Altered placental tryptophan metabolic pathway in human fetal growth restriction

IntroductionTryptophan is a substrate for kynurenine pathway metabolism in the placenta. We investigated if kynurenine metabolites change over gestation, if they are different between pregnancies with normal and fetal growth restriction (FGR), and if the oxygen environment modulated kynurenine pathway activity in the human placenta.MethodsTryptophan, kynurenine, and downstream kynurenine metabolites were determined in maternal venous blood, umbilical cord blood, and placental samples obtained in 1st and 3rd trimester pregnancies including FGR, and in the media of placental explants incubated with 20% or 5–8% O₂ for 24, 48 or 72 h.ResultsAll the major kynurenine metabolites were present in cord blood, and in general were higher than in maternal blood. IDO and TDO mRNA and protein expression, responsible for kynurenine production from tryptophan, were significantly lower in placentas from FGR pregnancies compared with control. Explants prepared from 1st and 3rd trimester placentas actively produced all the major kynurenine pathway metabolites which, together with expression of IDO, TDO, KYN-OHase and 3HAO mRNAs, were significantly lower after 24 h exposure to 5–8% O₂ compared to 20% O₂ConclusionsExpression and activity of the kynurenine pathway is present in the placenta from early gestation, and is down-regulated by hypoxia and in FGR pregnancies.     

Placental apoptosis and adhesion molecules expression in the placenta and the maternal placental bed of pregnancies complicated by fetal growth restriction with and without pre-eclampsia.

The aim of the study was to examine the expression of adhesion molecules VCAM-1 and ICAM-3 in placental tissue samples and placental bed (maternal decidual tissue) biopsies of pregnancies complicated by pre-eclampsia (PE) and fetal growth restriction (FGR), and to determine whether PE and FGR are associated with an increase in placental apoptosis. We studied placentas and placental bed samples of 49 third trimester pregnancies complicated by FGR (26 with associated PE, 23 without PE) and 25 normotensive healthy pregnant women. Placental apoptosis was assessed by the TUNEL method. Immunohistochemistry was used to assess expression of the VCAM-1 and ICAM-3. There was no significant difference in the staining intensity of VCAM-1 in placentas (p=0.472) and placental bed biopsies (p=0.754) of women delivering appropriate for gestational age and growth restricted fetuses (with and without associated PE). The amount of lymphocytes staining positively with ICAM-3 was significantly higher in both placental and placental bed biopsies of women delivering growth restricted fetuses compared with control pregnancies (p<0.001). Fetal growth restricted pregnancies with associated PE showed higher staining of ICAM-3 in placental compared with placental bed samples (p=0.049). In fetal growth restricted placentas, apoptotic nuclei were more abundant compared with control placentas (p<0.001). Increased expression of ICAM-3 on lymphocyte surface of both maternal and fetal side, suggests lymphocyte overactivation in PE and FGR. Increased placental apoptosis may play an important role in the pathogenesis or sequelae of PE.     

First-trimester serum analytes, biophysical tests and the association with pathological morphometry in the placenta of pregnancies with preeclampsia and fetal growth restriction

Objective

We test the hypothesis that first-trimester serum analytes, 4-D power Doppler placental vascular indices and uterine artery Doppler (UAD) predicts abnormal placental morphometry in pregnancies with preeclampsia (PE) and fetal growth restriction (FGR).

Study design

Maternal serum analytes (PAPP-A, hCG, ADAM12s, and PP13), bilateral UADs, and placental vascular indices were measured at 11-14 weeks in a nested-case control study within a prospective cohort of women followed from the first-trimester to delivery. Vascularization index (VI), flow index (FI), and vascularization flow index (VFI) were obtained from 4-D power Doppler histograms. Serum analytes were measured using immunofluorometric assays and values converted to multiples of the median (MoM) for gestational age. Morphometric analysis was performed on placentas from pregnancies complicated by PE (n = 13), gestational hypertension (HBP, n = 7) and FGR (defined as fetal weight <10th percentile with abnormal umbilical artery Doppler: n = 7); and 20 uncomplicated pregnancies. Two pregnancies had both FGR and PE. Each placenta was weighed and random samples taken, and fixed in formalin within 1 h of delivery. Hematoxylin & Eosin stained slides were analyzed by design-based stereology to quantify linear dimensions, surface areas and volumes of placental components. Paired t-test and ANOVA with adjustments for multiple comparisons were used.

Results

The surface areas of terminal and intermediate villi as well as the volume of terminal villi were significantly smaller in placentas from pregnancies complicated by FGR and PE. Compared with the control group the mean PAPP-A (MoM) was lower in the pregnancies with abnormal placenta morphometry (1.1 ± 0.5 versus 0.7 ± 0.5, P = 0.03). The morphometric indices were lower in those pregnancies with low PAPP-A and IUGR compared with preeclampsia.

Conclusion

First-trimester PAPP-A levels are associated with abnormal placental morphometry at delivery in pregnancies with PE and IUGR. These findings may explain the association between adverse pregnancy outcomes and first-trimester PAPP-A.     

Macroscopic and histological characteristics of retained placenta: A prospectively collected case-control study

IntroductionRetained placenta is a potentially fatal obstetric disorder due to postpartum hemorrhage, its pathophysiology is however unknown. We aimed to assess if retained placenta was associated with increased macroscopic and histological signs of placental maternal underperfusion, a pattern otherwise seen in preeclampsia and other disorders of defective placentation.MethodsThis was a case-control study of retained (n = 49) and non-retained (n = 47) placentas, collected from full-term singleton and otherwise healthy pregnancies, carried out at a tertiary level obstetric department. Macroscopic and histological analysis was performed. Signs of maternal placental underperfusion and signs of placental inflammation, fetal vascular thrombo-occlusive disease and increased placental attachment were recorded in a primary and secondary analysis respectively. Variables were compared groupwise using unconditional logistic regression or comparison of median or mean values.ResultsCompared to non-retained placentas retained placentas had a significantly smaller surface area (p = 0.05), were more oblong in shape (OR 5.24 95% CI:1.34–20.21) and showed overall more signs of maternal underperfusion (OR 2.52 95% CI: 1.07–5.87). There was no significant difference in signs of placental inflammation, fetal vascular thrombo-occlusive disease or placenta accreta but basal plate myometrial fibers were more common among retained placentas.ConclusionIn regard to shape, surface area and histological signs of maternal placental underperfusion, retained placentas showed a histological pattern similar to that seen in preeclamptic placentas.     

Fetoplacental vascular alterations associated with fetal growth restriction

Introduction

Placental functional impairment in pregnancies with fetal growth restriction (FGR) can arise from fetoplacental vascular abnormalities. We aimed to compare the micro and macrovasculature of placentas from normal pregnancies with those showing late onset FGR.

Methods

Placental arterial casts (n = 12 normal, 6 FGR) were prepared. Chorionic arterial number and inter-branch length were examined. Microvascular features were quantified in CD34-stained tissue sections obtained by systematic (n = 12 normal, 12 FGR) and targeted (n = 6 normal, 6 FGR) sampling from the placental periphery and centre.

Results

Adjusted for the weight of the placenta or the surface area of the chorionic plate, the number of chorionic arteries was similar in normal and FGR arterial casts. Inter-branch length per unit placental weight was greater in the first generation of arterial branches in FGR (p < 0.05). Villi in FGR placentas were more poorly vascularised, particularly at the periphery and in grossly visible hypovascular regions. Intermediate and terminal FGR villi in these areas exhibited reduced vessel lumens, loss of CD34, and infilling with CD34-negative cells of what appeared to be previously existing vascular spaces.

Conclusion

Differences in chorionic arterial branching patterns between normal and FGR placentas arise from differences in placental size. FGR placentas show microvascular regression and extreme hypovascularity in peripheral areas. These features may well limit the ability of the placenta to meet fetal nutrient requirements late in gestation. Targeted sampling is more effective than systematic random sampling in revealing vascular defects.     

The Expression of Connective Tissue Growth Factor in Pregnancies Complicated by Severe Preeclampsia or Fetal Growth Restriction

We tested the hypothesis that the expression of placental connective tissue growth factor (CTGF) is enhanced in pregnancies complicated by severe preeclampsia (PE) or fetal growth restriction (FGR). CTGF expression was analyzed using immunostaining, western blot and real-time quantitative PCR in placental samples obtained after third trimester cesarean deliveries without labor from women with severe PE (n = 11), idiopathic FGR (n = 14), or healthy controls (n = 14). Serum CTGF concentrations were analyzed using ELISA. We found that CTGF was stably expressed in villous trophoblasts throughout pregnancy. The expression of CTGF mRNA in placentas from severe PE or FGR was higher than placentas from controls. Whereas the levels of placental CTGF protein were similar between normal and severe PE, maternal and fetal serum CTGF levels were elevated in severe PE. Maternal CTGF levels were also distinctively elevated in women with PE or FGR with histological evidence of placental injury. The enhancement of CTGF expression as well as serum CTGF levels in clinical conditions attributed to placental dysfunction suggests a role for this secretary protein in the pathophysiology of placental injury or its sequelae.     

Expression of Enzymes Regulating Placental Ammonia Homeostasis in Human Fetal Growth Restricted Pregnancies

Functional placental insufficiency results in impaired feto-placental exchange, and subsequently in fetal growth restriction (FGR). We hypothesized that reductions in placental amino acid transporter activities in FGR pregnancies may be accompanied by abnormal expression of placental ammonia-handling enzymes. Term placentas were obtained from growth restricted (N = 11) and normal (N = 17) human pregnancies, and examined for glutamate dehydrogenase (GDH), glutamine synthetase (GS) and glutaminase (GA) mRNA and protein expression. Northern and Western blots were normalized on human actin mRNA and protein expression. For GA, the presence of mRNA coding the kidney isoform, and the absence of mRNA coding the liver isoform of the enzyme were demonstrated in the human placenta. In FGR pregnancies, placental expression of GDH mRNA was reduced (P < 0.05) compared to normal pregnancies (1.576 ± 0.144 vs. 2.092 ± 0.177, respectively; mean ± SE), whereas GS and GA mRNA expression was not different between the two types of pregnancy. GDH protein expression were also reduced (P < 0.05) in FGR placentas compared to normal placentas (1.055 ± 0.079 vs. 1.322 ± 0.053, respectively; mean ± SE). The GS and GA protein expression was not different in FGR pregnancies. Our data indicate that in cases of FGR, glutamate-to-oxoglutarate transformation in the placenta is limited, yet glutamine synthesis from and decomposition to glutamate seems to be preserved. This may reflect down-regulation of GDH in response to decreased fetal liver output and reduced umbilical artery glutamate concentrations in human FGR pregnancies.     

Isolation of basal membrane proteins from BeWo cells and their expression in placentas from fetal growth-restricted pregnancies

IntroductionThe syncytiotrophoblast, a key barrier between the mother and fetus, is a polarized epithelium composed of a microvillus and basal membrane (BM). We sought to characterize BM proteins of BeWo cells in relation to hypoxia and to investigate their expression in placentas from pregnancies complicated by fetal growth restriction (FGR).MethodsWe isolated the BM fraction of BeWo cells by the cationic colloidal silica method and identified proteins enriched in this fraction by mass spectrometry. We evaluated the effect of hypoxia on the expression and intracellular localization of identified proteins and compared their expression in BM fractions of FGR placentas to those from normal pregnancies.ResultsWe identified BM proteins from BeWo cells. Among BM proteins, we further characterized heme oxygenase-1 (HO-1), voltage-dependent anion channel-1 (VDAC1), and ribophorin II (RPN2), based on their relevance to placental biology. Hypoxia enhanced the localization of these proteins to the BM of BeWo cells. HO-1, VDAC1, and RPN2 were selectively expressed in the human placental BM fraction. C-terminally truncated HO-1 was identified in placental BM fractions, and its BM expression was significantly reduced in FGR placentas than in normal placentas. Interestingly, a truncated HO-1 construct was predominantly localized in the BM in response to hypoxia and co-localized with VDAC1 in BeWo cells.DiscussionHypoxia increased the BM localization of HO-1, VDAC1, and RPN2 proteins. FGR significantly reduced the expression of truncated HO-1, which was surmised to co-localize with VDAC1 in hypoxic BeWo cells.     

Placental dimethyl acetal fatty acid derivatives are elevated in preeclampsia

Preeclampsia (PE) was shown to affect the placental content and the transfer of polyunsaturated fatty acids (PUFA) to the fetus. Plasmalogens, a type of phospholipids with a vinyl-ether link at the sn-1 position, play an antioxidant role and are specifically enriched in PUFA at the sn-2 position. In this study, we characterized plasmalogen-derived dimethyl acetal (DMA) fatty acid derivatives, 16:0 DMA, 18:0 DMA, 9c-/11c-18:1 DMA and PUFA in the placenta of normotensive (n = 20) and PE (n = 20) pregnancies, according to the sampling site: peri-insertion or periphery. Phospholipid fatty acids from the placenta and maternal erythrocytes were identified by gas chromatography mass spectrometry and quantified by flame ionization detection. We found elevated total DMA in the PE placenta by 18% when compared to normotensive controls (p = 0.026). Moreover, the 16:0 DMA account for more than 55% of DMA fatty acids measured in the placenta, and its level is significantly higher in PE than controls (p = 0.018). Also, we found elevated placental PUFA, 20:5(n-3), 22:5(n-3) and a low level of 20:4(n-3) in PE compared to controls. Placental DMA was highly correlated with n-6 and n-3 PUFA in both, normotensive and PE pregnancies. In sum, elevated DMA fatty acids in the PE placenta could be an indirect defensive mechanism against oxidative stress and poor placental fatty acid transfer in PE.     

Placental Vascular Sonobiopsy Using Three-dimensional Power Doppler Ultrasound in Normal and Growth Restricted Fetuses

ObjectiveTo investigate placental vascular sonobiopsy using three-dimensional (3D) power Doppler ultrasound to assess placental vascularization in normal and growth restricted fetuses.MethodsPlacental vascular sonobiopsy using 3D power Doppler ultrasound with the VOCAL imaging analysis program was performed on 208 normal fetuses between 12 and 40 weeks of gestation and 13 pregnancies with fetal growth restriction (FGR) at 22–39 weeks' gestation. Only pregnancies with an entirely visualized anterior placenta were included in the study. 3D power Doppler indices related to placental vascularization (vascularization index (VI), flow index (FI) and vascularization flow index (VFI)) were calculated in each placenta. Intra- and inter-class correlation coefficients and intra- and inter-observer agreements of measurements were assessed.ResultsA weak linear relationship was found between the gestational age and VI, FI, and VFI, respectively. VI values in 8 of 13 FGR pregnancies (61.5%), FI value in one FGR pregnancy (7.7%) and VFI values of 6 FGR pregnancies (46.2%) were below ?1.5SD of the reference ranges for VI, FI and VFI, respectively. After 32 weeks of gestation, VI, FI, and VFI values in 10 FGR pregnancies were significantly lower compared to 79 normal pregnancies, respectively (P < 0.01). All 3D power Doppler indices (VI, FI and VFI) showed a correlation greater than 0.85, with good intra- and inter-observer agreements.ConclusionOur findings suggest that placental vascular sonobiopsy using 3D power Doppler ultrasound may provide new information on the assessment of placental vascularization in normal and FGR pregnancies, while placental perfusion is reduced in FGR compared to normal pregnancy. However, the data and its interpretation in our study should be taken with some degree of caution because of the small number of FGR subjects studied. Further studies involving a larger sample size of FGR pregnancies are needed to confirm the usefulness of placental vascular sonobiopsy using 3D power Doppler ultrasound in clinical practice.     

Placental function assessed visually using half-Fourier acquisition single-shot turbo spin-echo (HASTE) magnetic resonance imaging

IntroductionTo investigate a simple visual assessment method of placental function using half-Fourier acquisition single-shot turbo spin-echo (HASTE) magnetic resonance imaging (MRI).MethodsThe institutional review board approved this retrospective study of fetal MRI in 48 singleton pregnant women for whom placentas had undergone clinical pathological examinations. Two readers independently assessed the placentas using the HASTE scoring system, particularly emphasizing the visualization of the regular two-tone pattern inside and signal intensity (SI) of placental parenchyma referring to SI of the fetal kidney and liver. After categorization using the HASTE scoring system, the associations between the scores and the presence of pathologically proven placental insufficiency or of low birth weight less than the tenth percentile were examined using chi-square tests. The associations between the HASTE scores and the MRI findings previously reported to suggest placental insufficiency, such as placental thickness and placenta to amniotic fluid SI ratio, were also examined using Student t-tests.ResultsThe HASTE scores were associated significantly with the presence of pathologically proven placental insufficiency (P = .003 for reader 1; P = .04 reader 2) and birth weight less than the tenth percentile (P = .005 for reader 1; P = .003 for reader 2). The HASTE scores were associated significantly with the placenta thickness (P < .0001 for both readers) and the placenta to the amniotic fluid SI ratio (P < .0001 for both readers).DiscussionThe HASTE scoring system is feasible for use in clinical assessment of placental function and for diagnosing placental insufficiency.     

Protective proteins and telomere length in placentas from patients with pre-eclampsia in the last trimester of gestation

IntroductionVisfatin/nicotinamide phosphoribosyltransferase (Nampt), an enzyme involved in energy metabolism and sirtuins, SIRT1 and SIRT3, which are NAD-dependent deacetylases, are critical for cellular function. All three either regulate or are regulated by intracellular NAD+ levels and therefore available cellular energy, important for placental cell survival and successful pregnancy. This study investigates whether these protective proteins are involved in the placental pathophysiology of pre-eclampsia (PE) and if they are associated with 8-oxo-deoxyguanosine (8OHdG), a marker of oxidative damage or with placental telomere length.MethodsMaternal blood and placental samples were collected from 31 patients with PE and 30 controls between 31 and 40 weeks gestation. Quantitative immunohistochemistry was performed on placental specimens for visfatin/Nampt, SIRT1, SIRT3, and nuclear 8OHdG. Plasma visfatin was measured by ELISA and telomere length by Southern blot analysis of telomere restriction fragments.ResultsVisfatin/Nampt and SIRT1 in syncytiotrophoblast decreased in PE compared to controls (p < 0.0001, p = 0.004 respectively). SIRT3 decreased in PE most significantly at preterm (p = 0.002). 8OHdG was only significantly lower in preterm controls compared to term controls (p = 0.01) and correlated with SIRT1 in all samples (r = 0.27). Telomere length was not different in PE and controls.DiscussionDecreased visfatin/Nampt, SIRT1 and SIRT3 in syncytiotrophoblast in PE suggests a lack of placental reserve in metabolic energy efficiency, increased inflammation, and lower resistance to environmental stressors. However, there was little effect on nuclear function, or evidence of genomic DNA damage, which would lead to cellular senescence and death.     

Association of chorangiomas to hypoxia-related placental changes in singleton and multiple pregnancy placentas

IntroductionChorangiomas (CAs) are the most frequent non-trophoblastic tumor-like-lesions of the placenta, and since they occur with an unusual frequency in pregnancies at high altitude, they are considered as a part of a spectrum of hypoxia-related vascular lesions of the placenta. The aim of our study is to describe the morphological features of the CAs and to show associations between CAs and other hypoxia related morphological changes in placentas of singleton and multiple pregnancies.Materials and methodsPlacentas from singleton (121 vs 242) and multiple (49 vs 98) pregnancies, with and without CAs, respectively, were selected from a cohort of 15,742 placentas and enrolled into a case control study.ResultsSingleton placentas with CAs showed increased incidence of hypoxia-related placental changes including accelerated maturation of chorionic villi (OR = 2.40, p < 0.001), infarction (OR = 2.89, p < 0.001), decidual arteriopathy (OR = 3.24, p < 0.001), fetal thrombosis (OR = 4.05, p < 0.001) and hypercoiled umbilical cords (OR = 5.55, p < 0.001). The incidence of CAs in multiple placentas was higher in our studied cohort and a significant associated change was shown with fetal thrombosis (OR = 4.58, p = 0.017). There were no significant morphological changes between CAs in singleton compared to multiple pregnancies.DiscussionIn singleton placentas, CA is associated with several placental changes related to hypoxia, whereas in multiple pregnancies this relationship is not present. We speculate that CAs in multiple pregnancies might reflect an adaptive mechanism for relative hypoxia per se in these pregnancies.ConclusionOur study provides evidence that CAs are associated with an increased rate of hypoxia related changes in singleton placentas.     

Placental pathologies associated with intra-uterine fetal growth restriction complicated with and without oligohydramnios

Purpose  To compare the placental pathologies and perinatal outcomes in fetal growth restriction (FGR) pregnancies with and without oligohydramnios. Methods  A retrospective cohort study, comparing placental findings in all singleton deliveries with FGR. Results  Macroscopic placental findings were available for 1,104 singleton FGR pregnancies. A total of 397 placentas were microscopically examined; of which 89 placentas were of FGR neonates who had oligohydramnios. No significant differences in placental vascular mal-perfusion were found between pregnancies with and without oligohydramnios (69.3 vs. 74.3%; P = 0.357). Likewise, no significant differences were noted between the groups regarding diffuse villous fibrosis (10.1 vs. 4.9%; P = 0.573), and amnion cell metaplasia (65.9 vs. 64.3%; P = 0.779). Cases of FGR complicated with oligohydramnios had significantly higher rates of perinatal mortality (9.9 vs. 5.9%; P = 0.028), preterm deliveries (34.9 ± 3.4 vs. 35.4 ± 3.1 weeks of pregnancy; P = 0.041), and lower birth weight (1,737 ± 542 vs. 1,845 ± 467 g; P = 0.002) compared to FGR without oligohydramnios. Conclusions  Oligohydramnios is a significant risk factor for adverse perinatal outcome in FGR pregnancies; nevertheless, no significant differences in placental pathologies were noted. Presented in part at the 29th Annual Meeting of the Society of Maternal Fetal Medicine (SMFM), San Diego, CA, USA, 26–31 January 2009.     

Pattern of adhesive molecules expression in placenta of non-complicated ART pregnancies

ObjectiveTo investigate changes occurring in the morphometric parameters of chorionic villi and their vessels as well as in adhesive molecules expression in placenta of ART pregnancies.MethodsCase-control study including a total of 52 placentas of non-complicated pregnancies of women delivered by spontaneous conception (SC) (n = 26) compared with those of ART (n = 26). Histological and morphometric assessment of fetal chorionic villi as well as the expression of various adhesive molecules (ICAM-1, VCAM-1 and PECAM-1) were performed in fetal plasma and placenta.ResultsAlthough we did not observe any obvious changes in the histological structure of placenta of ART pregnancies, it showed a significant (p < 0.05) decrease in the syncytiotrophoblast cytoplasmic area accompanied with a significant increase (p < 0.05) in the vessel area and syncytiotrophoblast nuclear area without remarkable change in the total villous area or total syncytiotrophoblast % area. In addition, almost all levels of the assayed adhesive molecules were significantly increased (p < 0.05) in placenta as well as in fetal plasma of ART pregnancies compared with SC.ConclusionWe suggested in the current study that the altered adhesive molecules expression accompanying the increased vessel area and decreased syncytial cytoplasm area may indicate a subclinical endothelial stress in placenta of non-complicated ART pregnancies.     

Comparison of placental findings in type 1 and type 2 diabetic pregnancies

IntroductionThe aim of this study is to compare placental pathology and related clinical parameters between gravidas with type 1 and type 2 pregestational diabetes.MethodsThis is a retrospective cohort study of women with singleton gestations and pregestational diabetes who delivered at Women and Infants Hospital from 2003 to 2011. Pathology reports, maternal and neonatal outcomes were extracted and compared between the two groups.ResultsIn our cohort, 293 pregnancies were studied, including 117 with type 1 diabetes and 176 with type 2 diabetes. Women with type 1 diabetes had worse glycemic control during pregnancy, as characterized by higher HbA1c values and average fasting and postprandial blood sugars. More infants from the type 1 group were admitted to Neonatal ICU. Pregestational diabetes led to small for gestational age (SGA) placentas in nearly 20% pregnancies and large for gestational age (LGA) placentas in 30% of cases. Both groups shared similar incidences of preeclampsia and significant placental pathology related to uteroplacental (maternal) and fetal circulatory disorders; however, maternal decidual vasculopathy and placentas with insufficiency (fetal-to-placental weight ratio < 10th %tile) were more commonly found in placentas from women with type 2 diabetes.DiscussionBoth types of pregestational diabetes have significant impact on placental growth and development. The comparison between the two groups suggests different pathogenetic mechanisms and may be helpful for better management of diabetic pregnancy.     

Association of first-trimester angiogenic factors with placental histological findings in late-onset preeclampsia

ObjectiveTo explore in women with late-onset preeclampsia (PE) the association between maternal levels of angiogenic/antiangiogenic factors in the first trimester of pregnancy and histological findings attributable to placental underperfusion (PUP).MethodsA nested case-control cohort study was conducted in 73 women with pregnancies complicated by late-onset PE (>34 weeks at delivery) matched with controls. First trimester uterine artery Doppler (UtA); maternal levels of placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) were retrieved. Placentas were histologically evaluated using a hierarchical and standardized classification system. One-way ANOVA with linear polynomial contrast or linear-by-linear association test was performed to test the hypothesis of a linear association across study groups (controls, PE without PUP and PE with PUP).ResultsIn 54 (74%) placentas, 89 placental histological findings qualifying for PUP were found. Across study groups, significant values were observed in maternal levels of decreased PlGF (MoM values: 1.53, 1.41 and 1.37; p < 0.001), increased sFlt-1 (MoM values: 3.11, 3.11 and 3.22; p = 0.002), increased sFlt-1/PlGF ratio (MoM values: 2.3, 2.3 and 2.44; p < 0.001), abnormal UtA Doppler (MoM values: 1, 1.26 and 1.32; p < 0.001), and worse perinatal outcomes in terms of gestational age at delivery, cesarean section for not reassuring fetal status, birth weight and neonatal acidosis.DiscussionIn late-onset PE an imbalance of circulating angiogenic and anti-angiogenic factors already present at 8–10 weeks of pregnancy was associated with histological findings reflecting placental insufficiency. An early first trimester screening by angiogenic factors might help to identify patients with placental involvement among late-onset PE cases.ConclusionIn late-onset preeclampsia, first-trimester uterine Doppler and circulating levels of angiogenic/antiangiogenic factors are associated with placental underperfusion.     

Magnetic resonance imaging relaxation time measurements of the placenta at 1.5 T

Placental insufficiency is a major cause of fetal growth restriction (FGR) and accumulating evidence indicates several aspects of placental morphology are altered in this condition. MRI provides quantitative indices that may be used in non-invasive assessment of the human placenta, such as relaxation time measurements, T1 and T2. We hypothesised that placental relaxation times relate to alterations in placental tissue morphology and hence may be useful in identifying the changes associated with FGR. We report on the first phase of testing this hypothesis, in a study of women in normal pregnancy.

Aims

To assess relaxation time measurements in the placenta in normal pregnancy and correlate these with gestational age and stereological analyses of placental morphology following delivery.

Methods

30 women underwent MRI examination (1.5 T) between 20 and 41 weeks gestation. Placental T1 and T2 measurements were acquired from a mid-depth placental region, co-localised to a structural scan. Fixed, wax-embedded sections of these placentas collected at delivery were stained with hematoxylin/eosin and subjected to stereological analysis.

Results

Placental T1 and T2 show a significant negative correlation with gestation, (Pearson correlation p = 0.01, 0.03 respectively). 17 placentas were analysed stereologically. In the group as a whole there was no significant correlation between T1 and T2 and morphological features. However, in a subset of 7 pregnancies scanned within a week of delivery, a significant positive correlation was observed between the fibrin volume density and the ratio of fibrin: villous volume densities and T2 (Spearman correlation p = 0.02, 0.03 respectively).

Discussion

The correlations between placental T1 and T2 and gestation show that these variables are clearly influenced by changes in placental structure. Fibrin might be a key component but further work is needed to fully elucidate the major structural influences on placental T1 and T2.