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Pre-eclampsia and fetal growth restriction arise from disorders of placental development and have some shared mechanistic features. Initiation is often rooted in the maldevelopment of a maternal–placental blood supply capable of providing for the growth requirements of the fetus in later pregnancy, without exerting undue stress on maternal body systems. Here, we review normal development of a placental bed with a safe and adequate blood supply and a villous placenta–blood interface from which nutrients and oxygen can be extracted for the growing fetus. We consider disease mechanisms that are intrinsic to the maternal environment, the placenta or the interaction between the two. Systemic signalling from the endocrine placenta targets the maternal endothelium and multiple organs to adjust metabolism for an optimal pregnancy and later lactation. This signalling capacity is skewed when placental damage occurs and can deliver a dangerous pathogenic stimulus. We discuss the placental secretome including glycoproteins, microRNAs and extracellular vesicles as potential biomarkers of disease. Angiomodulatory mediators, currently the only effective biomarkers, are discussed alongside non-invasive imaging approaches to the prediction of disease risk. Identifying the signs of impending pathology early enough to intervene and ameliorate disease in later pregnancy remains a complex and challenging objective.Pre-eclampsia and fetal growth restriction are diseases of pregnancy that arise from disorders of placental development. This Review discusses healthy development of the placenta and considers disease mechanisms, biomarkers and diagnosis of pre-eclampsia and fetal growth restriction.

Background: There is an unexplained excess of cerebral palsy among male babies. There is also variation in the proportion of more severe cases by birth weight. It has recently been shown that the rate of cerebral palsy increases as intrauterine size deviates up or down from an optimum about one standard deviation heavier than population mean weight-for-gestation. Aims: To determine whether the gender ratio or the severity of cases also varies with intrauterine size. Methods: A total of 3454 cases of cerebral palsy among single births between 1976 and 1990 with sufficient data to assign case severity (based on intellectual impairment and walking ability) and to compare weight-for-gestation at birth to sex specific fetal growth standards, were aggregated from nine separate registers in five European countries. Results: The greater the degree to which growth deviates either up or down from optimal weight-for-gestation at birth, the higher is the rate of cerebral palsy, the larger is the proportion of male cases, and the more severe is the functional disability. Compared to those with optimum growth the risk of more severe cerebral palsy in male babies is 16 times higher for those with a birth weight below the 3rd centile and four times higher when birth weight is above the 97th centile. In contrast, for mild cerebral palsy in female babies the excess risks at these growth extremes are about half these magnitudes. Conclusions: Among singleton children with cerebral palsy, abnormal intrauterine size, either small or large, is associated with more severe disability and male sex.

1 in 5 women report cannabis use during pregnancy, with nausea cited as their primary motivation. Studies show that (-)-△9–tetrahydrocannabinol (Δ9-THC ), the major psychoactive ingredient in cannabis , causes fetal growth restriction, though the mechanisms are not well understood. Given the critical role of the placenta to transfer oxygen and nutrients from mother, to the fetus, any compromise in the development of fetal-placental circulation significantly affects maternal-fetal exchange and thereby, fetal growth. The goal of this study was to examine, in rats, the impact of maternal Δ9-THC exposure on fetal development, neonatal outcomes, and placental development. Dams received a daily intraperitoneal injection ( i.p .) of vehicle control or Δ9-THC (3 mg/kg) from embryonic ( E )6.5 through 22. Dams were allowed to deliver normally to measure pregnancy and neonatal outcomes, with a subset sacrificed at E19.5 for placenta assessment via immunohistochemistry and qPCR. Gestational Δ9-THC exposure resulted in pups born with symmetrical fetal growth restriction, with catch up growth by post-natal day ( PND )21. During pregnancy there were no changes to maternal food intake, maternal weight gain, litter size, or gestational length. E19.5 placentas from Δ9-THC-exposed pregnancies exhibited a phenotype characterized by increased labyrinth area, reduced Epcam expression (marker of labyrinth trophoblast progenitors), altered maternal blood space, decreased fetal capillary area and an increased recruitment of pericytes with greater collagen deposition, when compared to vehicle controls. Further, at E19.5 labyrinth trophoblast had reduced glucose transporter 1 ( GLUT1 ) and glucocorticoid receptor ( GR ) expression in response to Δ9-THC exposure. In conclusion, maternal exposure to Δ9-THC effectively compromised fetal growth, which may be a result of the adversely affected labyrinth zone development. These findings implicate GLUT1 as a Δ9-THC target and provide a potential mechanism for the fetal growth restriction observed in women who use cannabis during pregnancy.

Background Fetal growth restriction (FGR) contributes to over 30% of late-pregnancy stillbirth, yet its diagnosis is challenging because current methods rely on indirect surrogate markers (estimated fetal weight and umbilical artery) that often fail to detect fetal compromise, particularly in late-onset cases. We hypothesized that fetal cardiac remodeling could provide a more robust basis for prediction. This study aimed to develop and validate the cardiac remodeling for FGR prediction model (CR-FGR), a first-in-class machine learning approach designed to operationalize the concept of fetal cardiac remodeling as a direct marker for FGR prediction. Methods This multicenter study of singleton pregnancies included retrospective development ( n  = 663) and prospective validation in two independent cohorts (internal, n  = 224; external, n  = 51). The primary outcome was FGR (birth weight < 10th percentile). From 938 echocardiography videos, 222 cardiac parameters were extracted. A machine learning process selected the five most predictive parameters for the final logistic regression model (CR-FGR): right ventricular stroke volume/kg (RVSV/kg), cardiac output/kg (RVCO/kg), cardiac output (RVCO), left ventricular cardiac output (LVCO), and end-systolic area (RVESA). Results The CR-FGR model showed robust performance, with an area under the curve (AUC) of 0.872 (95% confidence interval (CI), 0.780–0.935) in the prospective internal testing set and 0.831 (95% CI, 0.674–0.947) in the external testing set. Its performance was comparable to a conventional EFW and Doppler model. Critically, the CR-FGR excelled in identifying challenging subgroups: it was highly effective for late-onset FGR (AUC 0.876, 95% CI, 0.748–0.951) and successfully detected FGR in many cases with normal umbilical artery Doppler, demonstrating its ability to capture pathology missed by traditional assessment. Conclusions We developed and validated the first machine learning model for FGR prediction based on fetal cardiac remodeling. This model establishes a new diagnostic strategy, offering a powerful, complementary tool that captures direct evidence of fetal compromise. It significantly enhances risk stratification, particularly for the clinically challenging late-onset and Doppler-normal phenotypes of FGR. Trial registration The Chinese Clinical Trial Registry, TRN: ChiCTR2000034182, Registration date: 27 June 2020.

Placental hypoxia can stimulate oxidative stress and mitochondrial dysfunction reducing placental efficiency and inducing fetal growth restriction (FGR). We hypothesized that chronic hypoxia inhibits mitochondrial function in the placenta as an underlying cause of cellular mechanisms contributing to FGR. Pregnant guinea pigs were exposed to either normoxia (NMX) or hypoxia (HPX; 10.5% O2) at 25 day gestation until term (65 day). Guinea pigs were anesthetized, and fetuses and placentas were excised at either mid (40 day) or late gestation (64 day), weighed, and placental tissue stored at –80°C until assayed. Mitochondrial DNA content, protein expression of respiratory Complexes I-V, and nitration and activity rates of Complexes I and IV were measured in NMX and HPX male (N = 6 in each treatment) and female (N = 6 in each treatment) placentas. Mitochondrial density was not altered by HPX in either mid- or late-term placentas. In mid gestation, HPX slightly increased expression of Complexes I-III and V in male placentas only, but had no effect on either Complex I or IV activity rates or nitrotyrosine expression. In late gestation, HPX significantly decreased CI/CIV activity rates and increased CI/CIV nitration in male but not female placentas exhibiting a sexual dimorphism. Complex I-V expression was reduced from mid to late gestation in both male and female placentas regardless of treatment. We conclude that chronic HPX decreases mitochondrial function by inhibiting Complex I/IV activity via increased peroxynitrite in a sex-related manner. Further, there may be a progressive decrease in energy metabolism of placental cell types with gestation that increases the vulnerability of placental function to intrauterine stress. Summary Sentence Chronic maternal hypoxia impairs mitochondrial function as an underlying cause of placental dysfunction, which may contribute to altered placental and fetal growth.

Mitochondria respond to a range of stimuli and function in energy production and redox homeostasis. However, little is known about the developmental and environmental control of mitochondria in the placenta, an organ vital for fetal growth and pregnancy maintenance in eutherian mammals. Using respirometry and molecular analyses, the present study examined mitochondrial function in the distinct transport and endocrine zones of the mouse placenta during normal pregnancy and maternal inhalation hypoxia. The data show that mitochondria of the two zones adopt different strategies in modulating their respiration, substrate use, biogenesis, density, and efficiency to best support the growth and energy demands of fetoplacental tissues during late gestation in both normal and hypoxic conditions. The findings have important implications for environmentally induced adaptations in mitochondrial function in other tissues and for compromised human pregnancy in which hypoxia and alterations in placental mitochondrial function are associated with poor outcomes like fetal growth restriction.

Purpose There is compelling evidence that interference of various anesthetics with synaptic functions and stress-provoking procedures during critical periods of brain maturation results in increased neuroapoptotic cell death. The hypothesis is that adverse intrauterine environmental conditions leading to intrauterine growth restriction (IUGR) with altered brain development may result in enhanced susceptibility to developmental anesthetic neurotoxicity. Methods This was a prospective, randomized, blinded animal study performed in a university laboratory involving 20 normal-weight (NW) and 19 IUGR newborn piglets. General inhalation anesthesia with isoflurane and nitrous oxide at clinically comparable dosages were administered for about 10 h. Surgical and monitoring procedures were accompanied by appropriate stage of general anesthesia. Resulting effects on developmental anesthetic and stress-induced neurotoxicity were assessed by estimation of apoptotic rates in untreated piglets and piglets after 10-h general anesthesia with MAC 1.0 isoflurane in 70 % nitrous oxide and 30 % oxygen. Results IUGR piglets exposed to different levels of isoflurane inhalation exhibited a significant increased apoptosis rate (TUNEL-positive neuronal cells) compared to NW animals of similar condition ( P  < 0.05). Cardiovascular and metabolic monitorings revealed similar effects of general anesthesia together with similar effects on brain electrical activity and broadly a similar dose-dependent gradual restriction in brain oxidative metabolism in NW and IUGR piglets. Conclusions There is no indication that the increased rate in neuroapoptosis in IUGR piglets is confounded by additional adverse systemic or organ-specific impairments resulting from administered mixed inhalation anesthesia. Developmental anesthetic and stress-induced neuroapoptosis presumably originated in response to fetal adaptations to adverse conditions during prenatal life and should be considered in clinical interventions on infants having suffered from fetal growth restriction.

Intrauterine growth retardation (IUGR), defined as impaired growth and development of the mammalian embryo/fetus or its organs during pregnancy, is a major concern in domestic animal production. Fetal growth restriction reduces neonatal survival, has a permanent stunting effect on postnatal growth and the efficiency of feed/forage utilization in offspring, negatively affects whole body composition and meat quality, and impairs long-term health and athletic performance. Knowledge of the underlying mechanisms has important implications for the prevention of IUGR and is crucial for enhancing the efficiency of livestock production and animal health. Fetal growth within the uterus is a complex biological event influenced by genetic, epigenetic, and environmental factors, as well as maternal maturity. These factors impact on the size and functional capacity of the placenta, uteroplacental blood flows, transfer of nutrients and oxygen from mother to fetus, conceptus nutrient availability, the endocrine milieu, and metabolic pathways. Alterations in fetal nutrition and endocrine status may result in developmental adaptations that permanently change the structure, physiology, metabolism, and postnatal growth of the offspring. Impaired placental syntheses of nitric oxide (a major vasodilator and angiogenic factor) and polyamines (key regulators of DNA and protein synthesis) may provide a unified explanation for the etiology of IUGR in response to maternal undernutrition and overnutrition. There is growing evidence that maternal nutritional status can alter the epigenetic state (stable alterations of gene expression through DNA methylation and histone modifications) of the fetal genome. This may provide a molecular mechanism for the role of maternal nutrition on fetal programming and genomic imprinting. Innovative interdisciplinary research in the areas of nutrition, reproductive physiology, and vascular biology will play an important role in designing the next generation of nutrient-balanced gestation diets and developing new tools for livestock management that will enhance the efficiency of animal production and improve animal well being.

Bronchopulmonary dysplasia (BPD) is a disease with a multi-factorial pathophysiology; however, current animal models lack complexity. We employed a double-hit model with an antenatal insult of foetal growth restriction paired with milder postnatal hyperoxia exposure. We induced foetal growth restriction (FGR) by injecting N(G)-nitro-L-arginine methyl ester (L-NAME) in the pregnant rabbit, and exposed preterm-born kittens to 70% hyperoxia for 7 days. L-NAME effectively induced FGR, and mortality rates were acceptable. The double-hit group exhibited adverse outcomes, including decreased lung compliance, increased airway resistance, and structural changes such as alveolar simplification and thickened septa. Gene expression analysis in the L-NAME group revealed downregulation of vascular growth factors, suggesting impaired vascular development. In contrast to traditional hyperoxia models, our double-hit approach enables lower hyperoxia exposure, aligning more closely with clinical practice guidelines in neonatology. The findings underscore the importance of antenatal factors in BPD pathophysiology and reinforce the need for refined animal models that accurately reflect the complexities of preterm lung development.

To interrogate the pathogenesis of intrauterine growth restriction (IUGR) and apply Artificial Intelligence (AI) techniques to multi-platform i.e. nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS) based metabolomic analysis for the prediction of IUGR. MS and NMR based metabolomic analysis were performed on cord blood serum from 40 IUGR (birth weight < 10th percentile) cases and 40 controls. Three variable selection algorithms namely: Correlation-based feature selection (CFS), Partial least squares regression (PLS) and Learning Vector Quantization (LVQ) were tested for their diagnostic performance. For each selected set of metabolites and the panel consists of metabolites common in three selection algorithms so-called overlapping set (OL), support vector machine (SVM) models were developed for which parameter selection was performed busing 10-fold cross validations. Area under the receiver operating characteristics curve (AUC), sensitivity and specificity values were calculated for IUGR diagnosis. Metabolite set enrichment analysis (MSEA) was performed to identify which metabolic pathways were perturbed as a direct result of IUGR in cord blood serum. All selected metabolites and their overlapping set achieved statistically significant accuracies in the range of 0.78-0.82 for their optimized SVM models. The model utilizing all metabolites in the dataset had an AUC = 0.91 with a sensitivity of 0.83 and specificity equal to 0.80. CFS and OL (Creatinine, C2, C4, lysoPC.a.C16.1, lysoPC.a.C20.3, lysoPC.a.C28.1, PC.aa.C24.0) showed the highest performance with sensitivity (0.87) and specificity (0.87), respectively. MSEA revealed significantly altered metabolic pathways in IUGR cases. Dysregulated pathways include: beta oxidation of very long fatty acids, oxidation of branched chain fatty acids, phospholipid biosynthesis, lysine degradation, urea cycle and fatty acid metabolism. A systematically selected panel of metabolites was shown to accurately detect IUGR in newborn cord blood serum. Significant disturbance of hepatic function and energy generating pathways were found in IUGR cases.