Intrauterine Growth Restriction Pregnancies Research Articles

Women with Gestational Diabetes Mellitus do not have compromised polyunsaturated fatty acid status

Pregnant women who develop pre-eclampsia (PE) and/or intra-uterine growth restriction (IUGR) have reduced polyunsaturated fatty acid (PUFA) status compared to healthy pregnancy(1). It is unknown if pregnant women diagnosed with Gestational Diabetes Mellitus (GDM), and their offspring, also have compromised PUFA status. To determine if women with GDM, and their offspring, have altered PUFA status compared to healthy pregnancy. Pregnant women were recruited from Glasgow Scotland, and Brisbane, Australia from antenatal clinics for this cross sectional study. Third trimester maternal blood samples were collected after an overnight fast and cord blood samples were collected at delivery. Plasma fatty acids were analysed using gas chromatography from women with GDM (n = 37) and healthy pregnancies (n = 27) and their respective offspring (n = 31, from women with GDM, and n = 27 from healthy women). T-tests were used to determine significant differences between maternal with GDM and healthy pregnancy, as well as for their offspring and significance was set at p<0.05. Previously, erythrocyte fatty acids were analysed from women with PE (n = 21), IUGR (n = 13) and healthy pregnancies (n = 86)(1). All results were expressed as mol percent of total fatty acids. There were no differences in maternal plasma arachidonic acid (4.51 ± 1.23 vs. 4.72 ± 0.64, p = 0.39) and plasma EPA & DHA (2.33 ± 0.74 vs 2.69 ± 1.04, p = 0.14) in women with GDM and healthy pregnancies, respectively. There were no differences in fetal plasma arachidonic acid (11.58 ± 2.26 vs. 12.63 ± 1.69, p = 0.08) and plasma EPA & DHA (4.44 ± 1.17 vs. 4.44 ± 1.00, p = 0.89) in offspring from women with GDM and healthy pregnancies, respectively. Women with PE and IUGR had approximately 25% lower erythrocyte EPA & DHA and 35% lower erythrocyte arachidonic acid compared to healthy pregnant(1). Offspring from women with PE and IUGR had approximately 25% lower erythrocyte EPA & DHA and 22% lower erythrocyte arachidonic acid compared to healthy pregnancy(1).Women with PE and IUGR had lower PUFA status likely due to reduced PUFA synthesis(1) and offspring from women with PE and IUGR had reduced PUFA status likely due to ectopic fat in placenta tissue(2). Women with GDM do not have compromised PUFA status suggesting there is no reduced synthesis and transport of PUFA. Offspring from women with GDM do not have reduced PUFA status suggesting there is no problem with PUFA transport across the placenta, unlike offspring from women with PE and/or IUGR. Women with GDM, and their offspring, do not have compromised plasma PUFA status compared to healthy pregnancy.

Characterizing Early Cardiac Metabolic Programming via 30% Maternal Nutrient Reduction during Fetal Development in a Non-Human Primate Model.

Intra-uterine growth restriction (IUGR) is a common cause of fetal/neonatal morbidity and mortality and is associated with increased offspring predisposition for cardiovascular disease (CVD) development. Mitochondria are essential organelles in maintaining cardiac function, and thus, fetal cardiac mitochondria could be responsive to the IUGR environment. In this study, we investigated whether in utero fetal cardiac mitochondrial programming can be detectable in an early stage of IUGR pregnancy. Using a well-established nonhuman IUGR primate model, we induced IUGR by reducing by 30% the maternal diet (MNR), both in males (MNR-M) and in female (MNR-F) fetuses. Fetal cardiac left ventricle (LV) tissue and blood were collected at 90 days of gestation (0.5 gestation, 0.5 G). Blood biochemical parameters were determined and heart LV mitochondrial biology assessed. MNR fetus biochemical blood parameters confirm an early fetal response to MNR. In addition, we show that in utero cardiac mitochondrial MNR adaptations are already detectable at this early stage, in a sex-divergent way. MNR induced alterations in the cardiac gene expression of oxidative phosphorylation (OXPHOS) subunits (mostly for complex-I, III, and ATP synthase), along with increased protein content for complex-I, -III, and -IV subunits only for MNR-M in comparison with male controls, highlight the fetal cardiac sex-divergent response to MNR. At this fetal stage, no major alterations were detected in mitochondrial DNA copy number nor markers for oxidative stress. This study shows that in 90-day nonhuman primate fetuses, a 30% decrease in maternal nutrition generated early in utero adaptations in fetal blood biochemical parameters and sex-specific alterations in cardiac left ventricle gene and protein expression profiles, affecting predominantly OXPHOS subunits. Since the OXPHOS system is determinant for energy production in mitochondria, our findings suggest that these early IUGR-induced mitochondrial adaptations play a role in offspring's mitochondrial dysfunction and can increase predisposition to CVD in a sex-specific way.

Increased 8-OHdG in umbilical cord blood represents the risk of preeclampsia with Intra-Uterine Growth Restriction (IUGR)

Link of Video Abstract: https://youtu.be/VsAy9X8XIAk Background: Preeclampsia is a pregnancy-related disease involving multi-organs, characterized by increased blood pressure in the second trimester of pregnancy. Preeclampsia can have short-term and long-term consequences for the mother and the fetus, including intra-uterine growth restriction (IUGR). One of the markers of DNA damage due to oxidative stress due to endothelial dysfunction in preeclampsia is the increase in 8-OHdG levels in cord blood. This study aims to see an increase in 8-OHdG levels in preeclampsia. Methods: This study was a cross-sectional study with a total of 41 patients with preeclampsia and 41 patients with healthy pregnant women at Wahidin Sudirohusodo Hospital and its network. Samples were taken using the purposive sampling method according to the inclusion criteria. This 8-OHdG level was examined using the ELISA kit at the HUMRC laboratory of Hasanuddin University Hospital. The data is then processed statistically using SPSS. Results: This study found 6 patients with PE + IUGR, 31 with PE, and 41 without PE. The examination results of 8-OHdG levels found significant differences between the 3 groups PE + IUGR, PE, and normal pregnancies, which showed a significant relationship between elevated 8-OHdG levels and the incidence of PE accompanied by IUGR (p = 0.006) Conclusion: Elevated 8-OHdG levels are found in preeclampsia, especially in preeclampsia accompanied by IUGR.

The effects of sildenafil citrate on intrauterine growth restriction: a systematic review and meta-analysis

BackgroundAn increase in vascular resistance of uterine vessels is associated with intrauterine growth restriction (IUGR). Sildenafil citrate, a phosphodiesterase-5 inhibitor that stabilizes cyclic guanosine monophosphate (cGMP) and increases nitric oxide levels, improves placental perfusion by dilation of spiral arteries and is beneficial in managing IUGR. This study aims to determine the effectiveness of sildenafil citrate in improving perinatal outcomes in IUGR pregnancies.MethodsMeta-analysis was performed on data extracted from all studies specific to sildenafil citrate in IUGR management, searching relevant articles on PubMed, Medline, Google Scholar, Embase, and Cochrane databases. Publications identified by the manual search, based on references in reviews, were also included. Dichotomous results were presented as risk ratio (95% confidence interval), while continuous results were expressed as mean difference (MD); samples represented by the random effects model.ResultsNine trials were included where the sildenafil citrate effect was compared with a placebo or no intervention. A significant increase in birth weight [SMD (95% CI), 0.69 (0.31, 1.07)] was seen in IUGR pregnancies managed with sildenafil. However, gestational age (SMD (95% CI), 0.44 (-0.05, 0.94], fetal death rate [RR (95% CI), 0.56 (0.17, 1.79)] in IUGR pregnancies was not changed by sildenafil. Neonatal death [RR (95% CI), 0.93 (0.47, 1.86)] and neonatal intensive care unit (NICU) admissions [RR (95% CI), 0.76 (0.50, 1.17)] were not significantly different between sildenafil and control groups.ConclusionSildenafil citrate increases birth weight and prolonged pregnancies but did not affect stillbirth rate, neonatal death, and NICU admission.Trial registrationThe study was registered in PROSPERO on September 18, 2021 (CRD42021271992).

Adenosine-ADORA2A Promotes Ang-Induced Angiogenesis in Intrauterine Growth Restriction Placenta via the Stat3/Akt Pathway.

Abnormal placental angiogenesis is an important cause of fetal intrauterine growth restriction (IUGR), but its underlying mechanisms and therapies remain unclear. Adenosine and its mediated signaling has been reported to be associated with the development of angiogenesis. However, whether the adenosine-related signaling plays a role in modulating angiogenesis in placenta and the IUGR pregnancy outcomes remains unclear. The angiogenesis and adenosine signaling expressions in normal and IUGR placentas were detected in different species. And the role of adenosine in regulating IUGR pregnancy outcomes was evaluated using diet-induced IUGR mouse model. Molecular mechanisms underlying adenosine-induced angiogenesis were investigated by in vitro angiogenesis assays and in vivo Matrigel plug assays. Here, we demonstrated poor angiogenesis and low adenosine concentration and downregulated expression of its receptor A2a (ADORA2A [adenosine A2a receptor]) in IUGR placenta. Additionally, the beneficial effects of adenosine in improving IUGR pregnancy outcomes were revealed in a diet-induced IUGR mouse model. Moreover, adenosine was found to effectively improve adenosine signaling and angiogenesis in IUGR mice placenta. Mechanistically, by using angiogenesis assays in vitro and in vivo, adenosine was shown to activate ADORA2A to promote the phosphorylation of Stat3 (signal transducer and activator of transcription 3) and Akt (protein kinase B), resulting in increased Ang (angiogenin)-dependent angiogenesis. Collectively, this study uncovers an unexpected mechanism of promoting placental angiogenesis by adenosine-ADORA2A signaling and advances the translation of this signaling as a prognostic indicator and therapeutic target in IUGR treatment.

Effects of intrauterine growth restriction on embryonic hippocampal dentate gyrus neurogenesis and postnatal critical period of synaptic plasticity that govern learning and memory function.

Intrauterine growth restriction (IUGR) complicates up to 10% of human pregnancies and is the second leading cause of perinatal morbidity and mortality after prematurity. The most common etiology of IUGR in developed countries is uteroplacental insufficiency (UPI). For survivors of IUGR pregnancies, long-term studies consistently show a fivefold increased risk for impaired cognition including learning and memory deficits. Among these, only a few human studies have highlighted sex differences with males and females having differing susceptibilities to different impairments. Moreover, it is well established from brain magnetic resonance imaging that IUGR affects both white and gray matter. The hippocampus, composed of the dentate gyrus (DG) and cornu ammonis (CA) subregions, is an important gray matter structure critical to learning and memory, and is particularly vulnerable to the chronic hypoxic-ischemic effects of UPI. Decreased hippocampal volume is a strong predictor for learning and memory deficits. Decreased neuron number and attenuated dendritic and axonal morphologies in both the DG and CA are additionally seen in animal models. What is largely unexplored is the prenatal changes that predispose an IUGR offspring to postnatal learning and memory deficits. This lack of knowledge will continue to hinder the design of future therapy to improve learning and memory. In this review, we will first present the clinical susceptibilities and human epidemiology data regarding the neurological sequelae after IUGR. We will follow with data generated using our laboratory's mouse model of IUGR, that mimics the human IUGR phenotype, to dissect at the cellular and molecular alterations in embryonic hippocampal DG neurogenesis. We will lastly present a newer topic of postnatal neuron development, namely the critical period of synaptic plasticity that is crucial in achieving an excitatory/inhibitory balance in the developing brain. To our knowledge, these findings are the first to describe the prenatal changes that lead to an alteration in postnatal hippocampal excitatory/inhibitory imbalance, a mechanism that is now recognized to be a cause of neurocognitive/neuropsychiatric disorders in at-risk individuals. Studies are ongoing in our laboratory to elucidate additional mechanisms that underlie IUGR-induced learning and memory impairment and to design therapy aimed at ameliorating such impairment.

Determination of maternal serum pro-inflammatory cytokine changes in intrauterine growth restriction.

To evaluate maternal serum inflammatory marker changes in intrauterine growth restriction (IUGR) pregnancies. 50 healthy pregnant women and 50 patients diagnosed with IUGR were enrolled. Maternal serum high sensitivity C-reactive protein (hsCRP), erythrocyte sedimentation rate (ESR), tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and IL-10 levels were measured before delivery and neonatal outcomes were evaluated. Birth weight, Apgar scores, and cord blood gas pH were lower in the IUGR group (p<0.001, p<0.001, p<0.001 and p=0.006, respectively). While the levels of ESR, hsCRP, IL-6, and TNF-α were higher, the IL-10 level was found to be lower in the IUGR group (p<0.001, p=0.033, p<0.001, p=0.004 and p<0.001, respectively). As ESR, hsCRP, and IL-6 levels increased, birth weight, Apgar scores, and cord blood gas pH decreased (p<0.001, p<0.001, p<0.001, p<0.001, p=0.02, p=0.002, p=0.001, p=0.03, p<0.001, p<0.001, p<0.001 and p=0.02, respectively). As TNF-α level increased, only birth weight and Apgar score at the 1st minute decreased (p=0.006 and p=0.048, respectively). As IL-10 level decreased, birth weight, Apgar scores, and cord blood gas pH decreased (p<0.001 for all). IL-6 (>3.2 pg/ml) had a sensitivity of 100%, specificity of 100%, PPV of 100% and NPV of 100%. While birth weight, Apgar score and cord blood pH decreased in IUGR cases, ESR, hsCRP, IL-6 and TNF-α levels increased. Combined measurement of these markers can be used for the diagnosis of IUGR.

ASSOCIATION BETWEEN MATERNAL BASAL GLUCOSE LEVEL AND INTRAUTERINE GROWTH RESTRICTION: A COMPARATIVE CROSS-SECTIONAL STUDY

Background: Intrauterine life is the most pivotal period of development that determines vital outcomes in postnatal life. Diabetes Mellitus may lead to disturbed fetal growth and maternal vasculopathy resulting in placental insufficiency with subsequent development of intrauterine growth restriction (IUGR). This study aims to find an association between hyperglycemia and the risk of IUGR, comparing pregnancies with IUGR with those with adequate for gestational age pregnancies.&#x0D; Methods: This cross sectional study was conducted in Federal Post Graduate Medical Institute (FPGMI) from January 2015 to January 2016, including 106 pregnant women using non-probability convenient sampling technique. Participants were divided into two groups: Group A comprises of pregnant women with adequate for gestational age pregnancies (n=53) and groups B includes pregnant women with intrauterine growth restricted pregnancies (n=53). Random blood sugar level was estimated by glucose/oxidase test and IUGR was confirmed by ultrasonography at 28-35 weeks of gestation. Shapiro-Wilk test was used to examine data normality and independent t-test was used to compare statistically significant difference. A p- value of &lt;0.05 was considered significant.&#x0D; Results: Mean basal sugar level of group A was 98.9 ± 7.1 mg/dL and that of group B was 97.9 ± 6.0mg/dL. This mean difference was not statistically significant (p-value= 0.566).&#x0D; Conclusion: We found no statistically significant association between raised maternal basal glucose level and the occurrence of intrauterine growth restriction at 28-35 weeks of pregnancy.

The management of neonatal herpes simplex virus infection in a small for gestational age neonate - Case report

Neonatal herpes simplex virus infections are rare, normally acquired through vertical transmission in the peripartum period, usually manifesting before 14 days of life and being identified on the basis of history, clinical and laboratory evaluation. We present the case of a small for gestational age male infant born at 38 weeks gestational age with neonatal herpes simplex virus infection. The diagnosis was delayed because the attention was focused on an unidentified bacterial infection. In cases where a clinical picture suggestive of infection is described, with laboratory tests that support the diagnosis of infection, but with cultures that do not highlight bacterial or mycological agents, we must not forget about viral agents, specifically among those newborns from intrauterine growth restricted pregnancies. Neonatal HSV infections can be present even in the absence of herpetic vesicles in the newborn and even if the mother is asymptomatic.

SLC38A4 Amino Acid Transporter Expression Is Significantly Lower in Early Preterm Intrauterine Growth Restriction Complicated Placentas.

Intrauterine growth restriction (IUGR), predominantly caused by placental insufficiency, affects partitioning of nutrients to the fetus. The system A sodium-coupled transporters (SNAT or SLC38), of types A1, A2, and A4, control non-essential amino acid uptake and supply. Here, we aimed to investigate the expression of these transporters across different placental disease cohorts and cells. To determine disease impact, transporter expressions at the gene (qPCR) and protein (western blots) level were assessed in gestationally matched placental tissues. Early (&lt;34 weeks), and late (34-36 weeks) onset IUGR cases with/out preeclampsia were compared to preterm controls. We also investigated level of transporter expression in primary trophoblasts under glucose deprivation (n = 6) and hypoxia conditions (n = 7). SLC38A4 protein was significantly downregulated in early preterm pregnancies complicated with IUGR with/out preeclampsia. There were no differences in late preterm IUGR cohorts. Furthermore, we demonstrate for the first time in primary trophoblast cells, that gene expression of the transporters was sensitive to and induced by glucose starvation. SLC38A4 mRNA expression was also significantly upregulated in response to hypoxia. Thus, SLC38A4 expression was persistently low in early preterm IUGR pregnancies, regardless of disease aetiology. This suggests that gestational age at delivery, and consequently IUGR severity, may influence loss of its expression.

Structural insights into the covalent regulation of PAPP-A activity by proMBP and STC2

Originally discovered in the circulation of pregnant women as a protein secreted by placental trophoblasts, the metalloprotease pregnancy-associated plasma protein A (PAPP-A) is also widely expressed by many other tissues. It cleaves insulin-like growth factor-binding proteins (IGFBPs) to increase the bioavailability of IGFs and plays essential roles in multiple growth-promoting processes. While the vast majority of the circulatory PAPP-A in pregnancy is proteolytically inactive due to covalent inhibition by proform of eosinophil major basic protein (proMBP), the activity of PAPP-A can also be covalently inhibited by another less characterized modulator, stanniocalcin-2 (STC2). However, the structural basis of PAPP-A proteolysis and the mechanistic differences between these two modulators are poorly understood. Here we present two cryo-EM structures of endogenous purified PAPP-A in complex with either proMBP or STC2. Both modulators form 2:2 heterotetramer with PAPP-A and establish extensive interactions with multiple domains of PAPP-A that are distal to the catalytic cleft. This exosite-binding property results in a steric hindrance to prevent the binding and cleavage of IGFBPs, while the IGFBP linker region-derived peptides harboring the cleavage sites are no longer sensitive to the modulator treatment. Functional investigation into proMBP-mediated PAPP-A regulation in selective intrauterine growth restriction (sIUGR) pregnancy elucidates that PAPP-A and proMBP collaboratively regulate extravillous trophoblast invasion and the consequent fetal growth. Collectively, our work reveals a novel covalent exosite-competitive inhibition mechanism of PAPP-A and its regulatory effect on placental function.

Placental plastics in young women from general population correlate with reduced foetal growth in IUGR pregnancies

Constant exposure to plastics particulates has raised concerns against human health, particularly when it comes to birth outcomes. The present study explores the first appraisal of plastic particles in fresh human placenta and its association with foetal growth in neonates. Specifically, 43 pregnant women from general population were selected and their placentas were analyzed by digital microscopy and Raman microspectroscopy for microplastics (MPs <5 mm). We used regression analysis to estimate associations between MPs count in placenta and neonatal anthropometric measurements. MPs were found in all (13 out of 13) intrauterine growth restriction (IUGR) pregnancies and their average abundance ranged from 2 to 38 particles per placenta, but were less than limit of detection (LOD) in normal pregnancies except three out of 30 subjects. This study is one of very few that detected MPs in human placenta in which particles <10 μm were the most abundant in both IUGR and normal pregnancies, accounting for up to 64%. Fragments clearly prevailed at normal pregnancies and fragments together with fibers predominated at IUGR placentas. Despite four different polymers forming the MPs being identified, the majority of MPs comprised of PE (polyethylene) and PS (polystyrene). Inverse associations between MPs exposure and birth outcomes were observed in terms of birth weight (r = - 0.82, p < 0.001), length (r = - 0.56, p < 0.001), head circumference (r = - 0.50, p = 0.001), and 1-min Apgar score (r = - 0.75, p < 0.001) among those with IUGR, compared to those that were nominated as normal pregnancies. While it seems plastic particles may affect placental-foetal interrelationship, the pattern of associations between their content in placenta and birth outcomes, however, shows evidence of a nonlinear or nonmonotonic dose response possibly through perturbation of gas and nutrients exchange which is worth future investigation.

Maternal neuropeptide galanin levels in pregnancies with intra-uterine growth restriction (IUGR): neurohormonal regulation of fetal weight.

Galanin is a neuroendocrine peptide with diverse biological actions in humans. Here, we evaluated plasma galanin levels in pregnant women with intrauterine growth restriction (IUGR) to elucidate the mechanism underlying the causal link between regulatory neuropeptides and IUGR. This prospective case-control study evaluated 40 IUGR pregnancies and 35 healthy body mass index (BMI) and age-matched second and third-trimester pregnant women at Istanbul Teaching and Research Hospital. Serums galanin levels were determined using an enzyme-linked immunosorbent assay (ELISA) kit according to the manufacturer's procedure. Median serum galanin levels were lower in the IUGR group (9.59pg/ml) than in the control group (12.1pg/ml), although statically insignificant. Galanin levels were significantly higher in the control group with a BMI ≥ 30 than in those with a BMI < 30; the IUGR group exhibited no significant difference. Galanin levels were higher in the control group premature births than in term pregnancies; the difference was insignificant in the IUGR group. Thus, IUGR minimally impacts circulating maternal galanin levels, indicating that while galanin might affect IUGR pathogenesis, it negligibly contributes to disease progression. The lack of correlation between galanin levels and maternal BMI and preterm pregnancies suggests a blunted neuropeptide response to hormonal stimulus in IUGR pregnancies, compared with the positive association with maternal BMI and negative association with healthy preterm pregnancies.

Uptake of Phosphate, Calcium, and Vitamin D by the Pregnant Uterus of Sheep in Late Gestation: Regulation by Chorionic Somatomammotropin Hormone.

Minerals are required for the establishment and maintenance of pregnancy and regulation of fetal growth in mammals. Lentiviral-mediated RNA interference (RNAi) of chorionic somatomammotropin hormone (CSH) results in both an intrauterine growth restriction (IUGR) and a non-IUGR phenotype in sheep. This study determined the effects of CSH RNAi on the concentration and uptake of calcium, phosphate, and vitamin D, and the expression of candidate mRNAs known to mediate mineral signaling in caruncles (maternal component of placentome) and cotyledons (fetal component of placentome) on gestational day 132. CSH RNAi Non-IUGR pregnancies had a lower umbilical vein–umbilical artery calcium gradient (p < 0.05) and less cotyledonary calcium (p < 0.05) and phosphate (p < 0.05) compared to Control RNAi pregnancies. CSH RNAi IUGR pregnancies had less umbilical calcium uptake (p < 0.05), lower uterine arterial and venous concentrations of 25(OH)D (p < 0.05), and trends for lower umbilical 25(OH)D uptake (p = 0.059) compared to Control RNAi pregnancies. Furthermore, CSH RNAi IUGR pregnancies had decreased umbilical uptake of calcium (p < 0.05), less uterine venous 25(OH)D (vitamin D metabolite; p = 0.055), lower caruncular expression of SLC20A2 (sodium-dependent phosphate transporter; p < 0.05) mRNA, and lower cotyledonary expression of KL (klotho; p < 0.01), FGFR1 (fibroblast growth factor receptor 1; p < 0.05), FGFR2 (p < 0.05), and TRPV6 (transient receptor potential vanilloid member 6; p < 0.05) mRNAs compared to CSH RNAi Non-IUGR pregnancies. This study has provided novel insights into the regulatory role of CSH for calcium, phosphate, and vitamin D utilization in late gestation.

Increased Colocalization and Interaction Between Decidual Protein Kinase A and Insulin-like Growth Factor-Binding Protein-1 in Intrauterine Growth Restriction.

Increased phosphorylation of decidual insulin-like growth factor-binding protein-1 (IGFBP-1) can contribute to intrauterine growth restriction (IUGR) by decreasing the bioavailability of insulin-like growth factor-1 (IGF-1). However, the molecular mechanisms regulating IGFBP-1 phosphorylation at the maternal-fetal interface are poorly understood. Protein kinase A (PKA) is required for normal decidualization. Consensus sequences for PKA are present in IGFBP-1. We hypothesized that the expression/interaction of PKA with decidual IGFBP-1 is increased in IUGR. Parallel reaction monitoring-mass spectrometry (PRM-MS) identified multiple PKA peptides (n=>30) co-immunoprecipitating with IGFBP-1 in decidualized primary human endometrial stromal cells (HESC). PRM-MS also detected active PKApThr197 and greater site-specific IGFBP-1 phosphorylation(pSer119), (pSer98+pSer101) (pSer169+pSer174) in response to hypoxia. Hypoxia promoted colocalization [dual immunofluorescence (IF)] of PKA with IGFBP-1 in decidualized HESC. Colocalization (IF) and interaction (proximity ligation assay) of PKA and IGFBP-1 were increased in decidua collected from placenta of human IUGR pregnancies (n=8) compared with decidua from pregnancies with normal fetal growth. Similar changes were detected in decidual PKA/IGFBP-1 using placenta from baboons subjected to maternal nutrient reduction (MNR) vs controls (n=3 each). In baboons, these effects were evident in MNR at gestational day 120 prior to IUGR onset. Increased PKA-mediated phosphorylation of decidual IGFBP-1 may contribute to decreased IGF-1 bioavailability in the maternal-fetal interface in IUGR.

Role of prenatal fetal echocardiography in the assessment of intrauterine growth restriction

BackgroundIntrauterine growth restriction (IUGR) is a common diagnosis in obstetrics and carries an increased risk of perinatal mortality and morbidity. Identification of IUGR is crucial because proper evaluation and management can result in a favourable outcome. Cardiovascular dysfunction and remodelling is a central feature of IUGR. The aim of the study was to use the left modified myocardial performance index (MPI), assess cardiac function in foetuses with intrauterine growth restriction (IUGR) compared to healthy foetuses, and to connect the relationship between changes in MPI and perinatal outcome. A prospective study was conducted with 60 singleton foetuses between 24 and 40 weeks of gestation without foetal chromosomal abnormalities or major malformations, divided into two groups: 30 women with intrauterine growth restriction (30 women) and another 30 women with normal pregnancies (foetal growth pattern appropriate for gestational age and normal heart findings with normal sinus rhythm) who were matched for gestational age and served as the controls. Trans-abdominal ultrasound examination was done with 3.5–7-MHz curvilinear Probe (GE Medical US equipment). The umbilical arteries, middle cerebral artery, and ductus venosus all had blood flow velocity waveforms recorded. The pulsatility index (PI), cerebroplacental ratio (CPR), and Doppler velocimetry (DV) of the umbilical artery were all measured. All foetuses had their myocardial performance index assessed. Normal and abnormal umbilical artery(UA) Doppler, as well as normal and abnormal MCA Doppler, were used to examine the intrauterine growth restriction group. Foetal growth restrictions (FGR) foetuses' Mod-MPI values were compared to gestation-matched controls. The outcomes of the perinatal period were documented.ResultsIntrauterine growth restriction foetuses with defective umbilical arteries Doppler had a substantially higher mean left myocardial performance index (mean 0.58 SD 0.093) than healthy foetuses (mean 0.45SD 0.070) (P 0.001). When compared to the control group, IUGR foetuses with abnormal left myocardial performance index had a significantly worse perinatal outcome and higher morbidity. When compared to intrauterine growth restriction foetuses with normal MPI, intrauterine growth restriction foetuses with defective left MPI had a significantly worse perinatal outcome (whether the UA Doppler was normal or abnormal). Based on the perinatal result, the foetal myocardial performance index was linked to the severity of foetal impairment in intrauterine growth restriction foetuses.ConclusionMPI has the potential to be a useful technique for evaluating IUGR pregnancies and predicting neonatal outcome. Within the IUGR foetuses, MPI foetal echocardiographic characteristics can define a high-risk group.

L-arginine supplementation improved neonatal outcomes in pregnancies with hypertensive disorder or intrauterine growth restriction: A systematic review and meta-analysis of randomized controlled trials

Previous research established that the availability of l-arginine affects placental vascular development and fetal growth. However, practical details associated with the effects of l-arginine supplementation on the neonatal outcomes of hypertensive disorder (HD) and intrauterine growth restriction (IUGR) pregnancies are limited. The PubMed, ScienceDirect, and Web of Science databases were searched for peer-reviewed literature published by September 30, 2021 to investigate the operational details of l-arginine supplementation in improving neonatal outcomes in complicated pregnancies. Standardized mean difference (SMD) and weighted mean difference (WMD) of continuous variables, as well as the risk ratio (RR) for categorical variables were pooled by random-effects models. The results indicated that l-arginine supplementation increased the plasma nitric oxide (NO) concentrations in IUGR pregnancies (SMD: 0.71; 95% CI: 0.45, 0.97; I2=0%), but decreased the risk of preeclampsia in HD mothers (RR: 0.49; 95% CI: 0.31, 0.76; I2=0%). Administration with l-arginine elevated birth weights both in hypertensive and IUGR pregnant women, with WMDs of 194.70g (95% CI: 58.21, 331.20; I2=44.2%) and 134.00g (95% CI: 43.53, 224.46; I2=42.4%), respectively. However, the intervention had no effect on gestational age except in HD pregnancies (WMD: 7.05d; 95% CI: 3.16, 10.95; I2=36.5%). l-arginine administration during pregnancy significantly reduced the small for gestational age (SGA) risk of fetus both in HD (RR: 0.51; 95% CI: 0.31, 0.83; I2=0.0%) and IUGR mothers (RR: 0.46; 95% CI: 0.25, 0.88; I2=0.0%). Subgroup analyses revealed that l-arginine supplementation at <4g/d dosage or for ≥1-month duration or in the third trimester had a greater effect on birth weights in HD women without proteinuria, but a higher l-arginine dosage was more beneficial for extending gestational age and reducing the risk of SGA in older pregnancies. Additionally, intravenous infusion of l-arginine, but not oral administration, significantly increased birth weight in IUGR pregnancies with elevated NO concentrations, although the recommended amount should be confined to <4g/d. These findings provide practical guidelines for l-arginine supplementation to improve the birth outcomes of complicated pregnancies. CRD42021246290 (https://www.crd.york.ac.uk/PROSPERO).

Neonatal and Long-Term Prognosis of Monochorionic Diamniotic Pregnancies Complicated by Selective Growth Restriction.

Background: There are few data concerning the neonatal and long-term prognosis of monochorionic biamniotic twin pregnancies (MCBA) complicated by selective intrauterine growth restriction (sIUGR). The aim of the study is to assess the neurological outcomes at two years of age of these newborns and compares these outcomes to those of newborns resulting from intrauterine growth restriction (IUGR) pregnancies. Methods: The study focuses on a cross-sectional prospective cohort of patients treated between 2012 and 2019 in Marseille, France. The primary endpoint is the overall score of the Ages and Stages questionnaires (ASQ) at two years, which assesses the global neurodevelopment. The secondary endpoint is the assessment of neonatal morbi-mortality for both groups (composite endpoint). Results: In total, 251 patients were included in the analysis: 67 in the sIUGR group and 184 in the IUGR group. There was no statistically significant difference in the overall ASQ score at two years but there was the finest motor skills impairment in the IUGR group. The areas most often impaired were communication and fine motor skills. There were no significant differences between the neonatal morbi-mortality of the two groups (adjusted OR = 0.95, p = 0.9). Conclusions: Newborns from MCBA pregnancies with sIUGR appear to have similar overall neurological development to IUGR. Notably, IUGR seems to have the most moderate neurobehavioral disorder (fine motor) as a consequence of impaired antenatal brain development due to placenta insufficiency leading to chronic hypoxia.

Comment on Yeste et al. Polyphenols and IUGR Pregnancies: Intrauterine Growth Restriction and Hydroxytyrosol Affect the Development and Neurotransmitter Profile of the Hippocampus in a Pig Model. Antioxidants 2021, 10, 1505.

Intrauterine growth restriction (IUGR) affects 5–10% of newborns and increases the risks of intrauterine demise, neonatal morbidity, and death. In their recent publication, Yeste et al. found the benefits of hydroxytyrosol supplementation on brain remodeling from an IUGR pig model. Additionally, we found a significant decrease in phenolic alcohol (tyrosol and hydroxytyrosol) intake in IUGR pregnant women. Altogether, these findings support the notion that dietetic interventions, through supplementation but mostly via a balanced diet, can ameliorate IUGR complications. Furthermore, diet intervention combined with early biomarkers may allow clinicians to eventually anticipate IUGR diagnosis and help avoid one of the most frequent causes of newborn mortality and morbidity.

The relationship between pregnancies complicated with fetal growth restriction and umbilical cord blood endocan concentrations

Abstract Objectives The main etiological factor in intrauterine growth restriction (IUGR) is the impairment of the fetoplacental unit. Due to the placental endothelial disintegrity and vascular permeability disruptions, endocan has been an interesting molecule to search for associations with IUGR. The aim of this study was to investigate the umbilical cord blood endocan concentrations in IUGR pregnancies. Methods This cross-sectional case-control study was conducted on 50 IUGR-complicated (patients) and 50 control pregnancies. The demographics and clinical findings were recruited from records. The umbilical cord blood was studied for endocan concentrations. Results The patient group compared to controls had significantly more previous IUGR history, lower maternal weight gain, an earlier gestational week at delivery, and more cesarean sections (p&lt;0.001). The umbilical cord endocan concentrations were significantly higher in patients than in controls (p&lt;0.001). Oligohydramnios (n=38) was significantly higher in the patients and had a significant relationship with high endocan concentrations (p&lt;0.001). Moderate and mild positive correlations were found among endocan concentration and biparietal diameter/head circumference and femur length values, respectively, while a moderate negative correlation was observed in abdominal circumference values (p&lt;0.001). Conclusions A significant increase in the umbilical cord blood endocan concentrations was found in IUGR pregnancies.