Placenta - Articles in Press

Maternal muscle mass may influence system A activity in human placenta - Corrected Proof

2010-03-08

Abstract: During pregnancy, nutrient partitioning between the mother and fetus must balance promoting fetal survival and maintaining nutritional status of the mother for her health and future fertility. The nutritional status of the pregnant woman, reflected in her body composition, may affect placental function with consequences for fetal development.We investigated the relationship between maternal body composition and placental system A amino acid transporter activity in 103 term placentas from Southampton Women's Survey pregnancies.Placental system A activity was measured as Na+-dependent uptake of 10 μmol/L 14C-methylaminoisobutyric acid (a system A specific amino acid analogue) in placental villous fragments. Maternal body composition was measured at enrolment pre-pregnancy; in 45 infants neonatal body composition was measured using dual-energy x-ray absorptiometry.Term placental system A activity was lower in women with smaller pre-pregnancy upper arm muscle area (r = 0.27, P = 0.007), but was not related to maternal fat mass. System A activity was lower in mothers who reported undertaking strenuous exercise (24.6 vs 29.7 pmol/mg/15 min in sedentary women, P = 0.03), but was not associated with other maternal lifestyle factors.Lower placental system A activity in women who reported strenuous exercise and had a lower arm muscle area may reflect an adaptation in placental function which protects maternal resources in those with lower nutrient reserves. This alteration may affect fetal development, altering fetal body composition, with long-term consequences.

New technology for investigating trophoblast function - Corrected Proof

R.J. Keogh — 2010-03-08

Abstract: Measuring trophoblast function involves performing end-point assays that represent the response at a single time point. New technology from Roche Applied Science enables continuous monitoring of cells in real-time using specialized culture dishes containing micro-electrodes. The xCELLigence System allows continuous measurement and quantification of cell adhesion, proliferation, migration and invasion, thus creating a true picture of trophoblast function. Lag and log growth phases can be determined thus pinpointing optimal times to treat and harvest cells. Use of this system will provide valuable insights into trophoblast functions as well as the behaviour of other cell types found at the maternal–fetal interface.

AMP-Deaminase from Developing Human Placenta - Corrected Proof

A. Swieca, I. Rybakowska, R. Milczarek, J. Klimek, K. Kaletha — 2010-03-08

Abstract: During pregnancy the activity of AMP-deaminase in developing human placenta gradually decreases, being in homogenates of mature, term placenta (∼40 week of gestation) one fourth to one third of that in homogenates of immature (∼25 week of gestation) organ. The gradual decrease of activity correlates inversely with the increasing presence of the form of enzyme predominating in homogenates of the mature placenta. The discrepancy observed indicate that isozymic pattern of AMP-deaminase in developing human placenta changes.

Analysis of Placental Tissue in Fabry Disease With and Without Enzyme Replacement Therapy - Corrected Proof

2010-03-02

Abstract: There are only a few reports on the histology of placental tissue of pregnancies from mothers with Fabry disease. Fabry disease is a lysosomal disorder caused by α-galactosidase A deficiency. Extensive glycosphingolipid (GSL) accumulation in fetal and maternal placenta tissue obtained from a Fabry mother and her affected male newborn has previously been reported. Here we report the evaluation of placenta tissue of two pregnancies in Fabry mothers, one of an unaffected male newborn (placenta A) and one of an affected female newborn (placenta B). The mother of the female affected offspring was treated with recombinant α-galactosidase A (enzyme replacement therapy, ERT) during the pregnancy (placenta B). Storage material was only detected in smooth muscle cells of the umbilical cord of placenta B. No accumulation was seen in both placentae. Combing these results with the outcome in two earlier described placentae, a heterogeneous picture emerges. This may be due to differences in disease severity in the mothers or severity of disease in their offspring. In addition, a possible effect of ERT on placental GSL accumulation could also explain lack of GSL storage in placenta B.

Comparison of l-serine uptake by human placental microvillous membrane vesicles and placental villous fragments - Corrected Proof

2010-02-25

Abstract: Both syncytiotrophoblast microvillous plasma membrane vesicles (MVM) and placental villous fragments are used to characterize the placental uptake of maternal substrate and to investigate changes in uptake associated with pathological conditions. However, the two techniques have not been directly compared. In this study uptake of 14C-l-serine was compared in placental villous fragments and in MVM prepared from the same placentas.14C-l-serine uptake into MVM vesicles was mediated by System L and System A and smaller unidentified Na+-dependent and Na+-independent components. In villous fragments an unidentified Na+-dependent component mediated the majority of 14C-l-serine uptake followed by System A and System L. The unidentified Na+-independent component of l-serine uptake was not detected in villous fragments.The ratio of System A activity to System L activity was similar in villous fragments and MVM vesicles. However, the unidentified Na+-dependent component in villous fragments was significantly higher than that in MVM vesicles. This indicates that the main differences in serine uptake mechanisms identified using the two techniques were not due to differences in System A and System L activity but to differences in the unidentified Na+-dependent component.This study suggests that uptake of l-serine into MVM vesicles and villous fragments via Systems A and L is comparable, but that this is not true for all components of l-serine uptake.

Maternal obesity up-regulates inflammatory signaling pathways and enhances cytokine expression in the mid-gestation sheep placenta - Corrected Proof

M.J. Zhu, M. Du, P.W. Nathanielsz, S.P. Ford — 2010-02-25

Abstract: Obesity in pregnant women is a growing public health concern. The placenta is a source of cytokines which can induce maternal gestational insulin resistance and alter nutrient transport to the fetus. Obesity induces placental inflammation at term, but the impact of obesity on placental inflammation earlier in pregnancy has not been defined. Using sheep as an experimental model, we hypothesized that maternal obesity (MO) would induce inflammation in the cotyledonary (COT) tissue of the placentome by mid-gestation. Nonpregnant ewes were randomly assigned to a control (C, 100% of NRC recommendations) or obese (OB, 150% of NRC) group from 60 days before conception to 75 day of gestation (dG), when ewes were necropsied and placental COT tissue collected for analyses. Free fatty acids content, triglyceride and cholesterol content were higher (P < 0.05) in the fetal plasma of OB compared to C ewes on day 75. MO increased mRNA levels of toll-like receptor (TLR) 2 (P < 0.05) and TLR4 (P = 0.06), macrophage markers cluster of differentiation (CD)11b (P = 0.06), CD14 and CD68 (P < 0.05), and proinflammatory cytokines tumor necrosis factor (TNF)α (P < 0.01), interleukin (IL)-6 (P < 0.05), IL-8(P < 0.01) and IL-18 (P = 0.06), in COT tissue. Inflammatory c-Jun N-terminal kinase (JNK)/c-Jun and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathways were up-regulated (P < 0.05) in COT of OB ewes. In conclusion, MO enhanced the placental inflammatory response in OB ewes at mid-gestation, possibly as a result of increased TLR4 and free fatty acids.

Human Decidual NK Cells from Gravid Uteri and NK Cells from Cycling Endometrium are Distinct NK Cell Subsets - Corrected Proof

2010-02-22

Abstract: Human NK cells from the decidua basalis of gravid uteri and from the cycling endometrium of women undergoing hysterectomy were isolated and compared by gene expression profiling using Affymetrix microarrays with probes representing ∼47,400 transcripts. Substantial differences indicate that these two types of NK cells represent distinct subsets.

Distinct Patterns of Gene-Specific Methylation in Mammalian Placentas: Implications for Placental Evolution and Function - Corrected Proof

H.K. Ng, B. Novakovic, S. Hiendleder, J.M. Craig, C.T. Roberts, R. Saffery — 2010-02-18

Abstract: The placenta has arisen relatively recently and is among the most rapidly evolving tissues in mammals. Several different placental barrier and structure types appear to have independently evolved common functional features. Specific patterns of gene expression that determine placental development in humans are predicted to be accompanied by specific profiles of epigenetic modification. However, the stratification of epigenetic modifications into those involved in conserved aspects of placental function, versus those involved in divergent placental features, has yet to begin. As a first step towards this goal, we have investigated the methylation status of a small number of gene-specific methylation events recently identified in human placenta, in a panel of placental tissue from baboon, marmoset, cow, cat, guinea pig and mouse. These represent disparate placental barrier types and structures. In this study we hypothesized that specific epigenetic markings may be associated with placental barrier type or function, independent of phylogeny. However, in contrast to our predictions, the majority of gene-specific methylation appears to track with phylogeny, independent of placental barrier type or other structural features. This suggests that despite the likelihood of epigenetic modification playing a role in the functioning and evolution of different placental subtypes, there is no evidence for an involvement of the gene-specific methylation profiles we have identified, in specifying these differences. Further studies, examining larger numbers of epigenetic modifications across phylogeny, are required to define the role of specific epigenetic modifications in the evolution of distinct placental structures.

Expression of thyroid hormone transporters in the human placenta and changes associated with intrauterine growth restriction - Corrected Proof

2010-02-18

Abstract: Thyroid hormones (TH) are important for the development of the human fetus and placenta from very early gestation. The transplacental passage of TH from mother to fetus and the supply of TH into trophoblasts require the expression of placental TH plasma membrane transporters. We describe the ontogeny of the TH transporters MCT8, MCT10, LAT1, LAT2, OATP1A2 and OATP4A1 in a large series (n = 110) of normal human placentae across gestation and describe their expression changes with intrauterine fetal growth restriction (IUGR n = 22). Quantitative RT-PCR revealed that all the mRNAs encoding TH transporters are expressed in human placenta from 6 weeks gestation and throughout pregnancy. MCT8, MCT10, OATP1A2 and LAT1 mRNA expression increased with gestation. OATP4A1 and CD98 (LATs obligatory associated protein) mRNA expression reached a nadir in mid-gestation before increasing towards term. LAT2 mRNA expression did not alter throughout gestation. Immunohistochemistry localised MCT10 and OATP1A2 to villous cytotrophoblasts and syncytiotrophoblasts, and extravillous trophoblasts while OATP4A1 was preferentially expressed in the villous syncytiotrophoblasts. Whilst MCT8 protein expression was increased, MCT10 mRNA expression was decreased in placentae from IUGR pregnancies delivered in the early 3rd trimester compared to age matched appropriately grown for gestational age controls. No significant change was found in the mRNA expression of the other transporters with IUGR. In conclusion, several TH transporters are present in the human placenta from early 1st trimester with varying patterns of expression throughout gestation. Their coordinated effects may regulate both transplacental TH passage and TH supply to trophoblasts, which are critical for the normal development of the fetus and placenta. Increased MCT8 and decreased MCT10 expression within placentae of pregnancies complicated by IUGR may contribute to aberrant development of the fetoplacental unit.

Differential expression of VE-cadherin and VEGFR2 in placental syncytiotrophoblast during preeclampsia – New perspectives to explain the pathophysiology - Corrected Proof

T. Groten, N. Gebhard, R. Kreienberg, E. Schleußner, F. Reister, B. Huppertz — 2010-02-18

Abstract: The pathophysiology of preeclampsia includes an unbalanced syncytiotrophoblast renewal from the underlying cytotrophoblast and increased necrotic/aponecrotic shedding of syncytiotrophoblast particles into the maternal circulation. These non-apoptotic syncytiotrophoblast fragments cause the maternal endothelial dysfunction underlying the syndrome of preeclampsia. In order to understand the pathophysiological changes at the fetomaternal interface in preeclampsia we studied the expression of VE-cadherin and vascular endothelial growth factor receptor-2 (VEGFR2) in preeclampsia. We show that VE-cadherin is expressed in the syncytiotrophoblast and is upregulated in fusing BeWo cells, while inhibition of VE-cadherin expression by siRNA does not block BeWo cell fusion. Our immunohistochemistry data show lower VE-cadherin expression in early onset preeclampsia compared to early controls. In late onset preeclampsia VE-cadherin was significantly more expressed compared to late controls. Concurrently VE-cadherin expression decreased significantly in control pregnancies towards term, but not in pregnancies complicated by preeclampsia. VEGFR2 expression was significantly reduced in all cases of preeclampsia compared to control placentas. Because of their close interaction in barrier function regulation we speculate that sustained expression of VE-cadherin in late onset preeclampsia could counteract VEGFR2 deficiency by enhancing survival pathway stimulation in the syncytiotrophoblast, thus preventing further decompensation of unbalanced villous trophoblast turnover.

Gestational age and dose influence on placental transfer of 63Ni in rats - Corrected Proof

X.-W. Wang, J.-Y. Gu, Z. Li, Y.-F. Song, W.-S. Wu, Y.-P. Hou — 2010-02-18

Abstract: The effects of gestational age and dose of nickel exposure on regulating and influencing placental transfer were investigated. Pregnant rats on gestational day (GD) 12, 15 or 20 were injected intraperitoneally with saline, 64, 320 or 640kBq/kg body weight of 63Ni. Twenty-four hours after administration, samples were harvested from each for measurement of radioactivity by liquid scintillation counting and for autoradiography. In placenta, amniotic fluid and fetal membrane, 63Ni concentrations increased with increasing doses and gestational age. In fetus, 63Ni concentrations reached a maximum on GD 15 and then declined on GD 20 although they maintained a dose-dependency for each GD group. In fetal blood on GD 20, 63Ni concentration increased dose-dependently and was higher than in maternal blood. The autoradiographs demonstrated that 63Ni radioactivity was located within placental basal lamina, fetal bones and most organs. These findings suggest that the nickel uptake, retention and transport in placenta increase dose- and gestation age-dependently, and nickel transfer through placental barrier is primarily from mother into the fetus, but hardly from fetus to mother.

Orphan Receptor Kinase ROR2 is Expressed in the Mouse Uterus - Corrected Proof

2010-02-11

Abstract: Objective: Wingless-type mouse mammary tumor virus integration site family, member 5A (WNT5A), is expressed in mouse decidua and is thought to play an important role in decidualization. We examined expression of the receptor for WNT5A, receptor tyrosine kinase-like orphan receptor 2 (ROR2), in the uteri of cycling and pregnant mice.Study design: Reverse transcription (RT)-PCR and immunohistochemistry were performed.Results: RT-PCR revealed that transcripts for Ror2, Wnt3a, Wnt5a and inhibitor of WNT signaling, Dickkopf homolog 1 (Dkk1), were present in the pregnant uterus. Immunohistochemistry revealed that in the virgin uterus, ROR2 is expressed in stromal cells and on the basal side of uterine gland and endometrial epithelial cells. During pregnancy, both the luminal and basal side of uterine gland epithelial cells expressed ROR2, stromal cell expression of ROR2 became more frequent and ROR2 expressing uterine Natural Killer (NK) cells and cells lining the maternal vascular space emerged. Immunofluorescence imaging and flow cytometry revealed that although uterine NK cells expressed ROR2, NK cells of the spleen were ROR2 negative.Conclusion: The expression of ROR2 by endometrial epithelial cells may suggest WNT signaling has roles in uterine epithelial cell polarity or implantation. Expression of ROR2 by uterine NK cells may suggest WNT signaling regulates uterine NK cell functions such angiogenesis and regulation of trophoblast migration. In summary, our results show that ROR2 expression by maternal uterine cells is influenced by pregnancy.

Changes in endovascular trophoblast invasion and spiral artery remodelling at term in a transgenic preeclamptic rat model - Corrected Proof

2010-02-08

Abstract: As a follow-up to our previous study which revealed a surprisingly deeper endovascular trophoblast (ET) invasion on day 18 in a transgenic preeclamptic (PE) rat model (hAngiotensinogen ♀ × hRenin ♂) compared to non-PE controls, we examined further changes in ET invasion and associated spiral artery (SA) remodelling at term (day 21). PE transgenic rats and non-PE reversely mated (RM) transgenic rats were compared to normal SD rats (C). Sections were stained to visualize trophoblast, fibrinoid, vascular smooth muscle (VSM) and endothelium. SA were evaluated in three depth levels in the mesometrial triangle (MT) using the KS-400 image analysis system. In separate transgenic rats, Doppler ultrasound was performed in uterine arteries, and the resistance indices (RI) were calculated. Although for the whole MT differences in ET invasion were no longer significant between the PE and C, indicating a partial catching up in C rats, there was still significantly more ET in the deepest level in the PE group as compared to the C and RM groups. At the same time the SA walls in PE rats contained significantly more fibrinoid (versus RM and C) and VSM (versus C). In all SA cross-sections, re-endothelialisation was prominent, but significantly different between PE and C group. The Doppler results showed a significantly lower RI in the arcuate uterine artery of the PE group compared to the C group. There was no evidence of elimination of deeply invaded ET at term, previously considered as a possible mechanism for restriction of vascular remodelling in human PE. The differences in vascular remodelling, previously described on day 18 by histology and Doppler data, were maintained on day 21, but there was extensive endothelial repair in the three groups. Atherosis-like lesions were observed in the three groups, most frequently in the RM group, but were never associated with placental infarcts.

Lack of Association between Unexplained Elevated Maternal Serum Alpha Fetoprotein and/or Human Chorionic Gonadotropin and the Occurrence of Placental Thrombotic Lesions - Corrected Proof

R. Salim, M. Okopnik, G. Garmi, Z. Nachum, N. Zafran, E. Shalev — 2010-02-04

Abstract: Objective: To investigate the significance of unexplained elevated maternal serum alpha fetoprotein (MSAFP) and/or human chorionic gonadotropin (HCG) on the occurrence of placental thrombotic changes.Study design: Between January 2007 to April 2009, placentas of all women who delivered and had unexplained elevated MSAFP and/or HCG (above 2 MOM) were sent to histological examination. Women were divided into 2 groups. Group A included women who had uneventful pregnancies and delivered at term. Group B included women with antepartum complications attributed to thrombosis. Women in both groups (A and B) had elevated MSAFP and/or HCG. Group C was a frequency matched group of women who had normal MSAFP and HCG levels with uneventful pregnancies and delivered at term.Main outcome measure: Incidence of placental thrombotic lesions in each group.Results: Of 9695 women who delivered during the study period there were 76 women with elevated MSAFP and or HCG, 48 in group A and 28 in Group B. Group C, included 30 women. The number of placentas in which any thrombotic lesion was identified was 22 (45.8%), 19 (67.9%) and 10 (33%) respectively. Changes differed significantly only between group B and C (p = 0.03). Although the rate of changes in group A was higher than in group C it did not reach statistical significance even when considering only women with two abnormal results (MSAFP and HCG) or when a cutoff of 2.5 MOM or more was set.Conclusion: Placental histopathological changes are associated with pregnancy complications and can only marginally be attributed to unexplained elevated MSAFP and/or HCG.

Aldosterone and Cortisol Acutely Stimulate Na+/H+ Exchanger Activity in the Syncytiotrophoblast of the Human Placenta: Effect of Fetal Sex - Corrected Proof

P.F. Speake, J.D. Glazier, S.L. Greenwood, C.P. Sibley — 2010-02-03

Abstract: Na+/H+ exchanger (NHE) activity regulates intracellular pH (pHi) in the placental syncytiotrophoblast. In other tissues aldosterone and cortisol have been shown to up-regulate NHE activity via an acute, non-genomic effect. Here we tested the hypothesis that these corticosteroids stimulate NHE in the syncytiotrophoblast. Villous fragments from term placentas were loaded with 1 μM BCECF (pH sensitive fluorescent dye) and the syncytiotrophoblast acidified with a pre-pulse of 20 mM NH4Cl. The Na+-dependent recovery of pHi from this acid load was taken as a measure of NHE activity (pH units/sec, mean ± SEM, n = number of placentas). In placental villi from female babies aldosterone significantly increased the rate of recovery of pHi from an acid load (0.0087 ± 0.0005 versus 0.0056 ± 0.0009 pH units/s, n = 8 p < 0.05 Paired Student's t-test) which was inhibited by the mineralocorticoid receptor antagonist, spironolactone (1 μM) but not the glucocorticoid antagonist mifepristone (1 μM). There was no effect on the rate of recovery from an acid load in villi from placenta from male babies. Alone, neither cortisol (1 μM, n = 5) nor carbenoxolone (100 μM, n = 9), an inhibitor of 11-β-hydroxysteroid dehydrogenase-2 (11-β-HSD-2), altered the rate of recovery from an acid load. However, simultaneous application of cortisol with carbenoxolone significantly increased the rate of recovery from an acid load but again only in placentas from female babies (0.0080 ± 0.0017 versus control 0.0037 ± 0.0005, p < 0.05 pH units/s, n = 9 Paired Student's t-test). Stimulation by cortisol in female tissue was inhibited by mifepristone but not spironolactone. In conclusion, syncytiotrophoblast NHE activity is increased acutely by aldosterone and, when 11-β-HSD-2 is blocked, by cortisol. These non-genomic effects are only evident in placentas from female babies and are mediated by classical mineralocorticoid and/or glucocorticoid receptors.

Expression and Transcriptional Regulation of Individual Pregnancy-specific Glycoprotein Genes in Differentiating Trophoblast Cells - Corrected Proof

2010-01-29

Abstract: Human pregnancy-specific glycoproteins (PSGs), encoded by eleven highly conserved genes, are the major placental polypeptides. Low PSG levels in maternal circulation have been associated with complicated pregnancies. However, expression of each PSG gene and their regulation during cytotrophoblast cell differentiation remain poorly explored. Herein, we analyze the expression of five PSG genes and demonstrate that they are almost undetectable in undifferentiated trophoblast, but are all transcribed in differentiated cells. Among them, PSG1, PSG3 and PSG5 genes achieve high mRNA levels while PSG7 and PSG9 are poorly expressed. In addition, total PSG proteins and transcripts markedly increase during trophoblast differentiation, preceding morphological syncytialization and βhCG expression. The 5′ regulatory region contributes to the transcriptional control of PSG gene induction in trophoblast cells undergoing differentiation. This responsive region in PSG3 maps within a 130bp promoter sequence, which overlaps the transcription start site and requires a functional Retinoic Acid Responsive Element (RARE) and a GA-binding protein (GABP) consensus site for basal and differentiation-dependent promoter activity, respectively.Present findings provide novel data for understanding the control of PSG gene expression and demonstrate that their proteins and transcripts represent early markers of trophoblast differentiation.

Altered global gene expressions of human placentae subjected to assisted reproductive technology treatments - Corrected Proof

Y. Zhang, Y. Cui, Z. Zhou, J. Sha, Y. Li, J. Liu — 2010-01-29

Abstract: Background: Researchers are more and more concerning the safety of fetus or offspring derived from assisted reproductive technology (ART) treatment. As the placenta is a critical organ that sustains and protects the fetus, we hypothesize that altered global gene expression of the placenta subjected to ART manipulation may reflect changes associated with ART procedures and subsequently causal related to offspring health.Methods: Three term placenta samples were obtained from patients undergone in vitro fertilization and embryo transfer due to oviductal factors only. Other three control placentae were from those underwent normal pregnancy. A GeneChip Affymetrix HG-U133 Plus 2.0 Array was utilized to analyze the genes. Using qRT-PCR we certified microarray data from 10 dysregulated genes. Five genes were localized precisely in the placenta as per immunohistochemistry.Results: Twenty-six differentially expressed genes were identified in the ART-treated placentae: 17 up-regulated; 9 down-regulated. Eighteen of these were classified into six groups according to critical placental function: immune response; transmembrane transport; metabolism; oxidative stress; cell differentiation; and other functions. Genes involved in immune response, such as ERAP2 and STAT4, and those regulating cell differentiations, such as MUC1, were discerned to be differentially expressed. These gene products were expressed in the placental villus tissues, either in the cytoplasm or in the membrane of syncytiotrophoblastic cells.Conclusion: To our knowledge, this is the first study in comparing differentially expressed genes in placentae from patients undergone ART treatment vs. those underwent normal pregnancy. Abnormal profiles of critical placental functioning genes, such as ERAP2, STAT4 and MUC1, may be valuable biomarkers to understand how the placenta affects fetal development and ART-derived offspring's health problems.

Erythropoietin Ameliorates Damage to the Placenta and Fetal Liver Induced by Exposure to Lipopolysaccharide - Corrected Proof

F. Dijkstra, M. Jozwiak, R. De Matteo, J. Duncan, N. Hale, R. Harding, S. Rees — 2010-01-27

Abstract: Intrauterine infection and inflammation have been causally linked to preterm birth and fetal brain injury. Using an ovine model of endotoxin–induced brain injury we have recently shown that recombinant human erythropoietin (rhEPO) reduces brain injury and protects against damage to myelination in major myelinated axon tracts. Our present objective was to determine whether rhEPO is also protective of the placenta and the fetal liver, organs which could influence fetal well-being. At 107 ± 1 days of gestational age (DGA) chronically catheterized fetal sheep were randomly assigned to receive, on 3 consecutive days, either: 1) an i.v. bolus dose of lipopolysaccharide (LPS; ∼0.9 μg/kg; n = 8); 2) i.v. bolus dose of LPS, followed at 1 h by 5000 IU/kg of rhEPO (LPS + rhEPO, n = 8); 3) rhEPO (n = 3). Seven untreated fetuses served as controls (n = 7). The placenta and fetal liver were examined histologically at 116 ± 1 DGA; a placental injury index was formulated comprising measures of placental area, apoptosis, tissue injury and the size of the intervillous space. In LPS-exposed fetuses this index was greater than in control or rhEPO alone fetuses (p < 0.02). Treatment of LPS-exposed fetuses with rhEPO resulted in a reduction in the index (p < 0.05) and in the extent of liver necrosis. We conclude that rhEPO offers protection to the placenta and fetal liver in the presence of acute inflammation.

Placental markers of twin-to-twin transfusion syndrome in diamniotic–monochorionic twins: A morphometric analysis of deep artery-to-vein anastomoses - Corrected Proof

2010-01-11

Abstract: Twin-to-twin transfusion syndrome (TTTS) is a multifactorial disorder that develops in 9–15% of diamniotic–monochorionic twin gestations. While the pathogenesis of TTTS remains poorly understood, unbalanced deep artery-to-vein (AV) anastomoses have traditionally been implicated in the gradual shift of blood from donor to recipient. The aim of this study was to define the placental markers of twin-to-twin transfusion syndrome, with special emphasis on the deep AV anastomoses. A prospective cohort of 284 consecutive diamniotic/monochorionic twin placentas was examined at Women and Infants Hospital between 2001 and 2008. Following exclusion of monoamniotic, multiple, disrupted and laser-treated placentas, 218 twin placentas (21 TTTS and 197 non-TTTS controls) formed the subject of this study. Placentas were injected with color-coded dyes. Anatomic characteristics and choriovascular anastomotic patterns of TTTS placentas were compared with non-TTTS controls. The TTTS placentas showed significantly higher frequencies of velamentous cord insertion, magistral vascular distribution patterns, uneven placental sharing, absence of AA anastomoses and presence of VV anastomoses. Deep AV anastomoses were identified in ≥95% of TTTS and non-TTTS placentas and were overall more abundant than previously reported. The total and net numbers of AV anastomoses were similar in both groups. However, the net cross-sectional area of AV anastomoses, which also takes into account the caliber of the vessels, was significantly smaller in TTTS placentas. There was no correlation between the direction of the AV imbalance and the twin donor/recipient status. In conclusion, TTTS has distinct placental characteristics, warranting their routine inclusion in the diamniotic–monochorionic placental pathology report. Our findings suggest imbalance of AV anastomoses is not required for the development for TTTS, although their presence, whether balanced or unbalanced, may contribute to the creation or perpetuation of the syndrome. Elucidation of the role of the various placental determinants in diamniotic–monochorionic twin gestations may lead to further refinement of therapeutic strategies.