Intrauterine Growth Restriction Cases Research Articles

Intrauterine Growth Restriction Caused by Underlying Congenital Cytomegalovirus Infection

Human cytomegalovirus (HCMV) is the major viral etiology of congenital infection and birth defects. Fetal transmission is high (30%-40%) in primary maternal infection, and symptomatic babies have permanent neurological, hearing, and vision defects. Recurrent infection is infrequently transmitted (2%) and largely asymptomatic. Congenital infection is also associated with intrauterine growth restriction (IUGR). To investigate possible underlying HCMV infection in cases of idiopathic IUGR, we studied maternal and cord sera and placentas from 19 pregnancies. Anti-HCMV antibodies, hypoxia-related factors, and cmvIL-10 were measured in sera. Placental biopsy specimens were examined for viral DNA, expression of infected cell proteins, and pathology. Among 7 IUGR cases, we identified 2 primary and 3 recurrent HCMV infections. Virus replicated in glandular epithelium and lymphatic endothelium in the decidua, cytotrophoblasts, and smooth muscle cells in blood vessels of floating villi and the chorion. Large fibrinoids with avascular villi, edema, and inflammation were significantly increased. Detection of viral proteins in the amniotic epithelium indicated transmission in 2 cases of IUGR with primary infection and 3 asymptomatic recurrent infections. Congenital HCMV infection impairs placental development and functions and should be considered as an underlying cause of IUGR, regardless of virus transmission to the fetus.

Metabolomic Profile of Umbilical Cord Blood Plasma from Early and Late Intrauterine Growth Restricted (IUGR) Neonates with and without Signs of Brain Vasodilation

ObjectivesTo characterize via NMR spectroscopy the full spectrum of metabolic changes in umbilical vein blood plasma of newborns diagnosed with different clinical forms of intrauterine growth restriction (IUGR).Methods23 early IUGR cases and matched 23 adequate-for-gestational-age (AGA) controls and 56 late IUGR cases with 56 matched AGAs were included in this study. Early IUGR was defined as a birth weight <10th centile, abnormal umbilical artery (UA) Doppler and delivery <35 weeks. Late IUGR was defined as a birth weight <10th centile with normal UA Doppler and delivery >35 weeks. This group was subdivided in 18 vasodilated (VD) and 38 non-VD late IUGR fetuses. All AGA patients had a birth weight >10th centile. 1H nuclear magnetic resonance (NMR) metabolomics of the blood samples collected from the umbilical vein at delivery was obtained. Multivariate statistical analysis identified several metabolites that allowed the discrimination between the different IUGR subgroups, and their comparative levels were quantified from the NMR data. ResultsThe NMR-based analysis showed increased unsaturated lipids and VLDL levels in both early and late IUGR samples, decreased glucose and increased acetone levels in early IUGR. Non-significant trends for decreased glucose and increased acetone levels were present in late IUGR, which followed a severity gradient when the VD and non-VD subgroups were considered. Regarding amino acids and derivatives, early IUGR showed significantly increased glutamine and creatine levels, whereas the amounts of phenylalanine and tyrosine were decreased in early and late-VD IUGR samples. Valine and leucine were decreased in late IUGR samples. Choline levels were decreased in all clinical subforms of IUGR.ConclusionsIUGR is not associated with a unique metabolic profile, but important changes are present in different clinical subsets used in research and clinical practice. These results may help in characterizing comprehensively specific alterations underlying different IUGR subsets.

Validity of umbilical artery Doppler waveform versus umbilical vein Doppler waveform in the prediction of neonatal outcome in intrauterine growth restriction cases

Abstract Objective To assess the neonatal outcome in relation to umbilical vein Doppler compared to umbilical artery Doppler in growth restricted fetuses. Methods A total of 72 pregnant women with singleton pregnancy between 28 and 38 weeks of gestation with risk of developing intrauterine growth restriction (IUGR) were recruited to the study. All women were subjected to full assessment via detailed history, clinical examination, obstetric assessment, routine laboratory assessment and ultrasonography examination for fetal assessment. Doppler examination of umbilical artery (UA) and umbilical vein (UV) was performed. Absent or reversed UA end diastolic flow (EDF) and pulsatile flow in the umbilical vein were examined for their efficacy to predict critical outcomes (still birth, neonatal death, IUGR). Results A total of 13 deaths (18%) were reported; 13.9% were neonatal deaths and 4.2% were stillbirths. Fetuses were grouped according to Doppler parameters: those with normal Doppler finding ( n = 35), those with resistance index (RI) ( n = 20), those with Absent UA EDF ( n = 10) and those with reversed UA EDF ( n = 7). Pulsatile UV waveform was reported among 9.7% of patients all of them had reversed UA EDF. Patients with absent/reversed EDF have significant association with critical neonatal outcomes as lower birth weight, perinatal deaths, and lower Apgar score. UV Doppler was abnormal in patients with more severe deterioration (patients with reversed UA EDF) while it was normal in all patients with increased RI and absent UA EDF. All cases with Pulsatile UV Doppler have shown higher incidence of critical neonatal outcomes. Conclusion UV Doppler assessment can aid in detection and prediction of critical perinatal outcomes however, it required further evaluation and assessment.

P08.16: Systematic thickness analysis of the adipose tissue around the fetal arm across gestation using 2D ultrasound images

year. Results: Three cases of intrauterine growth restriction (IUGR) at 35 and 29 weeks presented an aorta abdominal intima thickening and a condensation of the elastic fibers forming an evident internal elastic membrane with the presence of inflammatory elements, such as macrophages and activated endothelial cells. Two monochorionic twin pregnancies hesitated with the death of triplets at 25 weeks (IUGR and twin-to-twin transfusion syndrome); they presented an aortic hemorrhagic peri-adventitial dissociation. In both cases were present fetal Doppler abnormalities, in particular an increase of the systolic velocity of umbilical artery in presence of IUGR and an absent diastolic flow and ductus venosus alterations in twins. A Down fetus at 22 weeks showed a sub occlusive thrombosis of the abdominal aorta with delamination of the aortic wall and the presence of media-intimal foamy macrophages, without Doppler alterations in utero. Finally, a fetus with Potter’s syndrome at 23 weeks showed a partially organized thrombosis of the abdominal aorta and renal arteries with delamination of the wall and the presence of media-intimal foamy macrophages, as in IUGR ones. Conclusions: all the fetal intrauterine diseases described might be associated to a specific histological arterial findings which could represent underlying conditions predisposing of hypertension and vascular damage in adult life.

Cardiac function in early onset small for gestational age and growth restricted fetuses

ObjectiveTo examine cardiac function in appropriately grown, small for gestational age and intrauterine growth restricted fetuses and investigate the relationship between cardiac function and fetal arterial and venous Doppler parameters. Study designMyocardial performance index, isovolumetric contraction time, isovolumetric relaxation time, ejection time, and umbilical artery, middle cerebral artery and ductus venosus Doppler pulsatility index were measured for women between 24 and 32 weeks with small for gestational age and intrauterine growth restricted fetuses. Forty-eight appropriately grown, 11 small for gestational age and 12 intrauterine growth restricted cases were included. The relationship between cardiovascular parameters and gestation was defined and Doppler values converted to Z-scores in relation to gestational age. ResultsIn small for gestational age fetuses and fetuses with intrauterine growth restriction the myocardial performance index was 0.66 (0.63–0.7) and 0.64 (0.60–0.67), respectively, and compared to appropriately grown fetuses, at 0.45 (0.43–0.47), was significantly increased (p=0.001). No relationship was found between the myocardial performance index and arterial and venous Doppler Z-score. ConclusionSmall for gestational age and intrauterine growth restricted fetuses demonstrate altered cardiac function in the late second and early third trimester of pregnancy. Importantly, the myocardial performance index is raised in small for gestational age fetuses before the arterial and venous Doppler abnormalities that characterize hypoxia are evident.

Oxidative stress induces smooth muscle dedifferentiation in placental stem villus arteries through reduced hydrogen sulphide production by cystathionine-γ-lyase

Introduction: Intrauterine growth restriction (IUGR) is a leading cause of perinatal morbidity and mortality, and is often associated with abnormal Doppler umbilical artery waveforms indicative of increased vascular resistance. The increased resistance is thought to involve stem villus arteries (SVAs), but how it develops remains unknown. Oxidative stress following deficient maternal spiral artery conversion is believed to be the primary insult in unexplained cases of IUGR and pre-eclampsia. Cystathionine-g-lyase (CSE) has been reported to be downregulated in SVAs during IUGR and pre-eclampsia1. Methods: SVA explants from uncomplicated human pregnancies delivered by elective Caesarean section were subjected to oxidative stress in vitro by cycles of hypoxia-reoxygenation (HR), or to normoxia in the presence or absence of CSE inhibitor propargylglycine (10 mM) for 1 or 3 days. Results: HR induced oxidative stress, and vascular smooth muscle (SM) dedifferentiation, with reduced expression of the contractile proteins and differentiation markers SM Myosin Heavy Chain and SM a-actin. SM dedifferentiation was accompanied by acquisition of a synthetic phenotype characterised by increased SM proliferation, and marked ECM remodelling, as evidenced by changes in collagen deposition. HR also reduced CSE expression in SVAs and produced a decline in H2S production of similar magnitude. CSE inhibition under normoxic conditions increased the level of oxidative stress in SVAs and produced changes in SM marker expression similar to those induced by HR. Under oxidative stress, changes in Hsp90 and catalase levels were paradoxically correlated with changes in CSE expression. Conclusions: Our results show that oxidative stress can trigger, via CSE downregulation and reduced H2S signalling, a positive feedback loop of signalling that drives SM dedifferentiation into a synthetic phenotype. This could result in vascular remodelling, leading to compromised SVA distensibility, and hence increased SVA and placental resistance in pathological pregnancies. 1. Cindrova-Davies et al. 2013 Am J Pathol 182,1448-1458.

Value of annular M‐mode displacement vs tissue Doppler velocities to assess cardiac function in intrauterine growth restriction

To compare the ability of two different methods for longitudinal annular motion measurement, M-mode and tissue Doppler imaging (TDI), to demonstrate cardiac dysfunction in intrauterine-growth-restricted (IUGR) fetuses. Cardiac longitudinal annular motion in the basal free wall of the left ventricle (mitral annulus), interventricular septum and tricuspid annulus was assessed in 23 early-onset IUGR cases and 43 controls by TDI (annular peak velocities) and M-mode (displacement). All annular parameters were significantly decreased in the IUGR group with respect to controls using both methods. M-mode showed a trend towards equal performance as classifier between cases and controls, as compared to TDI, mainly in the tricuspid annulus. Both M-mode and TDI demonstrate annular motion changes and consequently cardiac dysfunction in IUGR fetuses. M-mode imaging is simpler to perform and could be as sensitive as TDI for detecting subtle changes.

Analysis of Doppler Criteria in the Diagnosis Of IUGR

Abstract Introduction: The assessment of the Doppler velocimetric indices of the uterine, umbilical and middle cerebral artery helps in diagnosing and monitoring pregnancies with fetal growth disorder. Material and method: Two groups were studied: the 1st group SGA (small for gestational age) including 22 fetuses whose birth weight was below the 10th percentile for gestational age and the 2nd group AGA (appropriate for gestational age) comprising 58 fetuses whose birth weight was between the 10th and 90th percentile. According to Doppler changes we could identify fetuses with intra uterine growth restriction (IUGR) and perform a comparative analysis of Doppler changes according to frequency and also assessed the predictive accuracy of some abnormal velocimetric indices for diagnosing SGA. Results: In the SGA group we found 8 fetuses with IUGR (36.3%), based on the fetal brain-sparing phenomenon indicated by Doppler changes. In the AGA group Doppler changes were observed in only 1 pregnancy (1.7%). The frequency of Doppler changes was significantly higher in the SGA group. The highest predictive accuracy for SGA was found for a cerebroplacental ratio (CPR) below 1.08 (88.89% PPV; 80.28% NPV; 36.36% Se and 98.28% Sp) with p &lt; 0.0001. Conclusions: Many cases of IUGR occur in pregnancies without evident risk factors as shown in this study. The most effective parameter for diagnosing SGA was found to be the CPR below 1.08.

Fetoplacental Oxygenation in an Intrauterine Growth Restriction Rat Model by Using Blood Oxygen Level–Dependent MR Imaging at 4.7 T

To investigate blood oxygen level-dependent (BOLD) magnetic resonance (MR) imaging in an intrauterine growth restriction (IUGR) rat model as a noninvasive in vivo tool to evaluate the response of the fetoplacental units (FPUs) to oxygenation All procedures were approved by the animal care committee. The study was performed between February and July 2010. The IUGR model based on the ligation of the left uterine vascular pedicle at embryonic day 17 of gestation was validated by weighing placentas and fetuses after MR imaging. FPUs in the left and right uterine horns were IUGR cases and controls, respectively. A small-animal 4.7-T MR imager was used. Multiple gradient-echo sequence (repetition time msec/echo time msec, 800/1.8-49.8) was performed at embryonic day 19. T2* relaxation time was measured before and after maternal hyperoxygenation for live FPUs in placenta, fetal liver, and brain. The effect of hyperoxygenation on BOLD MR imaging was analyzed with change in T2* between hyperoxygenation and ambient air. After dissection, live fetuses from both horns were identified and weighed. Changes in T2* were compared based on Student t tests. A mixed model was used to compare BOLD effect among horns and organs. Sixteen rats were studied. There was a significant fetal weight decrease in the IUGR FPUs (-21.9%; P < .001). Change in T2* differed significantly between IUGR cases and controls for placenta (5.25 msec vs 11.25 msec; P < .001) and fetal brain (3.7 msec vs 7.17 msec; P = .02), whereas there was no significant difference in the fetal liver (2.72 msec vs 3.18 msec; P = .47). BOLD MR imaging at 4.7 T can be used to evaluate the response to oxygenation in normal and IUGR FPUs. This technique has a potential role in the assessment of human pregnancy.

Is MicroRNA-376c a Biomarker or Mediator of Preeclampsia?

See related article, pp 864–872 The remodelling of uteroplacental arteries is a key process in the first half of human pregnancy. The transformation from low-flow/high-resistance to high-flow/low-resistance arteries that ensures sufficient blood supply to meet the requirements of the fetus is caused by a loss of elasticity and vasomotor control. This remodelling is facilitated by perivascular invasion of extravillous trophoblast cells and infiltration of vessel walls by endovascular trophoblast cells. Impaired trophoblast invasion of the myometrial segments is therefore associated with placental hypoperfusion and may play a role in the pathogenesis of some cases of intrauterine growth restriction and preeclampsia. Preeclampsia is a multisystem disorder of pregnancy triggered by placental ischemia and release of placental factors causing widespread endothelial dysfunction.1 The reasons for altered trophoblast invasion in preeclampsia are incompletely understood, but similarities between development of normal placenta and development of cancer point toward a key role of growth factors in normal and abnormal placentation.2 MicroRNAs (miRNA) are becoming increasingly recognized as critical regulators of cellular function. These short noncoding RNA species act via repression of gene targets mediated through binding to miRNA seed sequences usually, but not exclusively, located in the 3′-untranslated region. This interaction leads to a block in translation of the gene to protein or induction of messenger RNA degradation. As such, the expression pattern and potential dysregulation of individual miRNA species, or miRNA signatures in individual cells, tissues, and organs are critical in understanding the role of miRNAs in health and disease. Although the discovery of miRNA was initially made in 1993,3 it is only in recent years that full recognition of their broad importance in cellular homeostasis, as well as the potential of miRNAs as therapeutic entities and as biomarkers of disease has been established. In contrast to diseases such as those …

Associations of intrauterine growth restriction with placental pathological factors, maternal factors and fetal factors; clinicopathological findings of 257 Japanese cases.

Intrauterine growth restriction (IUGR) is the leading cause of fetal mortality and morbidity. As an etiology, each of placental findings, maternal factors and fetal factors has been reported to be associated with IUGR, although a comprehensive approach to examine all of these parameters as a cause of IUGR has not been reported. In the present study, therefore, we comprehensively examined the placental findings and maternal and fetal factors in the cases of IUGR (n=257, mean maternal age, 30 years; gestational weeks, 34 weeks) and normal growth pregnancies (n=258, mean maternal age, 30 years; gestational weeks, 33 weeks), and determined risk factors for IUGR. The prevalence of pregnancy hypertension (PHT) (19% vs. 8%, P<0.01), smoking habit (3% vs. 0.7%, P<0.05) and fetal anomaly (3.5% vs. 0.8%, P<0.05) were higher in IUGR cases than normal growth pregnancies. Pathologically, the prevalence of infarction (33% vs. 14%, P<0.05), fetal vessel thrombosis (22% vs. 6%, P<0.001) and chronic villitis (11% vs. 3%, P<0.001) were higher in IUGR cases than those in normal growth pregnancies. A multivariable regression analysis revealed that maternal factors (PHT), fetal factors (anomaly), and placental findings (infarction, fetal vessel thrombosis, and chronic villitis) are independently associated with increased risk of IUGR (all P<0.01).

Low maternal leptin levels in preeclamptic women with fetal growth restriction

Objective: We hypothesized that preeclamptic women with intrauterine growth restriction (IUGR) would have lower concentrations of leptin compared to women with normal fetal growth. Methods: A crosssectional study was performed in 20 cases of IUGR and 20 normal fetuses born to women diagnosed with preeclampsia. Blood samples were collected from mothers at term gestation and with fetal birth weight less than 2500 grams would categorized as IUGR. The subjects were recruited by consecutive sampling conducted in Hasan Sadikin Hospital and several network hospitals during the period of September-November 2012. Results: A significant difference (p = 0.015) in maternal serum leptin levels was found between IUGR (22.1 ng/ml) and normal fetuses (36.5 ng/ml). Serum levels of leptin in preeclamptic women with IUGR were lower than normal fetuses. Spearman correlation test between maternal serum leptin levels and birth weight in IUGR did not demonstrate a significant correlation, with r = -0.321 (p = 0.168). Conclusion: The maternal leptin concentrations in IUGR are lower than the normal fetus in preeclampsia cases, but there was not enough evidence to support that leptin is associated with birth weight in IUGR.

Active management of selective intrauterine growth restriction with abnormal Doppler in monochorionic diamniotic twin pregnancies diagnosed in the second trimester of pregnancy

This study aims to compare outcomes of active management of monochorionic diamniotic twin pregnancies complicated with severe intrauterine growth restriction (IUGR) of one twin before 24 weeks with continuous or intermittent absent or reversed end-diastolic flow (AREDF) in the umbilical artery, with or without twin-to-twin transfusion syndrome (TTTS). This study is a retrospective comparison of 45 consecutive cases of severe selective IUGR (s-IUGR) defined as an estimated fetal weight at or below the fifth centile with a >25% weight discordance and AREDF in the umbilical artery before 24 weeks and 166 consecutive cases of TTTS stage III, with AREDF in the donor (TTTS3D) and also with s-IUGR. These were treated by either selective laser photocoagulation of chorionic vessels (SLPCV) or cord coagulation (CC). The 166 cases of TTTS3D were treated by SLPCV, whereas 23 and 22 cases of s-IUGR were treated by SLPCV and CC, respectively. Overall survival was 52.17% or 45.45% in s-IUGR treated by SLPCV or CC, respectively, and 48.49% in TTTS3D. The survival of appropriately grown for gestational age (AGA) twins following CC (90.9%) was higher than that following SLPCV in s-IUGR (74%) or in recipient twins of TTTS3D (55.42%) (p = 0.001). Survival of the IUGR twin was 30% and 41.56% with SLPCV in s-IUGR and TTTS3D, respectively. Active management of severe IUGR with AREDF in the umbilical artery seems beneficial. Survival rates with SLPCV were similar in s-IUGR and TTTS3D. However, there was a trend for higher survival rates in the AGA twin for CC. The choice of the technique should be driven by objective counseling on survival of both IUGR and AGA twins and therefore by the utility-based ethical values expressed by the pregnant woman.

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.

Perinatal role of hepcidin and iron homeostasis in full‐term intrauterine growth–restricted infants

To prospectively investigate iron homeostasis in full-term intrauterine growth-restricted (IUGR) and appropriate-for-gestational-age (AGA) infants at birth, by evaluating cord blood concentrations of hepcidin (a bioactive molecule, principal regulator of iron metabolism, downregulated by hypoxia/iron deficiency and upregulated by inflammation), erythropoietin (EPO, a marker of prolonged fetal hypoxia), soluble transferrin receptor (sTfR, a marker of increased erythropoiesis and tissue iron deficiency), iron, ferritin, and unsaturated iron-binding capacity (UIBC). Serum cord blood samples from 47 well-defined IUGR and 104 AGA singleton, full-term infants were analyzed for concentrations of all the aforementioned parameters by enzyme immunoassays and spectrophotometry. Hepcidin concentrations were similar, while EPO concentrations were higher in IUGR cases than in AGA controls (P=0.047). Cord blood sTfR concentrations were increased in IUGR, compared to AGA infants (P=0.004), and negatively correlated with their customized centiles and birth weight (r=-0.238, P=0.003 and r=-0.157, P=0.050, respectively). Ferritin concentrations were lower in IUGR cases than in AGA controls (P=0.039). In both groups, no correlations were observed between cord blood hepcidin concentrations and iron status indices. Cord blood hepcidin concentrations in term IUGRs may remain unaffected, possibly due to a balance between hepcidin downregulation by chronic fetal hypoxia (indicated by higher EPO concentrations) and impaired iron metabolism (indicated by lower ferritin and higher sTfR concentrations) on the one hand, and hepcidin upregulation by the inflammatory state characterizing IUGRs, on the other. Furthermore, our findings may possibly indicate the need for regular follow-up for detection of iron-deficient anemia, not only in preterm but also in full-term IUGR neonates.

Atypical hemodynamic pattern in fetuses with hypercoiled umbilical cord and growth restriction

Objectives: To describe fetal and uterine hemodynamics in intrauterine growth restriction (IUGR) fetuses with hypercoiled umbilical cord. Methods: 102 pregnant women with IUGR fetuses were enrolled in the study. In these cases, hemodynamic indices and Doppler waveform profiles were evaluated. Results: In seven of the enrolled cases of IUGR, we found an anomalous umbilical coiling. They showed normal impedance to flow in utero-placental district and abnormal venous umbilical cord pulsatility with flow velocity higher than the umbilical artery. The ductus venosus showed a reduction of the forward flow and/or a reverse flow during atrial contractions. Two of these seven patients had early onset IUGR and a particular deteriorating hemodynamic profile with “brain sparing”, severe reverse flow in the ductus venosus, increased reverse flow in the inferior vena cava during atrial contraction and absent flow during the diastole in the umbilical arteries. Five patients had late onset of IUGR and three of these did not demonstrate these worsening hemodynamic alterations until term. Conclusions: In patients with fetal IUGR and hypercoiling without signs of placental insufficiency, we observed an “atypical” feto-maternal hemodynamic pattern. These IUGR fetuses with hypercoiling and fetal venous system hemodynamic alteration can be at high hypoxic risk.

Intrauterine growth restriction with abnormal umbilical artery Dopplers: a harbinger for preeclampsia?

Objective: To determine whether abnormal umbilical artery Doppler velocimetry in the setting of unexplained intrauterine growth restriction (IUGR) is predictive of preeclampsia. Methods: This was a retrospective cohort study of singleton pregnancies diagnosed with unexplained IUGR between 2005 and 2008. Subjects were classified based on the presence or absence of abnormal Dopplers. The proportions of preeclampsia in the two groups were compared. Results: A total of 268 cases were included in the study. There were 57 cases with abnormal umbilical artery Dopplers. Of those, preeclampsia was diagnosed in 8 (14.0%) cases. In turn, there were 211 cases with normal Dopplers. Of those, preeclampsia was diagnosed in 9 (4.3%) cases. After controlling for age and parity, patients with abnormal Dopplers were 2.9 times more likely to be diagnosed with preeclampsia. Conclusions: Cases of unexplained IUGR with abnormal umbilical artery Dopplers appear to be at increased risk of preeclampsia compared to those with normal Dopplers.

Risk of Perinatal Death in Early-Onset Intrauterine Growth Restriction according to Gestational Age and Cardiovascular Doppler Indices: A Multicenter Study

Objective: To assess the value of gestational age and cardiovascular Doppler indices in predicting perinatal mortality in a multicenter cohort of early-onset intrauterine growth-restricted (IUGR) fetuses. Methods: A multicenter prospective cohort study including 157 early-onset (<34 weeks) IUGR cases with abnormal umbilical artery (UA) Doppler was conducted. Cardiovascular assessment included the ductus venosus (DV), the aortic isthmus flow index (IFI), and the myocardial performance index (MPI). Isolated and combined values to predict the risk of perinatal death were evaluated by logistic regression and by decision tree analysis, where the gestational age at delivery, UA, and middle cerebral artery (MCA) were also included as covariates. Results: Perinatal mortality was 17% (27/157). All parameters were significantly associated with perinatal death, with individual odds ratios (OR) of 25.2 for gestational age below 28 weeks, 12.1 for absent/reversed DV atrial flow, 5.3 for MCA pulsatility index <5th centile, 4.6 for UA absent/reversed diastolic end-flow, 1.8 for IFI <5th centile, and 1.6 for MPI >95th centile. Decision tree analysis identified gestational age at birth as the best predictor of death (<26 weeks, 93% mortality; 26–28 weeks, 29% mortality, and >28 weeks, 3% mortality). Between 26 and 28 weeks, DV atrial flow allowed further stratification between high (60%) and low risk (18%) of mortality. Conclusions: Gestational age largely determines the risk of perinatal mortality in early-onset IUGR before 26 weeks and later than 28 weeks of gestation. The DV may improve clinical management by stratifying the probability of death between 26 and 28 weeks of gestation.

A distinct microvascular endothelial gene expression profile in severe IUGR placentas

The placental microvasculature is essential for efficient transfer of gases, nutrients and waste between the mother and fetus. Microvascular hypoplasia of the terminal villi is a common pathology in severe Intra Uterine Growth Restriction (IUGR). We used novel methods to obtain placental micro-vascular endothelial cells (PlMEC) from preterm control placentas (n = 3) and placentas from pregnancies with severe IUGR (n = 6) with absent or reversed end-diastolic velocity in the umbilical artery. Distal placental villous tissue was collected to enrich for intermediate and terminal villi. Tissue was digested and PlMEC positively selected using tocosylated magnetic Dynabeads labeled with Human Endothelial Antigen lectin. The purity of the PlMEC (94 ± 2 SD %) was assessed by CD31 and vimentin immunocytochemistry. RNA was extracted from the PlMEC samples and subjected to Affymetrix microarray analysis (U133Plus2 array chips). Comparison of preterm and IUGR PlMEC gene expression profiles identified BTNL9 and NTRK2 transcripts to be upregulated and SAA1 and SLAMF1 transcripts to be downregulated in all 6 IUGR cases relative to preterm controls. A third downregulated gene GNAS was identified to be near significance. Changes were demonstrated to be significant at the mRNA level by Real Time PCR in the PlMEC samples. Changes in the IUGR endothelium were confirmed at the protein level by immunohistochemistry for the 3 with available antibodies. We used a tissue microarray constructed from an independent cohort of placental samples from severe IUGR (n = 7), preeclamptic (n = 7), preterm control (n = 6) and term control (n = 6) pregnancies. Results confirmed differential endothelial expression of BTNL9, NTRK2 and SLAMF1 in IUGR versus preterm and term samples. These studies are the first to characterize PlMEC gene expression profiles thus we have advanced our understanding of the molecular basis of placental micro-vascular pathophysiology in fetal growth restriction.

Can placental growth factor in maternal circulation identify fetuses with placental intrauterine growth restriction?

We investigated whether decreased concentrations of placental growth factor (PlGF) in maternal circulation differentiated placental intrauterine growth restriction (IUGR) from constitutionally small fetuses. Excluding congenital syndromes, infection, and aneuploidy, we assumed IUGR with an abnormal placental pathology to be of placental origin. The study design included a single site, case-control study of 16 cases (9 placental IUGR, 7 constitutionally small) and 79 normal controls with singleton pregnancies. Plasma PlGF was measured by Triage PlGF immunoassay according to the product insert. A positive PlGF test was defined as a concentration less than the fifth percentile for gestational age for normal pregnancy. A positive PlGF test was found in 9 of 9 placental IUGR cases, 1 of 7 constitutionally small fetuses, and 4 of 79 controls (P < .0001). PlGF identified placental IUGR from constitutionally small fetuses with 100% sensitivity and 86% specificity (P = .0009). These preliminary data suggest PlGF may identify placental IUGR antenatally.