The potential impact of the fetal genotype on maternal blood pressure during pregnancy.

The heritability of pregnancy-induced hypertension (encompassing both gestational hypertension and preeclampsia) is around 0.47, suggesting that there is a genetic component to its development. However, the maternal genetic risk variants discovered so far only account for a small proportion of the heritability. Other genetic variants that may affect maternal blood pressure in pregnancy arise from the fetal genome, for example wild-type pregnant mice carrying offspring with Cdkn1c or Stox1 disrupted develop hypertension and proteinuria. In humans, there is a higher risk for preeclampsia in women carrying fetuses with Beckwith-Wiedemann syndrome (including those fetuses with CDKN1C mutations) and a lower risk for women carrying babies with trisomy 21. Other risk may be associated with imprinted fetal growth genes and genes that are highly expressed in the placenta such as GCM1. This article reviews the current state of knowledge linking the fetal genotype with maternal blood pressure in pregnancy.MRCThis is the Author Accepted Manuscript of Petry CJ, Beardsall K, Dunger DB. "The potential impact of the fetal genotype on maternal blood pressure during pregnancy". published in the Journal of Hypertension. The published version is available at http://dx.doi.org/10.1097/HJH.000000000000021

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 (β' = 0.078 (0.024-0.133); p = 0.005), head circumference (β' = 0.060 (0.012-0.107); p = 0.02), body mass index (β' = 0.067 (0.014-0.119); p = 0.01), and various skinfold thicknesses (β' = 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

Suckling a protein-restricted rat dam leads to diminished albuminuria in her male offspring in adult life: a longitudinal study.

BACKGROUND: Previous studies have shown that in male rats, exposure to maternal protein restriction either in utero or whilst suckling can have profound effects on both longevity and kidney telomere lengths. This study monitored albuminuria longitudinally in male rats whose mothers had been protein restricted either during pregnancy or lactation. METHODS: Pregnant Wistar rats were fed either a 20% ('control') or an 8% protein ('low protein') diet. At two days of age some of the pups were cross-fostered to dams fed the diet that was not given to their biological mothers. At weaning all pups were fed standard chow. Urine samples were collected for the measurement of albumin and creatinine at monthly intervals from two months-of-age. Longitudinal analysis was then performed using repeated measures analysis of variance. RESULTS: Overall estimated marginal geometric mean (95 % confidence interval) urine albumin to creatinine ratios were: control animals 79.5 (57.2 to approximately 110.6) g/mol (n = 6 litters, 24 animals in total), those exposed in utero to maternal protein restriction 71.0 (47.4 to approximately 106.5) (n = 4 litters, 16 animals in total), those exposed to maternal protein restriction whilst suckling 21.2 (14.7 to approximately 30.4) (n = 5 litters, 20 animals in total) (p < 0.001). These latter animals had lower albumin to creatinine ratios than either of the two other groups (both p < 0.001), which had ratios that were indistinguishable from each other (p = 1.0). Similar results were gained using 24 h. urine albumin excretion rates. These differences became evident from three months-of-age and were long-lasting. CONCLUSION: Animals exposed to maternal protein restriction whilst suckling exhibited lower urine albumin excretions during much of adult life. As urine albumin can be nephrotoxic, these rats therefore appeared to be relatively protected against future nephron damage like that previously observed in animals exposed to maternal protein restriction in utero

The association between age at menarche and later risk of gestational diabetes is mediated by insulin resistance.

AIMS: Associations have been reported between age at menarche and the later risk of gestational diabetes. However, it is not known whether these associations reflect differences in insulin sensitivity and/or pancreatic β-cell function in pregnancy. METHODS: We examined this question in women enrolled in the prospective Cambridge Baby Growth Study who recalled their age at menarche in questionnaires during pregnancy. Polynomial logistic and linear regression models were used to relate menarche timing to the risk of gestational diabetes, both unadjusted and adjusted for the Homeostasis Model Assessments of insulin resistance (HOMA IR) and pancreatic β-cell function (HOMA B) at week 28 of pregnancy. RESULTS: Age at menarche showed a U-shaped association with gestational diabetes risk (linear term: p = 9.5 × 10-4; quadratic term: p = 1.0 × 10-3; n = 889; overall model p = 8.1 × 10-3). Age at menarche showed a negative linear association with insulin resistance (HOMA IR: β = -0.13, p = 5.2 × 10-4, n = 771), which explained the relationship between age at menarche and gestational diabetes risk (adjusted linear term going from p = 0.03-0.08; adjusted quadratic term going from p = 0.04-0.08; n = 771). Age at menarche also showed a negative linear association with β-cell function (HOMA B: β = -0.11, p = 2.8 × 10-3, n = 771) but this did not attenuate the relationship between age at menarche and gestational diabetes (adjusted linear term p = 0.02; adjusted quadratic term p = 0.03, n = 771). CONCLUSIONS: These results suggest that the associations between age at menarche and risk of gestational diabetes and raised pregnancy glucose concentrations may be mediated by insulin resistance.Funding for this study has come from the Wellbeing of Women (the Royal College of Obstetricians and Gynaecologists, UK) (RG1644). Other core funding has come from the Medical Research Council (7500001180, G1001995, U106179472), European Union Framework 5 (QLK4-1999-01422), the Mothercare Charitable Foundation (RG54608), Newlife Foundation for Disabled Children (07/20), and the World Cancer Research Fund International (2004/03). In addition, there has been support from National Institute for Health Research Cambridge Biomedical Research Centre. KO is supported by the Medical Research Council (Unit Programme number: MC_UU_12015/2)

The influence of maternal pregnancy glucose concentrations on associations between a fetal imprinted gene allele score and offspring size at birth

Abstract Objective Previously we found that certain fetal imprinted genes represented as an allele score are associated with maternal pregnancy glucose concentrations. Recently it was reported that fetal polymorphisms with strong associations with birth weight tend to mediate these independently of increases in maternal pregnancy glucose concentrations. We therefore investigated whether potential associations between the fetal allele score and birth weight were related to maternal glucose concentrations in the Cambridge Baby Growth Study. Results The fetal imprinted gene allele score was positively associated with birth weight (β = 63 (17–109) g/risk allele, β′ = 0.113, p = 7.6 × 10−3, n = 405). This association was partially attenuated by adjusting for maternal glucose concentrations (β = 50 (4–95) g/risk allele, β′ = 0.089, p = 0.03, n = 405). The allele score was also positively associated with risk of being large for gestational age at birth (odds ratio 1.60 (1.19–2.15) per risk allele, p = 2.1 × 10−3, n = 660) and negatively associated with risk of being small for gestational age at birth (odds ratio 0.65 (0.44–0.96) per risk allele, p = 0.03, n = 660). The large for gestational age at birth association was also partially attenuated by maternal glucose concentrations. These results suggest that associations between the fetal imprinted gene allele score and size at birth are mediated through both glucose-dependent and glucose-independent mechanisms

Raised late pregnancy glucose concentrations in mice carrying pups with targeted disruption of H19delta13.

OBJECTIVE: We have hypothesized that variation in imprinted growth-promoting fetal genes may affect maternal glucose concentrations in pregnancy. To test this hypothesis we evaluated the effects of fetal disruption of murine H19(Delta13) on maternal glucose concentrations in pregnancy. RESEARCH DESIGN AND METHODS: Experimental mice were pregnant females that had inherited the disrupted H19(Delta13) from their fathers and were therefore phenotypically wild type due to imprinting; approximately half of their litters were null for H19(Delta13) through maternal inheritance of the disrupted gene. In control mice approximately half the litter paternally inherited the disrupted H19(Delta13), so the pups were either genetically wild type or phenotypically wild type due to imprinting. Blood glucose concentrations were assessed by intraperitoneal glucose tolerance tests on days 1, 16, and 18 of pregnancy. RESULTS: There were no differences in the glucose concentrations of control and experimental pregnant mice at day 1. However, at day 16 mothers carrying H19(Delta13)-null pups had a significantly higher area under the glucose tolerance test curves than controls (1,845 +/- 378 vs. 1,386 +/- 107 mmol * min * l(-1) [P = 0.01]) in association with increasing pregnancy-related insulin resistance. Although this difference lessened toward term, overall, mothers of maternally inherited H19(Delta13) mutants had significantly higher glucose concentrations during the last trimester (1,602 +/- 321 [n = 17] vs. 1,359 +/- 147 [n = 18] mmol * min * l(-1) [P = 0.009]). CONCLUSIONS: This study provides evidence that maternal glucose concentrations in pregnant mice can be affected by targeted disruption of fetal H19(Delta13). This implies that variable fetal IGF2 expression could affect risk for gestational diabetes

Multiple Micronutrient Supplementation during Pregnancy and Increased Birth Weight and Skinfold Thicknesses in the Offspring: The Cambridge Baby Growth Study

Multiple micronutrient supplementation (MMS) in pregnancy has previously been associated with positive effects on fetal growth, but its value in high-income countries remains controversial. In this study, we investigated effects of pregnancy MMS on offspring size at birth and adiposity, along with risks of various maternal outcomes of pregnancy, using the prospective Cambridge Baby Growth Study. Maternal MMS was reported in 528 out of 970 women who completed pregnancy questionnaires. Gestational diabetes (GDM) was assessed using results from 75 g oral glucose tolerance tests at week 28 of pregnancy. Offspring size at birth was assessed using standard anthropometric measurements and adiposity using skinfold calipers. MMS was associated with increased risk of developing GDM (risk ratio = 1.86 (1.13−3.08), p = 0.02), as well as increased offspring size at birth in terms of weight (p = 0.03), head circumference (p = 0.04), and flank, and subscapular and triceps skinfold thicknesses (p = 0.04, 0.03, and 0.003, respectively). There was no association with quadriceps skinfold thickness (p = 0.2), suggesting that the increased adiposity was partially regionalized. In women who underwent oral glucose tolerance testing, nearly all of these associations were attenuated by adjusting for GDM. These results suggest that the increased offspring size at birth, including (regionalized) adiposity associated with pregnancy, and MMS may be partially related to the development of GDM

Associations between paternally transmitted fetal IGF2 variants and maternal circulating glucose concentrations in pregnancy.

OBJECTIVE: To test the hypothesis that polymorphic variation in the paternally transmitted fetal IGF2 gene is associated with maternal glucose concentrations in the third trimester of pregnancy. RESEARCH DESIGN AND METHODS: A total of 17 haplotype tag single nucleotide polymorphisms in the IGF2 gene region were genotyped in 1,160 mother/partner/offspring trios from the prospective Cambridge Baby Growth Study (n = 845 trios) and the retrospective Cambridge Wellbeing Study (n = 315 trios) (3,480 samples in total). Associations were tested between inferred parent-of-origin fetal alleles, z scores of maternal glucose concentrations 60 min. after an oral glucose load performed at week 28 of pregnancy, and offspring birth weights. RESULTS: Using the minimum P value test, paternally transmitted fetal IGF2 polymorphisms were associated with maternal glucose concentrations; specifically, paternally transmitted fetal rs6578987 (P = 0.006), rs680 (P = 0.01), rs10770125 (P = 0.0002), and rs7924316 (P = 0.01) alleles were associated with increased maternal glucose concentrations in the third trimester of pregnancy and placental IGF-II contents at birth (P = 0.03). In contrast, there were no associations between maternal glucose concentrations and maternal or maternally transmitted fetal IGF2 genotypes. CONCLUSIONS: Polymorphic variation in paternally transmitted fetal IGF2 is associated with increased maternal glucose concentrations in pregnancy and could potentially alter the risk of gestational diabetes in the mother. The association may be at least partially mediated by changes in placental IGF2 expression

An Unbiased Lipidomics Approach Identifies Early Second Trimester Lipids Predictive of Maternal Glycemic Traits and Gestational Diabetes Mellitus.

OBJECTIVE: To investigate the relationship between early second trimester serum lipidomic variation and maternal glycemic traits at 28 weeks and to identify predictive lipid biomarkers for gestational diabetes mellitus (GDM). RESEARCH DESIGN AND METHODS: Prospective study of 817 pregnant women (discovery cohort, n = 200; validation cohort, n = 617) who provided an early second trimester serum sample and underwent an oral glucose tolerance test (OGTT) at 28 weeks. In the discovery cohort, lipids were measured using direct infusion mass spectrometry and correlated with OGTT results. Variable importance in projection (VIP) scores were used to identify candidate lipid biomarkers. Candidate biomarkers were measured in the validation cohort using liquid chromatography-mass spectrometry and tested for associations with OGTT results and GDM status. RESULTS: Early second trimester lipidomic variation was associated with 1-h postload glucose levels but not with fasting plasma glucose levels. Of the 13 lipid species identified by VIP scores, 10 had nominally significant associations with postload glucose levels. In the validation cohort, 5 of these 10 lipids had significant associations with postload glucose levels that were independent of maternal age and BMI, i.e., TG(51.1), TG(48:1), PC(32:1), PCae(40:3), and PCae(40:4). All except the last were also associated with maternal GDM status. Together, these four lipid biomarkers had moderate ability to predict GDM (area under curve [AUC] = 0.71 ± 0.04, P = 4.85 × 10-7) and improved the prediction of GDM by age and BMI alone from AUC 0.69 to AUC 0.74. CONCLUSIONS: Specific early second trimester lipid biomarkers can predict maternal GDM status independent of maternal age and BMI, potentially enhancing risk factor-based screening.This part of the Cambridge Baby Growth Study was funded by grants from the Wellbeing of Women (RG1644) and Diabetes UK (11/0004241). The lipidomics assays were supported by the Medical Research Council (UD99999906) and Cambridge Lipidomics Biomarker Research Initiative (G0800783). Core funding was also obtained through the Medical Research Council, European Union Framework 5 World Cancer Research Fund, Mothercare Foundation and the Newlife Foundation for Disabled Children. There has also been support from National Institute for Health Research Cambridge Biomedical Research Centre.This is the author accepted manuscript. The final version is available from the American Diabetes Association via https://doi.org/10.2337/dc16-086

Temporal Trends in Maternal Food Intake Frequencies and Associations with Gestational Diabetes: The Cambridge Baby Growth Study.

Funder: Wellcome TrustPrevious studies have suggested that in the first decade of this century the incidence of gestational diabetes (GDM) in pregnancy rose worldwide. In the Cambridge Baby Growth Study cohort we observed that this temporal trend was associated with an index of multiple deprivation and reductions in indices of insulin secretion. Deprivation level was not directly associated with GDM, suggesting that the temporal trend may relate more to other factors linked to it, such as dietary composition. In this study we investigated temporal trends in perceived food intake frequencies, derived from a qualitative, short questionnaire, in 865 pregnant Cambridge Baby Growth Study (CBGS) recruits. A number of food frequency ranks showed both temporal trends and associations with GDM, but of note is the frequency of egg consumption (negative temporal trend p = 0.03, slope = -6.2 ranks/year; negative association with GDM p = 3.0 × 10-8, slope = -0.002 increased risk/rank) as it was also positively associated with the insulin disposition index (p = 1.17 × 10-3, slope = 0.42 ranks. L/mmoL). These results are consistent with a potential protective effect of factors related to the frequency of egg consumption in pregnancy. Such factors may have contributed to the observed temporal trend in GDM risk but the overall detectable effect appears to have been small