Genetic and Environmental Influences on Fetal Growth Vary during Sensitive Periods in Pregnancy

Abstract

Aberrant fetal growth is associated with morbidities and mortality during childhood and adult life. Although genetic and environmental factors are known to influence in utero growth, their relative contributions over pregnancy is unknown. We estimated, across gestation, the genetic heritability, contribution of shared environment, and genetic correlations of fetal growth measures (abdominal circumference (AC), humerus length (HL), femur length (FL), and estimated fetal weight (EFW)) in a prospective cohort of dichorionic twin gestations recruited through the NICHD Fetal Growth Studies. Structural equation models were fit at the end of first trimester, during mid-gestation, late second trimester, and third trimester of pregnancy. The contribution of fetal genetics on fetal size increased with gestational age, peaking in late second trimester (AC = 53%, HL = 57%, FL = 72%, EFW = 71%; p < 0.05). In contrast, shared environment explained most of phenotypic variations in fetal growth in the first trimester (AC = 50%, HL = 54%, FL = 47%, EFW = 54%; p < 0.05), suggesting that the first trimester presents an intervention opportunity for a more optimal early fetal growth. Genetic correlations between growth traits (range 0.34–1.00; p < 0.05) were strongest at the end of first trimester and declined with gestation, suggesting that different fetal growth measures are more likely to be influenced by the same genes in early pregnancy.

Trans-ethnic meta-analysis of genome-wide association studies identifies maternal ITPR1 as a novel locus influencing fetal growth during sensitive periods in pregnancy

“…It is possible that the locus influences intra-uterine factors during late second trimester and early third trimester, a time period when the growing fetus's demand for oxygen and nutrients is high [13] and the placenta undergoes dramatic transitions to meet these fetal demands [52]. Consistent with these gestational age-dependent findings, we and others have previously found that the effects of fetal genetic variants on fetal growth may be gestation time-specific [53], and the influence of additive genetics on fetal weight increases with gestational age [11][12][13].…”

“…Offspring birthweight alone cannot represent the pattern of intrauterine growth at different times during gestation [11]. Previous studies have demonstrated that the genetic contribution to fetal growth, relative to in-utero environmental influences, varies over gestation [11][12][13]. Therefore, different genetic loci may influence fetal growth at different times of gestation, and the same genetic locus may have different effects on fetal growth due to its varied interactions with the in-utero environment by gestation timing [14].…”

Vaginal microbiota and cytokine levels predict preterm delivery in Asian women

“…Pregnancy is an important "formative period" where a series of interconnected physiological and cellular processes aim to support healthy fetal development [7]. These processes include maternal and paternal genetic factors, hormonal changes, immune system modulation, environmental factors, the microbiome and others [8,9].…”

Differential susceptibility effects of maternal sensitivity in childhood on small for gestational age adults’ wealth

“…Intrauterine growth restriction (IUGR) is an adaptation to adverse preconceptual and prenatal conditions such as malnutrition, poor placental supply, genetic disposition, or maternal stress by protecting the development of vital organs (i.e., the brain) while constraining the fetus from reaching its potential size (Gluckman, Hanson, Cooper, & Thornburg, 2008). These unfavorable conditions in utero may affect behavioral functioning and health in later life via prenatal programming during developmental periods of high organ plasticity (Barker, 2007; Gluckman et al, 2008; Workalemahu et al, 2018). IUGR is associated with small for gestational age (SGA) birth, low birth weight (<2,500 g), preterm birth (<37 weeks’ gestational age), and increased long-term morbidity (Raikkonen & Pesonen, 2009).…”