Intrauterine Growth Restriction Fetuses Research Articles

Murine maternal dietary restriction affects neural Humanin expression and cellular profile.

To understand the cellular basis for the neurodevelopmental effects of intrauterine growth restriction (IUGR), we examined the global and regional expression of various cell types within murine (Mus musculus) fetal brain. Our model employed maternal calorie restriction to 50% daily food intake from gestation day 10-19, producing IUGR offspring. Offspring had smaller head sizes with larger head:body ratios indicating a head sparing IUGR effect. IUGR fetuses at embryonic day 19 (E19) had reduced nestin (progenitors), β-III tubulin (immature neurons), Glial fibrillary acidic protein (astrocytes), and O4 (oligodendrocytes) cell lineages via immunofluorescence quantification and a 30% reduction in cortical thickness. No difference was found in Bcl-2 or Bax (apoptosis) between controls and IUGR, though qualitatively, immunoreactivity of doublecortin (migration) and Ki67 (proliferation) was decreased. In the interest of examining a potential therapeutic peptide, we next investigated a novel pro-survival peptide, mouse Humanin (mHN). Ontogeny examination revealed highest mHN expression at E19, diminishing by postnatal day 15 (P15), and nearly absent in adult (3months). Subanalysis by sex at E19yielded higher mHN expression among males during fetal life, without significant difference between sexes postnatally. Furthermore, femaleIUGR mice at E19had a greater increase in cortical mHN versus the male fetus over their respective controls. We conclude that maternal dietary restriction-associated IUGR interferes with neural progenitors differentiating into the various cellular components populating the cerebral cortex, and reduces cerebral cortical size. mHN expression is developmental stage and sex specific, with IUGR, particularly in the females, adaptively increasing its expression toward mediating a pro-survival approach against nutritional adversity.

Placental fibronectin staining is unaffected in pregnancies complicated by late-onset intrauterine growth restriction and small for gestational age fetuses.

To investigate the placental staining pattern of fibronectin, an extracellular matrix protein essential for trophoblastic invasion, in pre-eclampsia and fetal growth restriction. This was a retrospective study conducted at the University of Udine, including the placentas of women with pre-eclampsia and fetal growth restriction collected between January 1, 2001, and December 31, 2010. Fibronectin was evaluated in placental tissue micro-array by immunohistochemistry, describing localization and intensity of staining. The study included the placentas of 36 women with early-onset (delivery <34weeks of gestation) pre-eclampsia; 6 with early-onset HELLP syndrome; 17 with early-onset intrauterine growth restriction (IUGR); 14 with late-onset (delivery ≥34weeks of gestation) pre-eclampsia; 35 with late-onset IUGR; 18 with small for gestational age (SGA) fetuses (birth weight <10th percentile); and 64 controls. Fibronectin was present both at the cell surface and in the cytoplasm. Cytoplasm staining intensity resulted higher in early forms of pregnancy-related complications compared to controls, although this was statistically significant (P<0.05) only for early-onset pre-eclampsia (P=0.085 for HELLP syndrome; P=0.091 for IUGR). Also, late-onset forms of pre-eclampsia had stronger cytoplasmic and pericellular staining compared to controls (P<0.05). Interestingly, staining of both late-onset IUGR and SGA was comparable to controls. Fibronectin appeared to be unaffected in women with late-onset IUGR and SGA fetuses, suggesting a peculiar common pathogenetic pattern in these conditions.

The association between isolated oligohydramnios at term and placental pathology in correlation with pregnancy outcomes

IntroductionIsolated term oligohydramnios (ITO) is an obstetrical complication of which the etiology, management, and clinical importance are controversial. In attempt to deepen our understanding, we aimed to study placental pathology and pregnancy outcomes in pregnancies complicated by ITO. Materials and methods– Maternal demographics, neonatal outcomes, and placental histopathology reports of all pregnancies complicated by ITO at 370/7 to 410/7 weeks were reviewed. Excluded were cases complicated by hypertensive disorders, intrauterine fetal growth restriction, placental abruption, and deliveries of undiagnosed small for gestational age neonates. Results were compared between the ITO group and a control group matched for gestational age and mode of delivery. Placental lesions were classified according to the current “Amsterdam” criteria. Composite adverse neonatal outcome was defined as one or more of the following early complications: neonatal intensive care unit admission, sepsis, blood transfusion, phototherapy, respiratory morbidity, cerebral morbidity, necrotizing enterocolitis, or death. ResultsThe study group included 108 patients with ITO that were compared to matched controls. Placentas from the ITO group were characterized by higher rates of placental weights <10th centile (p < 0.001), abnormal cord insertion (p < 0.001), and maternal vascular malperfusion (MVM) lesions (p < 0.001). Neonates from the ITO group had lower birth weights (p < 0.002), and worse composite adverse neonatal outcome (p = 0.028) compared to controls. Conclusion– The current study demonstrates higher rates of placental MVM lesions, and worse neonatal outcome in pregnancies complicated by ITO. These novel findings suggest that ITO should be seen as part of the “placental insufficiency” spectrum.

204 Discriminating intrauterine growth-restricted piglets through near-infrared spectroscopy of amniotic fluids

The occurrence of intrauterine growth restriction (IUGR) is a great concern in animal production systems, leading to substantial economic losses. The multifactorial causes of IUGR make their prediction before or during pregnancy a challenging task. The amniotic fluid, containing chemical secretions of both the developing fetus and the amnion-allantois membrane, may offer a unique opportunity to investigate the causes of IUGR in piglets. Here we applied near-infrared spectroscopy (NIRS) as a rapid tool to discriminate the chemical composition of the amniotic fluid from IUGR fetuses at different gestational ages. The uteri of gravid sows were dissected at 60% (n=6 sows) and 90% (n=6 sows) of gestational age. Amniotic fluids were collected with a sterile 10-mL syringe connected to an 18-G needle under visual guidance, and samples without blood contamination were kept at 4°C while the fetus was measured. Samples were selected according to fetal weight and were classified as small (mean − 2 SD), medium (mean), and large (mean + 2 SD) sizes in each litter. Selected samples were kept at −80°C until NIRS transmittance spectra collection (350-2500nm). At 60% of gestational age, male fetuses weighed 96±1.2, 133±1.7, and 159±1.9g and female fetuses weighed 117±1.1, 137±1.8, and 152±1.8g for small, medium, and large groups, respectively. The fetal weights at 90% of gestational age averaged 517±0.6, 757±0.6, and 912±0.7g for males and 532±0.6, 718±0.9, and 911±0.6g for females for small, medium, and large sizes, respectively. Chemometric analysis of the amniotic fluid spectra was applied to the wavelength range 1300-1600nm using a balanced data set (n=425) with an 80/20 calibration/validation distribution for linear discriminant analysis (LDA-PCA). Overall, we were able to discriminate samples according to fetal size and gestational age; LDA-PCA showed the highest size classification occurring with spectra derived from the small fetuses with an accuracy of 94.5-100% and 100% and 70.6% for the calibration and validation processes from 60% and 90% of gestational age, respectively. By contrast, when the analysis considered each sex at 60% of gestational age, the medium and small fetuses presented the highest size classification for females and males correspondingly. At 90% of gestational age, the large fetuses presented the best discrimination for both sexes. In conclusion, we were able to detect and discriminate chemical changes of the amniotic fluid from different fetuses using NIRS, indicating that this fluid contains molecules that may characterise IUGR in piglets. These observations will permit future investigations to identify specific molecules associated with IUGR that would lead to possible real-time corrective actions before birth. This work was supported by USDA-ARS grant no. 58-6402-3-018.

Magnetic Resonance Imaging in Pregnancy with Intrauterine Growth Restriction: A Pilot Study.

Objective Intrauterine growth restriction (IUGR) is a major cause of late stillbirth, though not all compromised babies remain small or are considered growth restricted as pregnancy progresses. Fetal Magnetic Resonance Imaging (f-MRI) represents a second-line tool to study pregnancies with IUGR fetuses. The aim of our study was to evaluate the usefulness of f-MRI on predicting fetal growth and the offspring's perinatal respiratory outcome. Design All f-MRI performed between 2014 and 2016 in Siena were analysed. Pregnancies with IUGR (Study group (SG)) were recruited together with a control population (Control group (CG)), coupled for gestational age (GA) at the time of f-MRI (mean GA 31 wks). Neonatal information was collected. The f-MRI protocol consisted of T2w images. Six regions of interest (ROI) were placed as follows: 2 on the lung, 2 on the liver, and 2 on the amniotic fluid. The signal intensities (SI) of each ROI were measured. The SI lung to liver ratio (SI lung/liver) and SI lung to amniotic fluid ratio (SI lung/amniotic fluid) were obtained for each fetus. Each ratio was compared between SG and CG. Therefore, SG was divided into two subgroups: adequate and small for gestational age (AGA and SGA) newborns. All measurements were related to offspring's perinatal respiratory outcome. Results SI lung/liver was linearly related with GA at the time of f-MRI and with EFW. SI lung/amniotic fluid was significantly higher in SG than in CG (p = 0,014). In contrast, among SG, lower values of SI lung/amniotic fluid were found in the SGA compared to AGA (p = 0,036). The days of oxygen supply were higher in the SGA subgroup than in the AGA subgroup (p = 0,028). Conclusions SI lung/liver increases with fetal lung maturation and appears to be useful to estimate intrauterine fetal growth. SI lung/amniotic fluid seems to be a reliable predictive index to distinguish the IUGR fetuses that can recover their growth from those that were born SGA. f-MRI represents a promising frontier to predict IUGR fetus outcome, thus contributing to ameliorate the perinatal management.

Obeticholic Acid Protects against Gestational Cholestasis-Induced Fetal Intrauterine Growth Restriction in Mice.

Gestational cholestasis is a common disease and is associated with adverse pregnancy outcomes. However, there are still no effective treatments. We investigated the effects of obeticholic acid (OCA) on fetal intrauterine growth restriction (IUGR) during 17α-ethynylestradiol- (E2-) induced gestational cholestasis in mice. All pregnant mice except controls were subcutaneously injected with E2 (0.625 mg/kg) daily from gestational day (GD) 13 to GD17. Some pregnant mice were orally administered with OCA (5 mg/kg) daily from GD12 to GD17. As expected, OCA activated placental, maternal, and fetal hepatic FXR signaling. Additionally, exposure with E2 during late pregnancy induced cholestasis, whereas OCA alleviated E2-induced cholestasis. Gestational cholestasis caused reduction of fetal weight and crown-rump length and elevated the incidence of IUGR. OCA decreased the incidence of IUGR during cholestasis. Interestingly, OCA attenuated reduction of blood sinusoid area in placental labyrinth layer and inhibited downregulation of placental sodium-coupled neutral amino acid transporter- (SNAT-) 2 during cholestasis. Additional experiment found that OCA attenuated glutathione depletion and lipid peroxidation in placenta and fetal liver and placental protein nitration during cholestasis. Moreover, OCA inhibited the upregulation of placental NADPH oxidase-4 and antioxidant genes during cholestasis. OCA activated antioxidant Nrf2 signaling during cholestasis. Overall, we demonstrated that OCA treatment protected against gestational cholestasis-induced placental dysfunction and IUGR through suppressing placental oxidative stress and maintaining bile acid homeostasis.

Label-Free Proteomics of the Fetal Pancreas Identifies Deficits in the Peroxisome in Rats with Intrauterine Growth Restriction.

Aim The objective of the present study was to identify differentially expressed proteins (DEPs) in the pancreas of a fetus with intrauterine growth restriction (IUGR) and to investigate the molecular mechanisms leading to adulthood diabetes in IUGR. Methods The IUGR rat model was induced by maternal protein malnutrition. The fetal pancreas was collected at embryonic day 20 (E20). Protein was extracted, pooled, and subjected to label-free quantitative proteomic analysis. Bioinformatics analysis (GO and IPA) was performed to define the pathways and networks associated with DEPs. LC-MS results were confirmed by western blotting and/or quantitative PCR (q-PCR). The principal parameters of oxidative stress-superoxide dismutase (Sod) were determined in blood samples of fetal rats. Results A total of 57 DEPs (27 upregulated, 30 downregulated) were identified with a 1.5-fold change threshold and a p value ≤ 0.05 between the IUGR and the control pancreas. Bioinformatics analysis revealed that these proteins play important roles in peroxisome biogenesis and fission, fatty acid beta-oxidation (FAO), mitotic cell cycle, and histone modification. The peroxin Pex14 was downregulated in the IUGR pancreas as confirmed by western blotting and q-PCR. Pmp70, a peroxisomal membrane protein involved in the transport of fatty acids, was upregulated. Hsd17b4 and Acox1/2, which catalyze different steps of peroxisomal FAO, were dysregulated. Sod plasma concentrations in the IUGR fetus were higher than those in the control, suggesting partial compensation for oxidative stress. Multiple DEPs were related to the regulation of the cell cycle, including reduced Cdk1, Mcm2, and Brd4. The histone acetylation regulators Hdac1/2 were downregulated, whereas Sirt1/3 and acetylated H3K56 were increased in the IUGR fetal pancreas. Conclusion The present study identified DEPs in the fetal pancreas of IUGR rats by proteomic analysis. Downregulation of pancreas peroxins and dysregulation of enzymes involved in peroxisomal FAO may impair the biogenesis and function of the peroxisome and may underlie the development of T2 diabetes mellitus in adult IUGR rats. Disorders of cell cycle regulators may induce cell division arrest and lead to smaller islets. The present data provide new insight into the role of the peroxisome in the development of the pancreas and may be valuable in furthering our understanding of the pathogenesis of IUGR-induced diabetes.

Estimating fetal cholesterol synthesis rates by cord blood analysis in intrauterine growth restriction and normally grown fetuses

BackgroundCholesterol is an essential component in human development. In fetuses affected by intrauterine growth restriction (IUGR), fetal blood cholesterol levels are low. Whether this is the result of a reduced materno-fetal cholesterol transport, or due to low fetal de novo synthesis rates, remains a matter of debate. By analyzing cholesterol interbolites and plant sterols we aimed at deeper insights into transplacental cholesterol transport and fetal cholesterol handling in IUGR with potential targets for future therapy. We hypothesized that placental insufficiency results in a diminished cholesterol supply to the fetus.MethodsVenous umbilical cord sera were sampled post-partum from fetuses delivered between 24 weeks of gestation and at full term. IUGR fetuses were matched to 49 adequate-for-age delivered preterm and term neonates (CTRL) according to gestational age at delivery. Cholesterol was measured by gas chromatography-flame ionization detection using 5a-cholestane as internal standard. Cholesterol precursors and synthesis markers, such as lanosterol, lathosterol, and desmosterol, the absorption markers, 5α-cholestanol and plant sterols, such as campesterol and sitosterol, as well as enzymatically oxidized cholesterol metabolites (oxysterols), such as 24S- or 27-hydroxycholesterol, were analyzed by gas chromatography-mass spectrometry, using epicoprostanol as internal standard for the non-cholesterol sterols and deuterium labeled oxysterols for 24S- and 27-hydroxycholesterol.ResultsMean cholesterol levels were 25% lower in IUGR compared with CTRL (p < 0.0001). Lanosterol and lathosterol to cholesterol ratios were similar in IUGR and CTRL. In relation to cholesterol mean, desmosterol, 24S-hydroxycholesterol, and 27-hydroxycholesterol levels were higher by 30.0, 39.1 and 60.7%, respectively, in IUGR compared to CTRL (p < 0.0001). Equally, 5α-cholestanol, campesterol, and β-sitosterol to cholesterol ratios were higher in IUGR than in CTRL (17.2%, p < 0.004; 33.5%, p < 0.002; 29.3%, p < 0.021).ConclusionsCholesterol deficiency in IUGR is the result of diminished fetal de novo synthesis rates rather than diminished maternal supply. However, increased oxysterol- and phytosterol to cholesterol ratios suggest a lower sterol elimination rate. This is likely caused by a restricted hepatobiliary function. Understanding the fetal cholesterol metabolism is important, not only for neonatal nutrition, but also for the development of strategies to reduce the known risk of future cardiovascular diseases in the IUGR fetus.

Sustained maternal inflammation during the early third-trimester yields intrauterine growth restriction, impaired skeletal muscle glucose metabolism, and diminished β-cell function in fetal sheep1,2.

Maternal inflammation causes fetal intrauterine growth restriction (IUGR), but its impact on fetal metabolism is not known. Thus, our objective was to determine the impact of sustained maternal inflammation in late gestation on fetal inflammation, skeletal muscle glucose metabolism, and insulin secretion. Pregnant ewes were injected every third day from the 100th to 112th day of gestation (term = 150 d) with saline (controls) or lipopolysaccharide (LPS) to induce maternal inflammation and IUGR (MI-IUGR). Fetal femoral blood vessels were catheterized on day 118 to assess β-cell function on day 123, hindlimb glucose metabolic rates on day 124, and daily blood parameters from days 120 to 125. Fetal muscle was isolated on day 125 to assess ex vivo glucose metabolism. Injection of LPS increased (P < 0.05) rectal temperatures, circulating white blood cells, and plasma tumor necrosis factor α (TNFα) concentrations in MI-IUGR ewes. Maternal leukocytes remained elevated (P < 0.05) and TNFα tended to remain elevated (P < 0.10) compared with controls almost 2 wk after the final LPS injection. Total white blood cells, monocytes, granulocytes, and TNFα were also greater (P < 0.05) in MI-IUGR fetuses than controls over this period. MI-IUGR fetuses had reduced (P < 0.05) blood O2 partial pressures and greater (P < 0.05) maternofetal O2 gradients, but blood glucose and maternofetal glucose gradients did not differ from controls. Basal and glucose-stimulated insulin secretion were reduced (P < 0.05) by 32% and 42%, respectively, in MI-IUGR fetuses. In vivo hindlimb glucose oxidation did not differ between groups under resting conditions but was 47% less (P < 0.05) in MI-IUGR fetuses than controls during hyperinsulinemia. Hindlimb glucose utilization did not differ between fetal groups. At day 125, MI-IUGR fetuses were 22% lighter (P < 0.05) than controls and tended to have greater (P < 0.10) brain/BW ratios. Ex vivo skeletal muscle glucose oxidation did not differ between groups in basal media but was less (P < 0.05) for MI-IUGR fetuses in insulin-spiked media. Glucose uptake rates and phosphorylated-to-total Akt ratios were less (P < 0.05) in muscle from MI-IUGR fetuses than controls regardless of media. We conclude that maternal inflammation leads to fetal inflammation, reduced β-cell function, and impaired skeletal muscle glucose metabolism that persists after maternal inflammation ceases. Moreover, fetal inflammation may represent a target for improving metabolic dysfunction in IUGR fetuses.

Intrauterine Growth Restriction Programs Intergenerational Transmission of Pulmonary Arterial Hypertension and Endothelial Dysfunction via Sperm Epigenetic Modifications.

Intrauterine life represents a window of phenotypic plasticity which carries consequences for later health in adulthood as well as health of subsequent generations. Intrauterine growth-restricted fetuses (intrauterine growth restriction [IUGR]) have a higher risk of pulmonary arterial hypertension in adulthood. Endothelial dysfunction, characterized by hyperproliferation, invasive migration, and disordered angiogenesis, is a hallmark of pulmonary arterial hypertension pathogenesis. Growing evidence suggests that intergenerational transmission of disease, including metabolic syndrome, can be induced by IUGR. Epigenetic modification of the paternal germline is implicated in this transmission. However, it is unclear whether offspring of individuals born with IUGR are also at risk of developing pulmonary arterial hypertension and endothelial dysfunction. Using a model of maternal caloric restriction to induce IUGR, we found that first and second generations of IUGR exhibited elevated pulmonary arterial pressure, myocardial, and vascular remodeling after prolonged exposure to hypoxia. Primary pulmonary vascular endothelial cells (PVECs) from both first and second generations of IUGR exhibited greater proliferation, migration, and angiogenesis. Moreover, in 2 generations, PVECs-derived ET-1 (endothelin-1) was activated by IUGR and hypoxia, and its knockdown mitigated PVECs dysregulation. Most interestingly, within ET-1 first intron, reduced DNA methylation and enhanced tri-methylation of lysine 4 on histone H3 were observed in PVECs and sperm of first generation of IUGR, with DNA demethylation in PVECs of second generation of IUGR. These results suggest that IUGR permanently altered epigenetic signatures of ET-1 from the sperm and PVECs in the first generation, which was subsequently transferred to PVECs of offspring. This mechanism would yield 2 generations with endothelial dysfunction and pulmonary arterial hypertension-like pathophysiological features in adulthood.

DNA methylation profiles of genes associated with angiogenesis in the samples of placenta in pregnancies complicated by intrauterine growth restriction

Background Impairment in placental angiogenesis is blamed for the etiopathogenesis of intrauterine growth restriction (IUGR). Aim To assess the genes related to angiogenesis in placental biopsies of pregnancies complicated by IUGR that could be aberrantly methylated and adversely affect placental angiogenesis. Methods The methylation profiles of soluble fms-like tyrosine kinase-1 (sFLT-1), vascular endothelial growth factor (VEGF), and the placental growth factor (PIGF) were evaluated using Illumina MiSeq™ System in placental biopsies from term IUGR pregnancies without preeclampsia (n = 18) and healthy controls (n = 17). DNA was isolated from samples of tissue collected from the fetal side of the placenta. In the targeted regions, we have identified 30, 24, and 29 CpG islands (CpGi) within sFLT-1, VEGF and PIGF genes, respectively. CpGi which are most methylated in the promoter regions of three genes were selected for the study from the database http://www.ensembl.org. Result(s) IUGR fetuses had significantly lower placental and fetal birth weight than controls. The promoter of sFLT-1 at three CpGi and VEGF at six CpGi were the regions with significant methylation differences between IUGR and control placentas. sFLT-1 was hypermethylated at 265 and 352 CpGi; however, hypermethylation was lower in IUGR group compared to control group at this position. sFLT-1 was hypomethylated at 456 CpGi in IUGR group and hypermethylated at the same region in control group. VEGF was hypomethylated at 668, 703, and 710 CpGi in control and IUGR groups; however, hypomethylation at these positions was significantly higher in control group compared to IUGR. 776, 845, and 863 CpGi of VEGF promoter were significantly hypermethylated in IUGR group whereas hypomethylated in control group. The methylation profile of PIGF did not differ between the groups. After adjustment for the factors known to affect fetal birth weight, DNA methylation of VEGF 668 CpGi had a significant negative association with fetal birth weight in the control and the IUGR group and a positive association with IUGR pregnancies. Conclusion(s) Our results do not support the hypothesis that altered DNA methylation in the placental angiogenic genes is a major mechanism generally involved in IUGR. Only a specific region (at 668 CpGi) corresponding to the promoter of VEGF may serve as an epigenetic marker of IUGR and may be involved in the mechanism of IUGR. Large sample-sized studies are needed to understand the effects of DNA methylation on placental gene function and how they might influence fetal growth.

Aspirin, low molecular weight heparin, or both in preventing pregnancy complications in women with recurrent pregnancy loss and factor V Leiden mutation

Objective: The aim of this study was to compare the effects of low molecular weight heparin (LMWH), LMWH plus low dose aspirin, or low dose aspirin only on pregnancy outcomes in recurrent pregnancy loss (RPL) patients with factor V Leiden mutation (FVLM).Materials and methods: A total of 2764 RPL patients were evaluated in for the etiology of RPL. Mutations in factor V Leiden homozygous and heterozygous were determined. Subsequently, 196 of these patients were diagnosed with FVLM and included in the study; of these 174 completed the study. At the sixth week of gestation of subsequent pregnancy participants were randomly distributed into three groups. Group A (n = 61) was composed of patients with an oral dose of 100 mg aspirin daily, Group B (n = 59) consisted of patients using 40 mg enoxaparin and 100 mg orally aspirin daily, and Group C (n = 54) included patients using 40 mg enoxaparin daily during pregnancy.Results: Among the 174 patients who completed the study, the live birth and miscarriage rates were similar for the three groups (p = .843 and p = .694, respectively). There was no significant difference among the groups in rates of eclampsia, placental abruption, intrauterine fetal growth restriction and gestational diabetes mellitus. The number of preeclamptic patients was significantly higher in Group A than Groups B and C. The levels of preterm birth was significantly higher in Group A than Groups B and C.Conclusion: Using low dose aspirin, LMWH plus aspirin, or LMWH alone yielded comparable live birth rates in RPL patients with FVLM. However, LMWH decreased the risk of preeclampsia in this group of patients. LMWH might therefore have a preventive role regarding preeclampsia.

Intrauterine Growth Restriction: Transsectoral, Interdisciplinary and Multiprofessional Care for Pregnant Women and Newborns in a Feto-neonatal Pathway: A Project of the Innovationsfonds

Intrauterine growth restriction (IUGR) is present in fetuses that do not achieve their full in-utero growth potential. IUGR needs to be discriminated from small for gestational age (SGA) because IUGR newborns in particular experience long-term side effects from their small growth. IUGR fetuses have a significantly increased risk of prematurity and a distinct risk profile compared to adequate-for-gestational-age preterm newborns. Complications of prematurity are more frequent, including bronchopulmonary dysplasia, intraventricular hemorrhage, and meconium ileus. IUGR newborns are at risk of long-term health issues like cerebral palsy, impaired lung function, and delayed speech development. Interdisciplinary and interprofessional care of IUGR pregnancies in the context of a standardized health care research project is feasible: Pregnant women at risk are identified, early therapy with acetylsalicylic acid is started as indicated, risk-adapted care at level III centers is organized including psychosocial interventions and neonatal consultations. Postnatally, integrated neonatal care focusing on parent-child interaction and optimized nutrition is a hallmark. Afterwards, in-depth pediatric follow-up visits with local pediatricians help to identify growth and neurodevelopment problems early. The effects, acceptance. and cost efficiency of this approach are evaluated prospectively as part of an Innovationsfonds project.

Skeletal muscle amino acid uptake is lower and alanine production is greater in late gestation intrauterine growth-restricted fetal sheep hindlimb.

In a sheep model of intrauterine growth restriction (IUGR) produced from placental insufficiency, late gestation fetuses had smaller skeletal muscle mass, myofiber area, and slower muscle protein accretion rates compared with normally growing fetuses. We hypothesized that IUGR fetal muscle develops adaptations that divert amino acids (AAs) from protein accretion and activate pathways that conserve substrates for other organs. We placed hindlimb arterial and venous catheters into late gestation IUGR (n = 10) and control (CON, n = 8) fetal sheep and included an external iliac artery flow probe to measure hindlimb AA uptake rates. Arterial and venous plasma samples and biceps femoris muscle were analyzed by mass spectrometry-based metabolomics. IUGR fetuses had greater abundance of metabolites enriched within the alanine, aspartate, and glutamate metabolism pathway compared with CON. Net uptake rates of branched-chain AA (BCAA) were lower by 42%-73%, and muscle ammoniagenic AAs (alanine, glycine, and glutamine) were lower by 107%-158% in IUGR hindlimbs versus CON. AA uptake rates correlated with hindlimb weight; the smallest hindlimbs showed net release of ammoniagenic AAs. Gene expression levels indicated a decrease in BCAA catabolism in IUGR muscle. Plasma purines were lower and plasma uric acid was higher in IUGR versus CON, possibly a reflection of ATP conservation. We conclude that IUGR skeletal muscle has lower BCAA uptake and develops adaptations that divert AAs away from protein accretion into alternative pathways that sustain global energy production and nitrogen disposal in the form of ammoniagenic AAs for metabolism in other organs.

Lipopolysaccharide Downregulates 11β-Hydroxysteroid Dehydrogenase 2 Expression through Inhibiting Peroxisome Proliferator-Activated Receptor-γ in Placental Trophoblasts.

It is increasingly recognized that excessive glucocorticoids induce fetal intrauterine growth restriction (IUGR). Placental 11β-hydroxysteroid dehydrogenase 2 (11β-HSD2), a glucocorticoid-catalyzing enzyme, prevents active glucocorticoids from maternal circulation into the fetus, thus protecting against IUGR. Previous studies demonstrated gestational LPS exposure caused fetal IUGR. The aim of the current study was to investigate the effects of LPS on 11β-HSD2 in mice placentas and human placental trophoblasts. Pregnant ICR(CD-1) mice were i.p. injected with LPS (200 μg/kg) on gestational day 16. As expected, gestational LPS exposure downregulated 11β-HSD2 in mice placentas. In vitro, LPS downregulated 11β-HSD2 in human placental trophoblasts. Additional experiment showed that LPS, which activated NF-κB, suppressed rosiglitazone-induced activation of peroxisome proliferator-activated receptor-γ (PPARγ) in mice placentas and human placental trophoblasts. Moreover, NF-κB p65 knockdown and specific NF-κB inhibitor attenuated LPS-induced suppression of PPARγ nuclear translocation in human placental trophoblasts. In addition, NF-κB p65 knockdown attenuated LPS-induced downregulation of 11β-HSD2 in human placental trophoblasts. Mechanically, LPS promoted physical interaction between NF-κB p65 and PPARγ in the cytoplasm and nucleus of placental trophoblasts. Finally, pretreatment with rosiglitazone, a PPARγ agonist, partially alleviated LPS-induced reduction of fetal weight and crown-rump length. Taken together, these results suggest that LPS downregulates 11β-HSD2 through suppressing PPARγ in placental trophoblasts. Placental 11β-HSD2 downregulation may contribute partially to LPS-induced fetal IUGR.

Ultrasound Probe Pressure on the Maternal Abdominal Wall and the Effect on Fetal Middle Cerebral Artery Doppler Indices.

Background and Objectives: Doppler ultrasound of umbilical and fetal vessels is useful for monitoring fetal well-being, fetal anemia, intrauterine growth retardation, and other perinatal outcomes. The adverse perinatal outcome and circulatory changes can be reflected in fetal Doppler studies. The aim of this study was to evaluate the effect of increased pressure exerted on the maternal abdominal wall during routine ultrasound on the middle cerebral artery (MCA), resistance index (RI), pulsatility index (PI), and peak systolic velocity (PSV). Materials and Methods: A prospective study was conducted, in which we included 40 pregnant women between 24 + 0 and 41 + 3 gestational weeks (GW), with singleton pregnancies, without any associated pathologies, undergoing routine US examination. We recorded the flow velocity waveforms in the MCA, and we measured the RI, PI, PSV, and the applied pressure on to the maternal abdominal wall—needed for a proper evaluation of MCA. We then repeated the same measurements at two different higher pressure levels, at the same time having a proper image of the targeted vessel. Results: We found significant differences for the PI and RI levels with an increase in abdominal pressure (median PI 1.46, 1.58, and 1.92, respectively; median RI 0.74, 0.78, and 0.85, respectively; p < 0.05), for both PI and RI. At the same time, we found no significant differences for PSV in the studied group in relationship with increase in abdominal pressure (median PSV 39.56, 40.10, and 39.70, respectively; p > 0.05). Conclusions: The applied abdominal pressure by the examiner’s hand, during routine US scan in pregnancy, can modify the MCA parameters of blood flow resistance (PI and RI) when measured by Doppler US, thus influencing the diagnostic accuracy in a series of pregnancy associated pathologies, such as chronic fetal distress (CFD) or intrauterine growth restriction (IUGR).

Risk Factors for Intrauterine Growth Restriction: 9 Years Analysis in Tertiary Care Hospital

Background: Intrauterine growth restricted (IUGR) fetuses are at higher risk of developing neonatal complications and also known to develop metabolic syndrome in adult life. So, an early antenatal detection, choosing the optimal time and method of delivery and intervention when required could minimize the risk significantly.&#x0D; Objective: To find out the prenatal outcome and the maternal and placental risk factors.&#x0D; Methods: A prospective study was conducted from January 2010 to January 2019, at a Teaching Hospital. A singleton pregnancy, above 28 weeks of gestation with clinical diagnosis of IUGR and confirmed by ultrasonography were included in the study. The statistical analysis was performed by Statistical Package of Social Sciences (SPSS) 23.0 software.&#x0D; Results: Maternal risk factors like low pregnancy body mass index, preeclampsia, anaemia, hypothyroidism and placental factors like retro placental hemorrhage were mainly responsible for intrauterine growth restriction.&#x0D; Conclusions: The early identification of risk factors and management of the same antenatal is an important issue to prevent adverse prenatal outcomes associated with IUGR.

Complex multigestational anomalies

The increase in multiple gestation pregnancies has resulted in significant health care implications for both mother and child. Our ability to diagnose and intervene on an at-risk multi-gestation pregnancy has dramatically improved. It is important for the pediatric surgeon to be equipped with a basic fund of knowledge concerning these pregnancies. An understanding of amnionicity and chorionicity will equip the practitioner with the ability to identify which pregnancies are at risk for specific complications. This article highlights multi-gestation pregnancies that are monochorionic (single shared placenta) and can be complicated by twin-twin transfusion syndrome (TTTS), twin reversed arterial perfusion (TRAP) sequence, twin anemia polycythemia sequence (TAPS), or selective fetal intrauterine growth restriction (sIUGR). The risk of fetal demise is significant in these pregnancies. Understanding recommended surveillance and warning signs can alert surgeons to developing complications. Specialized fetal care centers possess the ability to intervene on these pregnancies in utero.

Structural coronary artery remodelling in the rabbit fetus as a result of intrauterine growth restriction

Intrauterine growth restriction (IUGR) is a fetal condition that affects up to 10% of all pregnancies and is associated with cardiovascular structural and functional remodelling that persists postnatally. Some studies have reported an increase in myocardial coronary blood flow in severe IUGR fetuses which has been directly associated to the dilatation of the coronary arteries. However, a direct measurement of the coronaries’ lumen diameter in IUGR has not been reported before. The aim of this paper is to perform, for the first time, a quantitative analysis of the effects of IUGR in cardiac geometry and coronary vessel size in a well-known rabbit model of IUGR using synchrotron-based X-ray Phase Contrast Tomography Imaging (X-PCI). Eight rabbit fetal hearts were imaged non-destructively with X-PCI. 3D reconstructions of the coronary arterial tree were obtained after semi-automatic image segmentation. Different morphometric features including vessel lumen diameter of the three main coronaries were automatically quantified. IUGR fetuses had more globular hearts and dilated coronary arteries as compared to controls. We have quantitatively shown that IUGR leads to structural coronary vascular tree remodelling and enlargement as an adaptation mechanism in response to an adverse environment of restricted oxygen and nutrients and increased perfusion pressure.

CD39 downregulation in chronic intervillositis of unknown etiology

Chronic intervillositis of unknown etiology (CIUE) is a rare placental lesion associated with infiltration of mononuclear inflammatory cells into the intervillous space, poor perinatal outcomes (intrauterine fetal demise or fetal growth restriction), and high rates of recurrence. CD39 is the ectonucleotidase that protects tissues from inflammatory stress and cell injury, which is localized on the surface of villi in normal placentas; however, its expression and role in CIUE are unknown. The aims of this retrospective study were to determine the expression of CD39 in CIUE and its significance in pregnancy outcomes. We compared the number of CD68- and CD3-positive cells, CD39 expression, and complement 4d (C4d) and fibrin deposition in placental tissues from patients with CIUE (n = 22) and gestational age-matched controls (n = 20), and between CIUE pregnancies with poor and good outcomes. The numbers of CD68- or CD3-positive cells were significantly higher (P < 0.0001), whereas CD39 expression on the surface of villi and endothelial cells of the stem villi was significantly lower in the CIUE group than that in controls (45% vs. 95%, P < 0.0001 and 77% vs. 96%, P < 0.001, respectively). C4d and fibrin deposition were also significantly increased in CIUE compared with those of controls. Furthermore, CD39 downregulation and the number of CD68 cells were strongly associated with poor pregnancy outcomes (P < 0.01 and P < 0.05, respectively), but other histological parameters (CD3, C4d, and fibrin) did not show this association. Our study suggests that CD39 downregulation is a useful marker of CIUE and is associated with poor pregnancy outcomes in patients with CIUE.