Placenta mediates the effect of maternal hypertension polygenic score on offspring birth weight: a study of birth cohort with fetal growth velocity data

Abstract Background Low birth weight (LBW) and fetal growth restriction are associated with the development of cardio-metabolic diseases later in life. A recent Mendelian randomization study concluded that the susceptibility of LBW infants to develop hypertension during adulthood is due to the inheritance of hypertension genes from the mother and not to an unfavorable intrauterine environment. Therein, a negative linear association has been assumed between genetically estimated maternal blood pressure (BP) and birth weight, while the observed relationship between maternal BP and birth weight is substantially different from that assumption. As many hypertension genes are likely involved in vasculature development and function, we hypothesized that BP-increasing genetic variants could affect birth weight by reducing the growth of the placenta, a highly vascular organ, without overtly elevating the maternal BP. Methods Using a birth cohort in the Japanese population possessing time-series fetal growth velocity data as a target and a GWAS summary statistics of BioBank Japan as a base data, we performed polygenic score (PGS) analyses for systolic BP (SBP), diastolic BP, mean arterial pressure, and pulse pressure. A causal mediation analysis was performed to assess the meditation effect of placental weight on birth weight reduced by maternal BP-increasing PGS. Maternal genetic risk score constituted of only “vasculature-related” BP single nucleotide polymorphisms (SNPs) was constructed to examine the involvement of vascular genes in the mediation effect of placental weight. We identified gestational week in which maternal SBP-increasing PGS significantly decreased fetal growth velocity. Results We observed that maternal SBP-increasing PGS was negatively associated with offspring birth weight. A causal mediation analysis revealed that a large proportion of the total maternal PGS effect on birth weight was mediated by placental weight. The placental mediation effect was remarkable when genetic risk score was constituted of “vasculature-related” BP SNPs. The inverse association between maternal SBP PGS and fetal growth velocity only became apparent in late gestation. Conclusions Our study suggests that maternal hypertension genes are strongly associated with placental growth and that fetal growth inhibition is induced through the intrauterine environment established by the placenta.

Download Full-text

The Presence of the d3-Growth Hormone Receptor Polymorphism Is Negatively Associated with Fetal Growth but Positively Associated with Postnatal Growth in Healthy Subjects

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2007-0176 ◽

2007 ◽

Vol 92 (7) ◽

pp. 2758-2763 ◽

Cited By ~ 34

Author(s):

Rikke Beck Jensen ◽

Signe Vielwerth ◽

Torben Larsen ◽

Gorm Greisen ◽

Henrik Leffers ◽

...

Keyword(s):

Birth Weight ◽

Fetal Growth ◽

Gestational Age ◽

Growth Velocity ◽

Intrauterine Growth Restriction ◽

Postnatal Growth ◽

Third Trimester ◽

Intrauterine Growth ◽

Prenatal Growth ◽

Ghr Gene

Abstract Context: A common polymorphism in the GH receptor (GHR) gene has been linked to increased growth response in GH-treated patients. No former study has focused on the association to prenatal growth. Objective: The aim of the study was to evaluate the association between the d3-GHR isoforms and spontaneous pre- and postnatal growth. Design: A prospective study was conducted on third-trimester fetal growth velocity (FGV), birth weight, birth length, and postnatal growth. Setting: The study was conducted at Copenhagen University Hospital. Participants: A total of 115 healthy adolescents were divided into those born small for gestational age (SGA) and appropriate for gestational age with or without intrauterine growth restriction. Main Outcome Measures: FGV was measured by serial ultrasonography, birth weight, birth length, and adolescent height. Isoforms of the d3-GHR gene (fl/fl, d3/fl, and d3/d3) were determined. Results: The prevalence of the d3-GHR isoforms was 50% but differed among the groups (P = 0.006), with a high prevalence (88%) in the group born SGA with verified intrauterine growth restriction. The d3-GRH allele were associated with decreased third-trimester FGV (P = 0.05) in SGA subjects. In the entire cohort, carriers of the d3-GHR allele had a significantly increased height (−0.10 vs. 0.34 sd score; P = 0.017) and change in height from birth to adolescence compared with carriers of the full-length GHR allele (0.57 vs. −0.02 sd score; P = 0.005). Conclusions: This study showed an increased spontaneous postnatal growth velocity in the carriers of the d3-GHR allele. Interestingly, we found the opposite effect on prenatal growth in the SGA group, with a decreased FGV in carriers of the d3-GHR allele.

Download Full-text

Leptin Concentrations in Maternal and Umbilical Cord Blood in Relation to Maternal Weight, Birth Weight and Weight of the Placenta

Bangladesh Journal of Obstetrics & Gynaecology ◽

10.3329/bjog.v23i1.3049 ◽

1970 ◽

Vol 23 (1) ◽

pp. 3-7 ◽

Cited By ~ 1

Author(s):

S Ishrat ◽

MW Rahman ◽

MR Rahman ◽

MZ Hussain ◽

S Jahan

Keyword(s):

Birth Weight ◽

Cord Blood ◽

Fetal Growth ◽

Leptin Receptor ◽

Venous Blood ◽

The Body ◽

Placental Weight ◽

Enzyme Linked Immunosorbent Assay ◽

Maternal Weight ◽

Serum Leptin

Objective: Leptin is a hormone which regulates adipose tissue mass of the body. Substantial increase of leptin during pregnancy and detection of leptin and leptin receptor in placenta have led to the speculation that leptin is a gestational hormone with a possible role in regulation of fetal growth. The study was done to find out whether maternal and cord blood leptin correlate with birthweight and weight of the placenta. Materials and methods: A prospective cross sectional study was undertaken in the Department of Obsterics and Gynecology, Bangabandhu Sheikh Mujib Medical University from January 2005 to June 2005. The study was carried out on 39 pairs of mothers and newborns. Maternal venous blood was sampled just before delivery. Cord blood was obtained, birth weight and placental weight measurements were taken just after delivery of the baby. Serum leptin levels were measured by enzyme linked immunosorbent assay. Results: Maternal serum leptin was 24.50 ng/ml (range- 13.15-45.60 ng/ml) and cord serum leptin was 6.50 ng/ml (range- 2.02-12.30 ng/ml). There was no correlation between maternal leptin and birth weight or between maternal leptin and placental weight. Cord leptin was significantly correlated with birth weight but not with placental weight. There was no correlation between maternal and cord blood leptin. There was no significant gender differences in cord blood leptin concentrations. Conclusions: There may be an important role of leptin in regulation of fetal growth and development. Placenta may not be a major source of leptin in maternal and feto-placental circulation. Maternal leptin cannot be a reliable marker of fetal growth. Keywords: Serum leptin, birth weight, placental weight doi: 10.3329/bjog.v23i1.3049 Bangladesh J Obstet Gynaecol, 2008; Vol. 23(1) : 3-7

Download Full-text

Fetal growth and ratio of placental weight to birth weight.

BMJ ◽

10.1136/bmj.304.6827.638-a ◽

1992 ◽

Vol 304 (6827) ◽

pp. 638-638 ◽

Cited By ~ 5

Author(s):

R. De Courcy-Wheeler ◽

C. Wolfe

Keyword(s):

Birth Weight ◽

Fetal Growth ◽

Placental Weight

Download Full-text

Fetal growth and ratio of placental weight to birth weight.

BMJ ◽

10.1136/bmj.304.6833.1052-a ◽

1992 ◽

Vol 304 (6833) ◽

pp. 1052-1052

Author(s):

D. G. Altman ◽

J. M. Bland ◽

L. Meyer

Keyword(s):

Birth Weight ◽

Fetal Growth ◽

Placental Weight

Download Full-text

Impact of fetal growth restriction on body composition and hormonal status at birth in infants of small and appropriate weight for gestational age

Acta Endocrinologica ◽

10.1530/eje-07-0286 ◽

2007 ◽

Vol 157 (5) ◽

pp. 605-612 ◽

Cited By ~ 51

Author(s):

R Verkauskiene ◽

J Beltrand ◽

O Claris ◽

D Chevenne ◽

S Deghmoun ◽

...

Keyword(s):

Body Composition ◽

Birth Weight ◽

Fetal Growth ◽

Gestational Age ◽

Growth Velocity ◽

Fetal Growth Restriction ◽

Hormonal Status ◽

Intrauterine Growth ◽

Igf I ◽

Igfbp 3

AbstractBackgroundFetal growth restriction (FGR) has been related to several health risks, which have been generally identified in small-for-gestational age (SGA) individuals.ObjectiveTo evaluate the impact of FGR on body composition and hormonal status in infants born either small- or appropriate-for-gestational age (AGA).MethodsFetal growth was assessed by ultrasound every 4 weeks from mid-gestation to birth in 248 high-risk pregnancies for SGA. Fetal growth velocity was calculated as change in the estimated fetal weight percentiles and FGR defined as its reduction by more than 20 percentiles from 22 gestational weeks to birth. Impact of FGR on body composition, cord insulin, IGF-I, IGF binding protein-3 (IGFBP-3), and cortisol concentrations was assessed in SGA and AGA newborns.ResultsGrowth-retarded AGA infants showed significantly reduced birth weight, ponderal index, percentage of fat mass, and bone mineral density when compared with AGA newborns with stable intrauterine growth. Cord IGF-I and IGFBP-3 concentrations were significantly decreased in growth-retarded infants in both SGA and AGA groups. Cord insulin concentration was significantly lower and cord cortisol significantly higher in AGA infants with FGR versus AGA newborns with stable intrauterine growth.After adjustment for gestational age and gender, birth weight was directly related to fetal growth velocity and cord IGF-I concentration. The variation in infant's adiposity was best explained by fetal growth velocity and cord insulin concentration.ConclusionsFGR affects body composition and hormonal parameters in newborns with birth weight within the normal range, suggesting these individuals could be at similar metabolic risks as SGA.

Download Full-text

Antenatal Vitamin D Preserves Placental Vascular and Fetal Growth in Experimental Chorioamnionitis Due to Intra-amniotic Endotoxin Exposure

American Journal of Perinatology ◽

10.1055/s-0038-1642033 ◽

2018 ◽

Vol 35 (13) ◽

pp. 1260-1270 ◽

Cited By ~ 4

Author(s):

Michael Cookson ◽

Sharon Ryan ◽

Gregory Seedorf ◽

R. Dodson ◽

Steve Abman ◽

...

Keyword(s):

Vitamin D ◽

Birth Weight ◽

Fetal Growth ◽

Vascular Development ◽

Vessel Density ◽

Placental Weight ◽

Late Gestation ◽

Saline Control ◽

Protective Effects ◽

High Power Field

Background Chorioamnionitis (CA) is associated with a high risk for the development of bronchopulmonary dysplasia (BPD) after preterm birth, but mechanisms that increase susceptibility for BPD and strategies to prevent BPD are uncertain. As a model of CA, antenatal intra-amniotic (IA) endotoxin (ETX) exposure alters placental structure, causes fetal growth restriction, increases perinatal mortality, and causes sustained cardiorespiratory abnormalities throughout infancy. Vitamin D (Vit D) has been shown to have both anti-inflammatory and proangiogenic properties. Antenatal IA treatment with Vit D (1,25-(OH)2D3) during IA ETX exposure improves survival and increases vascular and alveolar growth in infant rats. Whether IA ETX causes decreased placental vascular development and if the protective effects of prenatal Vit D treatment are due to direct effects on the fetus or to improved placental vascular development remain unknown. Objective The objective of this study was to determine if IA ETX impairs placental vascular development and Vit D metabolism, and whether 1,25-(OH)2D3 treatment improves placental vascularity after IA ETX exposure during late gestation in pregnant rats. Design/Methods Fetal rats were exposed to ETX (10 mg), ETX + 1,25-(OH)2D3 (1 ng/mL), 1,25-(OH)2D3 (1 ng/mL), or saline (control) via IA injection at E20 and delivered 2 days later. To assess placental vascular development, histologic sections from the placenta were stained for CD31 and vessel density per high power field (HPF) was determined and analyzed using Matlab software. To determine the effects of ETX on placental Vit D metabolism, Vit D receptor (VDR) and activity of the Vit D conversion enzyme, CYP27B1, were assayed from placental homogenates. Angiogenic mediators were measured by reverse transcription polymerase chain reaction by RNA extracted from placental tissue. Results IA ETX reduced placenta and newborn birth weights by 22 and 20%, respectively, when compared with controls (placental weight: 0.60 vs. 0.47 g; p < 0.0001; birth weight: 4.68 vs. 5.88 g; p < 0.0001). IA 1,25-(OH)2D3 treatment increased birth weight by 12% in ETX-exposed pups (5.25 vs. 4.68 g; p < 0.001). IA ETX decreased placental vessel density by 24% in comparison with controls (1,114 vs. 848 vessels per HPF; p < 0.05). Treatment with IA 1,25-(OH)2D3 increased placenta vessel density twofold after ETX exposure (1,739 vs. 848); p < 0.0001), and increased vessel density compared with saline controls by 56% (1,739 vs. 1,114; p < 0.0001). IA ETX decreased both VDR and CYP27B1 expression by 83 and 35%, respectively (p < 0.01). Conclusion IA ETX decreases placental growth and vessel density and decreases placental VDR and CYP27B1 protein expression, and that antenatal 1,25-(OH)2D3 restores placental weight and vessel density, as well as birth weight. We speculate that 1,25-(OH)2D3 treatment preserves placental function in experimental CA and that these effects may be mediated by increased vascular growth.

Download Full-text

Identifying Mediators Underlying the Intergenerational Cycle of Obesity: A Causal Mediation Analysis

Current Developments in Nutrition ◽

10.1093/cdn/nzaa063_053 ◽

2020 ◽

Vol 4 (Supplement_2) ◽

pp. 1655-1655

Author(s):

Tiange Liu ◽

Noel Mueller ◽

Sara Benjamin-Neelon

Keyword(s):

Birth Weight ◽

Gestational Age ◽

Mediation Analysis ◽

Mediation Effect ◽

Delivery Mode ◽

Z Score ◽

Causal Mediation ◽

Causal Mediation Analysis ◽

Intergenerational Cycle ◽

Infant Birth

Abstract Objectives To understand the mechanisms of the intergenerational cycle of obesity between women and offspring. Methods We recruited pregnant women into the Nurture study (North Carolina, US) and prospectively followed up their offspring until 1 year of age from 2013–2017. The exposure of this analysis was self-reported maternal pre-pregnancy body mass index (BMI) calculated using weight and height. The outcome was researcher-measured infant weight-for-length z-score (WFLZ) at 1 year, calculated based on the WHO Child Growth Standards. We conducted a causal mediation analysis to estimate the average mediation effect of each mediator, including gestational weight gain (GWG), delivery mode, infant birth weight-for-gestational age z-score, and duration of breastfeeding. We adjusted for maternal age, race, parity, smoking status prior to pregnancy, education, household income, food security, and gestational age (when not examining birth weight-for-gestational age z-score). Results We included 380 dyads. Among mothers, there were 65.5% black, 22.6% white, and 11.8% other/multiple race. Prior to pregnancy, 19.5% were overweight and 45.3% were obese. A 10 kg/m2 increment of pre-pregnancy BMI was associated with 0.16 (95% CI: 0.06, 0.27) higher infant WFLZ at 1 year. When examining mediators individually, birth weight-for-gestational age z-score had a statistically significant mediation effect (0.05, 95% CI: 0.02, 0.08), corresponding to 30.2% (95% CI: 20.0%, 62.9%) of the total effect of pre-pregnancy BMI on infant WFLZ. The average mediation effect by GWG was −0.04 (95% CI: −0.08, 0.00), by cesarean delivery was 0.01 (95% CI: −0.01, 0.04), and by breastfeeding duration was 0.02 (95% CI: −0.01, 0.06). Treating mediators as potential confounders for one another did not alter the results. Conclusions Infant birth weight-for-gestational age z-score mediated, in part (∼30%), the relation between maternal pre-pregnancy BMI and infant WFLZ at 1 year. In contrast, GWG, delivery mode, and breastfeeding were not mediators in our sample. This highlights the importance of primordial prevention of maternal obesity, ideally prior to conception, to mitigate the intergeneration cycle of obesity. Research exploring the potential mediating role of factors such as the gut microbiome is needed. Funding Sources The National Institutes of Health.

Download Full-text

Differential Nongenetic Impact of Birth Weight Versus Third-Trimester Growth Velocity on Glucose Metabolism and Magnetic Resonance Imaging Abdominal Obesity in Young Healthy Twins

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2011-0577 ◽

2011 ◽

Vol 96 (9) ◽

pp. 2835-2843 ◽

Cited By ~ 17

Author(s):

Kasper Pilgaard ◽

Thomas Hammershaimb Mosbech ◽

Louise Grunnet ◽

Hans Eiberg ◽

Gerrit Van Hall ◽

...

Keyword(s):

Birth Weight ◽

Fetal Growth ◽

Growth Velocity ◽

Insulin Action ◽

Abdominal Adiposity ◽

Resonance Imaging ◽

Third Trimester ◽

The Third ◽

Size At Birth

Abstract Context: Low birth weight is associated with type 2 diabetes, which to some extent may be mediated via abdominal adiposity and insulin resistance. Fetal growth velocity is high during the third trimester, constituting a potential critical window for organ programming. Intra-pair differences among monozygotic twins are instrumental in determining nongenetic associations between early environment and adult metabolic phenotype. Objective: Our objective was to investigate the relationship between size at birth and third-trimester growth velocity on adult body composition and glucose metabolism using intra-pair differences in young healthy twins. Methods: Fifty-eight healthy twins (42 monozygotic/16 dizygotic) aged 18–24 yr participated. Insulin sensitivity was assessed using hyperinsulinemic-euglycemic clamps. Whole-body fat was assessed by dual-energy x-ray absorptiometry scan, whereas abdominal visceral and sc fat (L1–L4) were assessed by magnetic resonance imaging. Third-trimester growth velocity was determined by repeated ultrasound examinations. Results: Size at birth was nongenetically inversely associated with adult visceral and sc fat accumulation but unrelated to adult insulin action. In contrast, fetal growth velocity during third trimester was not associated with adult visceral or sc fat accumulation. Interestingly, third-trimester growth was associated with insulin action in a paradoxical inverse manner. Conclusions: Abdominal adiposity including accumulation of both sc and visceral fat may constitute primary nongenetic factors associated with low birth weight and reduced fetal growth before the third trimester. Reduced fetal growth during vs. before the third trimester may define distinct adult trajectories of metabolic and anthropometric characteristics influencing risk of developing type 2 diabetes.

Download Full-text

Fetal growth retardation and increased placental weight in the spontaneously hypertensive rat

Reproduction Fertility and Development ◽

10.1071/rd9950639 ◽

1995 ◽

Vol 7 (3) ◽

pp. 639 ◽

Cited By ~ 18

Author(s):

BM Johnston

Keyword(s):

Birth Weight ◽

Fetal Growth ◽

Growth Retardation ◽

Spontaneously Hypertensive Rat ◽

Maternal Blood ◽

Placental Weight ◽

Fetal Growth Retardation ◽

Spontaneously Hypertensive ◽

Wky Rats ◽

Hypertensive Rat

Epidemiological studies have linked low birth weight and increased placental weight with increased risk of hypertension in adult life. It has been proposed that the cardiovascular changes which lead to hypertension are initiated in utero by processes associated with intrauterine growth retardation. The alternative possibility, that hypertension may result from genetic influences which also determine fetal and placental size, has had less support because birth weight is not determined genetically in humans. However, in the spontaneously hypertensive rat (SHR) essential hypertension is known to be transmitted genetically. Fetal and placental weights were, therefore, measured at Day 20 gestation in SHRs and compared with those in the normotensive Wistar Kyoto (WKY) control strain. Fetal weight (1.93 +/- 0.04 g) was significantly (P < 0.001) reduced in SHRs compared with WKY fetuses (2.23 +/- 0.01 g) but placental weight was heavier (P < 0.001) in SHRs (0.347 +/- 0.005 g) than in WKY rats (0.300 +/- 0.006 g) although litter size was not different. As expected, maternal blood pressure recorded under 1% halothane anaesthesia was higher (126 +/- 2.7 mm Hg) in SHR than WKY rats (100 +/- 2.1 mm Hg; 1 mm Hg = 133 Pa). In addition the concentration of maternal blood glucose in SHR was significantly (P < 0.001) higher (4.8 +/- 0.32 mM v. 3.7 +/- 0.11 mM) and the concentration of plasma insulin was significantly (P < 0.05) lower in SHRs (18.8 +/- 3.0 ng mL-1) than in WKY dams (29.4 +/- 3.1 ng mL-1). Thus, the data support human population studies which show an association between adult hypertension and a reduced fetal:placental weight ratio at birth. However, because hypertension in the SHR is genetically determined, these data suggest that fetal growth retardation and increased placental weight may also be determined genetically.

Download Full-text