Etiology Of Fetal Growth Restriction Research Articles

Maternal-fetal interfaces transcriptome changes associated with placental insufficiency and a novel gene therapy intervention.

The etiology of fetal growth restriction (FGR) is multifactorial, although many cases often involve placental insufficiency. Placental insufficiency is associated with inadequate trophoblast invasion resulting in high resistance to blood flow, decreased availability of nutrients, and increased hypoxia. We have developed a non-viral, polymer-based nanoparticle that facilitates delivery and transient gene expression of human insulin-like 1 growth factor ( hIGF1 ) in placental trophoblast for the treatment of placenta insufficiency and FGR. Using the established guinea pig maternal nutrient restriction (MNR) model of placental insufficiency and FGR, the aim of the study was to identify novel pathways in the sub-placenta/decidua that provide insight into the underlying mechanism driving placental insufficiency, and may be corrected with hIGF1 nanoparticle treatment. Pregnant guinea pigs underwent ultrasound-guided sham or hIGF1 nanoparticle treatment at mid-pregnancy, and sub-placenta/decidua tissue was collected 5 days later. Transcriptome analysis was performed using RNA Sequencing on the Illumina platform. The MNR sub-placenta/decidua demonstrated fewer maternal spiral arteries lined by trophoblast, shallower trophoblast invasion and downregulation of genelists involved in the regulation of cell migration. hIGF1 nanoparticle treatment resulted in marked changes to transporter activity in the MNR + hIGF1 sub-placenta/decidua when compared to sham MNR. Under normal growth conditions however, hIGF1 nanoparticle treatment decreased genelists enriched for kinase signaling pathways and increased genelists enriched for proteolysis indicative of homeostasis. Overall, this study identified changes to the sub-placenta/decidua transcriptome that likely result in inadequate trophoblast invasion and increases our understanding of pathways that hIGF1 nanoparticle treatment acts on in order to restore or maintain appropriate placenta function.

Gestational exposure to 1-NP induces ferroptosis in placental trophoblasts via CYP1B1/ERK signaling pathway leading to fetal growth restriction

Fetal growth restriction (FGR) is a prevalent complication in obstetrics, yet its exact aetiology remains unknown. Numerous studies suggest that the degradation of the living environment is a significant risk factor for FGR. 1-Nitropyrene (1-NP) is a widespread environmental pollutant as a representative substance of nitro-polycyclic aromatic hydrocarbons. In this study, we revealed that 1-NP induced FGR in fetal mice by constructing 1-NP exposed pregnant mice models. Intriguingly, we found that placental trophoblasts of 1-NP exposed mice exhibited significant ferroptosis, which was similarly detected in placental trophoblasts from human FGR patients. In this regard, we established a 1-NP exposed cell model in vitro using two human trophoblast cell lines, HTR8/SVneo and JEG-3. We found that 1-NP not only impaired the proliferation, migration, invasion and angiogenesis of trophoblasts, but also induced severe cellular ferroptosis. Meanwhile, the ferroptosis inhibitor ferrostatin-1 (Fer-1) effectively rescued 1-NP-induced trophoblast biological function impairment. Mechanistically, we revealed that 1-NP regulated ferroptosis by activating the ERK signaling pathway. Moreover, we innovatively revealed that CYP1B1 was essential for the activation of ERK signaling pathway induced by 1-NP. Overall, our study innovatively identified ferroptosis as a significant contributor to 1-NP induced trophoblastic functional impairment leading to FGR and clarified the specific mechanism by which 1-NP induced ferroptosis via the CYP1B1/ERK signaling pathway. Our study provided novel insights into the aetiology of FGR and revealed new mechanisms of reproductive toxicity of environmental pollutants.

Comparative Analysis of the Placental Microbiome in Pregnancies with Late Fetal Growth Restriction versus Physiological Pregnancies.

A comparative analysis of the placental microbiome in pregnancies with late fetal growth restriction (FGR) was performed with normal pregnancies to assess the impact of bacteria on placental development and function. The presence of microorganisms in the placenta, amniotic fluid, fetal membranes and umbilical cord blood throughout pregnancy disproves the theory of the "sterile uterus". FGR occurs when the fetus is unable to follow a biophysically determined growth path. Bacterial infections have been linked to maternal overproduction of pro-inflammatory cytokines, as well as various short- and long-term problems. Proteomics and bioinformatics studies of placental biomass allowed the development of new diagnostic options. In this study, the microbiome of normal and FGR placentas was analyzed by LC-ESI-MS/MS mass spectrometry, and the bacteria present in both placentas were identified by analysis of a set of bacterial proteins. Thirty-six pregnant Caucasian women participated in the study, including 18 women with normal pregnancy and eutrophic fetuses (EFW > 10th percentile) and 18 women with late FGR diagnosed after 32 weeks of gestation. Based on the analysis of the proteinogram, 166 bacterial proteins were detected in the material taken from the placentas in the study group. Of these, 21 proteins had an exponentially modified protein abundance index (emPAI) value of 0 and were not included in further analysis. Of the remaining 145 proteins, 52 were also present in the material from the control group. The remaining 93 proteins were present only in the material collected from the study group. Based on the proteinogram analysis, 732 bacterial proteins were detected in the material taken from the control group. Of these, 104 proteins had an emPAI value of 0 and were not included in further analysis. Of the remaining 628 proteins, 52 were also present in the material from the study group. The remaining 576 proteins were present only in the material taken from the control group. In both groups, we considered the result of ns prot ≥ 60 as the cut-off value for the agreement of the detected protein with its theoretical counterpart. Our study found significantly higher emPAI values of proteins representative of the following bacteria: Actinopolyspora erythraea, Listeria costaricensis, E. coli, Methylobacterium, Acidobacteria bacterium, Bacteroidetes bacterium, Paenisporsarcina sp., Thiodiazotropha endol oripes and Clostridiales bacterium. On the other hand, in the control group statistically more frequently, based on proteomic data, the following were found: Flavobacterial bacterium, Aureimonas sp. and Bacillus cereus. Our study showed that placental dysbiosis may be an important factor in the etiology of FGR. The presence of numerous bacterial proteins present in the control material may indicate their protective role, while the presence of bacterial proteins detected only in the material taken from the placentas of the study group may indicate their potentially pathogenic nature. This phenomenon is probably important in the development of the immune system in early life, and the placental microbiota and its metabolites may have great potential in the screening, prevention, diagnosis and treatment of FGR.

Integrated Placental Modelling of Histology with Gene Expression to Identify Functional Impact on Fetal Growth.

Fetal growth restriction (FGR) is a leading cause of perinatal morbidity and mortality. Altered placental formation and functional capacity are major contributors to FGR pathogenesis. Relating placental structure to function across the placenta in healthy and FGR pregnancies remains largely unexplored but could improve understanding of placental diseases. We investigated integration of these parameters spatially in the term human placenta using predictive modelling. Systematic sampling was able to overcome heterogeneity in placental morphological and molecular features. Defects in villous development, elevated fibrosis, and reduced expression of growth and functional marker genes (IGF2, VEGA, SLC38A1, and SLC2A3) were seen in age-matched term FGR versus healthy control placentas. Characteristic histopathological changes with specific accompanying molecular signatures could be integrated through computational modelling to predict if the placenta came from a healthy or FGR pregnancy. Our findings yield new insights into the spatial relationship between placental structure and function and the etiology of FGR.

Epigenetics Beyond Fetal Growth Restriction: A Comprehensive Overview.

Fetal growth restriction is a pathological condition occurring when the fetus does not reach the genetically determined growth potential. The etiology of fetal growth restriction is expected to be multifactorial and include fetal, maternal, and placental factors, the latter being the most frequent cause of isolated fetal growth restriction. Severe fetal growth restriction has been related to both an increased risk of perinatal morbidity and mortality, and also a greater susceptibility to developing diseases (especially cardio-metabolic and neurologicaldisorders) later in life. In the last decade, emerging evidence has supported the hypothesis of the Developmental Origin of Health and Disease, which states that individual developmental 'programming' takes place via a delicate fine tuning of fetal genetic and epigenetic marks in response to a large variety of 'stressor' exposures during pregnancy. As the placenta is the maternal-fetal interface, it has a crucial role in fetal programming, such that any perturbation altering placental function interferes with both in-utero fetal growth and also with the adult life phenotype. Several epigenetic mechanisms have been highlighted in modulating the dynamic placental epigenome, including alterations in DNA methylation status, post-translational modification of histones, and non-coding RNAs. This review aims to provide a comprehensive and critical overview of the available literature on the epigenetic background of fetal growth restriction. A targeted research strategy was performed using PubMed, MEDLINE, Embase, and The Cochrane Library up to January 2022. A detailed and fully referenced synthesis of available literature following the Scale for the Assessment of Narrative Review Articles guidelines is provided. A variety of epigenetic marks predominantly interfering with placental development, function, and metabolism were found to be potentially associated with fetal growth restriction. Available evidence on the role of environmental exposures in shaping the placental epigenome and the fetal phenotype were also critically discussed. Because of the highly dynamic crosstalk between epigenetic mechanisms and the extra level of complexity in interpreting the final placental transcriptome, a full comprehension of these phenomenon is still lacking and advances in multi-omics approaches are urgently needed. Elucidating the role of epigenetics in the developmental origins of health and disease represents a new challenge for the coming years, with the goal of providing early interventions and prevention strategies and, hopefully, new treatment opportunities.

Fetal growth restriction: associated genetic etiology and pregnancy outcomes in a tertiary referral center

BackgroundThe etiology of fetal growth restriction (FGR) is complex and currently, there is a paucity of research about the genetic etiology of fetal growth restriction. We investigated the genetic associations and pregnancy outcomes in cases of fetal growth restriction.MethodsA retrospective analysis of 210 pregnant women with fetal growth restriction was performed using karyotype analysis and single nucleotide polymorphism arrays (SNP-array). The differences in pathogenic copy number variation (CNV) detected by the two methods were compared. At the same time, the fetuses were divided into three groups: isolated FGR (n = 117), FGR with ultrasonographic soft markers (n = 48), and FGR with ultrasonographic structural anomalies (n = 45). Further, the differences in pathogenic copy number variations were compared among the groups.ResultsThe total detection rate of pathogenic CNVs was 12.4% (26/210). Pathogenic copy number variation was detected in 14 cases (6.7%, 14/210) by karyotype analysis. Furthermore, 25 cases (11.9%, 25/210) with pathogenic CNVs were detected using the SNP-array evaluation method. The difference in the pathogenic CNV detection rate between the two methods was statistically significant. The result of the karyotype analysis and SNP-array evaluation was inconsistent for 13 cases with pathogenic CNV. The rate of detecting pathogenic CNVs in fetuses with isolated FGR, FGR combined with ultrasonographic soft markers, and FGR combined with ultrasonographic structural malformations was 6.0, 10.4, and 31.1%, respectively, with significant differences among the groups. During the follow-up, 35 pregnancies were terminated, two abortions occurred, and 13 cases were lost to follow-up. Of the 160 deliveries, nine fetuses had adverse pregnancy outcomes, and the remaining 151 had normal postnatal growth and developmental assessments.ConclusionsEarly diagnosis and timely genomic testing for fetal growth restriction can aid in its perinatal prognosis and subsequent intervention.

Platelets in Fetal Growth Restriction: Role of Reactive Oxygen Species, Oxygen Metabolism, and Aggregation.

Fetal growth restriction (FGR) is mainly caused by failure of the uteroplacental unit. The exact pathogenesis remains unclear. The cause is thought to be related to abnormal platelet activation, which may result in microthrombus formation in the small vessels of the placenta. Reactive oxygen species (ROS) may initiate the pathological process of platelet activation. This study aimed to evaluate selected platelet parameters in pregnancy complicated by FGR and relate them to the severity of hemodynamic abnormalities. A total of 135 women (pregnant with FGR, with an uncomplicated pregnancy, and non-pregnant) were enrolled to study different platelet parameters: count (PLT), mean volume (MPV), ROS levels, intracellular oxygen level, oxygen consumption, and aggregation indices. No abnormalities in PLT and MPV were found in the FGR group, although it revealed increased ROS levels in platelets, lower platelet oxygen consumption, and intraplatelet deprivation. Aggregation parameters were similar as in uncomplicated pregnancy. No significant relationships were observed between hemodynamic abnormalities and the studied parameters. Platelets in pregnancies complicated by FGR may reveal an impaired oxidative metabolism, which may, in turn, lead to oxidative stress and, consequently, to an impaired platelet function. This study adds to the understanding of the role of platelets in the etiology of FGR.

Use of the angiogenic biomarker profile to risk stratify patients with fetal growth restriction

Novel angiogenic biomarker profiles have demonstrated emerging evidence for predicting preeclampsia onset, severity, and adverse outcomes. Limited data exist in screening patients with fetal growth restriction for preeclampsia development using angiogenic biomarkers. The objective of this study was to risk stratify patients with fetal growth restriction using a soluble fms-like tyrosine kinase-1 to placental growth factor ratio. Previously published cutoff of 38 was used to predict preeclampsia development and severity as well as adverse maternal or neonatal outcomes within a 2-week time period. This was a prospective observational cohort study performed in a single tertiary hospital. Patients with a singleton fetal growth restriction pregnancy between 24 and 37 weeks' gestation were evaluated using serial 2-week encounters from the time of enrollment to delivery. Pregnancies with proven genetic or infectious etiology of fetal growth restriction or congenital anomalies were excluded. Ultrasound growth and Doppler measurements were obtained at the start of every encounter with routine preeclampsia laboratory tests and blood pressure checks when clinically indicated. Maternal serum was collected for all serial encounters and measured for soluble fms-like tyrosine kinase-1 and placental growth factor after delivery in a double-blinded fashion. Maternal charts were reviewed for baseline demographic characteristics, pregnancy diagnoses and outcomes, and neonatal outcomes. A total of 45 patients were enrolled for a total of 77 encounters, with the median (quartile 1, quartile 3) gestational age of the study enrolled at 31.43 (28.14-33.57) weeks. Patients were divided into low-risk (ratio of <38) and high-risk (ratio of ≥38) groups. Baseline characteristics of patients did not show any marked differences, including preeclampsia labs or ultrasound parameters, between the 2 groups. Systolic and diastolic blood pressures upon enrollment were statistically elevated when soluble fms-like tyrosine kinase-1 to placental growth factor ratio was ≥38 (P=.02 and P=.01, respectively). Compared to patients with a low ratio, patients with a high ratio had a greater proportion of preeclampsia diagnosis, higher rates of preterm delivery under 34 and 37 weeks gestation, smaller neonatal birthweight, and a shorter time to delivery from testing to delivery. Among patients with fetal growth restriction, the soluble fms-like tyrosine kinase-1 to placental growth factor ratio may serve as a potential biomarker for identifying at risk patients for developing preeclampsia and subsequently preterm delivery.

Chromosomal microarray analysis of 85 fetus with growth restriction

Objective To investigate the clinical value of chromosomal microarray analysis (CMA) in identifying the genetic etiology of fetal growth restriction (FGR). Methods Eighty-five FGR cases were recruited from Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School from January 2014 to October 2016. Samples of amniotic fluid (n=74), skin tissues from aborted fetuses (n=9), umbilical cord blood (n=1) and peripheral blood from a premature infant (n=1) were collected. Affymetrix CytoScan 750K Array was used to detect copy number variation (CNV) in fetal samples. Microarray analysis or fluorescence quantitative polymerase chain reaction was further recommended for the parents if fetal CMA result was variants of unknown significance (VOUS). Karyotype analysis of umbilical cord blood was further recommended if fetal CMA result was chromosome mosaicism. Chromosome analysis of peripheral blood was further recommended for the parents if fetal CMA result of a fetus was submicroscopic CNVs. Adjusted Chi-square test was used as the statistical method. Results CMA was successful in all samples in identifying chromosomal abnormalities. Among the 36 isolated FGR cases (42.4%, 36/85), CMA identified in four cases of chromosome imbalance recombination and four cases of VOUS, and the rest 28 cases were normal. Besides, no CNV was detected. Among the other 49 FGR cases (57.6%, 49/85) with ultrasound abnormalities, there were five cases of VOUS, and five cases of chromosome imbalance recombination and nine cases of CNVs. No significance difference in the detection rate of chromosome imbalance recombination was observed between the isolated and non-isolated FGR groups [11% (4/36) vs 10% (5/49), adjusted χ2=0.000, P>0.999]. Parents of six cases of VOUS were further examined and the same variants was found in either one. One case of sex chromosome mosaicism was validated by cord blood karyotyping. One case of chromosome imbalance recombination was due to the paternal balanced translocation. Conclusions CMA is helpful in detecting the chromosome imbalance recombination in FGR cases. Key words: Fetal growth retardation; Microarray analysis; Chromosomes, human; DNA copy number variations

Temporal expression of genes involved in the placental tryptophan catabolism and transport contribute to the aetiology of fetal growth restriction

Temporal expression of genes involved in the placental tryptophan catabolism and transport contribute to the aetiology of fetal growth restriction

DNA Methylation and Expression Patterns of Selected Genes in First-Trimester Placental Tissue from Pregnancies with Small-for-Gestational-Age Infants at Birth1

Variations in DNA methylation levels in the placenta are thought to influence gene expression and are associated with complications of pregnancy, like fetal growth restriction (FGR). The most important cause for FGR is placental dysfunction. Here, we examined whether changes in DNA methylation, followed by gene expression changes, are mechanistically involved in the etiology of FGR. In this retrospective case-control study, we examined the association between small-for-gestational-age (SGA) children and both DNA methylation and gene expression levels of the genes WNT2, IGF2/H19, SERPINA3, HERVWE1, and PPARG in first-trimester placental tissue. We also examined the repetitive element LINE-1. These candidate genes have been reported in the literature to be associated with SGA. We used first-trimester placental tissue from chorionic villus biopsies. A total of 35 SGA children (with a birth weight below the 10th percentile) were matched to 70 controls based on their gestational age. DNA methylation levels were analyzed by pyrosequencing and mRNA levels were analyzed by real-time PCR. None of the average DNA methylation levels, measured for each gene, showed a significant difference between SGA placental tissue compared to control tissue. However, hypermethylation of WNT2 was detected on two CpG positions in SGA. This was not associated with changes in gene expression. Apart from two CpG positions of the WNT2 gene, in early placenta samples, no evident changes in DNA methylation or expression were found. This indicates that the already reported changes in term placenta are not present in the early placenta, and therefore must arise after the first trimester.

Identification of autophagic vacuoles and regulators of autophagy in villous trophoblast from normal term pregnancies and in fetal growth restriction

Fetal growth restriction (FGR) is a serious pregnancy complication associated with increased perinatal mortality and morbidity. Although the majority of cases with FGR result from placental dysfunction, the pathophysiology is incompletely understood. Autophagy is a physiological form of cell degradation exacerbated by nutrient and oxygen restriction, which are both thought to play a role in the aetiology of FGR. We hypothesized that autophagy is present in the normal human placenta and is exaggerated in FGR. Autophagy was assessed in electron micrographs from normal and FGR placentas and by Western blotting for LC3B and LAMP-2. The localization of regulators of autophagy was examined by immunohistochemistry. Culture of BeWo cells was used to investigate whether nutrient and/or oxygen deprivation can induce autophagy in trophoblast. Autophagy predominantly localized to the syncytiotrophoblast layer and autophagosomes were more frequent in FGR. The regulators LAMP-2, LC3B, Beclin-1, ATG 5, ATG9 and ATG16L1 were all present in villous trophoblast. LAMP-2 immunostaining was more punctate in FGR. In BeWo cells, culture in reduced oxygen tension and/or serum depleted conditions led to the appearance of autophagosomes which was associated with changes in LAMP-2 configuration. We conclude that autophagy in human term placenta may be involved in the placental dysfunction present in FGR.

Changes in the maternal cytokine profile in pregnancies complicated by fetal growth restriction

Fetal growth restriction (FGR) is an important and poorly understood condition of pregnancy, which results in significant fetal, neonatal and long-term morbidity and mortality. The aetiology of FGR is unknown and is likely to result from sub-optimal placental implantation and feto-maternal immunological interaction. The diagnostic criteria for FGR vary between studies, and the condition often occurs with preeclampsia (PET). We present a review of studies of maternal cytokines in FGR and compare these with studies of Small for Gestational Age and PET pregnancies.

The Role of Maternal Smoking in Effect of Fetal Growth Restriction on Poor Scholastic Achievement in Elementary School

Fetal growth restriction and maternal smoking during pregnancy are independently implicated in lowering intellectual attainment in children. We hypothesized that only reduction of fetal growth that is attributable to extrinsic causes (e.g., maternal smoking) affects intellectual development of a child. Cross-sectional survey of 3,739 students in Nova Scotia (Canada) in 2003 was linked with the perinatal database, parental interviews on socio-demographic factors and the performance on standardized tests when primarily 11–12 years of age, thereby forming a retrospective cohort. Data was analyzed using hierarchical logistic regression with correction for clustering of children within schools. The risk of poor test result among children born small-for-gestational-age (SGA) to mothers who smoked was 29.4%, higher than in any other strata of maternal smoking and fetal growth. The adjusted odds ratio among SGA children born to mothers who smoked was the only one elevated compared to children who were not growth restricted and born to mothers who did not smoke (17.0%, OR = 1.46, 95% CI 1.02, 2.09). Other perinatal, maternal and socio-demographic factors did not alter this pattern of effect modification. Heterogeneity of etiology of fetal growth restriction should be consider in studies that address examine its impact on health over life course.

The Cohen diabetic rat as a model for fetal growth restriction: Vitamins C and E reduce fetal oxidative stress but do not restore normal growth

Fetal growth restriction (FGR) describes newborns that were born small for gestational age. The etiology of FGR is unknown, but it is assumed that it is the consequences of both genetic and environmental factors, and that one of the important environmental factors is oxidative stress. In this study we used the Cohen diabetic (CD) rats (sensitive and resistant strains) and the original Sabra strain fed either high sucrose low copper diet-HSD or regular diet-RD to evaluate the genetic and environmental factors contributing to FGR. In addition, we treated the pregnant rats with antioxidants (vitamins C and E added to their food) to evaluate the effects of antioxidants in the prevention of FGR and in changing the redox state of the fetuses. Methods The study was performed on term 21-day-old fetuses of the three strains fed RD or HSD. Fetal and placental weight and fetal crown rump length were measured. Heart, kidneys, brain and liver were also weighted and studied. The fetal and placental redox status was investigated by studying the levels of Malondialdehyde (MDA) to determine the lipid peroxidation damage and by measuring the activity of catalase (CAT) and superoxide dismutase (SOD) enzymes. Similar studies were performed following the addition of 0.1% of vitamins C and E to the diet. Results FGR in the Cohen diabetic rats is a consequence of genetic (6–20% reduction in fetal weight in the CDr and CDs compared to Sabra) and environmental (11–36% reduction in fetal weight while on HSD) factors, with greater susceptibility in the CDs diabetic rats. Increased lipid peroxidation was observed in some of the organs only in HSD, however not only in the sensitive strain. In each organ, different patterns of anti oxidant capacity were observed. The addition of antioxidants to the food significantly reduced the signs of enhanced oxidative stress in all animals but partially restored normal fetal growth only in the diabetic CDs rats. This may imply that in this model oxidative stress is apparently not a major contributor to FGR. Conclusions Cohen diabetic rats are a good model for the study of the interaction of genetic and environmental factors in the development of FGR. Maternal nutrition can influence the antioxidant capacity of the fetal organs which is modified by antioxidants. However, FGR in our model does not seem to result primarily from enhanced oxidative stress, as it is only partially affected by the antioxidant treatment. Thus, the repeated observations of oxidative stress in SGA infants may be a resulting metabolic alteration of FGR and not the main cause.

Fetal growth restriction is associated with increased apoptosis in the chorionic trophoblast cells of human fetal membranes

The aim of the study was to determine the incidence and spatial distribution of apoptotic cell in fetal membranes obtained from human pregnancies complicated with fetal growth restriction (FGR) for which there was no established cause. Fetal membrane samples from normal ( n = 10) and FGR-affected ( n = 10) pregnancies were collected and stored following delivery. The incidence of apoptosis and the number of apoptotic cells in normal and FGR-affected fetal membranes were determined using immunohistochemistry and a monoclonal antibody for neo-epitope of cytokeratin-18, M30. The level of apoptotic proteins in FGR-fetal membranes compared to the normal tissue was determined using Western immunoblotting analysis. Multiple labeling of trophoblast cells using immunofluorescence markers was used to investigate regional differences in localization of apoptotic cells between normal and FGR-affected fetal membranes. Apoptosis was detected in both normal and FGR-affected fetal membranes. However, quantitative analysis of apoptotic cells by immunohistochemistry showed a significant increase in FGR-affected fetal membranes compared to normal ( p < 0.005). Furthermore, it was observed that apoptotic cells were predominantly localized to chorio-decidual layer of the fetal membrane. By using semi-quantitative analysis of Western immunoblotting, a significant increase in the levels of the apoptotic marker proteins poly-ribo (ADP) polymerase (PARP) and the neo-epitope of cytokeratin-18 were observed in FGR-affected fetal membranes compared to normal ( p < 0.005). Immunofluorescence studies further confirmed the restriction of the apoptotic cells to the chorionic trophoblast cells in FGR-affected fetal membranes. Our results document for the first time an increased incidence of apoptosis in FGR-affected fetal membranes, with the apoptotic cells restricted primarily to the chorionic trophoblast layer of the fetal membranes. Increased apoptosis in FGR-affected fetal membranes may impair functions of the fetal membranes that are important for normal fetal development and growth. Elucidation of the molecular mechanisms involved in the control of apoptosis in the chorionic trophoblast layer in the FGR-affected fetal membranes may provide further insights into the etiology of FGR.

Familial aggregation of fetal growth restriction in a French cohort of 7,822 term births between 1971 and 1985.

An association between fetal growth restriction and increased rates of metabolic and cardiovascular diseases in adulthood has been reported. This study evaluated familial aggregation of fetal growth restriction in term births. The population consisted of 3,505 sibships comprised of 7,822 full-term singleton infants born between 1971 and 1985 in Haguenau, France, and selected from a regional register of births. Sib-sib odds ratios were estimated for being born small for gestational age (SGA), defined as having a birth weight below the 10th percentile of the sex-specific curve of birth weight by week of gestation. SGA births were further stratified according to ponderal index (birth weight/length(3)). After adjustment for maternal factors, the sib-sib odds ratios were 4.8 (95% confidence interval (CI): 3.7, 6.3) for all SGA births, 7.7 (95% CI: 4.1, 14.7) for SGA births with a low ponderal index (<10th percentile), and 4.4 (95% CI: 2.3, 8.2) for SGA births with a normal ponderal index (25th-75th percentile). None of the maternal factors investigated significantly influenced the magnitude of these odds ratios. This strong residual sib-sib aggregation suggests a role for genetic and/or shared environmental factors in the etiology of fetal growth restriction, especially when associated with a low ponderal index.