Cause Of Fetal Growth Restriction Research Articles

Placental Malaria Induces a Unique Methylation Profile Associated with Fetal Growth Restriction.

Fetal growth restriction (FGR) is associated with perinatal death and adverse birth outcomes, as well as long-term complications, including increased childhood morbidity, abnormal neurodevelopment, and cardio-metabolic diseases in adulthood. Placental epigenetic reprogramming associated with FGR may mediate these long-term outcomes. Placental malaria (PM), characterized by sequestration of Plasmodium falciparum-infected erythrocytes in placental intervillous space, is the leading global cause of FGR, but its impact on placental epigenetics is unknown. We hypothesized that placental methylomic profiling would reveal common and distinct mechanistic pathways of non-malarial and PM-associated FGR. We analyzed placentas from a US cohort with no malaria exposure (n = 12) and a cohort from eastern Uganda, a region with a high prevalence of malaria (n = 12). From each site, 8 cases of FGR (defined as birth weight <10%ile for gestational age by Intergrowth-21 standard curves) and 4 healthy controls with normal weight were analyzed. PM was diagnosed by placental histopathology. We compared the methylation levels of over 850K CpGs of the placentas using Infinium MethylationEPIC v1 microarray. Non-malarial FGR was associated with 65 differentially methylated CpGs (DMCs), whereas PM-FGR was associated with 133 DMCs, compared to their corresponding controls without FGR. One DMC (cg16389901, located in the promoter region of BMP4) was commonly hypomethylated in both groups. We identified 522 DMCs between non-malarial FGR vs. PM-FGR placentas, which was independent of differing geographic location or cellular composition. Placentas with PM-associated FGR have distinct methylation profiles as compared to placentas with non-malarial FGR, suggesting novel epigenetic reprogramming in response to malaria. Larger cohort studies are needed to determine the distinct long-term health outcomes in PM-associated FGR pregnancies.

Integrated transcriptomic analysis and machine learning for characterizing diagnostic biomarkers and immune cell infiltration in fetal growth restriction.

Fetal growth restriction (FGR) occurs in 10% of pregnancies worldwide. Placenta dysfunction, as one of the most common causes of FGR, is associated with various poor perinatal outcomes. The main objectives of this study were to screen potential diagnostic biomarkers for FGR and to evaluate the function of immune cell infiltration in the process of FGR. Firstly, differential expression genes (DEGs) were identified in two Gene Expression Omnibus (GEO) datasets, and gene set enrichment analysis was performed. Diagnosis-related key genes were identified by using three machine learning algorithms (least absolute shrinkage and selection operator, random forest, and support vector machine model), and the nomogram was then developed. The receiver operating characteristic curve, calibration curve, and decision curve analysis curve were used to verify the validity of the diagnostic model. Using cell-type identification by estimating relative subsets of RNA transcripts (CIBERSORT), the characteristics of immune cell infiltration in placental tissue of FGR were evaluated and the candidate key immune cells of FGR were screened. In addition, this study also validated the diagnostic efficacy of TREM1 in the real world and explored associations between TREM1 and various clinical features. By overlapping the genes selected by three machine learning algorithms, four key genes were identified from 290 DEGs, and the diagnostic model based on the key genes showed good predictive performance (AUC = 0.971). The analysis of immune cell infiltration indicated that a variety of immune cells may be involved in the development of FGR, and nine candidate key immune cells of FGR were screened. Results from real-world data further validated TREM1 as an effective diagnostic biomarker (AUC = 0.894) and TREM1 expression was associated with increased uterine artery PI (UtA-PI) (p-value = 0.029). Four candidate hub genes (SCD, SPINK1, TREM1, and HIST1H2BB) were identified, and the nomogram was constructed for FGR diagnosis. TREM1 was not only associated with a variety of key immune cells but also correlated with increased UtA-PI. The results of this study could provide some new clues for future research on the prediction and treatment of FGR.

Molecular regulators of defective placental and cardiovascular development in fetal growth restriction.

Placental insufficiency is one of the major causes of fetal growth restriction (FGR), a significant pregnancy disorder in which the fetus fails to achieve its full growth potential in utero. As well as the acute consequences of being born too small, affected offspring are at increased risk of cardiovascular disease, diabetes and other chronic diseases in later life. The placenta and heart develop concurrently, therefore placental maldevelopment and function in FGR may have profound effect on the growth and differentiation of many organ systems, including the heart. Hence, understanding the key molecular players that are synergistically linked in the development of the placenta and heart is critical. This review highlights the key growth factors, angiogenic molecules and transcription factors that are common causes of defective placental and cardiovascular development.

N-acetylcysteine and Hydroxychloroquine Ameliorate ADMA-Induced Fetal Growth Restriction in Mice via Regulating Oxidative Stress and Autophagy.

Fetal growth restriction (FGR) seriously threatens perinatal health. The main cause of FGR is placental malperfusion, but the specific mechanism is still unclear, and there is no effective treatment for FGR. We constructed a FGR mouse model by adding exogenous asymmetric dimethylarginine (ADMA) through in vivo experiments and found that ADMA could cause placental dysplasia and induce the occurrence of FGR. Compared with the control group, reactive oxygen species (ROS) production in the placenta was increased in mice with FGR, and the expression of autophagy-related proteins p-AKT/AKT, p-mTOR/mTOR, and P62 was significantly decreased, while the expression of Beclin-1 and LC3-II was significantly increased in the FGR group. Furthermore, ADMA had a favorable effect in promoting the formation of autophagosomes. Hydroxychloroquine (HCQ) and N-acetylcysteine (NAC) improved ADMA-induced disorders of placental development and alleviated ADMA-induced FGR. This study found that ADMA could cause excessive autophagy of trophoblasts by increasing the level of oxidative stress, ultimately leading to the occurrence of FGR, and HCQ and NAC had therapeutic effects on ADMA-induced FGR.

Leptin deficiency, a potential mechanism for impaired fetal lung development in uteroplacental insufficiency?

Uteroplacental insufficiency (UPI) is a major cause of fetal growth restriction (FGR). Leptin, an adipokine, has been shown to play a vital role in fetal organogenesis. There is evidence reporting leptin deficiency in preterm and growth-restricted fetuses. In this issue of Pediatric Research, Yuliana et al. report leptin expression and lung development in UPI-induced FGR rats. UPI-induced FGR rats expressed decreased lung leptin and had impaired lung development, as shown by decreased surface area and lung volume. They also found a significant association between lung radial alveolar count, serum leptin, von Willebrand factor, and specific metabolites on metabolomic analyses. Previous studies on leptin supplementation in vivo have been associated with improvement in lung maturation; supporting the evidence, that leptin improves lung growth and development in FGR and may have future therapeutic potential in the improvement of respiratory outcomes in these infants. Future studies to support evidence of this association in humans are warranted.

Calorie restriction during gestation impacts maternal and offspring fecal microbiome in mice.

Maternal undernutrition is the most common cause of fetal growth restriction (FGR) worldwide. FGR increases morbidity and mortality during infancy, as well as contributes to adult-onset diseases including obesity and type 2 diabetes. The role of the maternal or offspring microbiome in growth outcomes following FGR is not well understood. FGR was induced by 30% maternal calorie restriction (CR) during the second half of gestation in C57BL/6 mice. Pup weights were obtained on day of life 0, 1, and 7 and ages 3, 4 and 16 weeks. Fecal pellets were collected from pregnant dams at gestational day 18.5 and from offspring at ages 3 and 4 weeks of age. Bacterial genomic DNA was used for amplification of the V4 variable region of the 16S rRNA gene. Multivariable associations between maternal CR and taxonomic abundance were assessed using the MaAsLin2 package. Associations between microbial taxa and offspring outcomes were performed using distance-based redundancy analysis and Pearson correlations. FGR pups weighed about 20% less than controls. Beta but not alpha diversity differed between control and CR dam microbiomes. CR dams had lower relative abundance of Turicibacter, Flexispira, and Rikenella, and increased relative abundance of Parabacteroides and Prevotella. Control and FGR offspring microbiota differed by beta diversity at ages 3 and 4 weeks. At 3 weeks, FGR offspring had decreased relative abundance of Akkermansia and Sutterella and increased relative abundance of Anaerostipes and Paraprevotella. At 4 weeks, FGR animals had decreased relative abundance of Allobaculum, Sutterella, Bifidobacterium, and Lactobacillus, among others, and increased relative abundance of Turcibacter, Dorea, and Roseburia. Maternal Helicobacter abundance was positively associated with offspring weight. Akkermansia abundance at age 3 and 4 weeks was negatively associated with adult weight. We demonstrate gut microbial dysbiosis in pregnant dams and offspring at two timepoints following maternal calorie restriction. Additional research is needed to test for functional roles of the microbiome in offspring growth outcomes.

Value of non-invasive prenatal testing for rare autosomal trisomies in fetuses

To evaluate the value of non-invasive prenatal testing(NIPT)for detecting rare autosomal trisomies in fetuses. We retrospectively analyzed the data of cases with rare autosomal trisomies detected by NIPT in our hospital from January, 2019 to April, 2023.Invasive prenatal diagnostic tests including chromosome karyotype analysis, chromosome microarray analysis, copy number variation sequencing, and fluorescence in situ hybridization were performed in all the cases after clinical counseling, and their test results and pregnancy outcomes were analyzed. Among 25 282 women receiving NIPT, 56(0.22%)were found to have high risks for rare autosomal trisomies in circulating plasma DNA.Trisomy 7 was the most frequently detected trisomy, accounting for 45% of the total cases(25/56), while trisomies 1, 4, 17, and 19 were not detected.Among the 46 cases with genetic results of the fetuses, 10 were identified to have true fetal mosaicism.The overall positive predictive value of NIPT was 22%(10/46)for rare autosomal trisomies, and 10% for trisomy 7(2/20).Of the 52 cases followed up for pregnancy outcomes, 33(63%)cases without fetal mosaicism resulted in normal live births, while 10 had unfavorable outcomes including fetal growth restriction, preterm birth, and maternal complications, and among them fetal growth restriction was the most typical and the earliest condition observed in these cases.Among the 22 followed up cases of non-true mosaicism for trisomy 7, 82% resulted in normal live births. NIPT increases the detection rate of true fetal mosaicism but with a low positive predictive value.Most of the cases with non-true mosaicism, particularly trisomy 7, can have favorable outcomes.NIPT can also be useful in identifying causes of fetal growth restriction in the second and third trimesters when invasive prenatal testing does not reveal abnormalities.

Alterations in the Gut Microbiome and Metabolisms in Pregnancies with Fetal Growth Restriction.

Fetuses diagnosed with fetal growth restriction (FGR) are at an elevated risk of stillbirth and adulthood morbidity. Gut dysbiosis has emerged as one of the impacts of placental insufficiency, which is the main cause of FGR. This study aimed to characterize the relationships among the intestinal microbiome, metabolites, and FGR. Characterization was conducted on the gut microbiome, fecal metabolome, and human phenotypes in a cohort of 35 patients with FGR and 35 normal pregnancies (NP). The serum metabolome was analyzed in 19 patients with FGR and 31 normal pregnant women. Multidimensional data was integrated to reveal the links between data sets. A fecal microbiota transplantation mouse model was used to determine the effects of the intestinal microbiome on fetal growth and placental phenotypes. The diversity and composition of the gut microbiota were altered in patients with FGR. A group of microbial species altered in FGR closely correlated with fetal measurements and maternal clinical variables. Fecal and serum metabolism profiles were distinct in FGR patients compared to those in the NP group. Altered metabolites were identified and associated with clinical phenotypes. Integrated multi-omics analysis revealed the interactions among gut microbiota, metabolites, and clinical measurements. Microbiota from FGR gravida transplanted to mice progestationally induced FGR and placental dysfunction, including impaired spiral artery remodeling and insufficient trophoblast cell invasion. Taken together, the integration of microbiome and metabolite profiles from the human cohort indicates that patients with FGR endure gut dysbiosis and metabolic disorders, which contribute to disease pathogenesis. IMPORTANCE Downstream of the primary cause of fetal growth restriction are placental insufficiency and fetal malnutrition. Gut microbiota and metabolites appear to play an important role in the progression of gestation, while dysbiosis induces maternal and fetal complications. Our study elaborates the significant differences in microbiota profiles and metabolome characteristics between women with FGR and normal pregnancies. This is the first attempt so far that reveals the mechanistic links in multi-omics in FGR, providing a novel insight into host-microbe interaction in placenta-derived diseases.

An miRNA-mRNA integrative analysis in human placentas and mice: role of the Smad2/miR-155-5p axis in the development of fetal growth restriction.

Introduction: Functional disorder of the placenta is the principal cause of fetal growth restriction (FGR), usually cured with suitable clinical treatment and good nursing. However, some FGR mothers still give birth to small for gestational age (SGA) babies after treatment. The ineffectiveness of treatment in such a group of patients confused physicians of obstetrics and gynecology. Methods: In this study, we performed a microRNA-messenger RNA integrative analysis of gene expression profiles obtained from Gene Expression Omnibus. Differentially expressed genes were screened and checked using quantitative polymerase chain reaction. Target genes of significantly changed microRNA were screened and enriched for Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses. Function of the obtained microRNA-messenger RNA was evaluated using HTR-8/SVneo trophoblast cells, human umbilical vein endothelial cells, and heterozygote male mice. Result: MiR-155-5p was upregulated (p = 0.001, fold-change = 2.275) in fetal-side placentals. Among the hub genes identified as key targets for miR-155-5p in fetal reprogramming, Smad2 was downregulated (p = 0.002, fold change = 0.426) and negatively correlated with miR-155-5p expression levels (r = -0.471, p < 1.0 E - 04) in fetal-side placental tissues. The miR-155-5p mimic blocks Smad2 expression and suppresses villous trophoblast cell and endothelial cell function (proliferation, migration, and invasion), indicating a close relationship with placental development. Luciferase assays further confirmed the targeting of miR-155-5p to Smad2. Furthermore, Smad2+/- heterozygote male mice were born small with low body weight (p = 0.0281) and fat composition (p = 0.013) in the fourth week post-natal. Discussion: We provide the first evidence of the role of the Smad2/miR-155-5p axis in the placental pathologies of FGR. Our findings elucidate the pathogenesis of FGR and provide new therapeutic targets.

Maladaptation of the maternal cardiovascular system as a cause of fetal growth restriction: Study rationale and design.

Maladaptation of the maternal cardiovascular system as a cause of fetal growth restriction: Study rationale and design.

Hippocampal mTOR Dysregulation and Morphological Changes in Male Rats after Fetal Growth Restriction

Fetal growth restriction (FGR) has been linked to long-term neurocognitive impairment, especially in males. To determine possible underlying mechanisms, we examined hippocampal cellular composition and mTOR signaling of male rat FGR offspring during main brain growth and development (postnatal days (PND) 1 and 12). FGR was either induced by a low-protein diet throughout pregnancy, experimental placental insufficiency by bilateral uterine vessel ligation or intrauterine stress by “sham” operation. Offspring after unimpaired gestation served as common controls. Low-protein diet led to a reduced cell density in the molecular dentate gyrus subregion, while intrauterine surgical stress was associated with increased cell density in the cellular CA2 subregion. Experimental placental insufficiency caused increased mTOR activation on PND 1, whereas intrauterine stress led to mTOR activation on PND 1 and 12. To determine long-term effects, we additionally examined mTOR signaling and Tau phosphorylation, which is altered in neurodegenerative diseases, on PND 180, but did not find any changes among the experimental groups. Our findings suggest that hippocampal cellular proliferation and mTOR signaling are dysregulated in different ways depending on the cause of FGR. While a low-protein diet induced a decreased cell density, prenatal surgical stress caused hyperproliferation, possibly via increased mTOR signaling.

Fetal growth restriction is characterized by changes in a biomarker of glycocalyx integrity

Placental insufficiency is a major cause of fetal growth restriction (FGR). The glycocalyx, a gel-like layer, covers the luminal surface of the endothelium and the intervillous space of the placenta, and it is crucial to maintain endothelial cell integrity and to prevent clotting. Syndecans are a major component of the glycocalyx. Syndecan-1 (SDC1) is a protoglycan produced by the syncytiotrophoblast that is capable of storing angiogenic factors and has important anticoagulant properties. This study was performed to determine whether FGR is associated with abnormalities in the glycocalyx, as reflected by SDC1 concentrations.

Severe early-onset fetal growth restriction: What do we tell the prospective parents?

Fetal growth restriction (FGR) is a common complication of pregnancy, associated withhigher risk of perinatal mortality and adverse health and developmental outcomes for surviving infants. True FGR relates to a pathological restriction of fetal growth resulting from complex interactions between maternal, placental, fetal, and environmental factors. Early-onset FGR (onset <32weeks' gestation) is often first suspected at routine mid-trimester sonographic assessment of fetal morphology, or identified aspart of the placental syndrome, commonly maternal pre-eclampsia. Prenatal investigations may identify the cause of FGR. Timing of delivery is guided by serial sonographic surveillance of fetal growth and well-being and maternal condition, balancing the risk of stillbirth with the benefits of advancing gestation. This is particularly pertinent to severe early-onset FGR, a leading iatrogenic cause of very preterm birth. Prognosis is largely determined by the severity of FGR and its causes, gestation at birth, and birthweight. Pregnancy termination may be considered. Antenatal careand delivery in a tertiary center, provided by a multi-disciplinary team with expertise in managing high-risk pregnancies, are imperative to optimizing outcomes.

Structural changes, increased hypoxia, and oxidative DNA damage in placenta due to maternal smokeless tobacco use.

Smokeless tobacco (SLT) consumption during pregnancy is a well-recognized health risk that causes placental damage including hypoxia and oxidative damage. Although consumption of SLT by women varies from region to region, majority of tea leave pluckers consume SLT for relieving stress and pain. Still, the effects of SLT consumption have not been evaluated in tea garden workers (TGW). While previous studies have attempted to report effects of cigarette smoke using in vitro model, hypoxia-inducible factor (HIF)-1α expression in human placentae from pregnant women exposed to SLT has not been previously studied. This study was aimed to explore the effects of SLT consumption on placental structure, expression of HIF-1α and oxidative DNA damage in sample population of TGW. A total of 51 placentae were collected from SLT users and nonusers (n=30 and 21, respectively) with full-term normal delivery, who were involved in the plucking of tea leaves during pregnancy in tea plantation. Low birth weight (LBW, i.e., weight <2,500 g) and normal birth weight (NBW) groups among both SLT user and nonuser were compared for the stated parameters. Placental tissues were processed for transmission electron microscopy (TEM) study and immunohistochemical analysis for the expression of HIF-1α and 8-hydroxy-2'-deoxyguanosine (8-OHdG). Altered ultrastructural characteristics were observed in the tertiary villi of LBW group among SLT users which included endothelial cells protrusion into capillary lumen, degenerated nuclei, significant thickening of trophoblast basement membrane and vasculo-syncytial membrane, abnormalities of the microvilli, swollen or damaged mitochondria, and dilatation in endoplasmic reticulum cisternae. Furthermore, significant reduction in the perimeter, area, and number of the stromal capillary of the tertiary villi of placenta were found in LBW group as compared with NBW group from the SLT users. Enhanced expression for HIF-1α and oxidative DNA damage (8-OHdG) biomarker was observed in SLT users as compared with nonusers. Maternal SLT exposure during pregnancy may be associated with villus hypoxia and consequently oxidative DNA damage. It is presumed that deleterious effect of SLT exposure on placenta could result in impairment of placental barrier, and restrict nutrient and oxygen supply from mother to fetus, and thus could be a cause of fetal growth restriction.

Recent Advances of MicroRNAs, Long Non-coding RNAs, and Circular RNAs in Preeclampsia.

Preeclampsia is a clinical syndrome characterized by multiple-organ dysfunction, such as maternal hypertension and proteinuria, after 20 weeks of gestation. It is a common cause of fetal growth restriction, fetal malformation, and maternal death. At present, termination of pregnancy is the only way to prevent the development of the disease. Non-coding RNAs, including microRNAs, long non-coding RNAs, and circular RNAs, are involved in important pathological and physiological functions in life cycle activities including ontogeny, reproduction, apoptosis, and cell reprogramming, and are closely associated with human diseases. Accumulating evidence suggests that non-coding RNAs are involved in the pathogenesis of preeclampsia through regulation of various physiological functions. In this review, we discuss the current evidence of the pathogenesis of preeclampsia, introduce the types and biological functions of non-coding RNA, and summarize the roles of non-coding RNA in the pathophysiological development of preeclampsia from the perspectives of oxidative stress, hypoxia, angiogenesis, decidualization, trophoblast invasion and proliferation, immune regulation, and inflammation. Finally, we briefly discuss the potential clinical application and future prospects of non-coding RNA as a biomarker for the diagnosis of preeclampsia.

Enhanced Nitrite-Mediated Relaxation of Placental Blood Vessels Exposed to Hypoxia Is Preserved in Pregnancies Complicated by Fetal Growth Restriction.

Nitric oxide (NO) is essential in the control of fetoplacental vascular tone, maintaining a high flow−low resistance circulation that favors oxygen and nutrient delivery to the fetus. Reduced fetoplacental blood flow is associated with pregnancy complications and is one of the major causes of fetal growth restriction (FGR). The reduction of dietary nitrate to nitrite and subsequently NO may provide an alternative source of NO in vivo. We have previously shown that nitrite induces vasorelaxation in placental blood vessels from normal pregnancies, and that this effect is enhanced under conditions of hypoxia. Herein, we aimed to determine whether nitrite could also act as a vasodilator in FGR. Using wire myography, vasorelaxant effects of nitrite were assessed on pre-constricted chorionic plate arteries (CPAs) and veins (CPVs) from normal and FGR pregnancies under normoxic and hypoxic conditions. Responses to the NO donor, sodium nitroprusside (SNP), were assessed in parallel. Nitrate and nitrite concentrations were measured in fetal plasma. Hypoxia significantly enhanced vasorelaxation to nitrite in FGR CPAs (p < 0.001), and in both normal (p < 0.001) and FGR (p < 0.01) CPVs. Vasorelaxation to SNP was also potentiated by hypoxia in both normal (p < 0.0001) and FGR (p < 0.01) CPVs. However, compared to vessels from normal pregnancies, CPVs from FGR pregnancies showed significantly lower reactivity to SNP (p < 0.01). Fetal plasma concentrations of nitrate and nitrite were not different between normal and FGR pregnancies. Together, these data show that nitrite-mediated vasorelaxation is preserved in FGR, suggesting that interventions targeting this pathway have the potential to improve fetoplacental blood flow in FGR pregnancies.

Cardiac function in fetal growth restriction.

Fetal growth restriction (FGR) is defined as the inability of the fetus to reach its growth potential. According to the onset of the disease is defined early (<32 weeks) or late (≥32 weeks). FGR is associated with an increased risk of adverse short- and long-term outcomes, including hypoxemic events and neurodevelopmental delay compared to normally grown fetuses and increased risk of complications in the infanthood and adulthood. The underlying cause of FGR is placental insufficiency leading to chronic fetal hypoxia that affects cardiac hemodynamic with different mechanism in early and late onset growth restriction. In early onset FGR adaptive mechanisms involve the diversion of the cardiac output preferentially in favor of the brain and the heart, while abnormal arterial and venous flow manifest in the case of further worsening of fetal hypoxia. In late FGR the fetal heart shows a remodeling of its shape and function mainly related to a reduction of umbilical vein flow. In this review we discuss the modifications occurring at the level of the fetal cardiac hemodynamic in fetuses with early and late FGR.

First-trimester utero-placental (vascular) development and embryonic and fetal growth: The Rotterdam periconception cohort

IntroductionImpaired placental development is a major cause of fetal growth restriction (FGR) and early detection will therefore improve antenatal care and birth outcomes. Here we aim to investigate serial first-trimester ultrasound markers of utero-placental (vascular) development in association with embryonic and fetal growth. MethodsIn a prospective cohort, we periconceptionally included 214 pregnant women. Three-dimensional power Doppler ultrasonography at 7, 9 and 11 weeks gestational age (GA) was used to measure placental volumes (PV) and basal plate surface area by Virtual Organ Computer-aided AnaLysis™, and utero-placental vascular volume (uPVV), crown-rump length (CRL) and embryonic volume (EV) by a V-scope volume rendering application. Estimated fetal weight (EFW) was measured by ultrasound at 22 and 32 weeks GA and birth weight percentile (BW) was recorded. Linear mixed models and regression analyses were applied and appropriately adjusted. All analyses were stratified for fetal sex. ResultsPV trajectories were positively associated with CRL (βadj = 0.416, 95%CI:0.255; 0.576, p < 0.001), EV (βadj = 0.220, 95%CI:0.058; 0.381, p = 0.008) and EFW (βadj = 0.182, 95%CI:0.012; 0.352, p = 0.037). uPVV trajectories were positively associated with CRL (βadj = 0.203, 95%CI 0.021; 0.384, p = 0.029). In girls, PV trajectories were positively associated with CRL (p < 0.001), EV (p = 0.018), EFW (p = 0.026), and uPVV trajectories were positively associated with BW (p = 0.040). In boys, positive associations were shown between PV trajectories and CRL (p = 0.002), and between uPVV trajectories and CRL (p = 0.046). DiscussionFirst-trimester utero-placental (vascular) development is associated with embryonic and fetal growth, with fetal sex specific modifications. This underlines the opportunity to monitor first-trimester placental development and supports the associations with embryonic and fetal growth.

FIGO (international Federation of Gynecology and obstetrics) initiative on fetal growth: best practice advice for screening, diagnosis, and management of fetal growth restriction.

Fetal growth restriction (FGR) is defined as the failure of the fetus to meet its growth potential due to a pathological factor, most commonly placental dysfunction. Worldwide, FGR is a leading cause of stillbirth, neonatal mortality, and short- and long-term morbidity. Ongoing advances in clinical care, especially in definitions, diagnosis, and management of FGR, require efforts to effectively translate these changes to the wide range of obstetric care providers. This article highlights agreements based on current research in the diagnosis and management of FGR, and the areas that need more research to provide further clarification of recommendations. The purpose of this article is to provide a comprehensive summary of available evidence along with practical recommendations concerning the care of pregnancies at risk of or complicated by FGR, with the overall goal to decrease the risk of stillbirth and neonatal mortality and morbidity associated with this condition. To achieve these goals, FIGO (the International Federation of Gynecology and Obstetrics) brought together international experts to review and summarize current knowledge of FGR. This summary is directed at multiple stakeholders, including healthcare providers, healthcare delivery organizations and providers, FIGO member societies, and professional organizations. Recognizing the variation in the resources and expertise available for the management of FGR in different countries or regions, this article attempts to take into consideration the unique aspects of antenatal care in low-resource settings (labelled “LRS” in the recommendations). This was achieved by collaboration with authors and FIGO member societies from low-resource settings such as India, Sub-Saharan Africa, the Middle East, and Latin America.

493 Using human monogenic disease to quantify the contribution of fetal insulin to birth weight

Fetal insulin affects birth weight, but the extent of this relationship has not been established in humans, nor whether it has any implications for postnatal growth. We sought to investigate this by studying birth size and postnatal growth in individuals with monogenic diseases which result in absent insulin secretion in utero. We studied birth size in individuals with a homozygous insulin gene (INS) mutation or pancreatic agenesis (n=64 for weight, n=17 for length) born after 31 weeks gestation and compared with international growth standards for gestational age and sex (SDS). Postnatal growth was studied in individuals with INS mutations. We analyzed serial measures of weight and length until the age of four years (n=10 and 9, respectively) and most recent available weight and height (n=16 and 15, respectively). In all individuals birth weight and length were low (median (IQR) SDS -3.11 (-3.53,-2.61) and -2.86 (-3.62,-1.90), respectively). Birth weight adjusted to 40 weeks gestation was 1711 g (95% CI 1601,1821 g) vs expected of 3320 g (Fig. 1), showing non-insulin-mediated growth represents 52% of normal birth weight at term. Catch-up growth was rapid with median (IQR) weight and length SDS -0.27 (-0.37,-0.17) and -0.30 (-1.33,0.002), respectively, at 12 months, and 0.02 (-0.35,0.78) and 0.00 (-0.34,0.21), respectively, at 24 months (Fig. 2). Most recent available weight and height SDS were 0.19 (-0.67,1.33) and -0.78 (-1.78,-0.19), respectively. Monogenic diseases resulting in absent fetal insulin have enabled us to answer fundamental questions about early growth in humans. Ultimately, fetal insulin accounts for half of birth weight at term and could be an important cause of fetal growth restriction that is characterised by rapid catch-up growth. Future studies investigating outcomes arising from low and high birth weight should determine differences in insulin and non-insulin-mediated fetal growth, and consider whether they might have different implications for pregnancy outcomes and long-term risk of disease.View Large Image Figure ViewerDownload Hi-res image Download (PPT)