Genetic Background of Fetal Growth Restriction.
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ABSTRACT:
SUBMITTER: Nowakowska BA
PROVIDER: S-EPMC8744929 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Beckwith-Wiedemann syndrome (BWS) is a complex imprinting disorder involving fetal overgrowth and placentomegaly, and is associated with a variety of genetic and epigenetic mutations affecting the expression of imprinted genes on human chromosome 11p15.5. Most BWS cases are linked to loss of methylation at the imprint control region 2 (ICR2) within this domain, which in mice regulates the silencing of several maternally expressed imprinted genes. Modelling this disorder in mice is confounded by the unique embryonic requirement for Ascl2, which is imprinted in mice but not in humans. To overcome this issue, we generated a novel model combining a truncation of distal chromosome 7 allele (DelTel7) with transgenic rescue of Ascl2 expression. This novel model recapitulated placentomegaly associated with BWS, but did not lead to fetal overgrowth.
| S-EPMC6262809 | biostudies-literature
Project description:PurposeFetal growth is a complex process involving maternal, placental and fetal factors. The etiology of fetal growth retardation remains unknown in many cases. The aim of this study is to identify novel human mutations and genes related to Silver-Russell syndrome (SRS), a syndromic form of fetal growth retardation, usually caused by epigenetic downregulation of the potent fetal growth factor IGF2.MethodsWhole-exome sequencing was carried out on members of an SRS familial case. The candidate gene from the familial case and two other genes were screened by targeted high-throughput sequencing in a large cohort of suspected SRS patients. Functional experiments were then used to link these genes into a regulatory pathway.ResultsWe report the first mutations of the PLAG1 gene in humans, as well as new mutations in HMGA2 and IGF2 in six sporadic and/or familial cases of SRS. We demonstrate that HMGA2 regulates IGF2 expression through PLAG1 and in a PLAG1-independent manner.ConclusionGenetic defects of the HMGA2-PLAG1-IGF2 pathway can lead to fetal and postnatal growth restriction, highlighting the role of this oncogenic pathway in the fine regulation of physiological fetal/postnatal growth. This work defines new genetic causes of SRS, important for genetic counseling.
| S-EPMC5846811 | biostudies-literature
Project description:The aim of this study was to identify growth-restricted fetuses using biometric parameters and to assess the validity and clinical value of individual ultrasound parameters and ratios, such as transcerebellar diameter/abdominal circumference (TCD/AC), head circumference/abdominal circumference (HC/AC), and femur length/abdominal circumference (FL/AC). In a retrospective single-center cross-sectional study, the biometric data of 9292 pregnancies between the 15th and 42nd weeks of gestation were acquired. Statistical analysis included descriptive data, quantile regression estimating the 10th and 90th percentiles, and multivariable analysis. We obtained clinically noticeable results in predicting small-for-gestational-age (SGA) and fetal growth restriction (FGR) fetuses at advanced weeks of gestation using the AC with a Youden index of 0.81 and 0.96, respectively. The other individual parameters and quotients were less suited to identifying cases of SGA and FGR. The multivariable analysis demonstrated the best results for identifying SGA and FGR fetuses with an area under the curve of 0.95 and 0.96, respectively. The individual ultrasound parameters were better suited to identifying SGA and FGR than the ratios. Amongst these, the AC was the most promising individual parameter, especially at advanced weeks of gestation. However, the highest accuracy was achieved with a multivariable model.
| S-EPMC9317726 | biostudies-literature
Project description:BACKGROUND:Ambient air pollution may affect fetal growth restriction (FGR) through several mechanisms. However, prior studies of air pollution and small-for-gestational age (SGA), a common proxy for FGR, have reported inconsistent findings. OBJECTIVE:We assessed air pollution in relation to physician-diagnosed FGR and population-based SGA in the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Consecutive Pregnancy Study (2002-2010). METHODS:Among 50,005 women (112,203 singleton births), FGR was captured from medical records and ICD-9 codes, and SGA determined by population standards for birthweight <10th, <5th and <3rd percentile. Community Multiscale Air Quality models estimated ambient levels of seven criteria pollutants for whole pregnancy, 3-months preconception, and 1st, 2nd and 3rd trimesters. Generalized estimating equations with robust standard errors accounted for interdependency of pregnancies within participant. Models adjusted for maternal age, race/ethnicity, pre-pregnancy body mass index, smoking, alcohol, parity, insurance, marital status, asthma and temperature. RESULTS:FGR was diagnosed in 1.5% of infants, and 6.7% were <10th, 2.7% <5th and 1.5% <3rd percentile for SGA. Positive associations of SO2, NO2 and PM10 and negative associations of O3 with FGR were observed throughout preconception and pregnancy. For example, an interquartile increase in whole pregnancy SO2 was associated with 16% (95% CI 8%, 25%) increased FGR risk, 17% for NO2 (95% CI 9%, 26%) and 12% for PM10 (95% CI 6%, 19%). Associations with SGA were less clear. CONCLUSIONS:Chronic exposure to air pollution may be associated with FGR but not SGA in this low-risk population.
| S-EPMC6203640 | biostudies-literature
Project description:BackgroundFetal growth restriction is commonly defined using small for gestational age (SGA) birth (birthweight < 10th percentile) as a proxy, but this approach is problematic because most SGA infants are small but healthy. In this proof-of-concept study, we sought to develop a new approach for identifying fetal growth restriction at birth that combines information on multiple, imperfect measures of fetal growth restriction in a probabilistic manner.MethodsWe combined information on birthweight, placental weight, placental malperfusion lesions, maternal disease, and fetal acidemia using latent profile analysis to classify fetal growth in births at the Royal Victoria Hospital in Montreal, Canada, 2001-2009. We examined the clinical characteristics and health outcomes of infants classified as growth-restricted and nongrowth-restricted by our model, and among the subgroup of growth-restricted infants who had a birthweight ≥10th percentile (i.e., would have been missed by the conventional SGA proxy).ResultsAmong 26,077 births, 345 (1.3%) were classified as growth-restricted by our latent profile model. Growth-restricted infants were more likely than nongrowth-restricted infants to have an Apgar score <7 (10% vs. 2%), have hypoglycemia at birth (17% vs. 3%), require neonatal intensive care unit admission (59% vs. 6%), die in the perinatal period (3.8% vs. 0.2%), and require an emergency cesarean delivery (42% vs. 15%). Risks remained elevated in growth-restricted infants who were not SGA, suggesting our model identified at-risk infants not detected using the SGA proxy.ConclusionsLatent profile analysis is a promising strategy for classifying growth restriction at birth in fetal growth restriction research.
| S-EPMC8478298 | biostudies-literature
Project description:Preeclampsia and fetal growth restriction (FGR) are major causes of the more than 5 million perinatal and infant deaths occurring globally each year, and both are associated with placental dysfunction. The risk of perinatal and infant death is greater in males, but the mechanisms are unclear. We studied data and biological samples from the Pregnancy Outcome Prediction (POP) study, a prospective cohort study that followed 4,212 women having first pregnancies from their dating ultrasound scan through delivery. We tested the hypothesis that fetal sex would be associated with altered placental function using multiomic and targeted analyses. We found that spermine synthase (SMS) escapes X-chromosome inactivation (XCI) in the placenta and is expressed at lower levels in male primary trophoblast cells, and male cells were more sensitive to polyamine depletion. The spermine metabolite N1,N12-diacetylspermine (DiAcSpm) was higher in the female placenta and in the serum of women pregnant with a female fetus. Higher maternal serum levels of DiAcSpm increased the risk of preeclampsia but decreased the risk of FGR. To our knowledge, DiAcSpm is the first maternal biomarker to demonstrate opposite associations with preeclampsia and FGR, and this is the first evidence to implicate polyamine metabolism in sex-related differences in placentally related complications of human pregnancy.
| S-EPMC6124516 | biostudies-literature
Project description:BackgroundPlacental insufficiency is an important mechanism underlying early-onset fetal growth restriction (eoFGR). Reduced placental function causes impaired metabolic and gaseous exchange. This unfavorable placental environment is among other processes characterized by increased oxidative stress. Systemic free thiols (FT) are known for their reactive oxygen species scavenging capacity, and higher plasma levels of FT are associated with a better outcome in a multitude of ischemic and inflammatory diseases. We aimed to investigate the relationships between systemic FT levels and maternal and perinatal clinical characteristics and outcomes.Study designIn a post hoc analysis of the Dutch Strider study, a cohort of women with eoFGR, we investigated the association between the maternal redox status (FT) levels at study inclusion, placental biomarkers, and maternal and neonatal outcomes in 108 patients.ResultsFT were significantly lower in pregnancies complicated with eoFGR with concurrent maternal hypertensive disorders (pregnancy-induced hypertension; ρ = -0.281 p = 0.004, pre-eclampsia; ρ = -0.505 p = 0.000). In addition, lower FT levels were significantly associated with higher systolic (ρ = -0.348 p = 0.001) and diastolic blood pressure (ρ = -0.266 p = 0.014), but not with the severity of eoFGR. FT levels were inversely associated with sFlt (ρ = -0.366, p < 0.001). A strong relation between systemic FT levels and PlGF levels was observed in women with pre-eclampsia at delivery (ρ = 0.452, p = 0.002), which was not found in women without hypertensive disorders (ρ = 0.008, p = 0.958).ConclusionsIn women with pregnancies complicated with eoFGR, FT levels reflect the severity of maternal disease related to the underlying placental insufficiency rather than the severity of the placental dysfunction as reflected in eoFGR or perinatal outcomes.
| S-EPMC10812523 | biostudies-literature
Project description:Objective: The aim of this study was to study growth patterns of children born after suspected fetal growth restriction (FGR) at term and to compare the effect of induction of labor (IoL) and expectant management (EM), also in relation to neurodevelopmental and behavioral outcome at age 2. Methods: We performed a 2 years' follow-up of growth of children included in the Disproportionate Intrauterine Growth Restriction Trial at Term (DIGITAT) study, a Randomized Controlled Trial (RCT) comparing IoL with EM in pregnancies with suspected FGR at term. We collected data on child growth until the age of 2 years. Standard deviation scores (SDSs) for height and weight were calculated at different ages. We assessed the effects of IoL compared with EM and the effects of a birth weight below or above the 3rd or 10th centile on catch-up growth. Target height SDSs were calculated using the height of both parents. Results: We found a significant increase in SDS in the first 2 years. Children born after EM showed more catch-up growth in the first month [height: mean difference -0.7 (95% CI: 0.2; 1.3)] and weight [mean difference -0.5 (95% CI: 0.3; 0.7)]. Children born with a birth weight below the 3rd and 10th centiles showed more catch-up growth after 1 year [mean difference -0.8 SDS (95% CI: -1.1; -0.5)] and after 2 years [mean difference -0.7 SDS (95% CI: -1.2; -0.2)] as compared to children with a birth weight above the 3rd and 10th centiles. SDS at birth had the strongest effect on adverse neurodevelopmental outcome at 2 years of age. Conclusion: After FGR at term, postnatal catch-up growth is generally present and associated with the degree of FGR. Obstetric management in FGR influences postnatal growth. Longer-term follow-up is therefore needed and should be directed at growth and physical health. Clinical Trial Registration: www.ClinicalTrials.gov, identifier SRCTN10363217.
| S-EPMC6598620 | biostudies-literature
Project description:Impaired fetal growth is one of the most important causes of prematurity, stillbirth and infant mortality. The pathogenesis of idiopathic fetal growth restriction (FGR) is poorly understood but is thought to be multifactorial and comprise a range of genetic causes. This research aimed to investigate non-coding RNAs (lncRNAs) in the placentas of male and female fetuses affected by FGR. RNA-Seq data were analyzed to detect lncRNAs, their potential target genes and circular RNAs (circRNAs); a differential analysis was also performed. The multilevel bioinformatic analysis enabled the detection of 23,137 placental lncRNAs and 4263 of them were classified as novel. In FGR-affected female fetuses' placentas (ff-FGR), among 19 transcriptionally active regions (TARs), five differentially expressed lncRNAs (DELs) and 12 differentially expressed protein-coding genes (DEGs) were identified. Within 232 differentially expressed TARs identified in male fetuses (mf-FGR), 33 encompassed novel and 176 known lncRNAs, and 52 DEGs were upregulated, while 180 revealed decreased expression. In ff-FGR ACTA2-AS1, lncRNA expression was significantly correlated with five DEGs, and in mf-FGR, 25 TARs were associated with DELs correlated with 157 unique DEGs. Backsplicing circRNA processes were detected in the range of H19 lncRNA, in both ff- and mf-FGR placentas. The performed global lncRNAs characteristics in terms of fetal sex showed dysregulation of DELs, DEGs and circRNAs that may affect fetus growth and pregnancy outcomes. In female placentas, DELs and DEGs were associated mainly with the vasculature, while in male placentas, disturbed expression predominantly affected immune processes.
| S-EPMC8072961 | biostudies-literature
Project description:Fetal growth restriction (FGR) occurs when the fetus does not reach its genetically programmed intrauterine potential for growth and affects ~5‑10% of pregnancies. This condition is one of the leading causes of perinatal mortality and morbidity associated with obstetric and neonatal complications. Placental dysfunction in FGR causes an impairment in the transfer of nutrients and oxygen from the mother to the developing fetus. Maternal adaptations to placental insufficiency may also play a role in the pathophysiology of FGR. The present study aimed to compare the proteome of the placentas of 18 women with the physiological course of pregnancy and eutrophic fetus [estimated fetal weight (EFW) >10th percentile; control group] and 18 women with late FGR (EFW <10th percentile) diagnosed after 32 weeks of pregnancy, according to the Delphi consensus (study group). The U. Mann‑Whitney test was used to compare two independent groups. The R. Spearman correlation coefficient significance test was used to assess the existence of a relationship between the analyzed measurable parameters. P<0.05 was considered to indicate a statistically significant difference. The tests showed the presence of 356 different proteins which were responsible for the regulation of gene transcription control, inhibiting the activity of proteolytic enzymes, regulation of trophoblast proliferation and angiogenesis and inflammatory response. In the FGR placental proteome, other detected proteins were mostly involved in response to oxidative stress, cellular oxidation and detoxication, apoptosis, hemostatic and catabolic processes, energy transduction protein interactions, cell proliferation, differentiation and intracellular signaling. The present study used chromatographic mass‑spectrometry to compare the placental proteome profiles in pregnancies complicated by late‑onset FGR and normal pregnancy. Comparative analysis of proteomes from normal and FGR placentas showed significant differences. Further research is needed to clarify maternal and fetal adaptations to FGR.
| S-EPMC9608316 | biostudies-literature