Common maternal and fetal genetic variants show expected polygenic effects on risk of small- or large-for-gestational-age (SGA or LGA), except in the smallest 3% of babies

Babies born clinically Small- or Large-for-Gestational-Age (SGA or LGA; sex- and gestational age-adjusted birth weight (BW) <10th or >90th percentile, respectively), are at higher risks of complications. SGA and LGA include babies who have experienced environment-related growth-restriction or overgrowth, respectively, and babies who are heritably small or large. However, the relative proportions within each group are unclear. We assessed the extent to which common genetic variants underlying variation in birth weight influence the probability of being SGA or LGA. We calculated independent fetal and maternal genetic scores (GS) for BW in 11,951 babies and 5,182 mothers. These scores capture the direct fetal and indirect maternal (via intrauterine environment) genetic contributions to BW, respectively. We also calculated maternal fasting glucose (FG) and systolic blood pressure (SBP) GS. We tested associations between each GS and probability of SGA or LGA. For the BW GS, we used simulations to assess evidence of deviation from an expected polygenic model. Higher BW GS were strongly associated with lower odds of SGA and higher odds of LGA (ORfetal = 0.75 (0.71,0.80) and 1.32 (1.26,1.39); ORmaternal = 0.81 (0.75,0.88) and 1.17 (1.09,1.25), respectively per 1 decile higher GS). We found evidence that the smallest 3% of babies had a higher BW GS, on average, than expected from their observed birth weight (assuming an additive polygenic model: Pfetal = 0.014, Pmaternal = 0.062). Higher maternal SBP GS was associated with higher odds of SGA P = 0.005. We conclude that common genetic variants contribute to risk of SGA and LGA, but that additional factors become more important for risk of SGA in the smallest 3% of babies.

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Common maternal and fetal genetic variants show expected polygenic effects on the probability of being born small- or large-for-gestational-age (SGA or LGA), except in the smallest 3% of babies

10.1101/2020.03.25.005660 ◽

2020 ◽

Author(s):

Robin N Beaumont ◽

Sarah J Kotecha ◽

Andrew R. Wood ◽

Bridget A. Knight ◽

Sylvain Sebert ◽

...

Keyword(s):

Blood Pressure ◽

Genetic Variation ◽

Birth Weight ◽

Systolic Blood Pressure ◽

Gestational Age ◽

Genetic Variants ◽

Fasting Glucose ◽

Large For Gestational Age ◽

Common Genetic Variation ◽

Genetic Contributions

AbstractBabies born clinically Small- or Large-for-Gestational-Age (SGA or LGA; sex- and gestational age-adjusted birth weight (BW) <10th or >90th percentile, respectively), are at higher risks of complications. SGA and LGA include babies who have experienced growth-restriction or overgrowth, respectively, and babies who are naturally small or large. However, the relative proportions within each group are unclear. We aimed to assess the extent to which the genetics of normal variation in birth weight influence the probability of SGA/LGA. We calculated independent fetal and maternal genetic scores (GS) for BW in 12,125 babies and 5,187 mothers. These scores capture the direct fetal and indirect maternal (via intrauterine environment) genetic contributions to BW, respectively. We also calculated maternal fasting glucose (FG) and systolic blood pressure (SBP) GS. We tested associations between each GS and probability of SGA or LGA. For the BW GS, we used simulations to assess evidence of deviation from an expected polygenic model.Higher BW GS were strongly associated with lower odds of SGA and higher odds of LGA (ORfetal=0.65 (0.60,0.71) and 1.47 (1.36,1.59); ORmaternal=0.80 (0.76,0.87) and 1.23 (1.15,1.31), respectively per 1 decile higher GS). Associations were in accordance with a polygenic model except in the smallest 3% of babies (Pfetal=0.0034, Pmaternal=0.023). Higher maternal GS for FG and SBP were associated with higher odds of LGA and SGA respectively (both P<0.01). While lower maternal FG and SBP are generally considered healthy in pregnancy, we found some evidence of association with higher odds of SGA (P=0.015) and LGA (P=0.14) respectively.We conclude that common genetic variants contribute to risk of SGA and LGA, but that additional factors become more important for risk of SGA in the smallest 3% of babies. Naturally low maternal glucose and blood pressure levels may additionally contribute to risk of SGA and LGA, respectively.Author SummaryBabies in the lowest or highest 10% of the population distribution of birth weight (BW) for a given gestational age are referred to as Small- or Large-for-Gestational-Age (SGA or LGA) respectively. These babies have higher risks of complications compared to babies with BW closer to the mean. SGA and LGA babies may have experienced growth restriction or overgrowth, respectively, but may alternatively just be at the tail ends of the normal growth distribution. The relative proportions of normal vs. sub-optimal growth within these groups is unclear. To examine the role of common genetic variation in SGA and LGA, we tested their associations with a fetal genetic score (GS) for BW in 12,125 European-ancestry individuals. We also tested associations with maternal GS (5,187 mothers) for offspring BW, fasting glucose and systolic blood pressure, each of which influences fetal growth via the in utero environment. We found all fetal and maternal GS were associated with SGA and LGA, supporting strong maternal and fetal genetic contributions to birth weight in both tails of the distribution. However, within the smallest 3% of babies, the maternal and fetal GS for BW were higher than expected, suggesting factors additional to common genetic variation are more important in determining birth weight in these very small babies.

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Large Reduction in Adiponectin During Pregnancy Is Associated With Large-for-Gestational-Age Newborns

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2017-00289 ◽

2017 ◽

Vol 102 (7) ◽

pp. 2552-2559 ◽

Cited By ~ 18

Author(s):

Tove Lekva ◽

Marie Cecilie Paasche Roland ◽

Annika E. Michelsen ◽

Camilla Margrethe Friis ◽

Pål Aukrust ◽

...

Keyword(s):

Birth Weight ◽

Mrna Expression ◽

Gestational Age ◽

Messenger Rna ◽

University Hospital ◽

Abdominal Circumference ◽

Large For Gestational Age ◽

Oral Glucose ◽

Intrauterine Environment ◽

Increased Risk

Abstract Context: Fetuses exposed to an obese intrauterine environment are more likely to be born large-for-gestational age (LGA) and are at increased risk of obesity in childhood and cardiovascular disease and/or type 2 diabetes mellitus as adults, but which factors that influence the intrauterine environment is less clear. Objective: To investigate the association between circulating levels of leptin and adiponectin, measured multiple times during pregnancy, and birth weight and prevalence of LGA or small-for-gestational-age infants. The association between birth weight and messenger RNA (mRNA) expression of adiponectin receptors and genes involved in nutrient transport in the placenta was also investigated. Design: Population-based prospective cohort [substudy of the STORK study (STORe barn og Komplikasjoner, translated as Large Babies and Complications)] from 2001 to 2008. Setting: University hospital. Patients or other participants: 300 women. Main Outcome Measures: Oral glucose tolerance test was performed twice along with adiponectin and leptin levels measured four times during pregnancy. Results: Circulating adiponectin was lower in mothers who gave birth to LGA offspring or had fetuses with high intrauterine abdominal circumference late in pregnancy. Adiponectin decreased most from early to late pregnancy in mothers who gave birth to LGA offspring, and the decrease was an independent predictor of birth weight. Adiponectin receptor 2 and system A amino acid transporter mRNA expression in placentas was negatively correlated with birth weight and was lower in placentas from LGA infants. Conclusions: Our findings suggest that maternal adiponectin may be an important predictor of fetal growth and birth weight, independent of body mass index and insulin resistance.

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Early Postnatal Metabolic Profile in Neonates With Different Birth Weight Status: A Pilot Study

Frontiers in Pediatrics ◽

10.3389/fped.2021.646860 ◽

2021 ◽

Vol 9 ◽

Author(s):

Serdar Beken ◽

Saygin Abali ◽

Neslihan Yildirim Saral ◽

Bengisu Guner ◽

Taha Dinc ◽

...

Keyword(s):

Birth Weight ◽

Amino Acid ◽

Energy Metabolism ◽

Gestational Age ◽

Weight Status ◽

Newborn Infants ◽

Ponderal Index ◽

Large For Gestational Age ◽

Metabolic Disturbances ◽

Intrauterine Growth

Introduction: Restricted or enhanced intrauterine growth is associated with elevated risks of early and late metabolic problems in humans. Metabolomics based on amino acid and carnitine/acylcarnitine profile may have a role in fetal and early postnatal energy metabolism. In this study, the relationship between intrauterine growth status and early metabolomics profile was evaluated.Materials and Methods: A single-center retrospective cohort study was conducted. Three hundred and sixty-one newborn infants were enrolled into the study, and they were grouped according to their birth weight percentile as small for gestational age (SGA, n = 69), appropriate for gestational age (AGA, n = 168), and large for gestational age (LGA, n = 124) infants. In all infants, amino acid and carnitine/acylcarnitine profiles with liquid chromatography-tandem mass spectrometry (LC-MS/MS) were recorded and compared between groups.Results: LGA infants had higher levels of glutamic acid and lower levels of ornithine, alanine, and glycine (p < 0.05) when compared with AGA infants. SGA infants had higher levels of alanine and glycine levels when compared with AGA and LGA infants. Total carnitine, C0, C2, C4, C5, C10:1, C18:1, C18:2, C14-OH, and C18:2-OH levels were significantly higher and C3 and C6-DC levels were lower in SGA infants (p < 0.05). LGA infants had higher C3 and C5:1 levels and lower C18:2 and C16:1-OH levels (p < 0.05). There were positive correlations between free carnitine and phenylalanine, arginine, methionine, alanine, and glycine levels (p < 0.05). Also, a positive correlation between ponderal index and C3, C5-DC, C14, and C14:1 and a negative correlation between ponderal index and ornithine, alanine, glycine, C16:1-OH, and C18:2 were shown.Conclusion: We demonstrated differences in metabolomics possibly reflecting the energy metabolism in newborn infants with intrauterine growth problems in the early postnatal period. These differences might be the footprints of metabolic disturbances in future adulthood.

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Colloid Osmotic Pressure in Newborn Infants: Variations with Birth Weight, Gestational Age, Total Serum Solids, and Mean Arterial Pressure

PEDIATRICS ◽

10.1542/peds.68.6.814 ◽

1981 ◽

Vol 68 (6) ◽

pp. 814-819

Author(s):

Paul Y. K. Wu ◽

Gary Rockwell ◽

Linda Chan ◽

Shu-Mei Wang ◽

Vikram Udani

Keyword(s):

Blood Pressure ◽

Birth Weight ◽

Osmotic Pressure ◽

Gestational Age ◽

Small For Gestational Age ◽

Newborn Infants ◽

Colloid Osmotic Pressure ◽

Large For Gestational Age ◽

Total Serum ◽

Arterial Blood

Colloid osmotic pressure (COP) of blood was measured directly at birth with the Wescor membrane colloid osmometer (model 4100) in 91 appropriately grown, 11 large, and nine small for gestational age "well" newborn infants. COP correlated directly with birth weight (r = .726, P < .00001) and gestational age (r = .753, P < .00001). COP values for small for gestational age (SGA) and large for gestational age (LGA) infants were found to fall within the 95% prediction interval with regard to birth weight and gestational age for appropriate for gestational age (AGA) infants. Simultaneous measurements of COP, total serum solids, and central arterial mean blood pressure were made. The results showed that COP correlated directly with total serum solids (r = .89, P < .0001) and mean arterial blood pressure (r = .660, P < .001). Among the factors evaluated, total serum solids was the best predictor of COP.

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Risk of small for gestational age babies in preterm delivery due to pregnancy-induced hypertension

Medical Journal of Indonesia ◽

10.13181/mji.v28i1.1795 ◽

2019 ◽

Vol 28 (1) ◽

pp. 57-62 ◽

Cited By ~ 1

Author(s):

Rima Irwinda ◽

Budi Iman Santoso ◽

Raymond Surya ◽

Lidia Firmiaty Nembo

Keyword(s):

Birth Weight ◽

Gestational Age ◽

Preterm Births ◽

Secondary Data ◽

Large For Gestational Age ◽

Fisher Exact Test ◽

Pregnancy Induced Hypertension ◽

Exact Test ◽

Induced Hypertension ◽

The Impact

BACKGROUND Pregnancy-induced hypertension (PIH) causes high maternal morbidity and mortality worldwide. This study aims to assess the impact of PIH on fetal growth according to gestational age in preterm deliveries.METHODS A prospective cohort study using secondary data was undertaken in Ende District, East Nusa Tenggara, Indonesia from September 2014 to August 2015. The t-test was performed to compare mean birth weight based on gestational week between normotensive and PIH women, continued by linear regression. The chi-square or Fisher exact test was also conducted to determine the probability of birthing small for the gestational age (SGA) and large for gestational age (LGA) babies between normotensive and PIH women.RESULTS A total of 1,673 deliveries were recorded in Ende Hospital over the 1-year study period, among which 182 cases involved preterm births. The PIH group had lower birth weight than normotensive women at each gestational age starting from 32–35 weeks (p=0.004; 95% CI 150.84–771.36). Normotensive women at gestational ages of 32 (p=0.05; 95% CI 0.01–0.83), 34 (p=0.37; 95% CI 0.01–4.12), and 36 (p=0.31; 95% CI 0.02–2.95) weeks had a lower risk of birthing SGA babies than PIH women; LGA babies were recorded at gestational ages of 33 (p=1.00; 95% CI 0.07–37.73) and 35 (p=0.31; 95% CI 0.34–63.07) weeks.CONCLUSIONS Poor perfusion of the uteroplacental is one of the reasons behind intrauterine growth restriction, which results in SGA babies born to PIH women.

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Gestational Weight Gain and Pregnancy Outcomes among Nulliparous Women

American Journal of Perinatology ◽

10.1055/s-0039-1696640 ◽

2019 ◽

Author(s):

Annie M. Dude ◽

William Grobman ◽

David Haas ◽

Brian M. Mercer ◽

Samuel Parry ◽

...

Keyword(s):

Weight Gain ◽

Birth Weight ◽

Gestational Weight Gain ◽

Gestational Age ◽

Small For Gestational Age ◽

Pregnancy Outcomes ◽

Large For Gestational Age ◽

Gestational Weight ◽

Excessive Gestational Weight Gain ◽

Hypertensive Disorders

Abstract Objective To determine the association between total gestational weight gain and perinatal outcomes. Study Design Data from the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-To-Be (NuMoM2b) study were used. Total gestational weight gain was categorized as inadequate, adequate, or excessive based on the 2009 Institute of Medicine guidelines. Outcomes examined included hypertensive disorders of pregnancy, mode of delivery, shoulder dystocia, large for gestational age or small for-gestational age birth weight, and neonatal intensive care unit admission. Results Among 8,628 women, 1,666 (19.3%) had inadequate, 2,945 (34.1%) had adequate, and 4,017 (46.6%) had excessive gestational weight gain. Excessive gestational weight gain was associated with higher odds of hypertensive disorders (adjusted odds ratio [aOR] = 2.05, 95% confidence interval [CI]: 1.78–2.36) Cesarean delivery (aOR = 1.24, 95% CI: 1.09–1.41), and large for gestational age birth weight (aOR = 1.49, 95% CI: 1.23–1.80), but lower odds of small for gestational age birth weight (aOR = 0.59, 95% CI: 0.50–0.71). Conversely, inadequate gestational weight gain was associated with lower odds of hypertensive disorders (aOR = 0.75, 95% CI: 0.62–0.92), Cesarean delivery (aOR = 0.77, 95% CI: 0.65–0.92), and a large for gestational age birth weight (aOR = 0.72, 95% CI: 0.55–0.94), but higher odds of having a small for gestational age birth weight (aOR = 1.64, 95% CI: 1.37–1.96). Conclusion Both excessive and inadequate gestational weight gain are associated with adverse maternal and neonatal outcomes.

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Large-for-gestational-age phenotypes and obesity risk in adulthood: a study of 195,936 women

Scientific Reports ◽

10.1038/s41598-020-58827-5 ◽

2020 ◽

Vol 10 (1) ◽

Cited By ~ 2

Author(s):

José G. B. Derraik ◽

Sarah E. Maessen ◽

John D. Gibbins ◽

Wayne S. Cutfield ◽

Maria Lundgren ◽

...

Keyword(s):

Birth Weight ◽

Gestational Age ◽

Reference Group ◽

Ponderal Index ◽

Large For Gestational Age ◽

Adjusted Relative Risk ◽

Obesity Risk ◽

Increased Risk ◽

Appropriate For Gestational Age ◽

Using Data

AbstractWhile there is evidence that being born large-for-gestational-age (LGA) is associated with an increased risk of obesity later in life, the data are conflicting. Thus, we aimed to examine the associations between proportionality at birth and later obesity risk in adulthood. This was a retrospective study using data recorded in the Swedish Birth Register. Anthropometry in adulthood was assessed in 195,936 pregnant women at 10–12 weeks of gestation. All women were born at term (37–41 weeks of gestation). LGA was defined as birth weight and/or length ≥2.0 SDS. Women were separated into four groups: appropriate-for-gestational-age according to both weight and length (AGA – reference group; n = 183,662), LGA by weight only (n = 4,026), LGA by length only (n = 5,465), and LGA by both weight and length (n = 2,783). Women born LGA based on length, weight, or both had BMI 0.12, 1.16, and 1.08 kg/m2 greater than women born AGA, respectively. The adjusted relative risk (aRR) of obesity was 1.50 times higher for those born LGA by weight and 1.51 times for LGA by both weight and height. Length at birth was not associated with obesity risk. Similarly, women born LGA by ponderal index had BMI 1.0 kg/m2 greater and an aRR of obesity 1.39 times higher than those born AGA. Swedish women born LGA by weight or ponderal index had an increased risk of obesity in adulthood, irrespective of their birth length. Thus, increased risk of adult obesity seems to be identifiable from birth weight and ignoring proportionality.

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Infants of Women with Polycystic Ovary Syndrome have Lower Cord Blood Androstenedione and Estradiol Levels

Endocrine Reviews ◽

10.1210/edrv.31.2.9981 ◽

2010 ◽

Vol 31 (2) ◽

pp. 255-256

Author(s):

Helen Anderson ◽

Naomi Fogel ◽

Stefan K. Grebe ◽

Ravinder J. Singh ◽

Robert L. Taylor ◽

...

Keyword(s):

Birth Weight ◽

Polycystic Ovary Syndrome ◽

Cord Blood ◽

Gestational Age ◽

Polycystic Ovary ◽

Large For Gestational Age ◽

Control Group ◽

Ovary Syndrome ◽

17 Hydroxyprogesterone ◽

Androgen Levels

ABSTRACT Context Prenatal androgen excess can cause a phenocopy of polycystic ovary syndrome (PCOS) in mammals. Retrospective studies have suggested that girls at risk for PCOS have low birth weight and prospective studies have suggested an increased prevalence of small for gestational age offspring in women with PCOS. Objective To determine whether infants of women with PCOS have reduced birth weight or increased intrauterine androgen levels. Design Prospective case-control study. Participants Thirty-nine PCOS and 31 control women and their infants. Main outcome measures Birth weight and mixed cord blood testosterone, androstenedione (A), dehydroepiandrosterone, 17-hydroxyprogesterone, estradiol (E2), and dihydrotestosterone levels. Results Mean birth weight did not differ but there was a significant increase in the prevalence of large for gestational age infants in the PCOS group. Cord blood E2 and A levels were lower (p < 0.05) but testosterone:E2 ratios did not differ in female PCOS compared to control offspring. There was no difference in E2 and A levels in the male PCOS and control offspring. There was no difference in 17-hydroxyprogesterone or in other androgen levels in either male or female PCOS offspring compared to their respective control group. Conclusion Infants of women with PCOS were more likely to be large for gestational age. Female offspring of affected women have lower cord blood A levels; other cord blood androgen levels do not differ compared to female control offspring. Cord blood E2 levels are also significantly decreased in PCOS, without any difference in the testosterone:E2 ratio, suggesting decreased fetal or placental production of steroids.

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Serum Microelements in Early Pregnancy and their Risk of Large-for-Gestational Age Birth Weight

Nutrients ◽

10.3390/nu12030866 ◽

2020 ◽

Vol 12 (3) ◽

pp. 866 ◽

Cited By ~ 2

Author(s):

Małgorzata Lewandowska ◽

Jan Lubiński

Keyword(s):

Birth Weight ◽

Early Pregnancy ◽

Gestational Age ◽

Preliminary Evidence ◽

Large For Gestational Age ◽

Female Fetus ◽

Appropriate For Gestational Age ◽

Nested Case Control ◽

Relationship Of

Excessive birth weight has serious perinatal consequences, and it “programs” long-term health. Mother’s nutritional status can be an important element in fetal “programming”; microelements such as selenium (Se), zinc (Zn), copper (Cu), and iron (Fe) are involved in many metabolic processes. However, there are no studies assessing the relationship of the microelements in the peri-conceptual period with the risk of excessive birth weight. We performed a nested case control study of serum microelements’ levels in the 10–14th week of pregnancy and assessed the risk of large-for-gestational age (LGA) newborns using the data from a prospective cohort of pregnant women recruited in 2015–2016 in Poznań, Poland. Mothers delivering LGA newborns (n = 66) were examined with matched mothers delivering appropriate-for-gestational age (AGA) newborns (n = 264). Microelements’ levels were quantified using mass spectrometry. The odds ratios of LGA (and 95% confidence intervals) were calculated by multivariate logistic regression. In the whole group, women with the lowest quartile of Se had a 3 times higher LGA risk compared with women in the highest Se quartile (AOR = 3.00; p = 0.013). Importantly, the result was sustained in the subgroup of women with the normal pre-pregnancy BMI (AOR = 4.79; p = 0.033) and in women with a male fetus (AOR = 6.28; p = 0.004), but it was not sustained in women with a female fetus. There were no statistical associations between Zn, Cu, and Fe levels and LGA. Our study provides some preliminary evidence for the relationships between lower serum Se levels in early pregnancy and a higher risk of large-for-gestational age birth weight. Appropriate Se intake in the periconceptual period may be important for optimal fetal growth.

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Leisure-Time Physical Activity in Pregnancy and the Birth Weight Distribution: Where Is the Effect?

Journal of Physical Activity and Health ◽

10.1123/jpah.9.8.1168 ◽

2012 ◽

Vol 9 (8) ◽

pp. 1168-1177 ◽

Cited By ~ 15

Author(s):

Lanay M. Mudd ◽

Jim Pivarnik ◽

Claudia B. Holzman ◽

Nigel Paneth ◽

Karin Pfeiffer ◽

...

Keyword(s):

Physical Activity ◽

Birth Weight ◽

Quantile Regression ◽

Gestational Age ◽

Weight Distribution ◽

Leisure Time ◽

Leisure Time Physical Activity ◽

Large For Gestational Age ◽

Birth Weight Distribution

Background:Leisure-time physical activity (LTPA) is recommended during pregnancy and has been associated with lower risk of delivering a large infant. We sought to characterize the effect of LTPA across the entire birth weight distribution.Methods:Women enrolled in the Pregnancy Outcomes and Community Health (POUCH) Study (1998–2004) were followed-up in 2007. Follow-up efforts were extensive for a subcohort and minimal for the remainder (nonsubcohort). Thus, 596 subcohort and 418 nonsubcohort women who delivered at term participated. Offspring were categorized as small-, appropriate-, or large-for-gestational-age (SGA, AGA, and LGA, respectively) based on gender and gestational age-specific birth weight z-scores (BWz). At follow-up, women recalled pregnancy LTPA and were classified as inactive, insufficiently active or meeting LTPA recommendations. Linear, logistic, and quantile regression analyses were conducted separately by subcohort status.Results:Meeting LTPA recommendations decreased odds of LGA significantly among the nonsubcohort (aOR = 0.30, 95% CI: 0.14–0.64) and nonsignificantly among the subcohort (aOR = 0.68, 95% CI: 0.34–1.34). In quantile regression, meeting LTPA recommendations reduced BWz among the upper quantiles in the nonsubcohort.Conclusions:LTPA during pregnancy lowered odds of LGA and reduced BWz among the upper quantiles, without shifting the entire distribution. LTPA during pregnancy may be useful for reducing risks of large fetal size.

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