Severe Fetal Growth Restriction Research Articles

Triphasic umbilical artery waveform: association with severe fetal growth restriction, fetal demise, and extreme velamentous cord insertion

Abstract Extreme Doppler abnormalities of the umbilical artery such as absent or reversed end diastolic velocity are associated with adverse perinatal outcomes. We present a case of a triphasic umbilical artery waveform identified at 24 weeks. The fetus was severely growth restricted with an estimated fetal weight of 314 g. A week later, fetal demise occurred. Placental pathology revealed a placental weight of 83 g, an extensive maternal floor infarction, and an extreme velamentous cord insertion 7 cm from the edge of the placental disc, with vessels entering at opposite poles of the placental disc and a single anastomotic bridging vessel on the chorionic plate connecting these two vascular poles. A triphasic umbilical artery waveform may be associated with a premorbid state and severe placental vascular abnormality. We hypothesize that the third and positive component in late diastole is present due to forward flow across the communicating bridging vessel into the contralateral entering vessel.

Gene and Cell Therapy Funding Opportunities in Horizon 2020: An Overview for 2014–2015

Gene and Cell Therapy Funding Opportunities in Horizon 2020: An Overview for 2014–2015

Uterine Compression Suture for Cesarean Hysterectomy: Possible Applications to Conditions other than Atonic Bleeding

Optimal management of severe early fetal growth restriction presents one of the greatest challenges in obstetrics. At present, a combination of several different monitoring modalities is used, including arterial and venous Doppler ultrasonography plus assessment of short-term fetal heart rate variation, without consensus on which of these should trigger the decision to deliver. Pathological Doppler waveforms in the ductus venosus (DV) have been found to be associated with adverse out come. However it is not clear how long a fetus in utero can withstand changes in presence of altered flussimetry and which are , specifically, the effects related to them during extrauterine life. Optimal management of severe early fetal growth restriction presents one of the greatest challenges in obstetrics. At present, a combination of several different monitoring modalities is used, including arterial and venous Doppler ultrasonography plus assessment of short-term fetal heart rate variation, without consensus on which of these should trigger the decision to deliver.

Gene Therapy Briefs

Human Gene TherapyVol. 25, No. 1 BriefsGene Therapy BriefsAlex PhilippidisAlex PhilippidisSearch for more papers by this authorPublished Online:20 Jan 2014https://doi.org/10.1089/hum.2013.2526AboutSectionsView articleView Full TextPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail View articleFiguresReferencesRelatedDetailsCited byPhase I/II Gene Therapy Trial of Fanconi Anemia Patients with a New Orphan Drug Consisting of a Lentiviral Vector Carrying the FANCA Gene: A Coordinated International Action (EuroFancolen)18 June 2015 | Human Gene Therapy Clinical Development, Vol. 26, No. 2Does Vascular Endothelial Growth Factor Gene Therapy Safely Improve Outcome in Severe Early-Onset Fetal Growth Restriction? (EVERREST)18 June 2015 | Human Gene Therapy Clinical Development, Vol. 26, No. 2 Volume 25Issue 1Jan 2014 InformationCopyright 2014, Mary Ann Liebert, Inc.To cite this article:Alex Philippidis.Gene Therapy Briefs.Human Gene Therapy.Jan 2014.12-16.http://doi.org/10.1089/hum.2013.2526Published in Volume: 25 Issue 1: January 20, 2014PDF download

Spiral Artery Remodeling and Trophoblast Invasion in Preeclampsia and Fetal Growth Restriction

Failure to transform uteroplacental spiral arteries is thought to underpin disorders of pregnancy, including preeclampsia and fetal growth restriction (FGR). In this study, spiral artery remodeling and extravillous-cytotrophoblast were examined in placental bed biopsies from normal pregnancy (n=25), preeclampsia (n=22), and severe FGR (n=10) and then compared with clinical parameters. Biopsies were immunostained to determine vessel wall integrity, extravillous-cytotrophoblast location/density, periarterial fibrinoid, and endothelium. Muscle disruption was reduced in myometrial spiral arteries in preeclampsia ( P =0.0001) and FGR ( P =0.0001) compared with controls. Myometrial vessels from cases with birth weight <5th percentile ( P <0.001), abnormal uterine Doppler ( P <0.01), abnormal umbilical artery Doppler ( P <0.001), and preterm delivery ( P <0.001) had less muscle destruction compared with >5th percentile. Fewer extravillous-cytotrophoblast surrounded both decidual and myometrial vessels in the normal group and preeclampsia group compared with the FGR group ( P =0.001). For myometrial vessels, the normal group contained more intramural extravillous-cytotrophoblast than in preeclampsia ( P =0.015). Decidual vessels in the FGR group had less fibrinoid deposition compared with controls ( P =0.013). For myometrial vessels, less fibrinoid was deposited in both the preeclampsia group ( P =0.0001) and the FGR group ( P =0.01) when compared with controls, and less fibrinoid was deposited in the preeclampsia group when compared with FGR group ( P <0.001). Myometrial vessels obtained from birth weights <5th percentile had less periarterial fibrinoid than those with >5th percentile ( P <0.02). A major defect in myometrial spiral artery remodeling occurs in preeclampsia and FGR that is linked to clinical parameters. Interstitial extravillous-cytotrophoblast is not reduced in preeclampsia but is increased in FGR.

Circulating MicroRNAs in Maternal Blood as Potential Biomarkers for Fetal Hypoxia In-Utero

Stillbirth affects 1 in 200 pregnancies and commonly arises due to a lack of oxygen supply to the fetus. Current tests to detect fetal hypoxia in-utero lack the sensitivity to identify many babies at risk. Emerging evidence suggests that microRNAs derived from the placenta circulate in the maternal blood during pregnancy and may serve as non-invasive biomarkers for pregnancy complications. In this study, we examined the expression of miRs known to be regulated by hypoxia in two clinical settings of significant fetal hypoxia: 1) labour and 2) fetal growth restriction. Six miRs (miR 210, miR 21, miR 424, miR 199a, miR 20b, and miR 373) were differentially expressed in pregnancies complicated by fetal hypoxia. In healthy term pregnancies there was a 4.2 fold increase in miR 210 (p<0.01), 2.7 fold increase in miR 424 (p<0.05), 2.6 fold increase in miR 199a (p<0.01) and 2.3 fold increase in miR 20b (p<0.05) from prior to labour to delivery of the fetus. Furthermore, the combined expression of miR 21 and miR 20b correlated with the degree of fetal hypoxia at birth determined by umbilical cord lactate delivery (r = 0.79, p = 0.03). In pregnancies complicated by severe preterm fetal growth restriction there was upregulation of the hypoxia-regulated miRs compared to gestation-matched controls: 3.6 fold in miR 210 (p<0.01), 3.6 fold in miR 424 (p<0.05), 5.9 fold in miR 21 (p<0.01), 3.8 fold in miR 199a (p<0.01) and 3.7 fold in miR 20b (p<0.01). Interestingly, the expression of miR 373 in gestation matched controls was very low, but was very highly expressed in FGR (p<0.0001). Furthermore, the expression increased in keeping with the degree of in-utero hypoxia estimated by fetal Doppler velocimetry. We conclude quantifying hypoxia-regulated miRs in the maternal blood may identify pregnancies at risk of fetal hypoxia, enabling early intervention to improve perinatal outcomes.

Expectant management of severe preeclampsia with severe fetal growth restriction in the second trimester

We investigated whether women with severe fetal growth restriction (FGR <5th percentile) associated with severe preeclampsia (PE) occurring in the second trimester are candidates for expectant management. This is a retrospective study involving 33 women who developed severe PE or superimposed PE in the second trimester and were expectantly managed at a tertiary center. They were divided into groups with and without severe FGR on admission (severe FGR (+) group: 17 women; severe FGR (-) group: 16 women) for comparison of the duration of pregnancy prolongation, major maternal complications, and perinatal outcomes. The data are presented as medians (range) or frequencies (percentage). The duration of pregnancy prolongation was 10days in both groups. Major maternal complications occurred in 5 of 17 women (29.4%) in the severe FGR (+) and 5 of 16 (31.3%) in the severe FGR (-) group, showing very similar incidence rates in the 2 groups. The perinatal survival rates were favorable at 82.4% (14/17) in the severe FGR (+) and 100% (16/16) in the severe FGR (-) group. Regarding expectant management of severe preeclampsia occurring in the second trimester, there was no difference in the duration of pregnancy prolongation between the groups with and without severe FGR on admission. Because favorable perinatal outcomes can be expected without compromising maternal safety by prolonging pregnancy as expectant management for severe FGR, it was suggested that women with severe FGR are suitable candidates for expectant management.

Amnioinfusion before 26 weeks' gestation for severe fetal growth restriction with oligohydramnios: Preliminary pilot study

The prognosis for severe fetal growth restriction (FGR) with severe oligohydramnios before 26 weeks' gestation (WG) is currently poor; furthermore, its management is controversial. We report the innovative new management of FGR, such as therapeutic amnioinfusion and tocolysis. For FGR and severe oligohydramnios before 26 WG complicated with absent or reversed umbilical artery end-diastolic flow velocity and/or deceleration by ultrasonography, we performed transabdominal amnioinfusion with tocolysis. Cases with multiple anomalies were excluded. Survival rate and long-term prognosis were analyzed. Among 570 FGR cases, 18 were included in the study. Mean diagnosis and delivery were at 22.6 ± 2.0 and 28.7 ± 3.3 WG. Median birthweight was 625 g (-4.2 standard deviation). Final survival rate was 11/13 (85%). There were five fetal deaths. In seven cases, oligohydramnios improved. Growth was detected in 10/18 fetuses. Furthermore, 8/8 decelerations, 4/12 cases of reversed umbilical artery end-diastolic flow velocity, 7/14 cases of brain-sparing effect, and 6/13 venous Doppler abnormalities were improved. When we detected umbilical cord compression, 8/10 cases were rescued. Eleven infants were followed up for an average of 5 years; one case of cerebral palsy with normal development and 10 cases with intact motor functions without major neurological handicap were confirmed. In cases of extremely severe FGR before 26 WG with oligohydramnios and circulatory failure, amnioinfusion might be a promising, innovative tool.

Defining the relationship between fetal Doppler indices, abdominal circumference and growth rate in severe fetal growth restriction using functional linear discriminant analysis

The relationship between Doppler measurements, size and growth rate in fetal growth restriction has not been defined. We used functional linear discriminant analysis (FLDA) to investigate these parameters taking account of the difficulties inherent in exploring relationships between repeated observations from a small number of cases. In 40 fetuses with severe growth restriction, serial abdominal circumference (AC), umbilical, middle cerebral artery (MCA) and ductus venosus Doppler pulsatility index measurements were recorded. In 11 singleton fetuses with normal growth, umbilical artery pulsatility index only was measured. Data were expressed as z-scores in relation to gestation and analysed longitudinally using FLDA. In severe growth restriction, the Spearman correlation coefficients between umbilical artery pulsatility index and AC z-score, MCA pulsatility index and AC z-score and ductus venosus pulsatility index z-score and AC z-score were, respectively: -0.36, p = 4.4 × 10(-7); 0.70, p = 1.1 × 10(-17) and -0.50, p = 8.1 × 10(-4). No relationship was seen between Doppler parameters and growth rate. There was no relationship between umbilical artery pulsatility index and AC nor growth rate in normally grown fetuses. In severe fetal growth restriction, Doppler changes are related to absolute fetal AC size, not growth rate.

Maternal floor infarction: Management of an underrecognized pathology

Maternal floor infarction is a relatively rare condition characterized clinically by severe early onset fetal growth restriction with features of uteroplacental insufficiency. It has a very high recurrence rate and carries a significant risk or fetal demise. Pathological characteristics include massive and diffuse fibrin deposition along the decidua basalis and the perivillous space of the basal plate. We present a case of recurrent maternal floor infarction and propose diagnostic clues as well as potential therapeutic options.

Placental abnormalities detected by ultrasonography in a case of confined placental mosaicism for trisomy 2 with severe fetal growth restriction

Clinical outcome of confined placental mosaicism (CPM) is varied, from normal pregnancy to intrauterine fetal death. It has been suggested that CPM for trisomy 2 is less likely to cause serious adverse effect on pregnancy. We hereby report a case of CPM for trisomy 2, which presented severe fetal growth restriction (FGR) and placental abnormalities. A 30-year-old woman was referred to our hospital at 17⁺² weeks because of marked FGR. Ultrasonography demonstrated prominent placental hypertrophy with multiple focal defects without any fetal structural abnormalities. Amniocentesis at 18⁺³ weeks revealed normal karyotype. Fetal growth rate worsened with gestational weeks, reaching -7 standard deviation at 36 weeks. At 37 weeks, the fetal condition suddenly deteriorated, ending in a stillbirth of a 756-g female baby. Postnatal cytogenetic analysis by array comparative genomic hybridization revealed trisomy 2 of the chorionic villi, and CPM for trisomy 2 was suggested as the cause of FGR and placental abnormalities.

A new method for measurement of placental elasticity: Acoustic radiation force impulse imaging

IntroductionThe velocities of the lateral shear waves (Vs; m s−1) generated by an acoustic radiation force impulse (ARFI) correlate with Young's modulus. Therefore, ARFI can be used as a new method to evaluate tissue elasticity. The aim of this study was to investigate the safety of ARFI imaging and the differences in placental elasticity in complicated cases. MethodsThe study population included 115 patients between 26 and 41 weeks gestation, who were divided into three groups, namely normal, fetal growth restriction (FGR) and pregnancy-induced hypertension (PIH). After delivery, the Vs values of the placenta were measured ex vivo. After ARFI imaging, microscopic examination was performed, the Vs values were compared among the three groups and the relationship between the Vs values and neonatal birthweight Z-score was investigated. ResultsNo histological changes were noted even after ARFI imaging. The Vs values in the FGR group were significantly higher than those in the normal group (1.94 ± 0.74 and 1.31 ± 0.35 m s−1, respectively; p < 0.05). The Vs values demonstrated a significant negative correlation with the Z-score. Moreover, as the Z-score became lower, the Vs values became higher in the range of Z-scores under −0.5 standard deviation (SD). DiscussionWe speculate that the increased Vs values in the FGR group may have been caused by histological changes, and that a more severe FGR might result in increased Vs values. ConclusionARFI imaging was observed to have no apparent histological damage to the placental tissue. Ex vivo placentas from the FGR group were significantly more firm. Moreover, Vs values and Z-scores of birthweight had a significant negative correlation. Additional investigations are needed about the utility of this method for the evaluation of placental function in vivo.

The role of CDX2 in trophoblast differentiation from human pluripotent tsem

s / Placenta 34 (2013) A1–A99 A22 [1] Stanley et al 2012. Hypertension. 59(5): 1021-8. [2] Constancia et al 2002. Nature. 417, 945-8. http://dx.doi.org/10.1016/j.placenta.2013.06.065 P1.29. THE ROLE OF CDX2 IN TROPHOBLAST DIFFERENTIATION FROM HUMAN PLURIPOTENT TSEM Chi-Wei Lu, Yasunari Seita Rutgers University, New Brunswick, NJ, USA Objective The unique requirement for Cdx2 in the development of mouse placental trophoblasts has been well-studied, in genetic models and through manipulating its expression in embryonic stem cells. The role of CDX2 in human trophoblast differentiation remains elusive. MethodsWe studied the involvement of CDX2 in trophoblast differentiation fromhumanembryonic and induced pluripotent stem cells (ESCs and iPSCs). Results From BMP4-induced trophoblast differentiation, we observed that CDX2 expressed in nearly 100% of cells, and largely overlapping with OCT4 expression, suggesting the model of their mutual transcription repression seen in the mouse is not conserved in humans. We tested whether CDX2 expression alone is associated with a trophoblast progenitor fate, through generating iPS cell lines with ectopic CDX2 expression. Two CDX2 expressing cell lines were analyzed, both expressing telomerase activity and capable of differentiation into syncytiotrophoblast after switching into serum containing media. However, in the cell line expressing CDX2 at a very high level, differentiation into mesoderm and endoderm lineages was also observed, suggesting the effect of CDX2 for trophoblast differentiation is dose dependent. Repressing CDX2 expression by shRNA does not blockade BMP4-induced trophoblast differentiation. Conclusion Altogether, our results suggest that while the mechanism of transcription regulation is different from the mouse, CDX2 in the human plays a conservative role in trophoblast development as being not necessary for differentiation, but sufficient for inducing a trophoblastic-stem cell like phenotype from pluripotent stem cells. http://dx.doi.org/10.1016/j.placenta.2013.06.066 P1.30. ENDOTHELIAL DYSFUNCTION OF THE FETOPLACENTAL CIRCULATION CONTRIBUTES TO THE INCREASED VASCULAR RESISTANCE OBSERVED IN FETAL GROWTH RESTRICTION Sarah Jones, Helen Bischof, Edward Johnstone, Sue Greenwood, Mark Wareing, Colin Sibley, Paul Brownbill University of Manchester, Manchester, UK Fetal growth restriction (FGR) affects 3-8% of pregnancies and is associated with increased risk of neonatalmorbidityandmortality. A hallmark of severe FGR is increased vascular resistance identified clinically using umbilical arteryDopplermeasurements. However, the sites andunderlyingmechanisms of increased vascular resistance in the fetoplacental circulation remain unclear. In this studywe tested the hypothesis that endothelial dysfunction and altered nitric oxide (NO) production in placental vessels contribute to the pathology of FGR. Dual perfusion was performed on placental cotyledons from normal pregnancies and those complicated by idiopathic FGR ( 5th centile). Vascular resistance and shear stress-induced vasodilatation of the fetal vasculaturewasmeasured in response to increasingflow rates (2-12ml/ min), and the role of NOwas examined using the NO synthase inhibitor Nunitro-L-arginine (L-NNA). Incremental increases in fetoplacental flow (212ml/min) in normal placentas elevated vascular resistance in a stepwise manner. This was significantly amplified in perfused cotyledons from FGR pregnancy, compared to those fromnormal pregnancy, particularly at higher flow rates (76.5 9mmHg versus 45.4 6mmHg at 12ml/min respectively; mean sem; n1⁄410 per group). Inhibition of eNOS by L-NNA moderately increased the resistance at high flow rates in normal placentas. In contrast, steady state vascular resistance in FGRplacentaswas augmentedby L-NNAat all flow rates. We propose that this effect of L-NNA may relate to increased levels of NO being produced to compensate for the increased resistance; a theory supported by our work on isolated endothelial cells (see separate abstract). In normal placentas increases in fetal-side flow ratewere followed by significant shear-induced vasodilatationwhichwas inhibited by L-NNA. In FGR placentas responses to shear-mediated vasodilatation were absent. In conclusion, placental vessels from pregnancies complicated by fetal growth restriction exhibit endothelial dysfunction and fail to adapt to increases in flow, resulting in increased vascular resistance. http://dx.doi.org/10.1016/j.placenta.2013.06.067 P1.31. MATERNAL ADMINISTRATION OF SILDENAFIL CITRATE ALTERS FETAL VASCULAR FUNCTION IN A MOUSE MODEL OF FETAL GROWTH RESTRICTION Lewis Renshall, Elizabeth Cowley, Susan Greenwood, Mark Dilworth, Mark Wareing Maternal and Fetal Research Centre, The University of Manchester,

Time spatial labeling inversion pulse magnetic resonance angiography in pregnancy with adenomyosis

Time spatial labeling inversion pulse (Time-SLIP) is a non-contrast magnetic resonance angiography (MRA) technique. No cases in which this technique was used during pregnancy have been reported. We report herein two cases with adenomyosis of the same size and location that underwent Time-SLIP MRA during pregnancy. In case 1, the blood flow within the adenomyosis was poor, and the uterine blood flow toward the placenta was normal, resulting in no fetal growth restriction (FGR). In case 2, the blood flow within the adenomyosis was quite rich, and placental blood flow seemed decreased, resulting in severe FGR. As well as the Doppler ultrasonography, Time-SLIP MRA was useful for evaluating uterine blood flow during pregnancy. This is the first report of the use of Time-SLIP MRA during pregnancy.

A case report of umbilical ring constriction with application of amnioinfusion.

This is a case report of a pregnant 38-year-old primigravida woman. Due to severe fetal growth restriction and oligohydramnios, she was referred to our tertiary perinatal center at 24weeks' gestation. To rule out chromosomal abnormalities and facilitate ultrasound evaluation of fetal morphology, we performed amniocentesis and subsequent amnioinfusion. Thereafter, a precise ultrasound examination revealed no obvious fetal morphological abnormalities except for a hyper-coiled cord and marginal placenta previa. During expectant management, the amount of amniotic fluid was maintained at 20-26mm for a few days; however, the pregnancy resulted in intrauterine fetal death after 26 weeks+5days of gestation. The stillborn infant weighed 530g (-3.3 SD) and had no obvious external abnormalities apart from umbilical ring constriction. Although a postmortem autopsy was not performed, it is suspected that the fetal growth restriction and the intrauterine fetal death were associated with the hyper-coiled cord and the umbilical ring constriction. It is thought that umbilical ring constriction might therefore be an irreversible fatal condition in cases with a hyper-coiled cord.

Quantifying mRNA coding growth genes in the maternal circulation to detect fetal growth restriction

To examine whether mRNA circulating in maternal blood coding genes regulating fetal growth are differentially expressed in (1) severe preterm fetal growth restriction (FGR) and (2) at 28 weeks' gestation in pregnancies destined to develop FGR at term. mRNA coding growth genes were measured in 2 independent cohorts. The first was women diagnosed with severe preterm FGR (<34 weeks' gestation; n = 20) and gestation matched controls (n = 15), where the mRNA was measured in both maternal blood and placenta. The second cohort was a prospective longitudinal study (n = 52) of women whom had serial ultrasound assessments of fetal growth. mRNA coding growth genes in maternal blood were measured at 28 and 36 weeks in pregnancies with declining growth trajectories (ending up with term FGR; n = 10 among the 52 recruited) and controls who maintained normal growth trajectory (n = 15). In women with severe preterm FGR, there was increased expression of placental growth hormone (6.3-fold), insulin-like growth factors (IGF1, 3.4-fold; IGF2, 5.0-fold), IGF receptors (2.1-fold) and IGF binding proteins (3.0-fold), and reduced expression of ADAM12 (0.5-fold) in maternal blood (and similar trends in placenta) compared with controls (P < .05). Notably, at 28 weeks' gestation there was increased IGF2 (3.9-fold), placental growth hormone (2.7-fold), and IGF BP2 (2.1-fold) expression in maternal blood in women destined to develop FGR at term (P < .05). Measuring mRNA coding growth genes in maternal blood may detect unsuspected severe preterm FGR already present in utero, and predict term FGR when measured at 28 weeks' gestation.

Fetal Growth Restriction (FGR)—Fetal Evaluation and Antepartum Intervention

Fetal growth restriction (FGR) is a pathological condition that refers to a fetus that fails to reach his/her genetically predetermined growth potential. By epigenetic effects, substrate and energy deprivation in utero modify fetal metabolism with possible life-long impacts. Management of FGR still represents one of the main challenges for the obstetricians, both for the complexities of management of severe early FGR and for the diagnostic difficulties in late and term FGR. Late onset and term FGR define an intrauterine trajectory of growth that falls below its potential late in gestation, after 34 and 37 weeks of gestation, respectively. Ultrasound biometry examination is crucial for an accurate diagnosis of FGR. Pregnancies at risk of FGR should be considered for longitudinal ultrasound monitoring beyond the routine ultrasound screening at 20 weeks of gestation. Functional assessment of placental and fetal circulation by Doppler velocimetry and blood flow volume, together with computerized assessment of fetal heart rate variability, are key examinations in early and late FGR to assess severity of the disease and monitor fetal wellbeing. Appropriate timing of delivery in early FGR might change the outcome, and appropriate monitoring in late and term FGR might avoid unnecessary interventions.

Circulating RNA coding genes regulating apoptosis in maternal blood in severe early onset fetal growth restriction and pre-eclampsia

To determine whether the intrinsic apoptosis pathway is differentially expressed in placenta and maternal blood in severe preterm fetal growth restriction (FGR) and pre-eclampsia (PE), and to examine whether circulating RNA in maternal blood may be potential biomarkers. Maternal blood samples and placental biopsies were collected from women with preterm: FGR (n=20), PE without FGR (n=8) and controls (n=20). Real-time PCR examined the expression of genes in the intrinsic apoptosis pathway in FGR and PE, stratified according to the severity of placental insufficiency. Severe preterm FGR, with or without PE, was associated with increased expression of BCL2, BCL-XL, BIM, BAD and Survivin in both the placenta and maternal blood (1.6 to 3.3-fold, P<0.05). In preterm PE, but not FGR, there was increased placental expression of BCL-XL and BCL2 (1.6 to 2.5-fold, P<0.05), but only BCL2 was significantly increased in the maternal blood (1.8-fold, P<0.05). Increased expression of genes of the intrinsic apoptosis pathway reflected the severity of FGR as determined by deteriorations in umbilical artery Doppler velocimetry. In severe early onset FGR there was increased expression of genes regulating intrinsic apoptosis in both the placenta and maternal blood. Circulating RNA regulating placenta apoptosis may be used to develop noninvasive novel biomarkers for FGR.

Umbilical uptakes and transplacental concentration ratios of amino acids in severe fetal growth restriction

This study examines the relationship between placental amino acid (AA) transport and fetal AA demand in an ovine fetal growth restriction (FGR) model in which placental underdevelopment induces fetal hypoxemia and hypoglycemia. Umbilical uptakes of AA, oxygen, glucose, and lactate were measured near term in eight experimental ewes (FGR group) and in eight controls (C group). The FGR group demonstrated significantly reduced umbilical uptakes of oxygen, glucose, lactate, and 11 AAs per kg fetus. The combined uptake of glucose, lactate, and AAs, expressed as nutrient/oxygen quotients, was reduced almost to 1.00 (FGR: 1.05 vs. C: 1.32, P ≤ 0.02). In contrast to a decrease in umbilical glucose concentration, all but one of the AAs that were transported from placenta to fetus demonstrated normal or elevated fetal concentrations, and five of the essential AAs were transported against a significantly higher feto/maternal (F/M) concentration ratio. This ratio peaked at the lowest fetal oxygen levels. We conclude that, in the hypoxic FGR fetus, the reduction in AA uptake is not due to a disproportionally small placental AA transport capacity. It is the consequence of decreased fetal oxidative metabolism and growth rate, which together reduce fetal AA demand.

Placental Specific mRNA in the Maternal Circulation Are Globally Dysregulated in Pregnancies Complicated by Fetal Growth Restriction

Fetal growth restriction (FGR) is a leading cause of perinatal mortality, yet no reliable screening test exists. Placental specific mRNA in the maternal circulation may reflect changes in the placental transcriptome in FGR and could be a novel biomarker for FGR. The aim of the study was to identify placental specific RNA detectable in the maternal circulation and examine whether they are differentially expressed in severe preterm FGR. In silico screening was used to identify placental specific RNAs. Their expression in cases of severe FGR vs controls was examined in both maternal blood and placenta by microarray, RT-PCR, and in situ hybridization. Via in silico analysis, we identified 137 genes very highly expressed in the placenta relative to other tissues. Using microarray, we found that they were detectable in the maternal blood and were globally dysregulated with preterm FGR; 75 genes (55%) had a ≥1.5-fold differential expression compared to controls. Eight genes (ERVWE-1, PSG1, PLAC4, TAC3, PLAC3, CRH, CSH1, and KISS1) were validated by RT-PCR to be significantly increased in both maternal blood and placenta in a larger cohort of severe FGR compared to controls. In situ hybridization confirmed PAPPA2 and ERVWE-1 localized to the syncytiotrophoblast. There is global differential expression of placental specific mRNA in the maternal blood in pregnancies complicated by severe preterm FGR. Placental specific mRNA in maternal blood may represent a new class of biomarkers for preterm FGR.