Idiopathic Intrauterine Growth Restriction Research Articles

Different intrauterine environments and children motor development in the first 6 months of life: a prospective longitudinal cohort

This prospective cohort longitudinal study examines the risk factors associated with different intrauterine environments and the influence of different intrauterine environments on children’s motor development at 3- and 6-months of life. Participants were 346 mother/newborn dyads enrolled in the first 24 to 48 h after delivery in public hospitals. Four groups with no concurrent condition composed the sample: mothers with a clinical diagnosis of diabetes, mothers with newborns small for gestational age due to idiopathic intrauterine growth restriction (IUGR), mothers who smoked tobacco during gestation, and a control group composed of mothers without clinical condition. Children were assessed at three- and six-months regarding motor development, weight, length, head circumference, and parents completed a socioeconomic questionnaire. The IUGR children had lower supine, sitting, and overall gross motor scores at 6 months than the other children’s groups. Anthropometric and sociodemographic characteristics negatively influenced gross motor development. IUGR and anthropometric and sociodemographic characteristics negatively impact motor development. Intrauterine environment impact child neurodevelopment.

Dysregulation of Oxygen Sensing/Response Pathways in Pregnancies Complicated by Idiopathic Intrauterine Growth Restriction and Early-Onset Preeclampsia.

Preeclampsia (PE) and intrauterine growth restriction (IUGR) are the leading causes of maternal and fetal morbidity/mortality. The central deficit in both conditions is impaired placentation due to poor trophoblast invasion, resulting in a hypoxic milieu in which oxidative stress contributes to the pathology. We examine the factors driving the hypoxic response in severely preterm PE (n = 19) and IUGR (n = 16) placentae compared to the spontaneous preterm (SPT) controls (n = 13) using immunoblotting, RT-PCR, immunohistochemistry, proximity ligation assays, and Co-IP. Both hypoxia-inducible factor (HIF)-1α and HIF-2α are increased at the protein level and functional in pathological placentae, as target genes prolyl hydroxylase domain (PHD)2, PHD3, and soluble fms-like tyrosine kinase-1 (sFlt-1) are increased. Accumulation of HIF-α-subunits occurs in the presence of accessory molecules required for their degradation (PHD1, PHD2, and PHD3 and the E3 ligase von Hippel–Lindau (VHL)), which were equally expressed or elevated in the placental lysates of PE and IUGR. However, complex formation between VHL and HIF-α-subunits is defective. This is associated with enhanced VHL/DJ1 complex formation in both PE and IUGR. In conclusion, we establish a significant mechanism driving the maladaptive responses to hypoxia in the placentae from severe PE and IUGR, which is central to the pathogenesis of both diseases.

Assessment of lead and mercury levels in maternal blood, fetal cord blood and placenta in pregnancy with intrauterine growth restriction

Introduction: Many studies reported that prenatal exposure to lead and mercury are correlated with reduced birth weight and size, and these metals can cause adverse effects on neurodevelopment. In this study, it was aimed to investigate and compare the lead and mercury levels in maternal blood, cord blood, and placenta in pregnant women with IUGR fetuses diagnosed using abnormal Doppler findings and pregnant women with healthy fetuses.
 Material: This study included 75 patients, comprising 41 in IUGR group and 34 in control group. Maternal venous blood, fetal cord blood and placental samples were taken during delivery period.
 Results: Mercury levels in maternal blood and fetal cord blood, and lead levels in the placenta were found to be significantly higher in the IUGR group than in healthy subjects. Correlation analysis revealed that measurement values of body weight, body height, and head circumference of fetus might be lower when mercury level was measured higher in maternal blood and fetal cord blood. Furthermore, fetal body weight and fetal body height also would be lower when lead level measured in placenta was higher. Logistic Regression analysis results revealed that mercury levels measured in fetal cord blood could be used as the best marker in predicting low fetal weight, low fetal body height, and low fetal head circumference.
 Conclusion: In conclusion, it was thought with this study results that in order to identify the etiology and to give therapeutic prenatal care of the IUGR in a fetus diagnosed as idiopathic IUGR it would be appropriate to measure the level of lead and especially mercury in the fetal cord blood during the prenatal follow-up period.

Telomere length in healthy newborns is not affected by adverse intrauterine environments.

Different intrauterine exposures are associated with different metabolic profiles leading to growth and development characteristics in children and also relate to health and disease patterns in adult life. The objective of this work was to evaluate the impact of four different intrauterine environments on the telomere length of newborns. This is a longitudinal observational study using a convenience sample of 222 mothers and their term newborns (>37 weeks of gestational age) from hospitals in Porto Alegre, Rio Grande do Sul (Brazil), from September 2011 to January 2016. Sample was divided into four groups: pregnant women with Gestational Diabetes Mellitus (DM) (n=38), smoking pregnant women (TOBACCO) (n=52), mothers with small-for-gestational age (SGA) children due to idiopathic intrauterine growth restriction (n=33), and a control group (n=99). Maternal and newborn genomic DNA were obtained from epithelial mucosal cells. Telomere length was assessed by qPCR, with the calculation of the telomere and single copy gene (T/S ratio). In this sample, there was no significant difference in telomere length between groups (p>0.05). There was also no association between childbirth weight and telomere length in children (p>0.05). For term newborns different intrauterine environments seems not to influence telomere length at birth.

Expression of e-NOS in Human Placentas of Idiopathic Intra Uterine Growth Restriction at Term

Endothelial nitric oxide synthase (e-NOS) is a chemical agent that involves in placental angiogenesis. It is conveyed through embryogenesis. In the contemporary study, we intended to examine the character of placental angiogenesis in the progress of intrauterine growth restriction (IUGR) by means of matching the levels of expression of e-NOS in normal-term pregnancy and IUGR placentas. Angiogenesis is one dominant factor in normal embryogenesis and hence the wellbeing of the newborn. The expression of e-NOS was planned using the streptavidin-biotin-peroxidase technique in placental tissues identified as normal (n = 33) and IUGR (n = 33) cases from mothers looking apparently normal. All were chosen at term pregnancy and obtained between 2nd of February of 2018 and 31th of January 2019 at selected hospitals. Outcomes were appraised semi-quantitatively. The expression of e-NOS marker as an immunohistochemistry total score and staining percentage were significantly greater (p < 0.05) in epithelial surface, smooth muscle cells of fetal vessels and the connective tissue terminal villous core of the IUGR placentas when matched with placentas collected from normal pregnancies at term. Encountered placental histochemical changes regarding the expression of the e-NOS angiogenic factor for idiopathic IUGR newborns raised the suspicion of that, it was caused by pure placental factors and could represent further requirement for Nitric Oxide to dilate fetal vessels to optimize functional requirement during placental insufficiency. The noticed Increased expression of e-NOS may be the result of inadequate uteroplacental perfusion supporting the proposal that abnormal angiogenesis plays a role in the pathophysiology of IUGR

Cortisol metabolism in pregnancies with small for gestational age neonates

Small for gestational age (SGA) newborns are often born from hypertensive pregnancies. This study aimed to compare the systemic metabolism of cortisol (F) in pregnancies with SGA and appropriate for gestational age (AGA) infants, considering both the normotensive (NT) and hypertensive patients. We hypothesized that the disturbances in systemic metabolism of F in pre-eclampsia (PE) might be attributed not to hypertension only, but to SGA. The study included 117 pregnants in the third trimester, divided into groups: NT pregnancy and SGA neonate (SGA-NT); NT pregnancy and AGA neonate (AGA-NT; controls), and respective groups with PE: SGA-PE and AGA-PE. We assessed the glucocorticoid balance with the function of enzymes involved in systemic metabolism of F: 11β-hydroxysteroid dehydrogenase type 1 and 2 (11β-HSD1 and 11β-HSD2), 5α- and 5β-reductase. The enzymes’ functions were estimated with the levels of F, cortisone (E), and their metabolites in plasma or urine, which we measured with HPLC-FLD and HPLC-MS/MS. The plasma F/E and urinary free F/E (UFF/UFE) ratios correlated significantly only in patients with the normal function of 5α- and 5β-reductase. The increased function of 11β-HSD2 was noted in all pre-eclamptic pregnancies. Increased function of 5α- and 5β-reductase was specific only for SGA-PE pregnancies, and the function of 5α-reductase was dependent on fetal sex. The SGA-NT pregnancies with male fetuses trended towards the higher function of renal 11β-HSD2 and 5β-reductase; SGA-NT pregnancies with female fetuses lacked any systemic glucocorticoid imbalance. In conclusion, systemic metabolism of F is the most intensive in pre-eclamptic pregnancies complicated by SGA with female fetuses. Our study supports the hypothesis about the different origins of PE and idiopathic intrauterine growth restriction and suggests the sex-specific mechanisms responsible for fetal growth restriction.

Maternal Serum and Fetal Cord Blood C-Reactive Protein Levels but not Procalcitonin Levels Are Increased in Idiopathic Intrauterine Growth Restriction.

BackgroundThe aim of the present study was to compare procalcitonin and CRP levels in maternal serum and fetal cord blood samples of patients with idiopathic intrauterine growth restriction (IUGR) vs. a control group of appropriate for gestational age (AGA) infants.Material/MethodsThe present prospective study included 43 patients: 27 patients with idiopathic IUGR (IUGR group) and 26 AGA infants at similar gestational ages (control group). Maternal serum and fetal cord blood samples were collected from the control group and IUGR group at time of delivery. Procalcitonin and CRP levels were analyzed in maternal blood. Procalcitonin and CRP levels were analyzed in fetal cord blood.ResultsThe median value of CRP levels in maternal blood was 47.5 mg/dl in the IUGR group and 15.255 mg/dl in the AGA group (p=0.001). The mdian CRP level in cord blood was 36.4 mg/dl (range, 17.3–47.2) in the IUGR group and 10.1 mg/dl (range, 4.07–16.5) in the control group, and the difference was statistically significant (p=0.001). The median maternal serum procalcitonin level was 0.05 μg/l in the IUGR group and 0.04 μg/l in the AGA group, and the difference was not statistically significant (p=0.435). The median procalcitonin value in fetal cord blood was 0.06 μg/l in the IUGR group and 0.04 μg/l in the AGA group, and the difference was not statistically significant (p=0.741).ConclusionsMaternal serum and fetal cord CRP levels were higher in the IUGR group; however, there was no difference in procalcitonin, which is another inflammatory indicator, between the groups.

Urotensin 2 and Oxidative Stress Levels in Maternal Serum in Pregnancies Complicated by Intrauterine Growth Restriction.

Background and objectives: In this study, the aim was to investigate Urotensin 2 (U-II) levels and oxidant/antioxidant system parameters in pregnancies with intrauterine growth restriction (IUGR). Materials and Methods: A total of 36 healthy, pregnant women who had not been diagnosed with IUGR and 36 pregnant women who had been diagnosed with IUGR at the Obstetrics and Gynecology Outpatient Clinic at Gaziantep University Hospital were enrolled in this study. The serum total antioxidant status (TAS), total oxidant status (TOS), thiol-disulfide levels, U-II measurements, and oxidative stress index (OSI) calculations were carried out at the biochemistry laboratory at Gaziantep University. Results: According to this study, there was no statistically significant difference between the group with IUGR and the control group of healthy, pregnant women in terms of total antioxidant status (TAS), total oxidant status (TOS), oxidative stress index (OSI), native thiol, total thiol, disulfide, disulfide/native thiol, disulfide/total thiol, native thiol/total thiol, and U-II values. There was, however, a positive linear correlation between TOS and total thiol levels in the group with IUGR (p = 0.021, r = 0.384), and a positive linear correlation between OSI and total thiol values in the control group (p = 0.049, r = 0.330). In addition, there was a negative correlation between disulfide levels and gestational weeks at birth in the group with IUGR (p = 0.027, r = 0.369). Conclusions: Consequently, there was no significant difference between the control group and the group with pregnancies complicated by idiopathic IUGR in terms of serum oxidant/antioxidant system parameters and U-II levels. It is necessary to conduct more extensive studies evaluating placental, maternal, and fetal oxidative stress in conjunction in order to investigate the role of oxidative stress in IUGR.

Histological changes of human placenta in early intrauterine growth restriction with and without preeclampsia

Background: Intra uterine growth restriction (IUGR) is a common pregnancy complication, pre-eclamsia (PE) is an importantcause of this complication and is responsible for maternal and fetal morbidity and mortality. Idiopathic intrauterine growthrestriction without obvious causes is not uncommon.Objective: The aim of this study is to examine the placental histology in both conditions trying to find specific criteria for eachdisorder.Materials and Methods: This study was conducted on three groups; group I was the control group, group II was preeclampsiainduced IUGR (PE-IUGR) group and group III was idiopathic IUGR (I-IUGR). Each group contained 15 placentas. Placentalspecimens from each group were analyzed histopathologically and immunohistochemically.Results: we found that PE-IUGR and I-IUGR cases in this study share common histological changes suggesting a similarpathogenesis. Maternal mal-perfusion lesions predominated in PE-IUGR. Findings consistent with fetal vascular malperfusionwere higher in I-IUGR. Hofbauer cells (HBC) were increased in both PE-IUGR and I-IUGR.Conclusion: abnormal utero-placental blood vessels and utero-placental insufficiency and the resulting histological changes inthe chorionic villi, and chronic inflammatory lesions may be the primary disease processes related to the placental pathologyof PE-IUGR and I-IUGR.

Association of Idiopathic IUGR with Placental Histological Morphometry

Association of Idiopathic IUGR with Placental Histological Morphometry

Human Placenta Expresses α2-Adrenergic Receptors and May Be Implicated in Pathogenesis of Preeclampsia and Fetal Growth Restriction

α2-Adrenergic receptors (α2ARs) are G-protein-coupled receptors involved in catecholamine signaling by extracellular regulated protein kinase 1 and 2 (ERK1/2) pathways. We examined placental expression and function of α2AR subtypes in women with severe preeclampsia (sPE) with and without intrauterine growth restriction (IUGR). Placental biopsies were analyzed from 52 women with i) sPE (n=8); ii) sPE+IUGR (n=9); iii) idiopathic IUGR (n=8); iv) idiopathic preterm birth (n=16); and v) healthy term controls (n=11). Expression of α2AR subtypes (α2A, α2B, α2C) and phospho-ERK1/2 (receptor activation marker) was investigated by immunohistochemistry and/or quantitative real-time RT-PCR. The effects of α2CAR knockdown on syncytialization (syncytin-1 and -2) and β-human chorionic gonadotropin secretion were examined in BeWo cells stimulated with forskolin. The effects of α2AR agonist UK 14,304 and specific α2CAR antagonist were tested, using a trophoblast migration assay. All three α2ARs were expressed and functionally active in human placenta with site-specific localization. Highest α2BAR and α2CAR mRNA expression was identified in sPE+IUGR. α2CAR knockdown increased expression of syncytin-1 and -2 but decreased secretion of β-human chorionic gonadotropin. UK 14,304 impaired trophoblast migration. The observed α2AR expression pattern suggests different function foreach subtype. α2CAR modulates trophoblast syncytialization and migration and may carry pathogenic role in sPE+IUGR.

Is there any relation between intrauterine growth restriction and platelet distribution width (PDW), platelet crit (PCT), mean platelet volume (MPV)? A prospective study

Aim: Intrauterine growth restriction (IUGR) is still an important pregnancy complication bringing on perinatal mortality and morbidity. Placental vascular dysfunction and subsequent obliteration of placental blood vessels are mostly accepted etiopathological factors of intrauterine growth restriction similar with preeclampsia. We aimed to investigate the possible difference between pregnant women suffering from intrauterine growth restriction and healty pregnant women for parameters of platelet count, platelet crit, platelet distribution crit and mean platelet volume. Material and Method: This case- control study was conducted with 179 pregnant women. The study population was consisted of 94 pregnant women complicated with idiopathic IUGR (study group) and 85 healty pregnant women (control group). IUGR group was divided in two subgroups according to umbilical artery doppler velocimetry measurements. Complete blood count parameters including hemoglobin, platelet count, platelet distribution width (PDW), platelet crit (PCT), mean platelet volume (MPV) and white blood cell count (WBC) were measured. Results: There was no significant difference between the groups for parameters of hemoglobin, PC and PCT. The mean amniotic fluid index of IUGR group was significantly lower than the control group (p=0.000). The mean WBC, MPV and PDW levels of IUGR group were significantly higher than the control group (p=0.013, p=0.047 and 0.035, respectively). The mean MPV level of IUGR group 1(umbilical artery S/D˃3) was significantly higher than that of IUGR group 2 (umbilical artery S/D<3) (p=0.045). Conclusions: In the present study, we observed a significant difference between IUGR and healty pregnant women for platelet parameters of MPV and PDW. Beside this, we also observed higher MPV values in IUGR patients with increased umblical artery resistance compared to that in IUGR patients with normal umblical artery blood flow. Further studies are needed to discuss our results.

Alterations in placental long chain polyunsaturated fatty acid metabolism in human intrauterine growth restriction.

Fatty acids (FA) are critical for fetal brain development and are transferred across the placenta by membrane-bound FA transport proteins (FATP), translocases (FAT/CD36), and cytosolic binding proteins (FABP). The cytosolic protein perilipin-2 aids in neutral lipid storage within lipid droplets. Decreased placental nutrient transport is believed to contribute to intrauterine growth restriction (IUGR); however, IUGR placental lipid transport and metabolism are poorly understood. We hypothesized that protein expression of FATPs, FABPs, and perilipin-2 in human placenta is decreased and placental lipid content and incorporation into lipid classes are reduced in IUGR. Placental tissue of idiopathic IUGR (n=25) and gestational age-matched, appropriately grown for gestational age (AGA) fetuses (n=19) was collected. We determined protein expression of FABP4 and perilipin-2 in placental homogenate and FATPs (2, 4, 6, CD36) in syncytiotrophoblast microvillous plasma membrane (MVM) by Western blot. Lipid droplet area (Oil Red O stain) and cellular FA content (GC/MS) were measured in chorionic villous tissue. MVM expression of FATP6 and CD36 was significantly increased in IUGR. The concentrations of seven n-6 and n-3 species long chain polyunsaturated FAs (LCPUFA) were significantly increased in the triglyceride fraction in IUGR vs AGA placenta. In summary, MVM FATP6 and CD36 protein expression is increased and LCPUFA are preferentially routed toward cellular storage in TG in the IUGR placenta, possibly to protect against oxidative stress associated with cellular FA accumulation. We speculate that these changes may be caused by impaired efflux of FA across the fetal-facing syncytiotrophoblast basal plasma membrane in IUGR placenta.

Mammalian target of rapamycin signaling is a mechanistic link between increased endoplasmic reticulum stress and autophagy in the placentas of pregnancies complicated by growth restriction

IntroductionIncreased endoplasmic reticulum (ER) stress and autophagy have been noted in the placentas of pregnancies complicated by idiopathic intrauterine growth restriction (IUGR); however, the cause of these phenomena remains unclear. We surmised that oxygen-glucose deprivation (OGD) may increase ER stress and autophagy and that mammalian target of rapamycin (mTOR) signaling is involved in regulating placental ER stress and autophagy in pregnancies complicated by IUGR. MethodsWe obtained placentas from women with normal term pregnancies and pregnancies complicated by IUGR to compare ER stress, mTOR signaling, and levels of autophagy-related proteins between the two groups and used primary cytotrophoblast cells treated with or without salubrinal (an ER stress inhibitor), MHY1485 (an mTOR activator), or rapamycin (an mTOR inhibitor) to investigate the effects of OGD on ER stress, mTOR activity, and autophagy levels in vitro. ResultsWomen with pregnancies complicated by IUGR displayed higher placental ER stress and autophagy levels but lower mTOR activity than women with normal pregnancies. Furthermore, OGD increased ER stress, regulated in development and DNA damage responses-1 (REDD1), phosphorylated tuberous sclerosis complex 2 (TSC2), and autophagy levels and decreased mTOR activity compared to the standard culture condition; however, the salubrinal treatment attenuated these changes. Moreover, the administration of MHY1485 or rapamycin to OGD-treated cells decreased or increased autophagy levels, respectively. DiscussionBased on our results, mTOR is a mechanistic link between OGD-induced ER stress and autophagy in cytotrophoblast cells; thus, mTOR plays an essential role in the pathogenesis of pregnancies complicated by IUGR.

The effect of low-dose aspirin on fetal weight of idiopathic asymmetrically intrauterine growth restricted fetuses with abnormal umbilical artery Doppler indices: a randomized clinical trial

Objective: To investigate the effect of aspirin on fetal weight in fetuses with idiopathic asymmetrical intrauterine growth restriction (IUGR) complicated by abnormal umbilical artery Doppler indices.Materials and methods: The study was a randomized controlled trial conducted at Woman’s Health Hospital, Assiut, Egypt, between June 2016 and the January 2017 included 60 pregnant women (28−30 weeks) with idiopathic asymmetrical IUGR associated with abnormal umbilical artery Doppler indices. Women were randomly assigned to group I (aspirin 75 mg) daily for four weeks or group II (no intervention). The primary outcome was the fetal weight after four weeks. Secondary outcomes included Doppler blood flow changes in the umbilical artery plus delivery and neonatal outcomes.Results: The estimated fetal weight and umbilical artery blood flow increased significantly in aspirin group (p = .00) when compared with no intervention group. As regard neonatal outcomes; aspirin group showed better results and encouraging outcomes (p < .05).Conclusions: Aspirin improves fetal weight and umbilical artery blood flow in idiopathic asymmetrical IUGR fetuses complicated by abnormal umbilical artery Doppler blood flow.

Somatic growth in the first six months of life of infants exposed to maternal smoking in pregnancy

BackgroundSome studies suggest a relationship between maternal smoking during pregnancy and not only intrauterine fetal growth restriction or low birth weight, but also with changes in the postnatal growth and development. The objective of the present study was to investigate the effects of smoking during pregnancy on infants growth in the first 6 months of life compared with a control group and a group with idiopathic intrauterine growth restriction.MethodsLongitudinal observational study using a convenience sample of newborns divided into three groups: infants of smoking mothers (tobacco), with idiopathic intrauterine growth restriction (IUGR) and a control group. The sample was selected from two hospitals in Porto Alegre, located in southern Brazil, between 2011 and 2015. Newborns were evaluated at birth, 7 and 15 days, and in the first, third, and sixth month. Anthropometric measures were weight, length and head circumference. The growth indicators used were expressed as z-scores. The analyses were performed using the generalized estimating equation method.ResultsThe sample included 273 mother/newborn pairs: 86 tobacco group, 34 IUGR group, and 153 control group. In terms of weight at birth, all groups differed significantly (p < 0.001). The birth length of tobacco and control groups were similar, but the IUGR group was lower than both (p < 0.001). We found no differences in growth trajectory between tobacco and control group, but there were differences in the growth of the IUGR group when compared with the other groups. At 6 months of age, all groups had similar anthropometric measurements.ConclusionIntrauterine growth restriction had major impact on the growth trajectory of the infants studied, regardless of other factors, such as smoking and diet.

The maternal serum thiol/disulfide homeostasis is impaired in pregnancies complicated by idiopathic intrauterine growth restriction

Purpose: To investigate the maternal serum thiol/disulfide homeostasis in pregnancies complicated by idiopathic intrauterine growth restriction (IUGR) and to compare the results with healthy pregnancies.Materials and methods: This descriptive cohort study included 55 pregnant women complicated by idiopathic IUGR and 57 similar gestational aged healthy pregnant women in the third trimester of gestation. Maternal serum samples were collected at the day of diagnosis and the thiol/disulfide homeostasis was measured by using an automated assay method. The patients were followed up until delivery and perinatal outcomes were recorded.Results: Maternal serum native thiol (308.1 ± 40.7 μmol/L vs. 282.4 ± 60.6 μmol/L) and total thiol (346.8 ± 48.1 μmol/L vs. 324.0 ± 62.2 μmol/L) concentrations were significantly lower in IUGR group compared with healthy controls (p: .010 and p: .032, respectively), whereas disulfide (19.3 ± 8.7 μmol/L vs. 20.8 ± 7.8 μmol/L) concentrations were similar between the groups (p: .350). Maternal serum disulfide/native thiol and disulfide/total thiol ratios were higher in IUGR group compared with healthy controls (p: .014 and p: .017, respectively), whereas native thiol/total thiol ratio was significantly lower in IUGR group compared with healthy controls (p: .016).Conclusions: This study suggests that there is an impaired maternal thiol/disulfide homeostasis in pregnancies complicated by idiopathic IUGR during the third trimester of gestation.

Placental Underperfusion in a Rat Model of Intrauterine Growth Restriction Induced by a Reduced Plasma Volume Expansion.

Lower maternal plasma volume expansion was found in idiopathic intrauterine growth restriction (IUGR) but the link remains to be elucidated. An animal model of IUGR was developed by giving a low-sodium diet to rats over the last week of gestation. This treatment prevents full expansion of maternal circulating volume and the increase in uterine artery diameter, leading to reduced placental weight compared to normal gestation. We aimed to verify whether this is associated with reduced remodeling of uteroplacental circulation and placental hypoxia. Dams were divided into two groups: IUGR group and normal-fed controls. Blood velocity waveforms in the main uterine artery were obtained by Doppler sonography on days 14, 18 and 21 of pregnancy. On day 22 (term = 23 days), rats were sacrificed and placentas and uterine radial arteries were collected. Diameter and myogenic response of uterine arteries supplying placentas were determined while expression of hypoxia-modulated genes (HIF-1α, VEGFA and VEGFR2), apoptotic enzyme (Caspase -3 and -9) and glycogen cells clusters were measured in control and IUGR term-placentas. In the IUGR group, impaired blood velocity in the main uterine artery along with increased resistance index was observed without alteration in umbilical artery blood velocity. Radial uterine artery diameter was reduced while myogenic response was increased. IUGR placentas displayed increased expression of hypoxia markers without change in the caspases and increased glycogen cells in the junctional zone. The present data suggest that reduced placental and fetal growth in our IUGR model may be mediated, in part, through reduced maternal uteroplacental blood flow and increased placental hypoxia.

Dysregulation of oxygen sensing/responsive pathways in pregnancies complicated by idiopathic intrauterine growth restriction and early onset preeclampsia

Dysregulation of oxygen sensing/responsive pathways in pregnancies complicated by idiopathic intrauterine growth restriction and early onset preeclampsia

The placental mTOR-pathway: correlation with early growth trajectories following intrauterine growth restriction?

Idiopathic intrauterine growth restriction (IUGR) is a result of impaired placental nutrient supply. Newborns with IUGR exhibiting postnatal catch-up growth are of higher risk for cardiovascular and metabolic co-morbidities in adult life. Mammalian target of rapamycin (mTOR) was recently shown to function as a placental nutrient sensor. Thus, we determined possible correlations of members of the placental mTOR signaling cascade with auxologic parameters of postnatal growth. The protein expression and activity of mTOR-pathway signaling components, Akt, AMP-activated protein kinase α, mTOR, p70S6kinase1 and insulin receptor substrate-1 were analysed via western blotting in IUGR v. matched appropriate-for-gestational age (AGA) placentas. Moreover, mTOR was immunohistochemically stained in placental sections. Data from western blot analyses were correlated with retrospective auxological follow-up data at 1 year of age. We found significant catch-up growth in the 1st year of life in the IUGR group. MTOR and its activated form are immunohistochemically detected in multiple placental compartments. We identified correlations of placental mTOR-pathway signaling components to auxological data at birth and at 1 year of life in IUGR. Analysis of the protein expression and phosphorylation level of mTOR-pathway components in IUGR and AGA placentas postpartum, however, did not reveal pathognomonic changes. Our findings suggest that the level of activated mTOR correlates with early catch-up growth following IUGR. However, the complexity of signals converging at the mTOR nexus and its cellular distribution pattern seem to limit its potential as biomarker in this setting.