 78, respectively). There were no apparent differences in markers of growth or other cardiometabolic factors. These results suggest that most of the associations of maternal iron supplementation in pregnancy on growth and adiposity evident at birth disappear during infancy, but there may be some evidence of long-term nutritional programming of blood pressure in mid-childhood.

Maternally transmitted foetal H19 variants and associations with birth weight.

This study was designed to test the hypothesis that polymorphic variation in maternally transmitted foetal H19 alleles is associated with offspring size at birth and alterations in maternal glucose concentrations in pregnancy. Inferred parent of origins of transmitted alleles from 13 haplotype tag SNPs in the H19 gene region from 845 family (mother, partner, offspring) trios from the prospective Cambridge Baby Growth Study and 315 trios from the retrospective Cambridge Wellbeing Study cohorts were tested for association with offspring size at birth measures, as well as maternal glucose concentrations 1 h after a glucose load at week 28 of pregnancy. The foetal rs2071094 allele inherited from the mother was associated with increased birth weight (p = 0.0015) adjusted for gestational age, parity and sex. In the Cambridge Baby Growth Study it was also associated with increased head circumference (p = 0.004), length (p = 0.017) and sum of skinfold thicknesses (p = 0.017) at birth. In contrast to these results there was no association between offspring birth weight and either the maternal rs2071094 genotype or the foetal allele from the father. None of the foetal alleles or maternal genotypes were associated with maternal glucose concentrations, neither were there any other associations with offspring birth weight. In conclusion, consistent with imprinting, common polymorphic variation in foetal H19 alleles transmitted only from the mother are associated with birth weight and other markers of size at birth. Polymorphic variation in H19 is not associated with significant changes in maternal glucose tolerance in the third trimester of pregnancy.

The High-Risk Type 1 Diabetes HLA-DR and HLA-DQ Polymorphisms Are Differentially Associated With Growth and IGF-I Levels in Infancy: The Cambridge Baby Growth Study.

OBJECTIVE: This study explored the link between HLA polymorphisms that predispose to type 1 diabetes and birth size, infancy growth, and/or circulating IGF-I in a general population-based birth cohort. RESEARCH DESIGN AND METHODS: The Cambridge Baby Growth Study is a prospective observational birth cohort study that recruited 2,229 newborns for follow-up in infancy. Of these, 612 children had DNA available for genotyping single nucleotide polymorphisms in the HLA region that capture the highest risk of type 1 diabetes: rs17426593 for DR4, rs2187668 for DR3, and rs7454108 for DQ8. Multivariate linear regression models at critical ages (cross-sectional) and mixed-effects models (longitudinal) were performed under additive genetic effects to test for associations between HLA polymorphisms and infancy weight, length, skinfold thickness (indicator of adiposity), and concentrations of IGF-I and IGF-binding protein-3 (IGFBP-3). RESULTS: In longitudinal models, the minor allele of rs2187668 tagging DR3 was associated with faster linear growth (P = 0.007), which was more pronounced in boys (P = 3 × 10-7) than girls (P = 0.07), and was also associated with increasing IGF-I (P = 0.002) and IGFBP-3 (P = 0.003) concentrations in infancy. Cross-sectionally, the minor alleles of rs7454108 tagging DQ8 and rs17426593 tagging DR4 were associated with lower IGF-I concentrations at age 12 months (P = 0.003) and greater skinfold thickness at age 24 months (P = 0.003), respectively. CONCLUSIONS: The variable associations of DR4, DR3, and DQ8 alleles with growth measures and IGF-I levels in infants from the general population could explain the heterogeneous growth trajectories observed in genetically at-risk cohorts. These findings could suggest distinct mechanisms involving endocrine pathways related to the HLA-conferred type 1 diabetes risk.

Associations between Maternal Iron Supplementation in Pregnancy and Changes in Offspring Size at Birth Reflect Those of Multiple Micronutrient Supplementation.

It was previously observed that in a population of a high-income country, dietary multiple micronutrient supplementation in pregnancy was associated with an increased risk of gestational diabetes (GDM) and increased offspring size at birth. In this follow-up study, we investigated whether similar changes are observed with dietary iron supplementation. For this we used the prospective Cambridge Baby Growth Study with records of maternal GDM status, nutrient supplementation, and extensive offspring birth size measurements. Maternal iron supplementation in pregnancy was associated with GDM development (risk ratio 1.67 (1.01-2.77), p = 0.048, n = 677) as well as offspring size and adiposity (n = 844-868) at birth in terms of weight (ß' = 0.078 (0.024-0.133); p = 0.005), head circumference (ß' = 0.060 (0.012-0.107); p = 0.02), body mass index (ß' = 0.067 (0.014-0.119); p = 0.01), and various skinfold thicknesses (ß' = 0.067-0.094; p = 0.03-0.003). In a subset of participants for whom GDM statuses were available, all these associations were attenuated by adjusting for GDM. Iron supplementation also attenuated the associations between multiple micronutrient supplementation and these same measures. These results suggest that iron supplementation may mediate the effects associated with multiple micronutrient supplementation in pregnancy in a high-income country, possibly through the increased risk of developing GDM.

Folic acid supplementation during pregnancy and associations with offspring size at birth and adiposity: a cohort study.

OBJECTIVE: Previously we observed that maternal multiple micronutrient supplementation in pregnancy was associated with increased offspring size at birth and adiposity, as well as with maternal gestational diabetes risk, in the Cambridge Baby Growth Study. In this study we therefore investigated whether folic acid supplementation specifically is associated with similar changes, to test the hypothesis that folic acid supplementation mediates such changes. RESULTS: The majority of mothers who reported supplementing with folic acid in pregnancy (n = 776 in total, 526 of which took multiple micronutrient preparations) did so either from pre- (n = 139) or post-conception (n = 637) largely for all or just the first half of pregnancy. A minority of mothers (n = 198) reported not supplementing with folic acid. Folic acid supplementation in pregnancy was not associated with birth weight [ß' = - 0.003, p = 0.9], height [ß' = - 0.013, p = 0.6], head circumference [ß' = 0.003, p = 0.09] or adiposity (ponderal index [ß' = 0.020, p = 0.5], skinfolds thicknesses [ß' = - 0.029 to + 0.008, p = 0.4-0.9]). Neither was it associated with the development of maternal gestational diabetes (risk ratio 1.2 [0.6‒2.2], p = 0.6). These results suggest that folic acid supplementation in pregnancy did not mediate the previously observed increases in offspring size at birth and adiposity, or the raised gestational diabetes risk, in response to supplementation with multiple micronutrients.

Pregnancy Serum DLK1 Concentrations Are Associated With Indices of Insulin Resistance and Secretion.

CONTEXT: Delta like noncanonical notch ligand 1 (DLK1) is a paternally expressed imprinted gene that encodes an epidermal growth factor repeat-containing transmembrane protein. A bioactive, truncated DLK1 protein is present in the circulation and has roles in development and metabolism. OBJECTIVE: We sought to investigate links between maternal pregnancy circulating DLK1 concentrations and: (1) maternal and fetal DLK1 genotypes, (2) maternal insulin resistance and secretion, and (3) offspring size at birth. PATIENTS, DESIGN, AND SETTING: We measured third-trimester maternal serum DLK1 concentrations and examined their associations with parentally transmitted fetal and maternal DLK1 genotypes, indices of maternal insulin resistance and secretion derived from 75-g oral glucose tolerance tests performed around week 28 of pregnancy, and offspring size at birth in 613 pregnancies from the Cambridge Baby Growth Study. RESULTS: Maternal DLK1 concentrations were associated with the paternally transmitted fetal DLK1 rs12147008 allele (P = 7.8 × 10-3) but not with maternal rs12147008 genotype (P = 0.4). Maternal DLK1 concentrations were positively associated with maternal prepregnancy body mass index (P = 3.5 × 10-6), and (after adjustment for maternal body mass index) with both maternal fasting insulin resistance (Homeostatic Model Assessment of Insulin Resistance: P = 0.01) and measures of maternal insulin secretion in response to oral glucose (insulinogenic index: P = 1.2 × 10-3; insulin disposition index: P = 0.049). Further positive associations were found with offspring weight (P = 0.02) and head circumference at birth (P = 0.04). CONCLUSION: These results are consistent with a partial paternal or placental origin for the maternal circulating DLK1 which may lead to increased maternal circulating DLK1 concentrations, stimulation of maternal insulin resistance and compensatory hyperinsulinemia during pregnancy, and the promotion of fetal growth.