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Introduction
Salwan Al-Nasiry currently works at the Department of Obstetrics and Gynecology, Maastricht University. Salwan does research in Obstetrics and Gynaecology. Their most recent publication is 'The choice for invasive prenatal tests after subfertility'.
Current institution
Maastricht University | UM
Department of Obstetrics and Gynecology
Current position
Gynecologist. Assistant Professor
Skills and Expertise
Research Experience
Aug 2011
Position
Gynecologist
Aug 2011
Position
gynaecologist
Jan 2011 - May 2019
Position
Gynecologist. Assistant Professor
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Maastricht University
Maastricht University
Hospital Clínic de Barcelona
Maastricht University
Universidad Tecnológica de Pereira
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The University of Queensland
Universitätsklinikum Schleswig - Holstein
Maastricht Universitair Medisch Centrum
Maastricht University
Maastricht University
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Projects
Projects (3)
In vitro models for trophoblast function
Understanding FGR: the role of reduced fetal growth velocities and placental biomarkers
Ex-vivo modelling of Preeclampsia
Research
Research Items (86)
Fetal growth restriction, i.e. the restriction of genetically predetermined growth potential due to placental dysfunction, is a major cause of neonatal morbidity and mortality. The consequences of inadequate fetal growth can be life-long, but the risks can be reduced substantially if the condition is identified prenatally. Currently, screening strategies are based on ultrasound detection of a small-for-gestational age fetus and do not take into account the underlying vascular pathology in the placenta. Measurement of maternal circulating angiogenic biomarkers placental growth factor, sFlt-1 (soluble FMS-like tyrosine kinase-1) are increasingly used in studies on fetal growth restriction as they reflect the pathophysiological process in the placenta. However, interpretation of the role of angiogenic biomarkers in prediction of fetal growth restriction is hampered by the varying design, population, timing, assay technique and cut-off values used in these studies.
Objective: To evaluate longitudinal changes of angiogenic biomarkers in early- (EO-PD) versus late-onset (LO-PD) placental dysfunction. Methods: Serum PlGF and sFlt-1 measured at different intervals in EO-PD (n= 43), LO-PD (n= 31) and controls (n = 133). Results: sFlt-1/PlGF ratio was higher at 16 weeks (30.6 vs 17.5), 20 weeks (29.3 vs 8.9) and 30 weeks (16.6 vs 6.7) in EO-PD vs controls (all p< 0.05), but not in LO-PD. Longitudinal changes for all intervals had higher AUC than single measurements. Conclusion: Longitudinal biomarker change between 12 and 30 weeks could improve prediction of EO-PD compared to single measurements.
Introduction: To study the association between placental pathology and neonatal birthweight and outcomes, and whether a combination of first trimester biomarkers and fetal growth velocity can predict placental lesions. Methods: The presence of maternal vascular malperfusion (MVM) lesions (Amsterdam criteria) was recorded in a retrospective cohort of singleton pregnancies in the Maastricht University Medical Centre, 2011-2018. First trimester maternal characteristics and PAPP-A, PlGF and sFlt-1 levels were collected. Fetal growth velocities were calculated (mm/week) from 20 to 32 weeks for abdominal circumference, biparietal diameter, head circumference and femur length. Data were compared between neonates with 'small for gestational age' (SGA < p10) and different categories of 'appropriate for gestational age (AGA)': AGAp10-30, AGAp30-50 and AGA > p50 (reference), using one-way ANOVA and post hoc test. Results: There were significantly more MVM lesions in the SGA group (94.6% p < .0001), but also in the AGAp10-30 (67.3% p < .0001) and AGAp30-50 (41.6% p = 0.002), compared to the reference AGA group (19.3%). The prediction of MVM for a 20% false-positive rate, with maternal characteristics was25.2%. The addition of birthweight percentile gave a prediction of 51.7% for MVM. However adding placental biomarkers and fetal growth velocities (instead of birthweight percentile) to the maternal characteristics, gave a prediction of 81.8% (PPV 49.5%, NPV 53.7%). Discussion: Placental MVM lesions correlated inversely with birthweight even in AGA neonates, and was associated with slower fetal growth and more adverse outcome in SGA neonates. A combination of first trimester biomarkers and fetal growth velocity had good prediction of placental MVM lesions, as an indicator of fetal growth restriction irrespective of neonatal weight.
Background/aims: Placental syndromes (PS) refer to pregnancy complications that include gestational hypertension, (pre)eclampsia, HELLP syndrome, and/or placental insufficiency-induced fetal growth restriction. These disorders are characterized by increased oxidative stress. This study aims to test the hypothesis that the abnormal hemodynamic adaptation to pregnancy, typical for early PS pregnancy, is accompanied by abnormal maternal levels of antioxidants relative to those in normal pregnancy. Methods: Before, and at 12, 16, and 20 weeks pregnancy, we measured trolox equivalent antioxidant capacity (TEAC), uric acid (UA), and TEACC (TEAC corrected for UA) in maternal serum of former PS patients, who either developed recurrent PS (rPS; n = 16) or had a normal next pregnancy (non-rPS; n = 23). Concomitantly, we also measured various hemodynamic variables. Results: rPS differed from non-rPS by higher TEACC levels before pregnancy (178 vs. 152 µM; p = 0.02) and at 20 weeks pregnancy (180 vs. 160 µM; p = 0.04). Only non-rPS responded to pregnancy by significant rises in hemodynamic measures. Conclusion: These data indicate that rPS pregnancies are preceded by an increase in antioxidant capacity, presumably induced by subclinical vascular injury and low-grade chronic inflammation.
Pathogenic variants in the X‐linked gene ZC4H2, which encodes a zinc‐finger protein, cause an infrequently described syndromic form of arthrogryposis multiplex congenita (AMC) with central and peripheral nervous system involvement. We present genetic and detailed phenotypic information on 23 newly identified families and simplex cases that include 19 affected females from 18 families and 14 affected males from 9 families. Of note, the 15 females with deleterious de novo ZC4H2 variants presented with phenotypes ranging from mild to severe, and their clinical features overlapped with those seen in affected males. By contrast, of the 9 carrier females with inherited ZC4H2 missense variants that were deleterious in affected male relatives, 4 were symptomatic. We also compared clinical phenotypes with previously published cases of both sexes and provide an overview on 48 males and 57 females from 42 families. The spectrum of ZC4H2 defects comprises novel and recurrent mostly inherited missense variants in affected males, and de novo splicing, frameshift, nonsense and partial ZC4H2 deletions in affected females. Pathogenicity of two newly identified missense variants was further supported by studies in zebrafish. We propose ZC4H2 as a good candidate for early genetic testing of males and females with a clinical suspicion of fetal hypo‐/akinesia and/or (neurogenic) AMC. This article is protected by copyright. All rights reserved.
Background and objectives: The aim of this study was to evaluate the value of adding fetal growth velocity and first trimester maternal biomarkers to baseline screening, for the prediction of small-for-gestational age (SGA) and adverse neonatal outcomes. Method: A retrospective cohort study was conducted of singleton pregnancies in the Maastricht University Medical Centre between 2012 and 2016. The biomarkers PAPP-A, β-hCG, PlGF, and sFlt-1 were measured at 11-13 weeks of gestational age (GA) and two fetal growth scans were performed (18-22 and 30-34 weeks of GA). Differences in biomarkers and growth velocities were compared between appropriate-for-gestational age (AGA; birth weight percentile 10-90) and SGA (birth weight percentile <10). Combinations of the biomarkers and fetal growth velocity were added to baseline screening for the prediction of SGA and adverse neonatal outcome. Results: We included 296 singleton pregnancies. Compared to AGA (n = 251), SGA neonates (n = 45) had significantly lower growth velocities in the abdominal circumference (mm/week): 10.1 ± 0.98 versus 10.8 ± 0.98, p = 0.001. Compared with AGA, the SGA neonates had higher sFlt-1 multiples of the median (MoM): 0.89 (0.55) versus 0.76 (0.44), p = 0.023, and a higher sFlt-1/PlGF MoM ratio: 1.09 (1.03) versus 0.90 (0.64), p = 0.027. For a 15% false-positive rate, the prediction of SGA neonates increased from 44.8% for the baseline screening model to 56.5% after the addition of fetal growth velocities, and to 73.9% after the further addition of maternal biomarkers (PPV 9.6%, NPV 82.4%). The corresponding AUC for the three models were 0.722, 0.804, and 0.839, respectively. In addition, AGA neonates with reduced fetal growth velocity had more adverse neonatal outcomes compared to the AGA reference group (12.4 vs. 3.9%, p = 0.013). Conclusions: Combining fetal growth velocity with first trimester biomarkers resulted in a better prediction of SGA compared to baseline screening parameters alone. This approach could possibly result in reduced adverse neonatal outcomes in neonates, who are at a potential risk due to late mild placental dysfunction.
Abstract Background Fetal growth restriction is, despite advances in neonatal care and uptake of antenatal ultrasound scanning, still a major cause of perinatal morbidity. Neonates with birth weight > 10th percentile are assumed to be appropriate-for-gestational-age (AGA), although many are at increased risk of perinatal morbidity, because of undetected mild restriction of growth potential. We hypothesized that within AGA neonates, reduced fetal growth velocities are associated with adverse neonatal outcome. Methods A retrospective cohort study of singleton pregnancies, in the Maastricht University Medical Centre (MUMC) between 2010 and 2016. Women had two fetal biometry scans (18–22 weeks and 30–34 weeks of gestational age) and delivered a newborn with a birth weight between the 10th–80th percentile. Differences in growth velocities of the abdominal circumference (AC), biparietal diameter (BPD), head circumference (HC) and femur length (FL) were compared between the suboptimal AGA (sAGA) (birth weight centiles 10–50) and optimal AGA (oAGA) (birth weight centiles 50–80) group. We assessed the association between velocities and neonatal outcomes. Results We included 934 singleton pregnancies. In the suboptimal AGA group, fetal growth velocities were lower (in mm/week): AC 10.72 ± 1.00 vs 11.23 ± 1.00 (p
The aim of this study was to test whether women who conceived after a period of subfertility are less likely to undergo invasive prenatal testing (IPT) and determine factors of influence in that decision. We conducted a retrospective study at the Maastricht University Medical Centre (MUMCþ) to compare the rates of IPT following abnormal results of combined first trimester screening (cFTS) or second trimester screening (STS), or because of advanced maternal age among women tested for the effect of type and duration of subfertility and history of fertility investigations and/or treatment. We included 977 women who underwent IPT between January 2010 and December 2013. The women who conceived after fertility investigations and/or treatment had lower rates of IPT following abnormal STS (12.6% vs. 20.0%, OR ¼ 0.58, 95% CI; 0.34-0.97). The difference was not statistically significant after correction for maternal age and severity of the foetal anomaly. Maternal age was, in contrast to fertility treatment or duration of subfertility, related to the choice of IPT among formerly subfertile women. Therefore, the lower uptake of IPT in women conceiving after a period of subfertility is dependent on the indication for IPT and maternal age and less on the type and duration of subfertility. ARTICLE HISTORY
Introduction Preeclampsia is a major health problem in human pregnancy, severely complicating 5–8% of all pregnancies. The emerging molecular mechanism is that conditions like hypoxic stress trigger the release of placental messengers into the maternal circulation, which causes preeclampsia. Our objective was to develop an in vitro model, which can be used to further elucidate the molecular mechanisms of preeclampsia and which might be used to find a remedy. Methods Human non-complicated term placentas were collected. Placental explants were subjected to severe hypoxia and the conditioned media were added to chorionic arteries that were mounted into a myograph. Contractile responses of the conditioned media were determined, as well as effects on thromboxane-A2 (U46619) induced contractility. To identify the vasoactive compounds present in the conditioned media, specific receptor antagonists were evaluated. Results Factors released by placental explants generated under severe hypoxia induced an increased vasoconstriction and vascular contractility to thromboxane-A2. It was found that agonists for the angiotensin-I and endothelin-1 receptor released by placental tissue under severe hypoxia provoke vasoconstriction. The dietary antioxidant quercetin could partially prevent the acute and sustained vascular effects in a concentration-dependent manner. Discussion Both the acute vasoconstriction, as well as the increased contractility to U46619 are in line with the clinical vascular complications observed in preeclampsia. Data obtained with quercetin supports that our model opens avenues for e.g. nutritional interventions aimed at treating or preventing preeclampsia.
Objectives: Preeclampsia (PE) is strongly associated with heart failure (HF) later in life. During preeclamptic pregnancy the left ventricle (LV) remodels in a concentric way. This aberrant remodelling often persists after delivery. The concentric remodelling during PE can induce molecular signatures that may explain the associated increased risk of HF. This signature may be evaluated in terms of microRNAs (miRNAs). This review evaluates existing literature on miRNA expression data in concentric remodelling on the one hand and PE on the other to generate a list of overlapping miRNA expression patterns in both. Methods: Literature was searched in the electronic database PubMed (NCBI). First, data on miRNA expression was extracted in relation to cardiac remodelling. Next, data was extracted on miRNAs in relation to (PE-complicated) pregnancy. The miRNA data was stratified based on its origin, whether miRNAs were isolated from humans, animals, tissue or the circulation. After extracting data on (PE) pregnancy and cardiac remodelling, we compared both in order to extract the overlapping miRNA's between PE and concentric remodelling. Results: Nine miRNAs overlap between concentric remodelling and PE-complicated pregnancy; miR-1, miR-18, miR-21, miR-29b, miR-30, miR-125b, miR-181b, miR-195 and miR-499-5p. Five miRNA's where found to be up-regulated in both PE pregnancy and cardiac remodelling (miR-18, miR-21, miR-125b, miR-195 and miR-499-5p) and two miRNA where downregulated in both (miR-1 and miR-30). Two other miRNAs showed an up-regulation during PE while showing a downregulation in cardiac remodelling (miR-29b and miR-181b). Conclusion: This review revealed nine miRNAs, potentially relevant for (aberrant) cardiac remodelling during pregnancy. This approach may be an innovative step in finding relevant biomarkers for complicated pregnancy on the one hand and its relation with remote cardiovascular disease (CVD) on the other hand.
Background/aim: Placental syndromes (PS) are characterized by endothelial dysfunction complicating placental dysfunction. Possible markers for endothelial dysfunction and amount of trophoblast are fibronectin and plasminogen activator inhibitor-2 (PAI-2), respectively. We aimed (1) to determine whether in women with recurrent PS (rPS), this complication is preceded by deviating fibronectin- and PAI-2-levels, and (2) whether this is dependent on pre-pregnant plasma volume (PV). Methods: In 36 former patients, we determined fibronectin- and PAI-2-levels in blood-samples collected preconceptionally and at 12-16 weeks in their next pregnancy. Differences were analyzed between pregnancies with rPS (n = 12) and without rPS (non-rPS, n = 24) using linear mixed models, with subanalyses based on pre-pregnant normal or subnormal PV. Results: We observed higher fibronectin-levels at 12-16 weeks (p < 0.05 and p < 0.01, respectively) and lower PAI-2-levels at 16 weeks (p < 0.01) in the rPS subgroup, the intergroup differences being larger in women with subnormal PV. Conclusion: We showed that former PS patients who developed rPS have raised fibronectin- and reduced PAI-2-levels already in early/mid pregnancy. These deviations are even more prominent in women with subnormal pre-pregnant PV, supporting development of a 2-step screening program for former patients to identify the high-risk subgroup of women who may benefit from closer surveillance.
Introduction Fetal growth restriction (FGR) is still a major cause of perinatal mortality despite advances in fetal ultrasound scanning. The traditional 10th birth weight percentile as a cut-off for defining FGR could miss many cases of relative FGR falsely labelled as appropriate for gestational age (AGA) by having a birth weight 10th percentile, but actually have a reduced growth velocity possibly due to a higher growth potential of a milder degree of placental dysfunction. Objectives Our objective was to study the role of reduced growth velocity in AGA neonates and its influence on adverse perinatal outcome. Methods We performed a retrospective study of singleton AGA (birth weight 10th centile) neonates born in the Maastricht University Medical Centre between 2011-2015, of whom fetal biometry scans were available in two periods: 18–22 weeks and 30–34 weeks of gestational age. Growth velocities of biparietal diameter (BPDv), head circumference (HCv), abdominal circumference (ACv) and femur length (FLv), were calculated in mm/week and compared between categories of birth weight percentiles (BWp) using logistic regression, one-way ANOVA and posthoc test, and correlated to a composite adverse perinatal outcome using chi-square test. Macroscopic and histological placental analysis were collected from the pathology register, and correlated to ACv and birthweight using chi-square test. Results We identified 407 AGA neonates with available neonatal outcomes: BWp 10–16 (N = 43), BWp 16–20 (N = 21), BWp 20–50 (N = 143), BWp 50–80 (N = 119), BWp 80 (N = 81). There was a significant linear correlation between growth velocities and BWp: BPDv (B = 6651 p = 0.016), ACv (B = 4286 p = 0.0001) and FLv (B = 9657 p = 0.0001). There was a significant difference in AC velocity (in mm/week, mean SD) between the BWp 50-80 (11,34 0,14, reference group) and BWp 10–16 (10,58 0,14 p = 0.002), BWp 16–20 (10,45 0,17, p = 0.008) and BWp 20–50 (10,61 0,13 p = 0.0001). A similar trend was observed with other growth parameters. We identified 39 placental analysis, there was no significant difference between ACv (in mm/week, mean SD) in the group with placental dysfunction (11,10 0,18) vs normal(10,98 0,18 p=0.789). However birthweight (in grams, mean SD) was significant lower in the group with placental dysfunction (2623 537) vs normal (3041 610, p = 0.029). Neonates with ACv p25 (vs. p75) had more composite adverse neonatal outcome OR = 2.02 95% CI = (1.012–4.03). Conclusions Detection of relative FGR remains a clinical challenge. Our findings suggest that AC growth velocity in early third trimester determine eventual birth weight and that neonates at the lower end of the AGA spectrum have a reduced AC velocity and a worse neonatal outcome. Larger studies are needed to confirm these findings in prospective cohort.
Introduction Intra-uterine growth restriction (IUGR), failure of the fetus to reach normal birth weight, represents an important health hazard among neonates, and is associated with increased mortality and morbidity later in life. It is postulated that IUGR is associated with an inefficient blood and gas-supply at the feto-maternal interface of the placenta resulting in fetal hypoxia and under nutrition. Objectives The aim of the present study is to analyze, placental maturation assuring adequate increase of gas exchange efficiency by histo-morphological analyses of placentas comparing control term placentas to those of term growth restricted fetuses. This includes analyses of the degree of terminal villi vascularization, the diffusion distance between fetal capillary and maternal blood and the syncytial trophoblast turnover. Methods Paraffin sections of placental samples from term IUGR (n = 10) and healthy term pregnancies (n = 11) were stained immunohistochemically for endothelial cells (CD31). This is followed by stereological evaluation by light microscopy and an Image Analyzer. Surface areas, distances and numbers from terminal villi (TV), numbers and area of fetal capillaries (FC), diffusion distances (DD), vascular-syncytial membranes (VSM) and apoptotic knots (AK), were recorded. Non-parametric analyses were applied and statistical significance was set at P < 0.05. Results The mean birth weight for the IUGR group (2353±285g) in accordance to the group definitions differed significantly (p < 0.001) from controls (3362 ± 432 g) whereas there was nearly no significant difference in gestational age (p = 0.049). No significant differences were found in maternal age (p = 0.28), BMI (p = 0.24) gravidity or parity. We observed less TV per field (p = 0.058), VSM’s (p = 0.31) and FC’s per TV (0.64) less area of FC per TV (p = 0.27) and shorter diffusion distances in IUGR compared to controls, however these differences are not statistically significant. VSM lengths were significantly shorter per TV (p = 0.04) in IUGR. Analysis of AK showed a significant increase (p = 0.002) in IUGR compared to controls. Conclusion TV’s are sites specialized in gas exchange. They comprise of VSM’s characterized by fusions of the basal membranes of the capillary endothelium and the syncytiotrophoblast layer making the diffusion distance shortest and thus gas exchange most efficient. There are less TV’s and shorter VSM’s in the IUGR samples. This diffusion deficit may be compensated, by decreasing the mean diffusion distance of all fetal capillaries. In addition the trophoblast turnover as measured by the presence of AK seems to be increased in IUGR. The preceding is supported by the theory of post-placental hypoxia. According to this theory both mother and placenta are normoxic whereas the fetus is hypoxic from fetoplacental malperfusion. This results in a reduced oxygen extraction from the placenta resulting in intra-placental hyperoxia. These high pO2 values inhibit villous growth resulting in decreased TV and shorter VSM’s, and accordingly cause IUGR. The high intra-placental pO2 leads to increased oxidative stress in the placenta and might also be the cause of the increased trophoblast turn over observed in IUGR.
Objectives Directly measuring the spiral arteries instead of the uterine arteries could better reflect the pathological process underlying placenta insufficiency related diseases collectively known as placenta syndrome (PS). The purpose of this study is to examine if the blood flow velocity of spiral arteries in placenta syndrome-pregnancies is higher compared to healthy pregnancies and can be affected by location of spiral arteries. Methods A cross sectional study was conducted in woman between 24 and 42 weeks of gestation reporting at the department of obstetrics in the MUMC+. Using a Voluson E8TM abdominal transducer with predefined settings, spiral artery flow velocity indices were measured in women with PS (preeclampsia, preterm delivery, pregnancy induced hypertension and intra uterine growth restriction) and compared to women with uncomplicated pregnancies. Results Spiral artery Dopplers were successfully obtained in 32 PS- and 14 control pregnancies. Both groups were comparable in characteristics, except for diastolic blood pressure (73.4 ± 12.1 vs. 62 ± 6.8 mmHg, p = 0.02). Mean peak systolic velocity (PSV) in spiral arteries showed a linear decrease with advancing gestational age in both groups (0.94 ± 0.5 cm/s/week), but was significant higher in PS-group (32.5 ± 8.7 cm/s) compared to control group (24.5 ± 7.1 cm/s, p = 0.03). As expected, the mean PSV of the centrally localized spiral arteries was lower compared to the peripherally localized spiral arteries in the control group (24.5 ± 7.1 cm/s vs. 34.1 ± 14.6 cm/s, p = 0.14). No such difference was found in the PS-group (34.3 ± 8.7 vs. 34.6 ± 23.4 cm/s, p = 0.87). Conclusions Mean blood flow velocity of spiral arteries in placental syndrome pregnancies is higher compared to healthy pregnancies, suggesting that inadequate conversion of the spiral arteries can lead to placental syndrome. These promising findings need to be tested in a prospective cohort to determine the predictive value of spiral artery Dopplers in high risk pregnancies.
Dear Lukman, The pathophysiology of preeclampsia is quite complex and not yet well understood. This issue is rarely taken into consideration in the our current pursuit of "simplified" predictive models. The best known models involve the combination of maternal history and characteristics (such as BMI and MAP), uterine art dopplers and placental biomarkers (such as PAPP-A or PLGF). See Ref. Akolekar at al. (2011). Prediction of early, intermediate and late pre-eclampsia from maternal factors, biophysical and biochemical markers at 11-13 weeks. Prenatal Diagnosis, 31(1), 66–74. The FMF online risk calculator is a good tool:  https://courses.fetalmedicine.com/calculator/pe?locale=en However, a real predictor is possibly still out there until we unravel the messages produced by the placenta and the process by which they act on maternal endothelium.
Hi Graycen, Your question is probably too broad to answer sufficiently. I agree with most of what said. It largely depends on the type of experiments you are planning: histology, RNA/DNA/protein expression, etc. For a comprehensive review of sampling and storage options i recoomend you this article: Burton et al. Placenta. 2014 Jan;35(1):9-22. Optimising sample collection for placental research. Good luck
Before you get upset by this strange question: I am NOT a cardiologist, just a simple gynecologist!
To explore to what extent the presence of cardiometabolic and cardiovascular risk constitutions differ between pregnancies complicated by small for gestational infancy, preeclampsia or a combination of both. We conducted a cohort study in women after pregnancies complicated by placental syndrome with fetal manifestations (small for gestational age (SGA) infancy (n=113)), maternal manifestations (preeclampsia (PE) (n=729)), or both (n=461). Independent sample t-test was used to compare cardiometabolic and cardiovascular risk factors between groups. Logistic regression was used to calculate odds ratios and adjusted odds ratios of the prevalence of the metabolic syndrome and its constituents between groups. Adjustments were made for maternal age, parity, smoking, interval between delivery and measurements and intra uterine fetal demise. The metabolic syndrome was present in 7.5% of women who delivered SGA infants, 15.6% of former preeclamptic women and in 19.8% women after pregnancy complicated by both SGA and PE. Hypertension was observed in 25% of former PE women and 15% of women with solely SGA. Women who delivered a SGA infant had lower global vascular compliance compared to former PE women without SGA. Cardiometabolic risk factors consistent with metabolic syndrome relate to the maternal- rather than to the fetal presentation ofplacental syndrome. Nonetheless, highest incidence of metabolic syndrome was observed in women with both PE and SGA PE relates to chronic hypertension, whereas increased arterial stiffness seems to be associated with women who deliver a SGA infant. Copyright © 2015 Elsevier Inc. All rights reserved.
A subgroup of preeclamptic women has spiral artery lesions termed decidual vasculopathy (DV) which relate to worse clinical outcome. We aimed to determine whether a history of preeclampsia (PE) with DV is associated with adverse overall and future pregnancy outcome, including increased recurrence risk of hypertensive diseases of pregnancy. Via posted survey women with PE and DV (DV positive) in the index pregnancy were compared to those without the lesions (DV negative) on overall and future pregnancy outcome. DV positive cases showed a higher incidence of chronic hypertension both preconceptionally and at time of survey, adjusted odds ratio 4.8 (2.0-11.9). The DV positive group had a higher overall incidence of pregnancies with gestational hypertension (22% vs 13%, p = 0.04), preterm birth (59% vs 45%, p = 0.02) and a lower birth weight centile (30 vs 39, p = 0.02). There was no difference in outcome of future pregnancies, irrespective of the use of prophylactic aspirin. Women with DV-associated PE have a higher overall incidence of adverse obstetric outcome and of chronic hypertension, indicating an underlying vascular pathology, putting them at risk for pregnancy and cardiovascular complications. These women constitute a target group for counseling, monitoring and possibly lifestyle or pharmacological interventions.
INTRODUCTION: Placental syndrome (PS) is a heterogeneous clinical entity characterized by placental insufficiency, a frequent pathological finding in PS is decidual vasculopathy (DV). To assess progression of PS, pulsation index (PI) of the middle cerebral artery (MCA) and the umbilical artery (UA) PI are used as an indication of fetal brain sparing and respectively placental perfusion. The cerebroplacental ratio (CPR) defined as MCA-PI/UA-PI is strongly related to perinatal outcome however it is not known what the relationship is between CPR and different types of PS. We hypothesized that subtypes of PS differ in CPR trend and prevalence of DV in the 2nd-3rd trimester. METHODS: We retrospectively studied 81 singleton pregnancies between 2011-2013 in a tertiary center in the Netherlands, divided into three subgroups: preeclampsia (PE), as defined by ISSHP criteria (n=13), intrauterine growth restriction (IUGR) defined as birth weight <10th percentile (n=55) and PE+IUGR (n=13). Dopplers of the MCA and UA were carried out between 19-38 weeks. After delivery the placenta was histologically examined for various abnormalities including DV. RESULTS: Compared to the population mean, the MCA-PI was lower, the UA-PI was higher and CPR was lower across all subgroups, especially in PE+IUGR and between 24-28 weeks. IUGR CPR followed the trend for the population mean, while in PE and PE+IUGR CPR showed a reversed trend across gestational age. Compared to IUGR, CPR was lower in PE (p=0.004) and PE+IUGR (p<0.001). Similarly, compared to IUGR gestational age at delivery was lower in PE (30w5d, p=0.008) and PE + IUGR (30w4d, p=0.006) and there was higher prevalence of DV in PE (62%, p=0.005) and PE+IUGR (62%, p=0.005) compared to IUGR (22%). CONCLUSIONS: PE and PE+IUGR have reversed CPR trend and more decidual vasculopathy compared to IUGR, suggesting that preeclampsia and IUGR have different pathophysiology. Moreover, CPR assessment at 24-28 weeks may play a role in identifying women who may benefit from individualized surveillance and interventions to reduce their high a priori risk of perinatal complications.
INTRODUCTION: Preeclamspia (PE) and intrauterine growth restriction (IUGR) are examples of placental dysfunction disorders otherwise referred to as placental syndrome (PS). PS is a characterized by placental insufficiency and abnormal release of trophoblast products into maternal circulation, such as PAPP-A and β-hCG. These markers, used in first trimester screening for Down syndrome, have also been used in various models to predict PS later in pregnancy. It is unclear how these placental biomarkers relate to different subtypes of PS. We hypothesized that subtypes of PS differ in first trimester levels of PAPP-A and β-hCG. METHODS: We retrospectively compared clinical outcome and first trimester biomarkers from control uncomplicated pregnancies (n=513) and pregnancies complicated by placental syndrome (n=218), further subdivided into: preeclampsia (PE, n=44), intrauterine growth restriction (IUGR=birth weight <10th percentile, n=62), PE+IUGR (n=5), gestational hypertension (GH, n=101), and HELLP syndrome (n=6). RESULTS: MoM PAPP-A was significantly lower in PE, IUGR and PE+IUGR groups (0.73, 0.69 and 0.57, resp.), but not in the GH and HELLP groups (0.92 and 1.17, resp.), compared to controls (0.99). Free b-hCG was not significantly altered in any of these groups. Using logistic regression, MoM PAPP-A had an adjusted OR of 0.30 (CI 0.13-0.75) for PE and 0.28 (CI 0.12-0.66) for IUGR. Using multivariate regression, MoM PAPP-A correlated negatively to mean BP, systolic BP, diastolic BP, and positively to neonatal weight, but not to proteinuria, platelet count or liver enzymes. CONCLUSIONS: A lower first trimester PAPP-A, but not b-hCG, is related to the later development of placental syndrome (PE and/or IUGR). GH and HELLP syndrome are not likely to be caused by placental dysfunction and should not be considered as placental syndromes. The prediction and management of preeclampsia should take into consideration the heterogeneous nature of the disease and stratify for placental function tests, such as PAPP-A.
To compare nonpregnant blood pressure and circulating metabolic factors between formerly pre-eclamptic women who did and did not deteriorate to eclampsia. Retrospective observational cohort study. Tertiary referral centre. Formerly pre-eclamptic women with (n = 88) and without (n = 698) superimposed eclampsia. Women who experienced pre-eclampsia with or without superimposed eclampsia during their pregnancy or puerperium were tested for possible underlying cardiovascular risk factors at least 6 months postpartum. We measured blood pressure and determined cardiovascular and metabolic risk markers in a fasting blood sample. Groups were compared using Mann-Whitney U test, Spearman's Rho test or Fisher's Exact test (odds ratios). Differences in postpartum blood pressures and features of the metabolic syndrome between formerly pre-eclamptic and formerly eclamptic women. Formerly pre-eclamptic women who developed eclampsia differed from their counterparts without eclampsia by a lower blood pressure (P < 0.01) with blood pressure correlating inversely with the likelihood of having experienced eclampsia (P < 0.001). In addition, formerly eclamptic women had higher circulating C-reactive protein levels than formerly pre-eclamptic women (P < 0.05). All other circulating metabolic factors were comparable. Finally, 40% of all eclamptic cases occurred in the puerperium. Formerly pre-eclamptic women with superimposed eclampsia have lower nonpregnant blood pressure compared with their counterparts without neurological sequelae with blood pressure negatively correlated to the occurrence of eclampsia. As about 40% of all eclamptic cases occur postpartum, routine blood pressure monitoring postpartum should be intensified. © 2015 Royal College of Obstetricians and Gynaecologists.
INTRODUCTION: After preeclampsia, the prevalence of asymptomatic Heart Failure stage B (HF-B), which precedes the symptomatic stage C, is about 1 in 4 women. Low cardiac preload and high afterload may relate to both, PE and HF. We hypothesise that low cardiac preload and increased after load in the first two years after PE relate to the development of remote HF-B. METHODS: In this prospective cohort study, we included 107 formerly preeclamptic women who where admitted to cardiovascular (CV) risk assessment at least 6 months postpartum. We measured PV (ml/m2) with the indicator dilution technique using I125-labelled albumin as proxy for cardiac preload. Total peripheral vascular resistance (TPVR in dynes/ sec/cm5) was obtained by (80.mean arterial pressure (MAP, mmHg))/CO. At least 2 years later, women where re-invited for a follow up screening including a cardiac ultrasound to diagnose HF-B according to the AHA criteria as left ventricular hypertrophy, concentric remodeling, systolic dysfunction, or asymptomatic valve disease. RESULTS: 25/107 (23%) women had HF-B at follow up of which 2/3 had concentric remodeling indicating mainly diastolic dysfunction. Former PE women who developed HF-B at FU, had a lower PV at postpartum screening than women who did not develop HF-B (1551 vs 1473 ml.m2; p <0.05) while TPVR was comparable in both groups. PV correlated with HF-B (r=-0.21, p trend 0.03) but not with TPVR (r=-0.06, p trend 0.54). CONCLUSIONS: Decreased PV, indicating reduced cardiac preload, relates to increased asymptomatic HF-B at follow up, while increased cardiac afterload as indicated by total peripheral vascular resistance did not relate to HF-B.
Objective To study the prevalence of metabolic syndrome in women after a pregnancy complicated by pre-eclampsia or small-for-gestational-age (SGA), both epitomes of placental syndrome. DesignA retrospective cohort study. SettingSingle tertiary centre for maternal medicine in the Netherlands. PopulationWomen with a history of pre-eclampsia in absence of SGA (n=742) or pregnancy complicated by normotensive SGA (n=147) between 1996 and 2010. Methods Women were routinely screened for underlying cardiometabolic and cardiovascular risk factors at least 6months postpartum. Logistic regression analysis was used to calculate the odds ratio and adjusted odds ratio for each group. Adjustments were made for age, maternal height, smoking, parity, and interval between delivery and measurement. Main outcome measuresPrevalence of the metabolic syndrome. ResultsThe prevalence of the metabolic syndrome in our population was two-fold higher for women with a history of pre-eclampsia (13.9%) compared with women with a history of SGA (7.6%). Calculated odds ratios for metabolic syndrome, fasting insulin, HOMA, and microalbuminuria were all higher for women with a history of pre-eclampsia compared with women with SGA. This difference persisted after adjustment for confounding factors: metabolic syndrome (adjusted odds ratio, aOR2.11; 95%confidence interval, 95% CI 1.00-4.47) and hyperinsulinaemia (aOR 1.78; 95%CI1.13-2.81) insulin resistance (HOMA(IR); aOR1.80; 95%CI1.14-2.86). Microalbuminuria (aOR1.58; 95%CI 0.85-2.93) did not reach the level of significance after adjustment for confounding factors. ConclusionsA history of pre-eclampsia, rather than SGA, was associated with metabolic syndrome, suggesting that it relates to maternal rather than fetal etiology of placental syndrome.
We present a case a right-sided retroperitoneal lymphatic malformation (LM), extending from the abdomen to the right thigh, without other abnormality, discovered at the second trimester scan. Fetal karyotype was 46, XY. After multidisciplinary counselling, parents chose for a termination of pregnancy. Pathology confirmed the isolated malformation. LM are benign congenital malformations of the lymphatic system. Their prevalence is 1-5/10 000. Prenatal mortality rate is overall of 50-100%, for associated malformations and karyotype abnormalities. Isolated LM can cause compression of adjacent organs. 95% are localized in the head, neck and axillary region. Retroperitoneal LM account for 1% of cases. Few case reports exist of isolated retroperitoneal LM. Limb affection is a typical feature of retroperitoneal LM. Most of them are left-sided, as opposed to our case. Pediatric complications are: hemorrhage, infection, mass rupture or twist. Fetal ultrasound is a reliable diagnostic tool and can be completed by MRI. It assesses prognostic factors and can be used to monitor tumor growth and fetal well-being. Main features are hypoechogenic, multicystic, multiseptated mass. Treatment of choice is surgery, with risk of resection of adjacent organs, recidive and high morbidity and mortality. Sclerotherapy can be a useful adjuvant tool. Parental counselling must be multidisciplinary. Discussion on mode of delivery is mandatory, due to the high risk of dystocia. Ring chromosome 18 is a rare genetic disorder characterized by developmental delay and facial anomalies caused by deletion of the tips of both the short and long arms of chromosome 18 forming a circular structure. We present a case referred at 20wk where detailed scan showed a fetus with single umbilical artery, echogenic bowel, echogenic cardiac focus, persistent left superior vena cava and partial corpus callosum agenesis. Amniocentesis revealed an abnormal CNV analysis with a pathogenic CNV loss of 9.0 Mbp in 18q22.3-q23 and a small (19 kbp) CNV loss in 18p11.32. The findings were suggestive of ring chromosome 18 which was subsequently confirmed by karyotyping in all examined cells. After receiving genetic counselling the couple opted for a pregnancy termination. A vaginal delivery followed of a 454g male fetus. Although this chromosomal anomaly has been previously reported prenatally it is usually encountered as an accidental finding on amniocentesis and frequently in association with mosaicism of chromosome 18. The genetic counselling is complex as the variable clinical presentations depends on the amount and type of genetic information lost according to the break points involved. However, in our case, the large distal 18q deletion was probably responsable for the fetal phenotype of multiple structural anomalies. Parental CNV array confirmed the de novo nature of the fetal ring chromosome 18 indicating a low recurrence rate.
Short oral presentation abstracts uneventful pregnancy. On two-and three-dimensional ultrasound scan in addition to color Doppler assessment, a preliminary diagnosis of a fetal mature teratoma in an undescended left testicle was based on following features: 1. male fetus; 2. a 2 cm single unilocular left fetal cystic mass located between the left kidney and urinary bladder and separated from both (figure A), with regular boundaries, and scarcely vascularized small intracystic solid component (figure C and D); 3. empty ipsilateral hemiscrotum (figure B). The woman had a spontaneous vaginal delivery at 37 weeks. Postnatal clinical examination and ultrasound confirmed the prenatal findings. The mass was excised on the 3rd day postpartum. Histopathological examination revealed a mature teratoma of an undescended left testicle. The baby is now 2 months old and is thriving well. Microcephalic osteodysplastic primordial dwarfism (MOPD) type I is characterized by microcephaly, skeletal dysplasia, central nervous system anomalies and facial dysmorphism. Mutations in the RNU4ATAC gene were recently identified to cause this rare disorder. We present a case of a primigravida referred at 19 + 5 weeks to our tertiary perinatal center with a suspicion of fetal anomalies. A detailed scan showed a severely growth restricted fetus with short long bones en abnormal hands/feet. Brain anomalies and facial dysmorphism were suspected. The couple decided to terminate the pregnancy. The autopsy revealed a girl with short stature and a microcephaly. The face showed a micro-/retrognathia, small underdeveloped ears without external auditory channels and a dysmorphic nose. The autopsy and MRI of the CNS showed severe anomalies, including hypoplasia of the hemispheres and aplasia of the spinal cord. The babygram confirmed the short extremities and showed a delayed ossification of the vertebral corpora. With these clinical findings MOPD-I was suspected. Genetic testing showed a compound heterozygosity for two mutations in the RNU4ATAC gene, which established the diagnosis. To our knowledge this is the first case of prenatal diagnosis of MOPD-I, caused by mutations in the RNU4ATAC gene. These mutations cannot be found with modern techniques like exome sequencing. Although it is a rare, in case of specific ultrasonographic findings, MOPD-I has to be in mind, because of its clinical consequences. In conclusion, we present a case of MOPD type I caused by mutations in the RNU4ATAC gene diagnosed prenatally.
Babies born after midtrimester preterm prelabour rupture of membranes (PPROM) are at risk to develop neonatal pulmonary hypoplasia. Perinatal mortality and morbidity after this complication is high. Oligohydramnios in the midtrimester following PPROM is considered to cause a delay in lung development. Repeated transabdominal amnioinfusion with the objective to alleviate oligohydramnios might prevent this complication and might improve neonatal outcome.Methods/design: Women with PPROM and persisting oligohydramnios between 16 and 24 weeks gestational age will be asked to participate in a multi-centre randomised controlled trial. Intervention: random allocation to (repeated) abdominal amnioinfusion (intervention) or expectant management (control). The primary outcome is perinatal mortality. Secondary outcomes are lethal pulmonary hypoplasia, non-lethal pulmonary hypoplasia, survival till discharge from NICU, neonatal mortality, chronic lung disease (CLD), number of days ventilatory support, necrotizing enterocolitis (NEC), periventricular leucomalacia (PVL) more than grade I, severe intraventricular hemorrhage (IVH) more than grade II, proven neonatal sepsis, gestational age at delivery, time to delivery, indication for delivery, successful amnioinfusion, placental abruption, cord prolapse, chorioamnionitis, fetal trauma due to puncture. The study will be evaluated according to intention to treat. To show a decrease in perinatal mortality from 70% to 35%, we need to randomise two groups of 28 women (two sided test, Ss-error 0.2 and alpha-error 0.05). This study will answer the question if (repeated) abdominal amnioinfusion after midtrimester PPROM with associated oligohydramnios improves perinatal survival and prevents pulmonary hypoplasia and other neonatal morbidities. Moreover, it will assess the risks associated with this procedure.Trial registration: NTR 3492 Dutch Trial Register (www.trialregister.nl).
INTRODUCTION: Preeclampsia (PE) is a hypertensive disease of pregnancy, complicating 2-8% of pregnancies. It is associated with risk of PE is higher in women with severe, early disease. Decidual vasculopathy (DV) is a term for spiral artery lesions found in a proportion aim of this study is to test the hypothesis that DV is associated with a pregnancies. METHODS: history of PE with (n=41, PE+DV) or without DV (n=49, PE-DV) during risk was calculated comparing the percentage of multiparous women with all pregnancies of the PE+DV group (n=150) to those in the PE-DV group (n=167). RESULTS:
Defective placentation is implicated in the etiology of preeclampsia (PE). Abnormal placental structure, thickness and the presence of placental hypoechoic lesions, known as placental lakes or echogenic cystic lesions, are frequently seen in placenta-related disorders. To summarize to what extent these ultrasound abnormalities are related to pregnancy outcome, we performed a literature review. Objective: to describe the characteristics of placental hypoechoic lesions and the correlation to pregnancy outcome and placental histology. Methods: Electronic searches: • TheCochraneLibrary • PUBMED • MEDLINE • EMBASE • CINAHL Inclusion criteria: studies reporting placental hypoechoic lesion, regardless of maternal age, gestational age or risk factors. Exclusion criteria: multiple gestations, fetal abnormalities, assisted pregnancy, placental tumours. Outcome measures: • Adversematernaloutcome:pregnancyinducedhypertension,preeclampsia, HELLP, diabetes, preterm delivery and placental abruption • Adverseneonataloutcome:smallforgestationalage,intra-uterinegrowth restriction, intra-uterine fetal death, low Apgar score, NICU administration, neonatal death • Ultrasound characteristics: echo density, flow within lesions, size, border • Placentalpathology Results: ltrasound characteristics of placental hypoechoic lesions: Most used term was placental lakes, described as a ≥ 2x2 cm sonolucent avillous vascular space with low flow swirling jets seen on colour Doppler. Prevalence of lesions: Overall prevalence of placental hypoechoic lesions was 7.6% (2.2-67%). Prevalance in high- vs low-risk pregnancy was 8.9 vs 7.4 respectively (p=0.04). Placental thickness > 3cm at 20 weeks of gestation was associated with the presence of placental lakes (OR: 6.3; 95% CI: 4.4-9.1). Many of the hypoechoic lesions were discovered in the second trimester. Placental pathology associated with hypoechoic lesions: Most found pathological abnormalities where: villous infarction (PPV: 63%) and intervillous thrombosis (PPV: 25%). Post partum ultrasound wired localisation increased the pathological detection rate (OR 1.9). Conclusion he presence of hypoechoic lesions should be considered as an important risk factor in developing placenta-related disorders. Routine ultrasound assessment of placental structure and texture can be of clinical importance in the follow-up of high-risk pregnancies.
There is a growing body of evidence suggesting that PE is a heterogeneous etiology.
Women with a history of preeclampsia (PE) have an increased prevalence of cardiometabolic, cardiovascular and prothrombotic risk factors. Remotely, these women are at increased risk of developing cardiovascular and thrombotic disease. Decidual vasculopathy (DV) describes vascular lesions in the maternal spiral arteries of the uterus which are found in approximately 40-60% of women with PE. DV is thought to be related to atherosclerosis because of their morphological similarity. The aim of this study is to investigate the association of cardiovascular and thrombogenic risk factors with DV in women with a history of PE. We retrospectively analyzed cardiovascular and thrombogenic risk of women with a history of PE, comparing cases with DV (n=95) to cases without the lesions (n=81) 7 months after index pregnancy. Data from a cohort of patients with a history of PE were matched with records from our pathology database. The DV group showed higher diastolic blood pressure (73 vs. 70mmHg, p=0.031), lower left ventricular stroke volume (71 vs. 76 ml, p=0.032), higher total peripheral vascular resistance (1546 vs. 1385, p=0.009) and higher percentage of low plasma volume (34% vs. 19%, p=0.030). DV did not relate to other cardiovascular parameters, urinary protein, body mass index, lipid or glucose metabolism parameters or thrombophilia. In this study, in women with a history of PE, cases with DV had increased cardiovascular risk, exhibiting circulatory alterations suggesting reduced venous reserves and elevated arterial tone, without metabolic or thrombophilic disturbances.
Een 33-jarige G3P2, zwanger van een triamniotio-sche trichoriale gemelli graviditeit, werd naar ons UMC verwezen. De voorgeschiedenis vermeldde een spontane partus en een zwangerschapsaf-breking in verband met Trisomie 21. Patiënte was spontaan zwanger geworden en tot een termijn van 33+5 verliep de zwangerschap ongecom-pliceerd. Bij deze termijn werd patiënte elders opgenomen in verband met hevige jeukklachten waarbij er een verdenking bestond op een pruritis gravidarum. Waarvoor, na het bepalen van de gal-zure zouten, werd gestart met Ursochol. Patiënte kwam twee dagen na opname echter spontaan in partu en werd in verband met plaatsgebrek op de afdeling neonatologie elders, overgeplaatst naar het UMC St Radboud bij een termijn van 34 weken. Bij aankomst was patiënte goed in partu met een ontsluiting van 5 cm. Bij echoscopisch onderzoek werden twee kinderen in hoofdligging en het derde kind in onvolkomen stuitligging gezien en waren er, zover te beoordelen, geen afwijkingen zichtbaar. Na counselling voor de modus partus werd besloten tot het verrichten van een primaire sectio caesarea die-zelfde nacht. Er werd een ongecompliceerde sectio verricht onder spinale anesthesie, waarbij twee jongens en een meisje werden geboren, allen met een goede start. Bij nadere inspectie van de uterus werden geen afwijkingen gezien. Echter bij inspectie van de ova-ria werd bilateraal een forse multicysteuze afwijking gezien (figuur 1). Omdat er twijfel bestond over het aanwezig zijn van een (borderline) maligniteit, werd telefonisch overlegd met de oncologische achterwacht. Hierna werd, ook na overleg met patiënte, besloten om een adnexextirpatie rechts te verrichten in verband met deze maligniteit. De procedure verliep ongecompli-ceerd. Het maken van een vriescoupe werd overwo-gen maar niet verricht. De grootte van het preparaat was 14 x 9 x 5,5 cm. De uiteindelijk pathologie-uitslag luidde: multipele theca-luteïne cysten (passend bij hyperreactio lutei-nalis) bij een meerlingzwangerschap.
In a proportion of patients with preeclampsia, unremodeled spiral arteries develop additional pathological changes, termed decidual vasculopathy (DV), or acute atherosis. DV has been correlated to adverse clinical outcome and increased placental pathology. However, it was unclear whether these effects pertained to individual features of DV. We performed a reanalysis of placental samples from preeclamptic pregnancies (n = 76), recording the number of vessels with DV, their location in the decidua and their morphological features. Results were correlated with clinical and placental parameters, using Spearman's rho test. P-value < 0.05 was considered significant. Total number of vessels with DV (totalDV) correlated with higher diastolic blood pressure, higher urine protein-to-creatinine ratio, shorter gestational age, lower birth weight, 5 min APGAR score and umbilical artery pH, and with increased accelerated villous maturity, infarction and hematoma formation, but not with HELLP syndrome markers. Additionally, there was a striking correlation of increased perinatal mortality with the number of vessels located in the decidua basalis (DVbas), and with vessels showing DV with thrombosis (DVthrom). Other morphological features, such as foam cell infiltration, did not increase correlation strength. In our study of preeclamptic placental samples, totalDV related to worse clinical outcome and increased placental pathology. Moreover, DVbas and DVthrom related to perinatal death. DV could be a manifestation of an underlying (vascular) pathology, increasing the risk of adverse pregnancy outcome. In preeclampsia, totalDV, DVbas and DVthrom correlated with increased placental pathology and adverse maternal and fetal outcome, most relevantly with perinatal mortality.
We report a case of lumbar kyphosis due to fused vertebra with 2D and 3D images. A routine scan at 16 weeks showed lumbar kyphosis (L1–2). Amniocentesis revealed a normal female karyotype, 46, XX and normal alfafoetoprotein (3.9 μg/ ml)). At 20 weeks the kyphosis was stable and on 2D ultrasound the conus medullaris ended at L 2, without suspicion for diastematomyelia. 3D ultrasound was helpful to diagnose fused vertebra causing the kyphosis. An MRI at 30 weeks confirmed the kyphosis without evidence of diastematomyelia. The child was born at 40 weeks (weight 3500 g, HC 35 cm and length 50 cm). Postnatal examination revealed a kyphosis at L 1–2 with ultrasound suggesting fused vertebra at that level. The conus medullaris ends at L2, without evidence for tethered cord.
The prenatal diagnosis of fetal coarctation is still challenging. It is mainly suspected by ventricular disproportion (smaller left ventricle than right ventricle). The sensitivity of ventricular discrepancy is however moderate for the diagnosis of coarctation and there is a high false positive rate. Prenatal diagnosis of coarctation is important because the delivery can be arranged in a centre with a pediatric cardiac intensive careand this reduces postnatal complications and longterm morbidity. For many years the prenatal diagnosis of coarctation has been investigated to improve specificity and sensitivity by several of measurements. This article reviews all relevant articles from 2000 until 2011 searching pubmed and the reference list of interesting articles. An overview of specific measurements and techniques that can improve the diagnosis of coarctation has been made, such as the isthmus diameter, ductal diameter, isthmus/ductal ratio, z-scores derived from measurements of the distal aortic isthmus and arterial duct, the presence of a shelf andisthmal flow disturbance. Also 3-dimensional (3D) and 4-dimensional (4D) imaging with or without STIC has been suggested to be used as newer techniques to improve diagnosis of coarctation in fetal life. Although more methods regarding prenatal diagnosis of coarctationare being investigated, the ultrasound specialist remains challenged to correctly diagnose this cardiac anomaly in prenatal life.
The prenatal diagnosis of fetal coarctation is still challenging. It is mainly suspected by ventricular disproportion (smaller left ventricle than right ventricle). The sensitivity of ventricular discrepancy is however moderate for the diagnosis of coarctation and there is a high false positive rate. Prenatal diagnosis of coarctation is important because the delivery can be arranged in a centre with a pediatric cardiac intensive careand this reduces postnatal compli- cations and longterm morbidity. For many years the prenatal diagnosis of coarctation has been investigated to improve specificity and sensitivity by several of measurements. This article reviews all relevant articles from 2000 until 2011 searching pubmed and the reference list of interesting articles. An overview of specific measurements and techniques that can improve the diagnosis of coarctation has been made, such as the isthmus diameter, ductal diameter, isthmus/ductal ratio, z-scores derived from measurements of the distal aortic isthmus and arterial duct, the presence of a shelf andisthmal flow disturbance. Also 3-dimensional (3D) and 4-dimensional (4D) imaging with or without STIC has been suggested to be used as newer techniques to improve diagnosis of coarctation in fetal life. Although more methods regarding prenatal diagnosis of coarctationare being investigated, the ultrasound specialist remains challenged to correctly diagnose this cardiac anomaly in prenatal life. Key words: Prenatal diagnosis, coarctation, ventricular disproportion, isthmus/ductal ratio, discrepancy great vessels, isthmal z-scores, Doppler, flow disturbance, shelf.
Background: Decidual vasculopathy (DV), or acute atherosis of maternal spiral arteries, is a histological placental finding seen in a proportion of pregnancies complicated by preeclampsia (PE). DV is characterized morphologically by infiltration of foamy macrophages within the vascular wall, and fibrinoid arterial medial necrosis. The clinical implications of DV are, however, unclear. Our aim was to study the association between DV and clinical outcome and placental histology in patients with PE. Study design: Placental sections from 107 pregnancies complicated by PE were analyzed in a case-control manner. 25 cases were excluded due to incomplete records or multiple pregnancy. Preeclamptic cases with DV (N = 41) and without DV (N= 41) were compared using Mann-Whitney test for various clinical and histological parameters. Also, in cases with umbilical artery pH <7.20, correlation between DV and all other parameters was tested using Spearman’s rho test. P values of <0.05 were considered significant. Results: In comparison to PE without DV, cases with DV had a significantly higher diastolic blood pressure (dBP), shorter gestational age (GA), lower birth weight (BW), and lower umbilical artery pH. Cases with DV had also more placental calcifications, perivascular leucocyte infiltration, and hematoma formation. No significant differences were found in age, BMI, use of MgSO4 or antihypertensives, protein to creatinine ratio (PtCR), markers for HELLP syndrome, birth weight percentile, APGAR scores, neonatal survival, placenta weight (PW), infarctions and ischemia. Significant correlation was found between pH <7.20 and DV, placenta weight, perivascular leucocyte infiltration, and hematoma formation. Means and p-value. Conclusion: In patients with PE, the presence of DV was associated with maternal, neonatal and placental indicators of disease severity, but not with proteinuria or HELLP syndrome. This suggests a role for DV in the pathogenesis of severe PE, possibly by aggravating an already compromised placental perfusion. Alternatively, DV could be a manifestation of underlying pathology (e.g. thrombophilia or immune-mediated disease) predisposing to severe PE.
Trophoblast fusion is an important process in placental development. Normally, fusion occurs in both villous cytotrophoblasts and extravillous interstitial trophoblasts. Abnormal fusion by the latter is thought to be related to defective trophoblast invasion and impaired spiral artery remodelling in the placental bed of preeclamptic women. Preeclampsia is a serious pregnancy complication, effected by endothelial dysfunction in response to placental factors. In Chapter 1, we discuss the pathophysiology of preeclampsia and propose our general hypothesis that different aspects of trophoblast fusion, as described in the various chapters of the thesis, could be linked to specific defects in preeclampsia. The mechanism of trophoblast fusion is discussed in Chapter 2, together with the models and techniques available to study fusion. Syncytin, a human retroviral gene product, is a major fusigenic protein for the trophoblast. Trials on syncytin were inconclusive due nonspecific immunostaining (Chapter 3). Due to the unreliable fusion capacity of cultured trophoblasts, we used the model of BeWo and JEG-3 trophoblast cell lines with different fusigenic capacity to study cell responses to forskolin and TNFα. The two cell lines showed different responses to both molecules in terms of viability, proliferation and apoptosis (Chapter 4). Furthermore, the Alamar Blue technique enabled us to study cell fusion in relation to cell viability, proliferation and invasion in response to TGF-β, a known inhibitor of invasion (chapter 5). Finally, an in vivo study of interstitial trophoblast fusion was performed using double immunostaining for E-cadherin and cytokeratin. In preeclampsia there was a higher percentage of clustered non-fused cells and of smaller giant cells compared to normal pregnancy, indicating a defect in interstitial trophoblast fusion (Chapter 6). Interestingly, in HELLP syndrome no such change was observed. The possibility that this indicates a different pathogenesis compared to preeclampsia is discussed (Chapter 7). Our findings suggest an interaction between fusigenic capacity to form placental bed giant cells and responses to cytokines. Further research into models of trophoblast fusion is eagerly anticipated.
During their invasion of the placental bed, interstitial trophoblasts fuse to multinuclear giant cells which are thought to have lost their invasive properties. Trophoblast fusion is associated with downregulation of E-cadherin, and persistent E-cadherin expression has been linked to defective placentation in preeclampsia. Since a previous study suggested 'premature' giant cell formation in preeclampsia, we started with the working hypotheses that fusion is increased in hypertensive pregnancies, and that the intensity of fusion correlates with the severity of disease. Using double immunostaining for E-cadherin and cytokeratin 7/17, nuclei in interstitially invasive trophoblasts (IT) in the myometrial compartment of the placental bed from normotensive pregnancies (NT, n=8), gestational hypertension (GH, n=4), preeclampsia (PE, n=9), and HELLP syndrome (n=5) were categorised according to the E-cadherin staining of the cell and their occurrence in single, clustered or multinuclear cells. GH and PE patients showed a higher percentage of nuclei in clustered non-fused E-cadherin-positive cells (P<0.01 and P<0.05), and in smaller (bi- and trinuclear) placental bed giant cells (P<0.05) compared to NT pregnancies, suggesting defective IT fusion. In contrast, in HELLP syndrome no such failed fusion could be discerned, which may support the idea of a heterogeneous aetiology of different hypertensive diseases of pregnancy. Since we are still ignorant about the specific role of mononuclear and multinuclear trophoblasts in the placental bed, it is not yet possible to relate the present findings to the pathogenesis of different categories of hypertensive pregnancies.
The current techniques for quantifying trophoblast viability, migration and invasion are mainly limited by the need to sacrifice the cells during the test procedure. In this study, the vital dye AB (AB) was used to quantify cell number and viability of BeWo and JEG-3 choriocarcinoma cells, as well as their migration and invasion through fibronectin-coated filters. AB was directly added to culture medium of incubated test and control cells. At various time intervals, the redox reaction, in which AB is reduced by the cells, was measured by absorbance readings at 540 and 630 nm. For cell migration and invasion, cells were cultured onto uncoated or fibronectin-coated inserts, respectively. AB reduction of migrated cells was normalized to that of control cells to calculate percentages of migration. This model was also tested in the presence of a reported inhibitor, transforming growth factor (TGF) beta. The curve of %AB reduction versus cell number was linear, with intra- and inter-assay Coefficient of Variations of 1.88%and 2.94%, respectively. AB reduction increased with both seeding concentrations and incubation time with AB. TGFbeta treatment caused a modest decrease in AB reduction in both JEG-3 and BeWo cells. TGFbeta treatment also decreased migration in BeWo, but not in JEG-3, cells. AB assay is a simple and reliable method for quantifying trophoblast viability, migration and invasion.
The interactions of trophoblasts with the cytokine network at the fetomaternal interface determine the pathway the cell undertakes, e.g. proliferation, differentiation and apoptosis. We used cultures of fusigenic BeWo and non-fusigenic JEG-3 choriocarcinoma cells to study the effects of inducers of syncytialisation (forskolin) and apoptosis [tumour necrosis factor-alpha (TNFalpha)] on differentiation, viability, proliferation and apoptosis. E-cadherin immunostaining showed that syncytium formation was confined to BeWo and not JEG-3 cells, while secretion of hCG was promoted by forskolin in both cell types implying a 'dissociation' between morphological and biochemical differentiation. Forskolin also had differential effects on cell viability (MTT reduction test) and proliferation (Ki67 immunostaining with MIB-1 monoclonal antibody), both decreasing in BeWo and increasing in JEG-3 cells. TNFalpha increased apoptosis (cytokeratin neo-epitope immunostaining with M30 monoclonal antibody) in both cell types, an effect which was blocked by epidermal growth factor selectively in JEG-3 cells. Our results suggest that the differential responses of BeWo and JEG-3 cells to inducers of syncytialization and apoptosis might be related to their fusigenic capacity. Caution is needed when extrapolating results obtained by these models to normal trophoblast populations. However, we speculate that these models can help identify key factors involved in trophoblast differentiation at the placental bed.
Objective: The aim of this study was to evaluate placental ischemia in pregnant rats as a model for preeclampsia. Methods: On day 14 of pregnancy, Wistar Charles River rats were randomly assigned into three groups. In OC rats, the abdominal aorta as well as the uterine arteries at the ovarian end were partially ligated, whereas in CC rats the aorta and the uterine arteries at the cervical end were ligated. Sham rats (SH) had a laparatomy but no ligation of the blood vessels was performed. In half of the rats from each group, the carotid artery was cannulated on day 14 of pregnancy, and the catheter was connected to a pressure transducer for daily measurement of blood pressure. The other rats were installed in metabolic cages on day 20 of pregnancy to collect urine samples. On day 21 fetuses were delivered by cesarean section, fetal and placental weight were recorded, and placentas were snap-frozen in liquid nitrogen for real-time PCR analysis of TNF-a. Blood was collected from the maternal aorta for analysis of hematologic parameters.
ackground: The fusion competent BeWo choriocarcinoma cell line is a useful in vitro model to study the regulatory mechanisms of syncytium formation and to identify possible factors maintaining placental function and structural integrity. Ca Objective: First, to study the viability of BeWo cells treated with tumour Cz necrosis factor-alpha (TNF-a), after Forskolin (Fk) induced 0 syncytialization. Second, to test a possible protective role of fibronectin and epidermal growth factor (EGE) against TNF-a cytotoxicity. Methods: BeWo choriocarcinoma cells possessing the capacity to syncytialize in response to Fk, were cultured on uncoated or fibronectin- coated 96-well plates at a concentration of 2x104 cell/mi. The medium was changed after 4 hours whilst adding EGF (5ng/ml) to half of the plates. After 24 hours the medium was changed again yet supplemented with 0, 10, 100 IiM Forskolin with or without TNF-a (1000 lU/ml). Cell viability was measured 48 and 72 hours after plating using the MTT assay, which is based upon the reduction of the tetrazolium salt MTT to Formazan. Absorbance was read at 550nm. Data were analysed using the one-way ANOVA test. Results: Fk at 100gM alone or in combination with TNF-a reduced cell viability (P<0.01) after 48 hours of culture. After 72 hours a similar reduction was also seen with TNF-a alone and in combination with Fk at lOjiM (p<0.01) (as shown in figure). EGF pre-treatment had no effect on cell viability. Fibronectin coating increased BeWo cell viability and protected the cells from the early TNF-a induced cytotoxicity in the absence of EGF (P<0.001). Conclusion: Forskolin has a negative effect on the viability of BeWo cells, probably related to the induction of syncytialization via a cAMP- dependent pathway. Additional TNF-a treatment decreased viability further. EGF pre-treatment had no effect, whereas fibronectin coating protected the BeWo cells from the early TNF-a induced cytotoxicity.
.Background: Investigating the functional diversity of available choriocarcinoma cell lines may reflect the heterogeneity of different trophoblast population in vivo. Objective; to compare the effect of Forskolin (Fk), epidermal growth factor (EGF) and tumour necrosis factor-alpha (TNF-a) on the viability of two distinct choriocarcinoma cell lines: the fusion non-competent JEG-3 and the fusion competent BeWo cells. Methods: Cells were cultured into fibronectin-coated 96-well plates at a concentration of 2x104 cell/mI. The medium was changed after 4 hours whilst adding EGF (5ng/ml) to half of the plates. After 24 hours the medium was changed again yet supplemented with 0, 100 pM Forskolin with or without TNF-a (1000 lU/ml). The MTT assay was used to measure cell viability 48 and 72 hours after plating, which is based upon the reduction of the tetrazolium salt MTT to Formazan. Absorbance was read at 550nm. Data were analysed using the one-way ANOVA test. Results: Fk and TNF-a alone or in combination decreased the viability of BeWo cells (P<0.01), while Fk enhanced viability of JEG-3 cells (P<0.01) even when TNF-a was added (P<0.01) (as shown in figure). Addition of EGF did not have any effect on BeWo cells while it decreased the viability of JEG-3 cells after 48 hours of culture. Conclusion: The effects of Forskolin, TNF-a as well as EGF on the viability of JEG-3 cells differ from those observed in BeWo cells. With Forskolin, loss of viability is seen in the syncytializing BeWo cells whereas it enhances the viability in the non-syncytializing JEG-3 cells. TNF-at seem to enforce the effect of Forskolin, while either no effect or an opposing effect is found with EGF in BeWo and JEG-3 cells respectively. These findings can give insight on the regulatory mechanisms of syncytialization in different trophoblast-like cells in culture and trophoblast subtypes in vivo.
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