Placenta-related Complications Research Articles

Morphologic development of the first-trimester utero-placental vasculature is positively associated with embryonic and fetal growth: the Rotterdam Periconception Cohort.

Is morphologic development of the first-trimester utero-placental vasculature associated with embryonic growth and development, fetal growth, and birth weight percentiles? Using the utero-placental vascular skeleton (uPVS) as a new imaging marker, this study reveals morphologic development of the first-trimester utero-placental vasculature is positively associated with embryonic growth and development, fetal growth, and birth weight percentiles. First-trimester development of the utero-placental vasculature is associated with placental function, which subsequently impacts embryonic and fetal ability to reach their full growth potential. The attribution of morphologic variations in the utero-placental vascular development, including the vascular structure and branching density, on prenatal growth remains unknown. This study was conducted in the VIRTUAL Placental study, a subcohort of 214 ongoing pregnancies, embedded in the prospective observational Rotterdam Periconception Cohort (Predict study). Women were included before 10 weeks gestational age (GA) at a tertiary referral hospital in The Netherlands between January 2017 and March 2018. We obtained three-dimensional power Doppler volumes of the gestational sac including the embryo and the placenta at 7, 9, and 11 weeks of gestation. Virtual Reality-based segmentation and a recently developed skeletonization algorithm were applied to the power Doppler volumes to generate the uPVS and to measure utero-placental vascular volume (uPVV). Absolute vascular morphology was quantified by assigning a morphologic characteristic to each voxel in the uPVS (i.e. end-, bifurcation-crossing-, or vessel point). Additionally, total vascular length (mm) was calculated. The ratios of the uPVS characteristics to the uPVV were calculated to determine the density of vascular branching. Embryonic growth was estimated by crown-rump length and embryonic volume. Embryonic development was estimated by Carnegie stages. Fetal growth was measured by estimated fetal weight in the second and third trimester and birth weight percentiles. Linear mixed models were used to estimate trajectories of longitudinal measurements. Linear regression analysis with adjustments for confounders was used to evaluate associations between trajectories of the uPVS and prenatal growth. Groups were stratified for conception method (natural/IVF-ICSI conceptions), fetal sex (male/female), and the occurrence of placenta-related complications (yes/no). Increased absolute vascular morphologic development, estimated by positive random intercepts of the uPVS characteristics, is associated with increased embryonic growth, reflected by crown-rump length (endpoints β = 0.017, 95% CI [0.009; 0.025], bifurcation points β = 0.012, 95% CI [0.006; 0.018], crossing points β = 0.017, 95% CI [0.008; 0.025], vessel points β = 0.01, 95% CI [0.002; 0.008], and total vascular length β = 0.007, 95% CI [0.003; 0.010], and similarly with embryonic volume and Carnegie stage, all P-values ≤ 0.01. Density of vascular branching was negatively associated with estimated fetal weight in the third trimester (endpoints: uPVV β = -94.972, 95% CI [-185.245; -3.698], bifurcation points: uPVV β = -192.601 95% CI [-360.532; -24.670]) and birth weight percentiles (endpoints: uPVV β = -20.727, 95% CI [-32.771; -8.683], bifurcation points: uPVV β -51.097 95% CI [-72.257; -29.937], and crossing points: uPVV β = -48.604 95% CI [-74.246; -22.961])), all P-values < 0.05. After stratification, the associations were observed in natural conceptions specifically. Although the results of this prospective observational study clearly demonstrate associations between first-trimester utero-placental vascular morphologic development and prenatal growth, further research is required before we can draw firm conclusions about a causal relationship. Our findings support the hypothesis that morphologic variations in utero-placental vascular development play a role in the vascular mechanisms involved in embryonic and fetal growth and development. Application of the uPVS could benefit our understanding of the pathophysiology underlying placenta-related complications. Future research should focus on the clinical applicability of the uPVS as an imaging marker for the early detection of fetal growth restriction. This research was funded by the Department of Obstetrics and Gynecology of the Erasmus MC, University Medical Centre, Rotterdam, The Netherlands. There are no conflicts of interest. Registered at the Dutch Trial Register (NTR6854).

The transcriptional regulatory network modulating human trophoblast stem cells to extravillous trophoblast differentiation

During human pregnancy, extravillous trophoblasts play crucial roles in placental invasion into the maternal decidua and spiral artery remodeling. However, regulatory factors and their action mechanisms modulating human extravillous trophoblast specification have been unknown. By analyzing dynamic changes in transcriptome and enhancer profile during human trophoblast stem cell to extravillous trophoblast differentiation, we define stage-specific regulators, including an early-stage transcription factor, TFAP2C, and multiple late-stage transcription factors. Loss-of-function studies confirm the requirement of all transcription factors identified for adequate differentiation, and we reveal that the dynamic changes in the levels of TFAP2C are essential. Notably, TFAP2C pre-occupies the regulatory elements of the inactive extravillous trophoblast-active genes during the early stage of differentiation, and the late-stage transcription factors directly activate extravillous trophoblast-active genes, including themselves as differentiation further progresses, suggesting sequential actions of transcription factors assuring differentiation. Our results reveal stage-specific transcription factors and their inter-connected regulatory mechanisms modulating extravillous trophoblast differentiation, providing a framework for understanding early human placentation and placenta-related complications.

The impact of serum estradiol and progesterone levels during implantation on obstetrical complications and perinatal outcomes in frozen embryo transfer.

This study sought to evaluate obstetric complications and perinatal outcomes in frozen embryo transfer (FET) using either a natural cycle (NC-FET) or a hormone therapy cycle (HT-FET). Furthermore, we investigated how serum levels of estradiol (E2) and progesterone (P4) on the day of and 3 days after embryo transfer (ET) correlated with clinical outcomes in the two groups. We conducted a retrospective, single-center study from January 1, 2015, to December 31, 2019. The study included couples who underwent NC-FET or HT-FET resulting in a singleton live birth. Serum levels of E2 and P4 were measured on the day of and 3 days after ET. The primary outcomes assessed were preterm birth rate, low birth weight, macrosomia, hypertensive disorders in pregnancy, gestational diabetes mellitus, postpartum hemorrhage, and placenta-related complications. A total of 229 singletons were included, with 49 in the NC-FET group and 180 in the HT-FET group. There were no significant differences in obstetric complications and perinatal outcomes between the two groups. The NC-FET group had significantly higher serum levels of P4 (17.2 ng/mL vs 8.85 ng/mL; p < 0.0001) but not E2 (144 pg/mL vs 147 pg/mL; p = 0.69) on the day of ET. Additionally, 3 days after ET, the NC-FET group had significantly higher levels of both E2 (171 pg/mL vs 140.5 pg/mL; p = 0.0037) and P4 (27.3 ng/mL vs 11.7 ng/mL; p < 0.0001) compared with the HT-FET group. Our study revealed that although there were significant differences in E2 and P4 levels around implantation between the two groups, there were no significant differences in obstetric complications and perinatal outcomes. Therefore, the hormonal environment around implantation did not appear to be the primary cause of differences in obstetric and perinatal outcomes between the two EM preparation methods used in FET.

The Apelinergic System in Pregnancy.

The apelinergic system is a highly conserved pleiotropic system. It comprises the apelin receptor apelin peptide jejunum (APJ) and its two peptide ligands, Elabela/Toddler (ELA) and apelin, which have different spatiotemporal localizations. This system has been implicated in the regulation of the adipoinsular axis, in cardiovascular and central nervous systems, in carcinogenesis, and in pregnancy in humans. During pregnancy, the apelinergic system is essential for embryo cardiogenesis and vasculogenesis and for placental development and function. It may also play a role in the initiation of labor. The apelinergic system seems to be involved in the development of placenta-related pregnancy complications, such as preeclampsia (PE) and intrauterine growth restriction, but an improvement in PE-like symptoms and birth weight has been described in murine models after the exogenous administration of apelin or ELA. Although the expression of ELA, apelin, and APJ is altered in human PE placenta, data related to their circulating levels are inconsistent. This article reviews current knowledge about the roles of the apelinergic system in pregnancy and its pathophysiological roles in placenta-related complications in pregnancy. We also discuss the challenges in translating the actors of the apelinergic system into a marker or target for therapeutic interventions in obstetrics.

Assessment of First-Trimester Utero-Placental Vascular Morphology by 3D Power Doppler Ultrasound Image Analysis Using a Skeletonization Algorithm: The Rotterdam Periconception Cohort

ABSTRACT Abnormal uteroplacental vascular development is one of the primary causes of the major disorders of pregnancy. Identification of this aberrant development in the preconception stage and in the first trimester, when measures to prevent complications are most effective, remains a challenge. Recent advances in offline imaging processing and Doppler techniques have allowed ultrasonographic analysis of placental volume (PV) and uteroplacental vascular volume (uPVV) in the first trimester. The ability of ultrasound to assess specific vascular morphology is not fully understood. The aim of this study was to investigate morphologic development of the first-trimester human uteroplacental vasculature in vivo using 3-dimensional power Doppler ultrasound and advanced image processing to generate the uteroplacental vascular skeleton (uPVS). Data were obtained from the VIRTUAL Placenta study, an ongoing observational study including adult women carrying a singleton pregnancy at less than 10-week gestational age (GA). At least 2 study visits were scheduled in the first trimester, at 7, 9, and 11 weeks' GA. The image quality of ultrasound scans was scored on a 4-point scale ranging between 0 (optimal) and 3 (unusable), and PV was measured using VOCAL software. The uPVV was measured using a virtual reality desktop system with the V-scope volume-rendering application. A skeletonization algorithm was then applied to the uPVV segmentation to generate the uPVS, and 7 morphological uPVS characteristics were used to determine the density of vascular branching within the placenta. A total of 214 women from the VIRTUAL cohort were eligible for inclusion, and 81% of all ultrasound data were of sufficient quality for generation of the uPVS. The distribution of endpoints, vessel points, bifurcation points, and crossing points in the uPVS and the distribution of uPVS characteristics per cm3 uPVV show consistent morphologic patterns throughout the first trimester. Moderate to strong positive correlations between uPVS characteristics and PV and strong positive correlations between uPVS characteristics and uPVV were identified. All uPVS characteristics increased significantly through the first trimester, except for uPVS average length, which remained constant between 7, 9, and 11 weeks' GA. When stratifying for placenta-related complications among the cohort, no significant differences in the uPVS characteristics were seen at 7 weeks' GA (n = 94). However, at 9 weeks (n = 170), there were significantly fewer number of vessel points (P = 0.040), bifurcation points (P = 0.050), crossing points (P = 0.020), and a shorter total network length (P = 0.023) among pregnancies with placenta-related complications. At 11 weeks' GA (n = 129), uPVS average vascular thickness was significantly lower in pregnancies with placenta-related complications (P = 0.007), but no other uPVS differences were observed. At 11 weeks' GA, pregnancies with placenta-related complications were found to have an increased density of vascular branching in the uPVV. The results of this study demonstrate a quantitative morphologic analysis of the human uteroplacental vasculature in the first trimester of pregnancy and key differences in the vascular morphology between pregnancies with and without placenta-related complications.

Elevated homocysteine activates unfolded protein responses and causes aberrant trophoblast differentiation and mouse blastocyst development

Hyperhomocysteinemia may arise from folate/vitamin B12 deficiency, genetic polymorphisms, kidney disease, or hypothyroidism. It is associated with an increased risk of early pregnancy loss and placenta‐related complications of pregnancy, including pre‐eclampsia and fetal growth restriction. While the majority of studies of hyperhomocysteinemia focus on epigenetic changes secondary to metabolic disruption, the effects of homocysteine toxicity on placental development remain unexplored. Here, we investigated the influence of hyperhomocysteinemia on early blastocyst development and trophoblast differentiation. Exposure of cultured blastocysts to high homocysteine levels reduces cell number in the trophectoderm layer, most likely through increased apoptosis. Homocysteine also promotes differentiation of a trophoblast stem cell line. Both effects diminish the stem cell pool, and are mediated in an endoplasmic reticulum (ER) unfolded protein response (UPRER)‐dependent manner. Targeted alleviation of UPRER may therefore provide a new therapeutic intervention to improve pregnancy outcome in women with hyperhomocysteinemia.

Placental Abnormalities and Placenta-Related Complications Following In-Vitro Fertilization: Based on National Hospitalized Data in China

IntroductionEmerging evidence has shown that in-vitro fertilization (IVF) is associated with higher risks of certain placental abnormalities or complications, such as placental abruption, preeclampsia, and preterm birth. However, there is a lack of large population-based analysis focusing on placental abnormalities or complications following IVF treatment. This study aimed to estimate the absolute risk of placental abnormalities or complications during IVF-conceived pregnancy.MethodsWe conducted a retrospective cohort study of 16 535 852 singleton pregnancies with delivery outcomes in China between 2013 and 2018, based on the Hospital Quality Monitoring System databases. Main outcomes included placental abnormalities (placenta previa, placental abruption, placenta accrete, and abnormal morphology of placenta) and placenta-related complications (gestational hypertension, preeclampsia, eclampsia, preterm birth, fetal distress, and fetal growth restriction (FGR)). Poisson regression modeling with restricted cubic splines of exact maternal age was used to estimate the absolute risk in both the IVF and non-IVF groups.ResultsThe IVF group (n = 183 059) was more likely than the non-IVF group (n = 16 352 793) to present placenta previa (aRR: 1.87 [1.83–1.91]), placental abruption (aRR: 1.16 [1.11–1.21]), placenta accrete (aRR: 2.00 [1.96–2.04]), abnormal morphology of placenta (aRR: 2.12 [2.07 to 2.16]), gestational hypertension (aRR: 1.55 [1.51–1.59]), preeclampsia (aRR: 1.54 [1.51–1.57]), preterm birth (aRR: 1.48 [1.46–1.51]), fetal distress (aRR: 1.39 [1.37–1.42]), and FGR (aRR: 1.36 [1.30–1.42]), but no significant difference in eclampsia (aRR: 0.91 [0.80–1.04]) was found. The absolute risk of each outcome with increasing maternal age in both the IVF and non-IVF group presented two patterns: an upward curve showing in placenta previa, placenta accreta, abnormal morphology of placenta, and gestational hypertension; and a J-shape curve showing in placental abruption, preeclampsia, eclampsia, preterm birth, fetal distress, and FGR.ConclusionIVF is an independent risk factor for placental abnormalities and placental-related complications, and the risk is associated with maternal age. Further research is needed to evaluate the long-term placenta-related chronic diseases of IVF patients and their offspring.

First-trimester maternal haemodynamic adaptation to pregnancy and placental, embryonic and fetal development: the prospective observational Rotterdam Periconception cohort.

ObjectiveTo investigate whether first‐trimester maternal haemodynamic adaptation impacts placental, embryonic and fetal development as well as birth outcomes in pregnancies with and without placenta‐related complications.DesignProspective observational cohort.SettingA Dutch tertiary hospital.PopulationTwo hundred and fourteen ongoing pregnancies.MethodsAt 7, 9 and 11 weeks of gestation, we assessed maternal haemodynamic adaptation (mean arterial blood pressure [MAP], uterine artery [UtA] blood flow) and placental development (placental volume [PV], uteroplacental vascular volume [uPVV]) using three‐dimensional power Doppler ultrasound volumes, and embryonic development (crown–rump length, embryonic volume). At 22 and 32 weeks of gestation, fetal development was assessed by estimated fetal weight. Birth outcomes (birthweight, placental weight) were extracted from medical records. Linear mixed modelling and linear regression analyses were applied.Main outcome measuresBirthweight centile and placental weight.ResultsIn placenta‐related complications (n= 55, 25.7%), reduced haemodynamic adaptation, i.e. higher UtA pulsatility index (PI) and resistance index (RI) trajectories, was associated with smaller increase in PV (β = −0.559, 95% CI −0.841 to −0.278, P< 0.001; β = −0.579, 95% CI −0.878 to −0.280, P< 0.001) and uPVV trajectories (UtA PI: β = −0.301, 95% CI −0.578 to −0.023, P= 0.034). At birth, reduced haemodynamic adaptation was associated with lower placental weight (UtA PI: β = −0.502, 95% CI −0.922 to −0.082, P= 0.022; UtA RI: β = −0.435, 95% CI −0.839 to −0.032, P= 0.036). In pregnancies without placenta‐related complications, higher MAP trajectories were positively associated with birthweight centile (β = 0.398, 95% CI 0.049–0.748, P= 0.025).ConclusionsReduced first‐trimester maternal haemodynamic adaptation impacts both placental size and vascularisation and birthweight centile, in particular in pregnancies with placenta‐related complications.Tweetable abstractReduced first‐trimester maternal haemodynamic adaptation to pregnancy impairs early placental development.

Low Molecular Weight Heparins (LMWH) and Implications along Pregnancy: a Focus on the Placenta.

Low molecular weight heparins (LMWH) have been largely studied for their use during pregnancy. The biology and the pharmacology of these molecules are well known and may be summarized in three main mechanisms of action: anti-coagulant, anti-inflammatory, and immunomodulant. The clinical implications of these drugs during pregnancy are mainly related to their action on the placenta, because of the presence of specific molecular and cellular targets, particularly at the trophoblast-endometrial interface. As well as for the prevention and treatment of thromboembolism, LMWH have been largely investigated for the improvement of embryo implantation and for the prevention of placenta-related complications such as preeclampsia, fetal growth restriction, and intrauterine fetal death. However, data on this topic are still unclear. The present review discusses the biological features, the mechanisms of action, and the possible contribution of LMWH to the success of placentation along pregnancy, pointing out the need for future basic science and clinical researches in this important field with the final aim to improve clinical practice in high-risk pregnancies.

Correlation between endometrial thickness and perinatal outcome for pregnancies achieved through assisted reproduction technology.

Objective To explore the relationship between endometrial thickness and perinatal outcome in assisted reproductive techniques (ART). Methods A retrospective cohort study was conducted in 1139 infertile women who underwent ART treatment from January 2011 to July 2014. Four groups were divided by endometrial thickness on the human chorionic gonadotropin (HCG) trigger day in fresh embryo transfer cycles or on the progesterone administration day in frozen embryo transfer cycles, as group A (<8 mm), group B (8-10 mm), group C (10-14 mm) and group D (≥14 mm). Two other groups were delineated according to whether uterine lesions were present. The incidence of premature rupture of membranes (PROM), postpartum hemorrhage (PPH) and other common perinatal complications were observed subsequently. Results It was found that the highest incidence of PROM and PPH was in group A (P < 0.05). The incidence of PROM in group B was higher than in groups C and D (P < 0.05). The occurrence of mothers entering the intensive care unit (ICU) was significantly higher in group A than in group B (P < 0.05). However, no significant differences were found in other adverse outcomes. There was no difference in the incidence of adverse perinatal outcome when the endometrial thickness of pre-implantation was not attenuated by uterine lesions. Conclusion The incidence of PROM and PPH increased significantly when the thickness of the endometrium was less than 10 mm before implantation. Correspondingly, the number of mothers treated in the ICU was also higher under these circumstances. To reduce such perinatal placenta-related complications, we should maximize the thickness of the endometrium before transplantation of embryos.

Role of Endoplasmic Reticulum Stress in Proinflammatory Cytokine–Mediated Inhibition of Trophoblast Invasion in Placenta-Related Complications of Pregnancy

Shallow extravillous trophoblast (EVT) invasion is central to the pathophysiology of many pregnancy complications. Invasion is mediated partially by matrix metalloproteinases (MMPs). MMP-2 is highly expressed in early pregnancy. MMP activity can be regulated by proinflammatory cytokines, which also induce endoplasmic reticulum (ER) stress in other cells. We investigated whether proinflammatory cytokines regulate MMP-2 activity through ER stress response pathways in trophoblast before exploring potential regulatory mechanisms. There was increased immunoreactivity of heat shock 70-kDa protein 5, also known as 78-kDa glucose regulated protein, in cells of the placental bed, including EVTs, in cases of early-onset preeclampsia compared with normotensive controls. Treating EVT-like JEG-3 and HTR8/SVneo cells with ER stress inducers (tunicamycin and thapsigargin) suppressed MMP2 mRNA and protein expression, secretion, and activity and reduced their invasiveness. A cocktail of proinflammatory cytokines (IL-1β, tumor necrosis factor-α, and interferon-γ) suppressed MMP-2 activity in JEG-3 cells and was accompanied by activation of the PKR-like ER kinase (PERK)–eukaryotic translation initiation factor 2A (EIF2A) arm of the ER stress pathway. Knockdown of ATF4, a downstream transcriptional factor of the PERK-EIF2A pathway, by small interference RNA, restored MMP2 expression but not cellular proteins. However, suppression of EIF2A phosphorylation with a PERK inhibitor, GSK2606414, under ER stress, restored MMP-2 protein. ER stress regulates MMP-2 expression at both the transcriptional and translational levels. This study provides the first mechanistic linkage by which proinflammatory cytokines may modulate trophoblast invasion through ER stress pathways.

The impact of periconceptional maternal lifestyle on clinical features and biomarkers of placental development and function: a systematic review.

Worldwide, placenta-related complications contribute to adverse pregnancy outcomes, such as pre-eclampsia, fetal growth restriction and preterm birth, with implications for the future health of mothers and offspring. The placenta develops in the periconception period and forms the interface between mother and embryo/fetus. An unhealthy periconceptional maternal lifestyle, such as smoking, alcohol and under- and over-nutrition, can detrimentally influence placental development and function. The impact of maternal lifestyle on placental health is largely unknown. Therefore, we aim to summarize the evidence of the impact of periconceptional maternal lifestyle on clinical features and biomarkers of placental development and function throughout pregnancy. A comprehensive search in Medline, Embase, Pubmed, The Cochrane Library Web of Science and Google Scholar was conducted. The search strategy included keywords related to the maternal lifestyle, smoking, alcohol, caffeine, nutrition (including folic acid supplement intake) and body weight. For placental markers throughout pregnancy, keywords related to ultrasound imaging, serum biomarkers and histological characteristics were used. We included randomized controlled trials and observational studies published between January 2000 and March 2017 and restricted the analysis to singleton pregnancies and maternal periconceptional lifestyle. Methodological quality was scored using the ErasmusAGE tool. A protocol of this systematic review has been registered in PROSPERO International prospective register of systematic reviews (PROSPERO 2016:CRD42016045596). Of 2593 unique citations found, 82 studies were included. The median quality score was 5 (range: 0-10). The findings revealed that maternal smoking was associated with lower first-trimester placental vascularization flow indices, higher second- and third-trimester resistance of the uterine and umbilical arteries and lower resistance of the middle cerebral artery. Although a negative impact of smoking on placental weight was expected, this was less clear. Alcohol use was associated with a lower placental weight. One study described higher second- and third-trimester placental growth factor (PlGF) levels after periconceptional alcohol use. None of the studies looked at caffeine intake. Adequate nutrition in the first trimester, periconceptional folic acid supplement intake and strong adherence to a Mediterranean diet, were all associated with a lower resistance of the uterine and umbilical arteries in the second and third trimester. A low caloric intake resulted in a lower placental weight, length, breadth, thickness, area and volume. Higher maternal body weight was associated with a larger placenta measured by ultrasound in the second and third trimester of pregnancy or weighed at birth. In addition, higher maternal body weight was associated with decreased PlGF-levels. Evidence of the impact of periconceptional maternal lifestyle on placental health was demonstrated. However, due to poorly defined lifestyle exposures and time windows of investigation, unstandardized measurements of placenta-related outcomes and small sample sizes of the included studies, a cautious interpretation of the effect estimates is indicated. We suggest that future research should focus more on physiological consequences of unhealthy lifestyle during the critical periconception window. Moreover, we foresee that new evidence will support the development of lifestyle interventions to improve the health of mothers and their offspring from the earliest moment in life.

Inherited Thrombophilia and Pregnancy Complications: Should We Test?

Recurrent miscarriages and pregnancy-related complications cause significant stress to couples looking for successful pregnancy outcome as well as to health care professionals. There is conflicting evidence with respect to the presence and the strength of associations between inherited thrombophilia and these complications. A complete thrombophilia screen is expensive, and no proven effective treatment for women with recurrent miscarriage and inherited thrombophilia is currently available. Based on the concept of microvascular thrombosis of the placenta, women with recurrent miscarriage and placenta-related complications frequently get treated with antithrombotic therapy. In this narrative review, the authors explore the evolving understanding and evidence of inherited thrombophilia in recurrent miscarriages and other pregnancy complications, and whether antithrombotic treatment would modify pregnancy outcome in women with inherited thrombophilia. Finally, they provide some personal recommendations based on available evidence for clinical practice. In summary, inherited thrombophilia testing is not required outside a clinical trial for women with recurrent pregnancy losses or late pregnancy complications. The presence of thrombophilia markers does not generally indicate additional therapy during pregnancy, even if a heritable thrombophilic defect is found in women with recurrent miscarriages or late pregnancy complications.

Placental development and function in women with a history of placenta-related complications: a systematic review.

Women with a history of placenta-related pregnancy complications, such as preeclampsia, intrauterine growth restriction or preterm delivery, have an increased risk for recurrence of such complications. This recurrence is likely the result of underlying endothelial dysfunction that leads to abnormal placentation, especially in complications with an early onset. This study provides an overview of biomarkers of placental development and function in pregnancies from women with a history of placenta-related complications. A systematic literature search was conducted limited to human studies and including keywords related to a history of placenta-related complications and markers of placental development and function. Two independent reviewers assessed eligibility and quality of 1553 retrieved unique articles. Five articles reporting on placental development and function in women with an obstetric history of preeclampsia (n=3), intrauterine growth restriction (n=1) and preterm delivery (n=2) were eligible for quality assessment. We identified associations between a history of preeclampsia and abnormal placental histological findings at term in the current pregnancy, but found contradictory results regarding presence of uterine artery notching. In women with a history of very preterm delivery (<32weeks), one study showed associations with abnormal placental histology. Literature on the association between a history of placenta-related complications and placental development and function in subsequent pregnancies is scarce and studies are heterogeneous. However, literature shows that placenta-related pregnancy complications are associated with subsequent placental histology.

Placenta-related complications in women carrying a foetus with congenital heart disease

Introduction: Recent studies pointed to an intrinsically angiogenic imbalance in CHD in the maternal and foetal circulation suggestive of impaired placentation.Objectives: To assess whether pregnant women with a CHD foetus are at greater risk of placenta-related complications.Methods: Perinatal results of women with a CDH foetus were compared with those of a non-selected population followed up at our centre. Multiple pregnancies and chromosomal abnormalities were excluded from the analysis.Results: About 279 pregnancies with CHD foetuses were included. Mothers were classified in three groups according to the foetal cardiac defect: 104 (37.3%) atrioventricular defect, 102 (36.5%) conotruncal anomalies and 73 (26.2%) left-ventricular outflow tract obstruction. A significantly higher incidence of pre-eclampsia was observed in the CHD group compared with the normal population (5.7% versus 1.2% p < 0.0001) [OR 5.96 (95% CI – 3.19–10.54)]. About 9.7% of foetuses with CHD had < 3rd birth weight percentile compared with 3% for the normal population [OR 3.32 (95% CI – 2.39–4.56)]. A higher incidence of stillbirth was also observed in the CHD group compared with the normal population (2.5% versus 0.4%) [OR 9.45 (95% CI – 3.35–23.3)].Conclusions: Women carrying a foetus with CHD have a high risk of pre-eclampsia and intrauterine growth restriction. The relationship between CHD and placenta-related complications could be an encouraging topic for future research.

Altered folate metabolism modifies cell proliferation and progesterone secretion in human placental choriocarcinoma JEG-3 cells.

Folate is an essential B vitamin required for de novo purine and thymidylate synthesis, and for the remethylation of homocysteine to form methionine. Folate deficiency has been associated with placenta-related pregnancy complications, as have SNP in genes of the folate-dependent enzymes, methionine synthase (MTR) and methylenetetrahydrofolate dehydrogenase 1 (MTHFD1). We aimed to determine the effect of altered folate metabolism on placental cell proliferation, viability and invasive capacity and on progesterone and human chorionic gonadotropin (hCG) secretion. Human placental choriocarcinoma (JEG-3) cells cultured in low folic acid (FA) (2 nM) demonstrated 13% (P<0.001) and 26% (P<0.001) lower proliferation, 5.5% (P=0.025) and 7.5% (P=0.004) lower invasion capacity, and 5 to 7.5% (P=0.004-0.025) lower viability compared with control (20 nM) or supplemented (100 nM) cells, respectively. FA concentration had no effect on progesterone or hCG secretion. Small interfering RNA (siRNA) knockdown of MTR gene and protein expression resulted in 17.7% (P<0.0001) lower proliferation and 61% (P=0.014) higher progesterone secretion, but had no effect on cell invasion and hCG secretion. siRNA knockdown of MTHFD1 gene expression in the absence of detectable changes in protein expression resulted in 10.3% (P=0.001) lower cell proliferation, but had no effect on cell invasion and progesterone or hCG secretion. Our data indicate that impaired folate metabolism can result in lower trophoblast proliferation, and could alter viability, invasion capacity and progesterone secretion, which may explain in part the observed associations between folate and placenta-related complications.

Relationship of mid-trimester serum screening markers and adverse pregnancy outcomes

To explore the relationship of mid-trimester serum screening markers and adverse pregnancy outcomes. We retrospectively reviewed all obstetric patients with mid-trimester screening data who delivered at our department from September 2010 to November 2012. Adjusted effects were estimated with Logistic regression analysis. A total of 3 618 cases were enrolled. The level of free β-subunit of human chorionic gonadotropin (fβ-hCG) [ ≥ 2.2 (multiple of median) MOM] was associated with the risk of pregnancy-related hypertension (OR = 2.06, 95%CI 1.18-3.60, P < 0.01). And fβ-hCG ( ≥ 2.2 MOM) and alpha-fetoprotein (AFP) ( ≥ 1.88 MOM) were associated with the development of placenta-related complications (P < 0.01, 0.05 respectively). Additionally, maternal weight was associated with the risk of pregnancy-related hypertension and placenta-related complications (both P < 0.05). The mid-trimester screening markers fβ-hCG and AFP are associated the risk of adverse pregnancy outcomes. And their value may predict the risk of adverse pregnancy outcomes.

Prevention of Perinatal Death and Adverse Perinatal Outcome Using Low-Dose Aspirin

The leading causes of perinatal death are preterm birth, fetal abnormalities, and impaired placentation leading to preeclampsia and fetal growth restriction. Prophylactic use of low-dose aspirin beginning at 16 weeks’ gestation or less has been associated with significant reductions in the prevalence of these placenta-related complications. Improving deep placentation could reduce the incidence of several adverse pregnancy outcomes and rate of perinatal death. This systematic review and meta-analysis of recent randomized trials were done to compare the effect of early and late administration of aspirin on the risk of perinatal death and other adverse outcomes. EMBASE, PubMed, Cochrane Central Register of Controlled Trials, and Web of Science were searched for relevant citations from 1965 to October 2011. Only prospective, randomized controlled trials involving pregnant women treated with low-dose aspirin (≤150 mg), with or without dipyridamole (≤300 mg), were included. Control groups had to have received placebo or no treatment. All studies that involved women who initiated treatment at 16 weeks or less and at more than 16 weeks’ gestation were included. The main outcome was perinatal mortality (fetal death after 16 weeks’ gestation or neonatal death before 28 days). Secondary outcomes were preeclampsia, severe preeclampsia, fetal growth restriction, preterm birth, placental abruption, birth weight, and gestational age at delivery. Review Manager 5.0.25 and SAS 9.2 software were used for analysis. Relative risks (RRs) were calculated and pooled for global analysis with 95% confidence intervals (CIs) and stratified according to gestational age at entry (≤16 or >16 weeks). Forty-two of 66 studies meeting inclusion criteria were included (27,222 women randomized) in the final analysis. When compared with controls, treatment with low-dose aspirin started at 16 weeks’ gestation or less compared with low-dose aspirin started at more than 16 weeks’ gestation was associated with a greater reduction in perinatal death (RR = 0.41; 95% CI, 0.19–0.92 vs RR = 0.93; 95% CI, 0.73–1.19; P = 0.02), preeclampsia (RR = 0.47; 95% CI, 0.36–0.62 vs RR = 0.78; 95% CI, 0.61–0.99; P < 0.01), severe preeclampsia (RR = 0.18; 95% CI, 0.08–0.41 vs RR = 0.65; 95% CI, 0.40–1.07; P < 0.01), fetal growth restriction (RR = 0.46; 95% CI, 0.33–0.64 vs RR = 0.98; 95% CI, 0.88–1.08; P < 0.001), and preterm birth (RR = 0.35; 95% CI, 0.22–0.57 vs RR = 0.90; 95% CI, 0.83–0.97; P < 0.001). The difference in RR according to gestational age at entry remained statistically significant (P = 0.03) when comparing women recruited at 16 weeks or less with those recruited at 16 to 24 weeks (RR = 1.01; 95% CI, 0.49–2.08; P = 0.99). In 7 studies (22%) reporting the reasons for perinatal death, 17 (65%) of 26 perinatal deaths were related to preeclampsia, fetal growth restriction, or placental abruption. Similar effects of early aspirin prophylaxis were found in women who received 80 mg or less daily and those who received 100 mg or more daily and in women selected using abnormal uterine artery Doppler as an inclusion criterion as compared with those selected using anamnesis factors only. These results suggest that prophylaxis with low-dose aspirin can lead to significant reductions in perinatal death, preeclampsia, fetal growth restriction, and preterm birth provided treatment is started at 16 weeks’ gestation or less. The beneficial effect of aspirin likely results from an improvement in the transformation of uterine spiral arteries. Abnormal uterine artery blood flow is present as early as 12 weeks’ gestation in women who will later develop preeclampsia. Because low-dose aspirin improves uterine artery blood flow between the first and the second trimesters, such a regimen should probably be initiated at 8 to 12 weeks’ gestation in high-risk women.

PP109. Risk of preeclampsia in homologous and oocyte donation IVF pregnancies

Women who conceived by donor oocyte in vitro fertilization (IVF) are at high risk for placenta-related complications, because of advanced maternal age, nulliparity and maybe for an altered immune response. The aim of this case-control study is to compare the incidence and the characteristics of preeclampsia in women who conceived by oocyte donor or by homologous IVF. Data were collected from 65 consecutive women who conceived through oocyte donor IVF and 71 consecutive pregnancies from homologous IVF in women older than 35years (control group), who attended our institution between 2009 and 2011. Data are expressed as percentage, average and standard deviation (SD). Statistical analysis was performed by chi-square test for unpaired data and the results were considered significant with p<0.05. Thirteen women from the donor oocyte group were excluded because of first trimester miscarriage, ectopic pregnancy and lack of data. After the exclusion, 52 pregnancies from oocyte donation were compared to the control group. Baseline characteristics, such as maternal age, BMI, parity and prevalence of twin pregnancies were similar in the two groups. Preexisting hypertension was present only in the oocyte donor IVF group (n=6 cases). The risk of preeclampsia was significantly related to oocyte donor IVF (27% vs 5.6%, p=0.0024 OR=6.17), even when only singleton pregnancies were considered (16.7 vs 1.9%; p=0.02, OR=9). When women with preexisting hypertension were excluded, the incidence of severe preeclampsia remained significant (p=0.02). This result was not confirmed when both preexisting hypertension and twin pregnancies were excluded (p=0.09), even if the percentage of cases was higher in the oocyte donor IVF group (10.7% vs 1.85%). Three cases of life threatening severe preeclampsia occurred before the 24th week, two of which required interruption of pregnancy; one case was complicated by eclampsia. The two groups did not show significant differences in terms of prevalence of IUGR, both in multiple and singleton pregnancies, even if percentage values were higher in the donor IVF group (multiple: 21.2% vs 11.3%, p=0.21/ singleton 10% vs 5.6%, p=0.48). IVF with oocyte donation stands as an independent risk factor for preeclampsia. The risk of developing a severe and early preeclampsia may be increased when chronic hypertension occurs.

First‐trimester serum PAPP‐A and fβ‐hCG concentrations and other maternal characteristics to establish logistic regression‐based predictive rules for adverse pregnancy outcome

To determine the clinical relevance of maternal characteristics and first-trimester serum concentrations of pregnancy-associated plasma protein A (PAPP-A) and free beta human chorionic gonadotrophin (fβ-hCG) in predicting placenta-related complications, miscarriage and preterm delivery. DESIGN, SETTING AND POPULATION: A historical cohort study of data of the National Institute for Public Health and the Environment of first-trimester screening tests performed between July 2002 and May 2006 was done. Data from 28 566 (64.1%) tests were eligible for analysis. By logistic regression, predictive rules were made based on PAPP-A and fβ-hCG concentrations, maternal smoking, maternal weight and age, low birth weight, stillbirth and hypertensive disorders, miscarriage and preterm birth. Predictive values were analysed with the area under the curve (AUC) of receiver operating curves (ROC). Predictive for placenta-related complications were low PAPP-A, low fβ-hCG, smoking and weight (AUC 54%). For miscarriage low PAPP-A, low fβ-hCG and maternal age (MA) were predictive (AUC 78%) and for preterm delivery low PAPP-A, smoking, MA and maternal weight (AUC 55%). Only the predictive model for miscarriage had a clinically relevant predictive value of 28%. Results together do not justify closer surveillance of chromosomally normal pregnancies with PAPP-A or fβ-hCG levels below the fifth percentile.