The sFlt-1/PlGF-ratio and the risk of preeclampsia-related adverse outcomes in subsequent pregnancies with signs and symptoms of a preeclampsia.

OBJECTIVES: This study characterizes the outcome of two subsequent pregnancies with suspected preeclampsia (PE). We investigated the diagnostic accuracy of clinical signs, Doppler examinations, and the soluble fms-like tyrosine kinase-1 (sFlt-1) to placental growth factor (PlGF)-ratio to predict PE-related adverse outcomes (AO). The sFlt-1/PlGF-ratio of the first pregnancy was compared to the outcome of the subsequent pregnancy. STUDY DESIGN: A total of 1928 patients at risk for preeclampsia were screened, of them 1117 were eligible for inclusion. Of these, 84 women presented with suspected PE in two subsequent pregnancies. OUTCOME MEASURES: Diagnostic accuracy of clinical markers was assessed. Associations between the sFlt-1/PlGF-ratio in the first and the odds of an AO in the subsequent pregnancy were investigated with logistic regression. RESULTS: The prevalence of AOs decreased from 27.4 % in the first to 17.9 % in the second pregnancy. Comparison of the accuracy of the different clinical markers for an AO showed a high specificity for an sFlt-1/PlGF-ratio at the cut-off of ≥ 85 in both pregnancies (81.3 %, 95 % CI 63.6-92.8 vs 92.6 %,95 % CI 83.7-97.6), but a lower sensitivity in the second pregnancy (92.9 %, 95 % CI 66.1-99.8 vs 33.3%, 95 % CI 11.8-61.6). An elevated sFlt-1/PlGF-ratio in the first did not increase the odds of an AO in the subsequent pregnancy. CONCLUSIONS: The prevalence of AOs decreases in subsequent pregnancies. Our finding that the sFlt-1/PlGF-ratio of the first was not related to the outcome of the subsequent pregnancy suggests that angiogenic markers are only a within-pregnancy short-term tool to assess AOs.

Socioeconomic inequities during COVID 19 pandemic increase preterm birth and low birth weight in the most underprivileged.

BACKGROUND: The mitigation measures implemented to face the healthcare emergency brought by COVID 19 pandemic generated an increase in socioeconomic inequities in the most underprivileged population which is also the most threatened in their human rights. In Uruguay, this population is assisted in the public health care system. To analyze how these measures impacted on these mothers and their neonates we selected outcomes that most contributed to neonatal mortality. OBJECTIVE: To analyze the incidence of Preterm Birth (PB), Intrauterine Growth Restriction (IUGR) and Low Birth Weight (LBW) in the public health care system in Uruguay, during the period of time in which the strictest measures were adopted to mitigate the COVID 19 pandemic in 2020 (para-pandemic period) compared to the same period in 2019 (pre-pandemic). METHODS: A retrospective, cross sectional, descriptive study was performed to compare PB, IUGR and LBW from 15 March to 30 September 2019 (before COVID 19 pandemic) to the same period of 2020 (when COVID 19 pandemic bloomed), in the public health care subsystem. The analysis was performed with data from the national perinatal database system (SIP). RESULTS: In 2020, a significative increase in PB, RR: 1.14 (CI 95%: 1.03-1.25), and in LBW, RR: 1.16 (CI 95% 1.02-1.33), was registered compared to 2019 (pre-pandemic period). IUGR also showed an increase, but without statistical significance (4.6% in 2019 vs 5.2% in 2020, RR 1.13 CI 95% 0.98-1.31). The compared groups showed no differences in the distribution of biological confounding variables that could explain the increase in incidence of the main outcomes. CONCLUSIONS: In the absence of other factors that could explain the results we consider that social crisis associated to the restrictive measures implemented in the country to dwindle the effect of the pandemic exacerbated the adverse conditions that affect the reproductive process for those underprivileged women assisted in the public sector, increasing PB and LBW. It is important to consider the future impact of these results on neonatal and infant mortality and to implement social measures to reduce the damage as soon as possible.

Role of Transcerebellar Diameter and Transcerebellar Diameter/Abdominal Circumference Ratio in Assessing Fetal Growth and Diagnosing Intrauterine Growth Restriction.

Background In obstetrics, accurately determining gestational age (GA) is a critical aspect of managing pregnancy and evaluating fetal growth and development. Intrauterine growth restriction (IUGR) is characterized by the failure of the fetus to reach its potential growth. Early detection of IUGR is crucial for optimal obstetric care to reduce fetal complications and neonatal morbidity and mortality. The purpose of the current research is to determine the role of transcerebellar diameter (TCD) and the TCD/abdominal circumference (AC) ratio in assessing fetal growth and diagnosing IUGR. Methods In the sample, there were 600 expectant mothers with GA exceeding 28 weeks. We measured TCD and AC and then calculated the TCD/AC ratio. We used IBM SPSS Statistics for Windows, V. 22.0 (IBM Corp., Armonk, NY), for statistical analysis. The data was subjected to statistical tests, including Pearson's correlation coefficient, coefficient of determination, and tests of validity. Results The current research demonstrates a strong linear correlation between TCD and GA. Additionally, there was no notable disparity in TCD measurements between normal and IUGR fetuses with the same GA. There was an insignificant relationship between the TCD/AC ratio and GA, with a constant TCD/AC ratio in the third trimester of pregnancy in normal fetuses. The mean TCD/AC ratio was 14.72±0.89 (mean±standard deviation), and a cut-off value of 16.5 was determined to diagnose IUGR. Conclusion TCD can serve as a reliable measure for GA estimation during the third trimester in pregnant women with uncertain last menstrual period (LMP) or no dating scan and IUGR fetuses. In diagnosing IUGR, the TCD/AC ratio has demonstrated greater sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). The TCD/AC ratio is a GA-independent measure that can be used to diagnose IUGR.

Mtnr1b deletion disrupts placental angiogenesis through the VEGF signaling pathway leading to fetal growth restriction.

The placenta, as a "transit station" between mother and fetus, has functions delivering nutrients, excreting metabolic wastes and secreting hormones. A healthy placenta is essential for fetal growth and development while the melatonergic system seems to play a critical physiological role in this organ since melatonin, its synthetic enzymes and receptors are present in the placenta. In current study, Mtnr1a and Mtnr1b knockout mice were constructed to explore the potential roles of melatonergic system played on the placental function and intrauterine growth retardation (IUGR). The result showed that Mtnr1a knockout had little effect on placental function while Mtnr1b knockout reduced placental efficiency and increased IUGR. Considering the extremely high incidence of IURG in sows, the pregnant sows were treated with melatonin. This treatment reduced the incidence of IUGR. All the evidence suggests that the intact melatonergic system in placenta is required for its function. Mechanistical studies uncovered that Mtnr1b knockout increased placental oxidative stress and apoptosis but reduced the angiogenesis. The RNA sequencing combined with histochemistry study identified the reduced angiogenesis and placental vascular density in Mtnr1b knockout mice. These alterations were mediated by the disrupted STAT3/VEGFR2/PI3K/AKT pathway, i.e., Mtnr1b knockout reduced the phosphorylation of STAT3 which is the promotor of VEGFR2. The downregulated VEGFR2 and its downstream elements of PI3K and AKT expressions, then, jeopardizes the angiogenesis and placental development.

Nicotinamide improves the impaired extravillous trophoblast cell invasion induced by PM2.5 exposure-associated increase of TNFα secretion through the ROS/NF-κB/FLT1 pathway.

It has been well acknowledged that maternal exposure to fine particulate matters (PM2.5) might lead to poor pregnancy outcomes including the intrauterine growth restriction (IUGR) by interfering with the placental development. Our previous studies have demonstrated that maternal PM2.5 exposure induces IUGR, accompanied with increased maternal circulating TNFα level and impaired extravillous trophoblast cells (EVTs) invasion in mice. In this study, HTR8/SVneo cells, the immortalized human EVTs line, were used to assess effects and the underlying molecular mechanisms of nicotinamide on the impaired EVTs invasion. Our results showed that, the placental FLT1 protein level was significantly increased whereas maternal serum nicotinamide concentration was remarkably decreased in PM2.5-exposured pregnant mice at GD17.5 (vaginal plug day=GD0.5), compared to that in normal GD17.5 pregnant mice. FLT1 expression in HTR8/SVneo cells was significantly up-regulated by TNFα treatment, and the down-regulated FLT1 expression effectively abated the inhibitory effects of TNFα on HTR8/SVneo cells migration and invasion. Meanwhile, TNFα promoted reactive oxygen species (ROS) production and NF-κB signaling pathway activation in HTR8/SVneo cells in a dose-dependent manner. Nicotinamide treatment significantly reversed the effects of TNFα on cell migration and invasion, as well as the FLT1 expression, ROS production and NF-κB pathway activation. In summary, increased TNFα induced by PM2.5 exposure inhibits EVTs invasion by activating the ROS/NF-κB/FLT1 signaling pathway, and this adverse effect could be attenuated by nicotinamide treatment, suggesting a potential application in the clinical intervention of PM2.5-induced IUGR.

Different Lengths of Gestational Exposure to Secondhand Smoke or e-Cigarette Vapor Induce the Development of Placental Disease Symptoms.

Exposure to cigarette smoke is known to induce disease during pregnancy. Recent evidence showed that exposure to secondhand smoke (SHS) negatively impacts fetal and placental weights, leading to the development of intrauterine growth restriction (IUGR). Electronic cigarettes (eCigs) represent a phenomenon that has recently emerged, and their use is also steadily rising. Even so, the effects of SHS or eCigs during gestation remain limited. In the present study, we wanted to characterize the effects of SHS or eCig exposure at two different important gestational points during mouse pregnancy. C57/Bl6 mice were exposed to SHS or eCigs via a nose-only delivery system for 4 days (from 14.5 to 17.5 gestational days (dGA) or for 6 days (from 12.5 dGA to 17.5 dGA)). At the time of necropsy (18.5 dGA), placental and fetal weights were recorded, maternal blood pressure was determined, and a dipstick test to measure proteinuria was performed. Placental tissues were collected, and inflammatory molecules in the placenta were identified. Treatment with SHS showed the following: (1) a significant decrease in placental and fetal weights following four days of exposure, (2) higher systolic and diastolic blood pressure following six days of exposure, and (3) increased proteinuria after six days of exposure. Treatment with eCigs showed the following: (1) a significant decrease in placental weight and fetal weight following four or six days of exposure, (2) higher systolic and diastolic blood pressure following six days of exposure, and (3) increased proteinuria after six days of exposure. We also observed different inflammatory markers associated with the development of IUGR or PE. We conclude that the detrimental effects of SHS or eCig treatment coincide with the length of maternal exposure. These results could be beneficial in understanding the long-term effects of SHS or eCig exposure in the development of placental diseases.

Acute-on-chronic: using magnetic resonance imaging to disentangle the haemodynamic responses to acute and chronic fetal hypoxaemia.

Introduction: The fetal haemodynamic response to acute episodes of hypoxaemia are well characterised. However, how these responses change when the hypoxaemia becomes more chronic in nature such as that associated with fetal growth restriction (FGR), is less well understood. Herein, we utilised a combination of clinically relevant MRI techniques to comprehensively characterize and differentiate the haemodynamic responses occurring during acute and chronic periods of fetal hypoxaemia. Methods: Prior to conception, carunclectomy surgery was performed on non-pregnant ewes to induce FGR. At 108-110 days (d) gestational age (GA), pregnant ewes bearing control (n = 12) and FGR (n = 9) fetuses underwent fetal catheterisation surgery. At 117-119 days GA, ewes underwent MRI sessions where phase-contrast (PC) and T2 oximetry were used to measure blood flow and oxygenation, respectively, throughout the fetal circulation during a normoxia and then an acute hypoxia state. Results: Fetal oxygen delivery (DO2) was lower in FGR fetuses than controls during the normoxia state but cerebral DO2 remained similar between fetal groups. Acute hypoxia reduced both overall fetal and cerebral DO2. FGR increased ductus venosus (DV) and foramen ovale (FO) blood flow during both the normoxia and acute hypoxia states. Pulmonary blood flow (PBF) was lower in FGR fetuses during the normoxia state but similar to controls during the acute hypoxia state when PBF in controls was decreased. Conclusion: Despite a prevailing level of chronic hypoxaemia, the FGR fetus upregulates the preferential streaming of oxygen-rich blood via the DV-FO pathway to maintain cerebral DO2. However, this upregulation is unable to maintain cerebral DO2 during further exposure to an acute episode of hypoxaemia. The haemodynamic alterations required at the level of the liver and lung to allow the DV-FO pathway to maintain cerebral DO2, may have lasting consequences on hepatic function and pulmonary vascular regulation after birth.

RNA-seq reveals differentially expressed lncRNAs and circRNAs and their associated functional network in HTR-8/Svneo cells under hypoxic conditions.

Placental hypoxia is hazardous to maternal health as well as fetal growth and development. Preeclampsia and intrauterine growth restriction are common pregnancy problems, and one of the causes is placental hypoxia. Placental hypoxia is linked to a number of pregnancy illnessesv. To investigate their potential function in anoxic circumstances, we mimicked the anoxic environment of HTR-8/Svneo cells and performed lncRNA and circRNA studies on anoxic HTR-8/Svneo cells using high-throughput RNA sequencing. The miRNA target genes were predicted by integrating the aberrant expression of miRNAs in the placenta of preeclampsia and intrauterine growth restriction, and a ceRNA network map was developed to conduct a complete transcriptomic and bioinformatics investigation of circRNAs and lncRNAs. The signaling pathways in which the genes were primarily engaged were predicted using GO and KEGG analyses. To propose a novel explanation for trophoblastic organism failure caused by lncRNAs and circRNAs in an anoxic environment.

Transamniotic Stem Cell Therapy Modulates Uterine Natural Killer CellActivity in the Hypoxia Model of Intrauterine Growth Restriction.

Intrauterine growth restriction (IUGR) pathophysiology is driven by abnormal uterine natural killer cell (uNK) activity leading to placental dysfunction. Transamniotic stem cell therapy (TRASCET) with mesenchymal stem cells (MSCs) can improve experimental IUGR by mechanisms not fully understood. We sought to examine TRASCET's effects in downstream products of uNKs in a model of IUGR: 15 Sprague-Dawley dams were exposed to alternating hypoxia (10.5% O2) from gestational day 15 (E15) until term (E21). Their fetuses (n = 189) were divided into four groups. One group remained untreated (n = 52), whereas three groups received volume-matched intraamniotic injections of either saline (sham, n = 44) or a suspension of amniotic fluid-derived MSCs, either in their native state (TRASCET, n = 50) or "primed" to an enhanced antiinflammatory phenotype (TRASCET-Primed, n = 43). Normal fetuses served as controls (n = 33). At term, various analyses were performed, including ELISA for surrogates of placental inflammation and uNK activity. Statistical comparisons included Bonferroni-adjusted criterion. Overall survival from hypoxia was 74% (140/189). Placental efficiency was lower in untreated and sham but normalized in both TRASCET groups (P < 0.01-0.47). Interleukin-17, a stimulator of uNKs, was elevated from normal in all groups (P < 0.01 for all). Interferon-gamma, released from activated uNKs, was elevated in all groups except sham but lower than the untreated in both TRASCET groups (P ≤ 0.01-0.06). Tumor necrosis factor-alpha, also produced by uNKs, was elevated in untreated and sham (P < 0.01 for both), but normalized by TRASCET (P = 0.05) and even lowered from normal in TRASCET-Primed (P < 0.01). Vascular endothelial growth factor, also released by uNKs, was elevated in untreated and sham but lower than normal in both TRASCET groups (P < 0.01 for all). We conclude that TRASCET with MSCs modulates the activity of placental uNKs in experimental IUGR, with distinct effects on their downstream products. This mechanistic insight may inform the development of novel strategies for the management of this disease.

Dietary glycine supplementation activates mechanistic target of rapamycin signaling pathway in tissues of pigs with intrauterine growth restriction.

The mechanistic target of rapamycin (mTOR) cell signaling pathway serves as the central mechanism for the regulation of tissue protein synthesis and growth. We recently reported that supplementing 1% glycine to corn- and soybean meal-based diets enhanced growth performance between weaning and market weights in pigs with intrauterine growth restriction (IUGR). Results of recent studies have revealed an important role for glycine in activating mTOR and protein synthesis in C2C12 muscle cells. Therefore, the present study tested the hypothesis that dietary glycine supplementation enhanced the mTOR cell signaling pathway in skeletal muscle and other tissues of IUGR pigs. At weaning (21 d of age), IUGR pigs and litter mates with normal birth weights (NBW) were assigned randomly to one of the two groups: supplementation with either 1% glycine or 1.19% l-alanine (isonitrogenous control) to a corn- and soybean meal-based diet. Tissues were obtained from the pigs within 1 wk after the feeding trial ended at 188 d of age to determine the abundances of total and phosphorylated forms of mTOR and its two major downstream proteins: eukaryotic initiation factor 4E-binding protein-1 (4EBP1) and ribosomal protein S6 kinase-1 (p70S6K). Results showed that IUGR decreased (P < 0.05) the abundances of both total and phosphorylated mTOR, 4EBP1, and p70S6K in the gastrocnemius muscle and jejunum. In the longissimus lumborum muscle of IUGR pigs, the abundances of total mTOR did not differ (P > 0.05) but those for phosphorylated mTOR and both total and phosphorylated 4EBP1 and p70S6K were downregulated (P < 0.05), when compared to NBW pigs. These adverse effects of IUGR in the gastrocnemius muscle, longissimus lumborum muscle, and jejunum were prevented (P < 0.05) by dietary glycine supplementation. Interestingly, the abundances of total or phosphorylated mTOR, 4EBP1, and p70S6K in the liver were not affected (P > 0.05) by IUGR or glycine supplementation. Collectively, our findings indicate that IUGR impaired the mTOR cell signaling pathway in the tissues of pigs and that adequate glycine intake was crucial for maintaining active mTOR-dependent protein synthesis for the growth and development of skeletal muscle.

Soybean meal is the major source of dietary protein for growing pigs in many regions of the world, including North America, South America, and Asia. However, this conventional feedstuff is recognized to be severely deficient in glycine (the most abundant amino acid in the bodies of animals, including pigs). Compared to pigs with normal birth weights (NBW), pigs with intrauterine growth restriction (IUGR) have a lower ability to synthesize glycine and reduced growth performance between weaning and market weights. Results of recent studies with cultured muscle cells have revealed that glycine stimulates the mechanistic target of rapamycin (mTOR) cell signaling pathway (the master activator of initiation of protein synthesis in tissues) to promote protein synthesis and cell growth. There is also evidence that the mTOR pathway is impaired in the skeletal muscle of young IUGR pigs. Thus, dietary glycine supplementation may play an important role in maintaining an active mTOR cell signaling pathway for the growth of tissues, particularly skeletal muscle. Results of this study indicated that market-weight IUGR pigs had lower abundances of both total and phosphorylated mTOR, as well as its downstream target proteins in the gastrocnemius muscle, longissimus lumborum muscle, and jejunum, when compared with NBW pigs. In contrast, neither IUGR nor glycine supplementation affected the mTOR cell signaling pathway in the liver of pigs. Taken together, these novel findings indicate that IUGR pigs have insufficient cell signaling via the mTOR cell pathway in a tissue-specific manner during their growing-finishing phases of development and that this negative impact of IUGR can be mitigated by supplementing corn- and soybean meal-based diets with 1% glycine.

High amniotic fluid fractalkine and MIP-1ß levels are associated with intrauterine growth restriction: a prospective cohort study.

Background/aim: Proinflammatory chemokines have been shown to play crucial roles in implantation, spiral artery invasion, and the fetomaternal immunological response. In this context, we investigated the levels of fractalkine (CX3CL1) and chemokine CC motif ligand 4 (CCL4 or MIP-1ß) in maternal serum and amniotic fluids in pregnant women with intrauterine growth restriction (IUGR). Materials and methods: This prospective cohort study was carried out at Firat University Obstetrics Clinic between January 1, 2022 and July 1, 2022. Group (G) 1: The control group consisted of 40 pregnant women who underwent elective cesarean section (CS) at 38-40 weeks of gestation. G2: A total of 40 pregnant women with IUGR at 28-37 weeks of gestation were included in the study group. Levels of tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1ß), interferon-gamma (IFN-γ), hypoxia-inducible factor-1 alpha (HIF-1α), macrophage inflammatory protein-1 beta (MIP-1ß), and fractalkine were measured in maternal serum and amniotic fluid samples obtained during CS. Results: When maternal age was compared, no statistically significant difference was observed between G1 and G2 (p = 0.374). The number of gravidity was found to be statistically higher in G1 compared to G2 (p = 0.003). The mean gestational week was statistically higher in G1 (p < 0.001). Maternal serum MIP-1ß (p = 0.03) and IFN-γ (p = 0.006) levels were higher in G1. The birth weight of the baby (p < 0.001) and umbilical cord blood gas pH value (p < 0.001) at birth were higher in G1. HIF-1α (p < 0.001), fractalkine (p < 0.001), MIP-1ß (p < 0.001), TNF-α (p = 0.007), IL-1ß (p < 0.001), and IFN-γ levels (p = 0.007) in amniotic fluid were higher in G2. Conclusion: Elevated levels of proinflammatory factors, including fractalkine and MIP-1ß, along with inflammatory factors such as TNF-α, IL-1ß, and IFN-γ, as well as increased HIF-1α levels in amniotic fluid, are associated with intrauterine growth restriction (IUGR) attributed to a hypoxic amniotic environment.

IL1ß-NFκß-Myocardin signaling axis governs trophoblast-directed plasticity of vascular smooth muscle cells.

Vascular smooth muscle cell (VSMC) plasticity is fundamental in uterine spiral artery remodeling during placentation in Eutherian mammals. Our previous work showed that the invasion of trophoblast cells into uterine myometrium coincides with a phenotypic change of VSMCs. Here, we elucidate the mechanism by which trophoblast cells confer VSMC plasticity. Analysis of genetic markers on E13.5, E16.5, and E19.5 in the rat metrial gland, the entry point of uterine arteries, revealed that trophoblast invasion is associated with downregulation of MYOCARDIN, α-smooth muscle actin, and calponin1, and concomitant upregulation of Smemb in VSMCs. Myocardin overexpression or knockdown in VSMCs led to upregulation or downregulation of contractile markers, respectively. Co-culture of trophoblast cells with VSMCs decreased MYOCARDIN expression along with compromised expression of contractile markers in VSMCs. However, co-culture of trophoblast cells with VSMCs overexpressing MYOCARDIN inhibited their change in phenotype, whereas, overexpression of transactivation domain deleted MYOCARDIN failed to elicit this response. Furthermore, the co-culture of trophoblast cells with VSMCs led to the activation of NFκß signaling. Interestingly, despite producing IL-1ß, trophoblast cells possess only the decoy receptor, whereas, VSMCs possess the IL-1ß signaling receptor. Treatment of VSMCs with exogenous IL-1ß led to a decrease in MYOCARDIN and an increase in phosphorylation of NFκß. The effect of trophoblast cells in the downregulation of MYOCARDIN in VSMCs was reversed by blocking NFκß translocation to the nucleus. Together, these data highlight that trophoblast cells direct VSMC plasticity, and trophoblast-derived IL-1ß is a key player in downregulating MYOCARDIN via the NFκß signaling pathway.

Long-term benefits of exclusive human milk diet in small for gestational age neonates: a systematic review of the literature.

Evidence about feeding practices' consequences in small for gestational age newborns is not well established because they are less likely to initiate and continue breastfeeding than other newborns. Our aim was to study current knowledge about the benefits of exclusive human milk diet after 2 years of age in small for gestational age newborns. A systematic review of the literature was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline criteria. Pubmed and Scopus were searched for studies published from databases inception until June 2, 2023. Included articles were analysed and synthesised. Risk of bias and level of evidence assessments were performed. They were enrolled small for gestational age newborns fed by breastfeeding, breast milk or donor milk. The systematic review included 9 articles which were related to 4 health domains: neurodevelopment, cardiovascular, somatic growth and bone mineralization and atopy. Extracted data support a beneficial effect of breastfeeding on these outcomes. Better quality of evidence and longer follow-up are needed.

Placental and serum levels of human α-Klotho in preeclampsia & intra-uterine growth retardation: A potential sensitive biomarker?

INTRODUCTION: α-Klotho protein has three isoforms: a transmembrane (mKL), a shed- soluble isoform, and a circulating soluble isoform (sKL). mKL is expressed in the kidney and placenta, while sKL is detectable in blood and urine. It is known that α-Klotho levels fluctuate during pregnancy mainly in women with complications such as preeclampsia (PE) and intra-uterine growth restriction (IUGR). METHODS: Forty-nine participants were divided into two groups: healthy and complicated pregnancy (PE, IUGR or both). Tissue samples (2 cm3) from the maternal side, Blood and urine samples were collected during pregnancy and postpartum. Samples were subjected to biochemical (WB), histological (H&E and IHC) staining as well as genetic analysis (qPCR). RESULTS: Blood αKL levels were preserved in both healthy and complicated pregnancies. Significantly lower blood αKL concentrations were found in PE postpartum (PP) compared to levels during pregnancy, and were significantly lower compared with postpartum of a healthy pregnancy. αKL activity was reduced in complicated pregnancies vs. healthy pregnancies. Placen tal mKL levels (ELISA) and expression (WB) were lowered in complicated pregnancies compared with the healthy pregnancies group. Additionally, we found a significant decline in the expression of mKL mRNA in PE/IUGR placentas compared with the healthy group. DISCUSSION: Several studies have focused on the involvement of αKL in normal placentation during pregnancy. Our results suggest lower function of sKL in complicated pregnancy compared with a control, and present differences in placental mKL levels as well as tissue and gene expression between healthy and complicated pregnancy. In light of our results, we conclude that complicated pregnancy is associated with in decline in mKL.

Prenatal Identification of a Missense Mutation of the L1CAM Gene Associated With Hydrocephalus Using Next-Generation Sequencing.

We present the case of a 35-year-old pregnant woman who visited our department for a routine ultrasonography screening scan for fetus anatomy during the 22nd week of gestation. Our report revealed a male fetus with marked hydrocephalus and severe intrauterine growth retardation. After extensive counseling, the couple decided to proceed with an invasive diagnosis via amniocentesis. The cytogenetic analysis showed findings related to clinical history and ultrasound findings related to the presence of a nucleotide change in c.578T>C with an amino acid change in p.Leu198Pro of the L1CAM gene. The result was reported as a hemizygote missense L1CAM gene variant of unknown significance. After extensive parental counseling, the couple decided on pregnancy termination. We report the present case of L1CAM mutation in p.Leu198Pro to add to the limited knowledge regarding the clinical presentation of mutations of the L1CAM gene with emphasis on prenatal diagnosis.

Effects of foetal size, sex and developmental stage on adaptive transcriptional responses of skeletal muscle to intrauterine growth restriction in pigs.

Intrauterine growth restriction (IUGR) occurs both in humans and domestic species. It has a particularly high incidence in pigs, and is a leading cause of neonatal morbidity and mortality as well as impaired postnatal growth. A key feature of IUGR is impaired muscle development, resulting in decreased meat quality. Understanding the developmental origins of IUGR, particularly at the molecular level, is important for developing effective strategies to mitigate its economic impact on the pig industry and animal welfare. The aim of this study was to characterise transcriptional profiles in the muscle of growth restricted pig foetuses at different gestational days (GD; gestational length ~ 115 days), focusing on selected genes (related to development, tissue injury and metabolism) that were previously identified as dysregulated in muscle of GD90 fetuses. Muscle samples were collected from the lightest foetus (L) and the sex-matched foetus with weight closest to the litter average (AW) from each of 22 Landrace x Large White litters corresponding to GD45 (n = 6), GD60 (n = 8) or GD90 (n = 8), followed by analyses, using RT-PCR and protein immunohistochemistry, of selected gene targets. Expression of the developmental genes, MYOD, RET and ACTN3 were markedly lower, whereas MSTN expression was higher, in the muscle of L relative to AW littermates beginning on GD45. Levels of all tissue injury-associated transcripts analysed (F5, PLG, KNG1, SELL, CCL16) were increased in L muscle on GD60 and, most prominently, on GD90. Among genes involved in metabolic regulation, KLB was expressed at higher levels in L than AW littermates beginning on GD60, whereas both IGFBP1 and AHSG were higher in L littermates on GD90 but only in males. Furthermore, the expression of genes specifically involved in lipid, hexose sugar or iron metabolism increased or, in the case of UCP3, decreased in L littermates on GD60 (UCP3, APOB, ALDOB) or GD90 (PNPLA3, TF), albeit in the case of ALDOB this only involved females. In conclusion, marked dysregulation of genes with critical roles in development in L foetuses can be observed from GD45, whereas for a majority of transcripts associated with tissue injury and metabolism differences between L and AW foetuses were apparent by GD60 or only at GD90, thus identifying different developmental windows for different types of adaptive responses to IUGR in the muscle of porcine foetuses.

Comparative Effects on Fetal Hematopoiesis and Placental Inflammation From Mesenchymal and Hematopoietic Stem Cells as Agents of Transamniotic Stem Cell Therapy (TRASCET) in a Syngeneic Model of Intrauterine Growth Restriction.

PURPOSE: We compared transamniotic stem cell therapy (TRASCET) using either mesenchymal (MSCs) or hematopoietic (HSCs) stem cells on fetal hematopoiesis in a syngeneic model of intrauterine growth restriction (IUGR). METHODS: Lewis dams exposed to cycling hypoxia (10.5% O2) in late gestation had their fetuses (n = 83) either receiving no intervention (untreated; n = 9), or intra-amniotic injections of either HSCs (HSC; n = 34), MSCs primed to an enhanced anti-inflammatory phenotype (primed-MSC; n = 28), or saline (sham; n = 12). Normal controls (n = 18) were also studied. Complete peripheral blood counts and placental ELISA for inflammation and angiogenesis markers were performed at term. RESULTS: Overall survival from hypoxia was 41% (34/83). Red blood count (RBC), hematocrit (Hct) and hemoglobin levels (Hb) were all significantly decreased from normal in all hypoxia groups. TRASCET with primed-MSC had significantly higher RBC, Hct, and Hb levels than sham (p = 0.01-0.03, pairwise), though not than untreated (which had no surgical blood loss). The HSC group had only significantly higher Hb levels than sham (p = 0.005). TRASCET with primed-MSC had significantly lower levels of placental TNF-α than sham (p = 0.04), but not untreated. CONCLUSIONS: MCSs seem more effective than HSCs in enhancing hematopoiesis when used as donor cells for TRASCET in a syngeneic model of IUGR. LEVEL OF EVIDENCE: N/A (animal and laboratory study).

Levels of serum ß-human chorionic gonadotropin after embryo transfer and subsequent miscarriage, pre-eclampsia, and intrauterine growth restriction.

Background: This study aimed to examine maternal serum concentration of ß-human chorionic gonadotropin (ß-hCG) on Day 16 after embryo transfer and risk of miscarriage, pre-eclampsia, and intrauterine growth restriction (IUGR). Methods: In this study, we evaluated 125 pregnancies following in vitro fertilization (IVF). ß-hCG concentrations were measured on the morning of Day 16 after embryo transfer. Baseline characteristics of the study participants were also recorded. Results: Concentrations of ß-hCG on Day 16 after embryo transfer were inversely associated with the higher risk of miscarriage (p < 0.001), but did not with pre-eclampsia and IUGR (p > 0.05). Spearman's correlation coefficient showed a reverse and significant association between ß-hCG and higher risk of miscarriage (σ = 0.531 and p < 0.001). There was a significant association between frozen embryo transfer and the risk of IUGR and pre-eclampsia (p = 0.005 and p = 0.023, respectively). Conclusions: Maternal serum concentrations of ß-hCG on Day 16 after IVF/embryo transfer were associated with the higher risk of miscarriage, but not pre-eclampsia and IUGR.

Intrauterine Growth Restriction and Placenta Previa: A Clinical Case Report of an Advanced-Age Pregnancy.

Exploring the intricacies of managing high-risk pregnancies complicated by intrauterine growth restriction (IUGR), placenta previa, and a single umbilical artery requires a comprehensive understanding of their etiologies, mechanisms, and treatment recommendations. This case report delves into the clinical course of a 34-year-old smoker with a pre-pregnancy body mass index of 14.2 kg/m2, shedding light on the considerations posed by a pregnancy in which several risk factors are superimposed on one another. IUGR, affecting 10%-15% of pregnancies, elevated the risk of adverse outcomes during labor and delivery, necessitating careful antenatal monitoring. Placenta previa, with an incidence of 0.3% to 2% in pregnancies, introduced further complications impacting delivery modes and raising the risk of hemorrhage. This report aims to showcase the interconnectedness between these various obstetrical complications and risk factors, to guide maternal-fetal-medicine specialists in making informed decisions during the management of high-risk pregnancies.

Phenotype of early-onset fetal growth restriction in sheep.

Introduction: Fetal growth restriction (FGR) is a common pregnancy complication, caused by placental insufficiency, with serious adverse consequences for development in utero and postnatal wellbeing. There are no antenatal treatments to improve growth or organ development in FGR, and animal models are essential to mimic the physiological adaptations in FGR and to assess potential interventions. This study aimed to identify the temporal nature of reduced developmental trajectory in fetuses with FGR, and to examine the effects of common factors that may mediate differential growth such as glucocorticoid treatment. We hypothesised that the trajectory of growth would be adversely impacted by FGR. Methods: FGR was induced via surgical placental insufficiency in fetal sheep (89 days gestation/0.6 gestation; n=135) and compared to age-matched controls over the last third of gestation and into neonatal life (n=153). Results: Body weight of FGR fetuses/lambs was significantly reduced compared to controls (p<0.0001) from 127 days of gestation (term is 148 days), with increased brain:body weight ratio (p<0.0001) indicative of brain sparing. All biometric measures of body size were reduced in the FGR group with the exception of biparietal (head) diameter. The trajectory of body growth in the last trimester of sheep pregnancy was significantly reduced in the FGR group compared to controls, and stillbirth rate increased with longer gestation. Discussion: This work provides a well characterised FGR animal model that mimics the known physiological adaptations in human pregnancy and can be used to determine the efficacy of potential interventions.