Intrauterine Growth Restriction Patients Research Articles

QRS-T Angles as Markers for Heart Sphericity in Subjects With Intrauterine Growth Restriction: A Simulation Study.

Changes induced by intrauterine growth restriction (IUGR) in cardiovascular anatomy and function that persist throughout life have been associated with a higher predisposition to heart disease in adulthood. Together with cardiac morphological remodelling, evaluated through the ventricular sphericity index, alterations in cardiac electrical function have been reported by characterization of the depolarization and repolarization loops, and their angular relationship, measured from the vectorcardiogram. The underlying relationship between the morphological remodelling and the angular variation of QRS and T-wave dominant vectors, if any, has not been explored. The aim of this study was to evaluate this relationship using computational models based on realistic heart and torso in which IUGR-induced morphological changes were incorporated by reducing the ventricular sphericity index. Specifically, we departed from a control model and we built eight different globular heart models by reducing the base-to-apex length and enlarging the basal ventricular diameter. We computed QRS and T-wave dominant vectors and angles from simulated pseudo-electrocardiograms and we compared them with clinical measurements. Results for the QRS to T angles follow a change trend congruent with that reported in clinical data, supporting the hypothesis that the IUGR-induced morphological remodelling could contribute to explain the observed angle changes in IUGR patients. By additionally varying the position of the ventricles with respect to the torso and the electrodes, we found that electrode displacement can impact the quantified angles and should be considered when interpreting the results.

P-224 Basonuclin 1 prevents intrauterine growth restriction via inhibiting necroptosis

Abstract Study question Is basonuclin 1 (BNC1) involved in intrauterine growth restriction (IUGR), and what’s the underlying mechanism? Summary answer BNC1 is significantly decreased in the placenta of IUGR patients. BNC1 deficiency engenders IUGR in Bnc1 truncation mutation (Bnc1tr/tr) mice model by inducing placental necroptosis. What is known already IUGR is among the leading causes of perinatal morbidity and mortality. IUGR occurs due to multiple factors, including genetic, placental, fetal, and maternal factors. Among which genetic factors remain largely unknown. Our previous exploration found that Bnc1 mutationmice exhibit low birth weight and survival rates, indicating BNC1 may play a potential role in fetal and placental development. Necroptosis is a recently recognized cell death pathway that may contribute to placental pathophysiology in IUGR patients. While the underlying mechanism remains largely unknown. Study design, size, duration A clinical retrospective cohort study of 40 IUGR patients (diagnosed by Hadlock ultrasound measurements) and 40 controls were included (2017–2022) for placenta collection. Bnc1 targeted mutation mouse was on a C57BL/6 J background. Male and female mice of the Bnc1+/tr genotype were mated to produce Bnc1+/+, Bnc1+/tr, and Bnc1tr/tr mice. Placenta and fetuses were obtained on the 15th and 18th days of pregnancy. Participants/materials, setting, methods The following analyses were performed: (i) Immunohistochemistry for detecting the location and expression of BNC1 in the placenta of humans and mice, (ii) placental and fetal weights for evaluation of IUGR development, (iii) morphometric evaluation of fetal utilizing Alcian blue and alizarin red staining, (iv) morphometric evaluation of placental compartments utilizing H&E staining, TUNEL staining, and TEM analysis, (v) RNA sequencing (RNA-seq) of placental tissues. Main results and the role of chance BNC1 was specifically highly expressed in trophoblasts and endothelial cells in the early and mature placental development stages of humans and mice. The expression of BNC1 was significantly decreased in the placenta of IUGR patients compared to the control group (P < 0.0001). In the mice model, the number of Bnc1tr/tr fetuses was significantly decreased compared with wild-type Bnc1+/+ fetuses on the 18th day of pregnancy. While the number of Bnc1tr/tr fetuses and Bnc1+/+ fetuses was similar on the 15th day of pregnancy, indicating the loss of Bnc1tr/tr fetuses between the two stages. Besides, both the Bnc1tr/tr fetal and placental weights were significantly decreased on the 15th day of pregnancy compared with Bnc1+/+ fetuses and placenta (P < 0.01). The Bnc1 truncation mutation caused poor development of the placental labyrinthine layer with an increased number of TUNEL-positive foci. Transmission electron microscopy also revealed a disorganized labyrinthine layer with defects in cytoplasm translucence, loss of plasma membrane integrity, swollen mitochondria, and decondensed chromatin. Finally, RNA sequencing of placental tissues indicated BNC1 deficiency-induced IUGR may be modulated by necroptosis. In conclusion, we found a relationship between the disturbed BNC1 expression and the occurrence of IUGR through necroptosis. Limitations, reasons for caution This study used only Bnc1 truncation mutation mice model, the other animal model with placenta-conditional knockout mice was needed to consolidate the results. Besides, further mechanism exploration should be conducted in both human and mouse cell lines. Wider implications of the findings Our work suggests a new gene related to the development of IUGR, which provides early diagnosis and treatment for managing IUGR, thus improving outcomes for both fetal and gravida. Trial registration number not applicable

Altered Epigenetic Profiles in the Placenta of Preeclamptic and Intrauterine Growth Restriction Patients.

Intrauterine growth restriction (IUGR) and preeclampsia (PE) are placental pathologies known to complicate pregnancy and cause neonatal disorders. To date, there is a limited number of studies on the genetic similarity of these conditions. DNA methylation is a heritable epigenetic process that can regulate placental development. Our objective was to identify methylation patterns in placental DNA from normal, PE and IUGR-affected pregnancies. DNA was extracted, and bisulfite was converted, prior to being hybridized for the methylation array. Methylation data were SWAN normalized and differently methylated regions were identified using applications within the USEQ program. UCSC's Genome browser and Stanford's GREAT analysis were used to identify gene promoters. The commonality among affected genes was confirmed by Western blot. We observed nine significantly hypomethylated regions, two being significantly hypomethylated for both PE and IGUR. Western blot confirmed differential protein expression of commonly regulated genes. We conclude that despite the uniqueness of methylation profiles for PE and IUGR, the similarity of some methylation alterations in pathologies could explain the clinical similarities observed with these obstetric complications. These results also provide insight into the genetic similarity between PE and IUGR and suggest possible gene candidates plausibly involved in the onset of both conditions.

Ischemia modified albumin levels in intrauterine growth restriction: levels are increased in fetal cord blood but not in maternal blood.

In this study, our aim was to determine the differences between intrauterine growth restriction (IUGR) and normal birth weight fetuses in terms of ischemia modified albumin (IMA) levels. For this purpose, we measured ischemia modified albumin levels in the cord blood of fetuses and venous blood of mothers. This study is a prospective study conducted at University of Health Sciences Tepecik Training and Research Hospital between January 2018 and December 2019. According to the inclusion/exclusion criteria, 227 patients were included in the study. Participants were divided into two groups according to the presence (patient group) or absence (control group) of intrauterine growth restriction (IUGR). In addition to routine parameters recorded during pregnancy, the IMA levels and Doppler USG findings of all participants were recorded. The mean cord blood serum IMA levels of the patient group were significantly elevated compared to controls (p = 0.038). Whereas mean maternal blood serum IMA levels were similar among groups (p = 0.453). The cord blood and mother blood serum IMA levels were not significantly different with regard to the presence or absence of perinatal asphyxia. In the literature, studies evaluating IMA levels in the cord and maternal blood of IUGR fetuses are limited. In IUGR patients, IMA level is expected to increase and in our study, IMA levels were significantly increased but the presence of oxidative stress has not been found to affect IMA levels.

The Role of oxLDL in Intrauterine Growth Restriction and Its Relationship with Thiol Homeostasis

Intrauterine growth restriction(IUGR) affects about 9% of whole pregnancies.It is known that there is an increased risk of mortality and morbidity in infants.It is a serious disease that causes complications such as acute and chronic pulmonary diseases, necrotizing enterocolitis, intraventricular hemorrhage and retinopathy in the future.We aimed to study the role of oxidized low density lipoprotein (OxLDL), which is an significant risk factor in cardiovascular diseases,in IUGR and its relationship with thiol homeostasis. 38 women with IUGR and 38 healthy pregnant were included in this study.Serum total thiol and native thiol levels were analyzed with fully automatic autoanalysers in patients and controls.Serum OxLDL levels were also measured by ELISA method. According to the results of the study,it was found that OxLDL was significantly higher in the patient group compared to the control group(27.29±3.32 and 10.64±1.05 ng/mL,respectively,p <0.05).However, there was no significant difference between thiol parameters(p> 0.05).In addition, there was a negative correlation between oxLDL and native thiol and OxLDL and total thiol in the IUGR group. Oxidative stress is an important factor in the formation of OxLDL.OxLDL is an effective molecule in all stages of atherosclerosis. It appears that increased oxidative stress in IUGR patients increases OxLDL.Increased OxLDL in pregnancies complicated by IUGR may increase the risk of developing cardiovascular disease for both mother and fetus later in life.Therefore, developing treatment for OxLDL in IUGR patients may protect both mother and child from future dangers.

Glutathione and oxidized nicotinamide adenine dinucleotide (NAD+) redox status in plasma and placental tissue of Saudi patients with intrauterine growth restriction.

Objectives:To assess the oxidation state and gene expression profiles of relevant enzymes in intrauterine growth restriction (IUGR) patients in Saudi Arabia.Methods:Current case-control study involved plasma and placental tissue samples from 25 IUGR patients and 25 healthy pregnant (HP) women attending the Obstetrics and Gynecology Clinic, King Khalid University Hospital, Riyadh, Saudi Arabia, between April and November 2017. We compared hydrogen peroxide, superoxide anions, malondialdehyde, and oxidative stress markers levels and the activities of glutathione-related enzymes (glutathione peroxidase [GPx], glutathione reductase [GR], glutathione S-transferase [GST], glutamate cysteine ligase [GCL], glutathione synthetase [GS], reduced glutathione [GSH], oxidized glutathione [GSSG], and oxidized nicotinamide adenine dinucleotide [NAD+], and reduced NAD [NADH]) between the 2 groups. We also compared differential expression levels of glutathione-related enzyme genes using reverse transcription-quantitative polymerase chain reaction.Results:Oxidative stress markers significantly differed in IUGR samples, while GSH levels and GPx, GR, GST, GCL, and GS activities and their placental mRNA transcriptional levels were significantly lower. Plasma and placental NAD+ levels were also significantly lower, while NADH levels were significantly higher, causing lowered NAD+-NADH ratios in the IUGR group compared to control.Conclusions:Intrauterine growth restriction patients show a metabolic shift in favor of oxidation compared to HP women.

Intrauterine Growth Restriction Is Associated with Unique Features of the Reproductive Microbiome.

Intrauterine growth restriction (IUGR) is an obstetrical complication with an increased risk of perinatal mortality and morbidity. The uterus, once considered to be a sterile environment, has now been described in recent microbiome studies to harbor diverse commensal placenta microbiota, as well as potentially pathogenic flora known to cause infection. Therefore, in this pilot study, we tested whether IUGR was associated with changes to the reproductive microbiome. The reproductive microbiome was surveyed using 16S sequencing (20 IUGR, 20 controls). Alpha and beta diversity were compared, and differential taxa features associated with IUGR were identified. Microbial screening of the placenta demonstrated a diverse range of flora predominantly including Proteobacteria, Fusobacteria, Firmicutes, and Bacteroidetes. Neither alpha- nor beta-diversity was significantly different by IUGR status. However, at the taxa level, IUGR patients had significantly higher prevalence of Neisseriaceae, mucosal β-hemolytic bacteria known to uptake iron-bound host proteins including hemoglobin. Moreover, the increase in anaerobic bacteria such as Desulfovibrio reflects the emergence of a hypoxic environment in the IUGR placenta. Further analysis of the reproductive microbiome of IUGR samples showed lower levels of H202-producing Bifidobacterium and Lactobacillus that switch from respiration to fermentation, a less energetic metabolic process, when oxygen levels decrease. Source tracking analysis showed that the placental microbial contents were predominantly contributed from an oral source, as compared to a gut or vaginal source. Our results suggest that the reproductive microbiome profiles may, in the future, constitute potential biomarkers for fetal health during pregnancy, while Neisseriaceae may constitute promising therapeutic targets for IUGR treatment.

Functionally significant polymorphisms of ESR1and PGR and risk of intrauterine growth restriction in population of Central Russia

ObjectiveThis study aimed to investigate the role ofESR1 and PGR gene polymorphisms in development of intrauterine growth restriction (IUGR) among Russian women in Central Russia. Study designThis case–control study recruited a total of 520 women in the third trimester of pregnancy, including 196 IUGR patients and 324 controls. The participants were unrelated women of self-reported Russian ethnicity. Participants were genotyped at 4 functionally significant polymorphisms of theESR1 (rs2234693, rs9340799) and the PGR (rs484389, rs1042838) genes. The association analysis was performed using logistic regression. Two polymorphisms, which were associated with IUGR, and 26 polymorphisms linked to them (r2≥0.6) were analyzed for their functional significance in silico. ResultsHaplotype TG of loci rs2234693-rs9340799ESR1 (OR = 1.94, рperm = 0.006) was associated with an increased risk of IUGR. Allele T of rs2234693 decreases expression of ESR1 in thyroid gland, allele T of rs2234693 and allele G of rs9340799 increase affinity to eight transcription factors (AP-4, HEN1, E2A, LBP-1, RP58, LUN, Ets and Hand). The loci that are linked (r2≥0.6) to the IUGR-associated SNPs, have the cis-eQTL value (expression ESR1 in thyroid gland) and showed their regulatory effects in organs and tissues related to pathogenesis of IUGR. ConclusionHaplotype TG defined by polymorphisms rs2234693-rs9340799 of theESR1 gene is associated with the development of IUGR in Russian women from Central Russia.

Diffusion-weighted imaging of placenta in intrauterine growth restriction with worsening Doppler US findings

We aimed to compare the placental diffusion difference between intrauterine growth restriction (IUGR) patients with worsening Doppler ultrasonography (US) findings and control group with normal Doppler US findings by using diffusion-weighted imaging (DWI). We performed a prospective study to compare the placental diffusion difference in 63 patients (gestational week, 28-34 weeks), including 50 IUGR patients (mean gestational week, 30 weeks 3 days ±16.2 days) with worsening Doppler US findings and 13 patients with normal Doppler US findings (mean gestational week, 29 weeks 4 days ±12.3 days) by using DWI (b value, 0-1000 s/mm2). We classified IUGR patients into three groups according to the reference values of the umbilical artery pulsatility index (PI) chart. Placenta apparent diffusion coefficient (ADC) calculations were performed by freehand drawn regions-of-interest (ROIs) (min, 8.04 cm2; max, 200 cm2). Placental ADC values in IUGR patients (mean, 1.624±0.181 ×10-³ mm²/s; range, 1.35-1.96 ×10-3 mm2/s) were significantly reduced compared with the control group (mean, 1.827±0.191 ×10-³ mm²/s; range, 1.35-2.84 ×10-3 mm2/s) (P = 0.001). For adjusted ROI area calculation, ADC values were significantly lower in groups 3, 2 and 1, respectively, compared with the control group (P < 0.05); and there was no significant difference between groups 1 and 2 (P > 0.05). Preeclampsia significantly reduced the placental diffusion compared with patients without preeclampsia (P = 0.003). Gestational aging did not significantly affect ADC values in control patients (r=0.08, P = 0.561). The sensitivity, specificity, negative and positive predictive values of ADC to detect IUGR were 72%, 84.6%, 44%, and 94.7% with a cutoff value of 1.727 ×10-3 mm2/s, respectively. The diagnostic estimation of placental ADC values to predict the severity of IUGR is comparable to that of umbilical artery PI. Considering that at the very early onset of IUGR, placental diffusion diminishes, ADC as a marker for IUGR in lieu of umbilical artery PI has the potential to determine the threshold for decreased placental diffusion. Therefore, DWI should be added to routine fetal MRI to show diffusion changes in placenta.

Mitochondrial implications in human pregnancies with intrauterine growth restriction and associated cardiac remodelling.

Intrauterine growth restriction (IUGR) is an obstetric complication characterised by placental insufficiency and secondary cardiovascular remodelling that can lead to cardiomyopathy in adulthood. Despite its aetiology and potential therapeutics are poorly understood, bioenergetic deficits have been demonstrated in adverse foetal and cardiac development. We aimed to evaluate the role of mitochondria in human pregnancies with IUGR. In a single‐site, cross‐sectional and observational study, we included placenta and maternal peripheral and neonatal cord blood mononuclear cells (PBMC and CBMC) from 14 IUGR and 22 control pregnancies. The following mitochondrial measurements were assessed: enzymatic activities of mitochondrial respiratory chain (MRC) complexes I, II, IV, I + III and II + III, oxygen consumption (cell and complex I‐stimulated respiration), mitochondrial content (citrate synthase [CS] activity and mitochondrial DNA copy number), total ATP levels and lipid peroxidation. Sirtuin3 expression was evaluated as a potential regulator of bioenergetic imbalance. Intrauterine growth restriction placental tissue showed a significant decrease of MRC CI enzymatic activity (P < 0.05) and CI‐stimulated oxygen consumption (P < 0.05) accompanied by a significant increase of Sirtuin3/β‐actin protein levels (P < 0.05). Maternal PBMC and neonatal CBMC from IUGR patients presented a not significant decrease in oxygen consumption (cell and CI‐stimulated respiration) and MRC enzymatic activities (CII and CIV). Moreover, CS activity was significantly reduced in IUGR new‐borns (P < 0.05). Total ATP levels and lipid peroxidation were preserved in all the studied tissues. Altered mitochondrial function of IUGR is especially present at placental and neonatal level, conveying potential targets to modulate obstetric outcome through dietary interventions aimed to regulate Sirtuin3 function.

Cardiac left heart morphology and function in newborns with intrauterine growth restriction: relevance for long-term assessment.

To asses the cardiac morphology and functional changes specific for newborns from intrauterine growth restriction(IUGR) pregnancies. A cohort of IUGR infants were evaluated by serial echocardiographies at deliveryand at the first and six months follow-ups. IUGR newborn delivery status was compared to that of newborns in the controlgroup according to gestational age (AGA). Left heart measurements were significantly lower in IUGR newbornscompared to AGA babies. Left ventricular size increased at follow-up inthe IUGR group (p<0.05). Systolic dysfunction (the myocardial performance index (MPI)> 0.47) was identified in 40% of the neonates in the IUGR group (16/40), respectively4.76% in the control group. IUGR neonates had a significantly increased proportion of systolic malfunction (p=0.004). IUGR patients had reduced left ventricle dimensions compared to AGA babies. The MPI stands out as a marker of leftheart function in newborns. Systolic dysfunction was a hallmark of the cardiac adaptation in IUGR neonates.

Disturbed angiogenesis in intrauterine growth restriction-compromised placentas at term

Purpose of investigation: The aim of this study was to compare levels of selected angiogenesis-related proteins in intrauterine growth restriction (IUGR)-compromised and normal placentas at term. Materials and Methods: Stromatal tissue of placental villi of gestationally matched IUGR patients and controls (both groups of n=32, gestational age between 39+0 and 40+6 gtt) was separated by microdissection. After separation, placental tissue was homogenised on ice (2′10 min, 2,000 rpm) and centrifuged (2'5 min, 5,000 rpm). Proteins of supernatant were fractionated by 8% or 10% SDS-PAGE and Tie-1, Tie-2, VEGFR-1, VEGFR-2, and MMP-2 levels were measured by Western blot using appropriate primary and secondary antibodies. Results: In the IUGR group, compared to the control group, there was a significantly lower level of Tie-1 (67.1% of controls, p p p = 0.001), and a significantly higher level of Tie-2 (119% of controls, p = 0.023). MMP-2 was increased in the IUGR group (127% of controls, p Conclusions: Placental levels of Tie-1, Tie-2, VEGFR-1, and VEGFR-2 are altered in pregnancies complicated by IUGR. Compared with that in normal pregnancies, the level of MMP-2 was upregulated. The present authors speculate that the results of this study represent the angiogenic imbalance observed in IUGR pregnancies; thereby resulting in poor and disturbed angiogenesis underlying delayed development of the fetus.

Placental MRI shows preservation of brain volume in growth-restricted fetuses who suffer substantial reduction of putative functional placenta tissue (PFPT)

ObjectiveRecently, a potentially useful diagnostic approach based on MR diffusion-tensor-imaging (DTI) was reported for the estimation of putative functional placenta tissue (PFPT), thus providing direct information about placental function. Yet, the relation between reduced PFPT and the phenomenon of brain-sparing remains unclear. This study aimed to investigate the relation between brain-sparing and reduced PFPT volume, as found in fetuses with intrauterine growth restriction (IUGR). MethodsA total of 40 consecutive patients with a US-based diagnosis of placental IUGR were examined using fetal MRI. A control group of 78 patients who received fetal MRI, due to non-placental pathologies, was established. A somatic energy index was calculated as IE=1–(Vbrain/Vpfpt) from brain and PFPT volumes measured with DTI in both groups. IE, Vpfpt, and Vbrain were analyzed with respect to the gestational week. ResultsVbrain corrected for gestational weeks was no different between both groups, while Vpfpt was significantly reduced in IUGR patients. IE was significantly different between both groups and indicated a higher Vbrain at a comparable Vpfpt. ConclusionsFetuses with IUGR show preserved energetic resources necessary for brain growth. Because IE drops in IUGR more rapidly as pregnancy progresses, depending on Vpfpt, IE could prove useful for estimating fetal well-being.

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.

Maternal endothelial damage as a disorder shared by early preeclampsia, late preeclampsia and intrauterine growth restriction.

Preeclampsia (PE) and intrauterine growth restriction (IUGR) are separate disease entities that have frequently been reported as sharing the same pathogenesis. In both of them, angiogenesis disorders and generalized endothelial damage with an accompanying inflammation are the dominant symptoms. In this study, we attempted to prove that both these processes demonstrate the same profile in early PE, late PE and IUGR patients, while the only difference is in the degree of exacerbation of the lesions. In 167 patients divided into four groups, three of those with early PE, late PE and IUGR and one control group, fms-like tyrosine kinase-1 (sFlt-1), placental growth factor (PlGF), high sensitive c-reactive protein (hsCRP) and fibronectin were determined. The behavior of these parameters in each of the groups was studied, and correlations between them were sought for. Higher concentrations of sFlt-1, hsCRP and fibronectin and a lower concentration of PlGF were found in the study groups compared to the control group. Significant correlations were observed between the factors concerned. The higher values of disordered angiogenesis markers, endothelial damage markers and inflammatory markers both in the PE and the intrauterine growth restriction (IUGR) groups suggest the existence of shared disorders in the development of these pathologies. The correlations between disordered angiogenesis markers and endothelial damage markers argue in favor of a mutual relationship between these two processes in the development of pathologies evolving as secondary to placental ischemia. The results obtained confirm that the lesion profiles are the same in both PE and IUGR patients, which can be utilized in developing common diagnostic criteria.

A Common Profile of Disordered Angiogenic Factor Production and the Exacerbation of Inflammation in Early Preeclampsia, Late Preeclampsia, and Intrauterine Growth Restriction.

Preeclampsia and intrauterine growth restriction are two separate disease entities that, according to numerous reports, share the same pathogenesis. In both, angiogenesis disorders and generalized inflammation are the dominant symptoms. In this study, we hypothesized that both diseases demonstrate the same profile in early preeclampsia, late preeclampsia, and intrauterine growth restriction patients, with the only difference being the degree of exacerbation of lesions. One hundred sixty-seven patients were enrolled in the study and divided into four groups: early preeclampsia, late preeclampsia, and intrauterine growth restriction groups, and one control group. Concentrations of the angiogenesis and inflammatory markers soluble fms-like tyrosine kinase receptor 1, placental growth factor, high-sensitivity C-reactive protein, and interleukin-6 were determined, and the behavior of these markers and correlations among them were studied. Higher concentrations of soluble fms-like tyrosine kinase receptor 1, high-sensitivity C-reactive protein, and interleukin-6 and a lower concentration of placental growth factor were observed in the study groups compared with the control group. No differences in concentrations of the studied markers were found among the study groups but significant correlations were observed. The higher values for the angiogenesis and inflammatory markers both in preeclampsia patients and patients with intrauterine growth restriction of placental origin compared with the control group suggest the existence of the same underlying disorders in the development of these pathologies. The observed mutual correlations for disordered angiogenesis and inflammatory markers are suggestive of a mutual relationship between these processes in the development of pathologies evolving secondary to placental ischemia. The same lesion profile was observed for both preeclampsia and ‘placental’ intrauterine growth restriction patients, which could be used in developing common diagnostic criteria for pregnant patients.

Circulating mRNA for epidermal growth factor‐like domain 7 (EGFL7) in maternal blood and early intrauterine growth restriction. A preliminary analysis

To evaluate the alteration in epidermal growth factor-like domain 7 (EGFL7) mRNA expression in maternal blood from pregnancies affected by early-onset intrauterine growth restriction (IUGR) at 20-24 weeks. Case-control study encompassing six women with pregnancies affected by IUGR (cases) matched in a 1 : 7 ratio for gestational age and fetal gender with 42 controls. We quantified EGFL7 mRNA expression in normal and IUGR patients. Matched rank-sum analysis and multiples of median were used to evaluate differences of the marker of interest between cases and controls. Spearman regression analysis was used to correlate the estimated fetal weight at blood sampling with the EGFL7 mRNA values. The mean observed rank in the IUGR group was significantly higher than that of controls (6.67 vs 4.19, p = 0.01). Pregnancies affected with IUGR exhibited 1.70-fold higher levels of maternal EGFL7 mRNA compared with matched controls (p = 0.014). EGFL7 mRNA values were inversely correlated with estimated fetal weight (Spearman's ρ = -0.429, p = 0.198). Early IUGR at 20-24 weeks' gestation is associated with higher values of EGFL7 expression in maternal plasma.

Regulation of the human endogenous retroviral Syncytin‐1 and cell–cell fusion by the nuclear hormone receptors PPARγ/RXRα in placentogenesis

Cytotrophoblast (CT) cell fusion into a syncytiotrophoblast is obligatory for placentation and mediated by the human endogenous retrovirus (HERV)-W envelope gene Syncytin-1. Abnormal placentation is associated with preeclampsia (PE), HELLP and intrauterine growth restriction (IUGR). In placentogenesis, the MAP-kinase p38α regulates PPARγ/RXRα signaling and target genes, like leptin, resistin, ABCG2, and hCG. The aim of this study was to analyze PPARγ/RXRα signaling and target gene regulation using primary CT cultures, the trophoblastic cell line BeWo and placental tissues from patients with normal and abnormal placentation. CT from four different human control placentae and BeWo cells demonstrated that Syncytin-1, other signaling members and CT cell fusions were regulated with PPARγ/RXRα activators troglitazone and 9-cis retinoic acid, via protein kinase A and p38α inhibition. Significant discordant regulations between CTs and BeWo were found. Two PPARγ/RXRα-response-elements from upstream regulatory elements and the 5'LTR of HERV-W were confirmed with DNA-protein binding assays using nuclear extracts and recombinant PPARγ/RXRα proteins. These promoter elements were validated with luciferase assays in the presence of PPARγ/RXRα modulators. Furthermore, troglitazone or 9-cis retinoic acid treatment of siRNA-PPARγ and siRNA-RXRα transfected BeWo cells proved the requirement of these proteins for Syncytin-1 regulation. Thirty primary abnormal placentae from PE, HELLP and IUGR patients compared to 10 controls showed significant deregulation of leptin RNA and protein, p38α, phospho-p38α, PPARγ, ABCG2, INSL4 and Syncytin-1. Our study characterized PPARγ/RXRα signaling in human CT and cell fusions identifying Syncytin-1 as a new target gene. Based on these results, a disturbed PPARγ/RXRα pathway could contribute to pathological human pregnancies.

Perinatal outcomes and maternal clinical characteristics in IUGR with absent or reversed end-diastolic flow velocity in the umbilical artery

The aim of this study was to evaluate the effect of absent or reversed end-diastolic umbilical artery Doppler flow on neonatal outcome independent of oligohydramnios, gestational age, and maternal factors. From January 2004 to March 2010 we reviewed 76 cases at our hospital, which were diagnosed with intrauterine growth restriction (IUGR). Among those cases, the existence of absent or reversed end-diastolic velocity of umbilical artery (AEDV) was considered abnormal. We set the group that had no abnormal signs as the control group (57 cases), and compared it with the AEDV group (19 cases). Logistic regression was used to control for oligohydramnios and gestational age. The gestational age was lower in the AEDV group compared to that of the control group. Neonatal weight, platelet count were also lower in the AEDV group and serum SGOT level, the frequency of non-reassuring fetal heart beat pattern were higher in AEDV group compared to that of the control group independent of gestational age. Perinatal outcomes such as Apgar score at 1 min below 4, use of a ventilator, admission to the neonatal intensive care unit (NICU), respiratory disease, neurologic disease, neonatal sepsis, anemia, thrombocytopenia, and neonatal mortality were statistically less favorable in the AEDV group compared to those in the control group independent of gestational age and presence of oligohydramnios. There were more intrauterine fetal death histories and preeclampsia in the AEDV group compared the control group. The waveform of umbilical artery Doppler velocity is an informative parameter of perinatal outcomes independent of gestational age or the presence of oligohydramnios in IUGR patients. It is especially important to check the waveform of umbilical artery Doppler velocity in IUGR patients with preeclampsia and IUGR patients with FDIU history.

Microarray analysis of placental tissue in intrauterine growth restriction

Besides foetal or maternal disorders, placental dysfunction is a major cause of intrauterine growth restriction (IUGR). Although numerous macro- and histopathological changes have been described, little is known about the precise aetiology and the contribution of foetal/placental genes in this disorder. Placental tissues of 20 IUGR and control neonates were analysed by microarray technique. Four of the regulated genes with possible relevance in the pathogenesis of IUGR and its consequences were further studied in placentas of 27 IUGR and 35 control newborns. Elevated gene expression of leptin, corticotrophin-releasing hormone (CRH), and IGF-binding protein-1 (IGFBP-1) in IUGR placentas could be confirmed in the larger group by real-time PCR, whereas prolactin showed no significant difference. Accordingly, protein expression of leptin and IGFBP-1 depicted by Western blot was elevated in IUGR, prolactin was not different. Birthweight standard deviation score (SDS) correlated negatively to leptin, IGFBP-1, and CRH, whereas placental weight correlated only to IGFBP-1. Leptin correlated negatively to gestational age of IUGR patients and positively to placental score, a marker of severity of impaired foeto-placental circulation. As confirmed in a large group of IUGR and control samples, the up-regulated factors leptin, IGFBP-1, and CRH may serve as candidate genes for the prediction of subsequent metabolic consequences in IUGR newborns. These three factors may not only influence growth of the foetus, but might also interact with programming of its metabolic functions, which has to be determined in an ongoing study.