Despite occasional reports of vertical transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during pregnancy, the question of placental infection and its consequences for the ...newborn remain unanswered. Herein, we analyzed the placentas of 31 coronavirus disease 2019–positive mothers by reverse transcriptase PCR, immunohistochemistry, and in situ hybridization. Only one case of placental infection was detected, which was associated with intrauterine demise of the fetus. Differentiated primary trophoblasts were then isolated from nonpathologic human placentas at term, differentiated, and exposed to SARS-CoV-2 virions. Unlike for positive control cells Vero E6, the virus inside cytotrophoblasts and syncytiotrophoblasts or in the supernatant 4 days after infection was undetectable. As a mechanism of defense, we hypothesized that trophoblasts at term do not express angiotensin-converting enzyme 2 and transmembrane protease serine 2 (TMPRSS2), the two main host membrane receptors for SARS-CoV-2 entry. The quantification of these proteins in the placenta during pregnancy confirmed the absence of TMPRSS2 at the surface of the syncytium. Surprisingly, a transiently induced experimental expression of TMPRSS2 did not allow the entry or replication of the virus in differentiated trophoblasts. Altogether, these results underline that trophoblasts are not likely to be infected by SARS-CoV-2 at term, but raise concern about preterm infection.
The frequency of twin gestations has increased over the last few decades, mainly due to maternal age at childbearing, and the use of assisted reproductive technologies. Twins are at higher risk of ...aneuploidy, structural anomalies, and placental abnormalities. Some of the placental and umbilical cord abnormalities found in twin gestations are nonspecific and can be found in singleton gestations (ie, placenta previa, placental abruption, single umbilical artery, velamentous cord insertion, vasa previa, etc). However, other anomalies are unique to twin gestations, and are mainly associated with monochorionic twins–these include intraplacental anastomosis and cord entanglement. Most of these conditions can be diagnosed with ultrasound. An accurate and early diagnosis is important in the management of twin gestations. Determination of chorionicity, amnionicity, and the identification of placental anomalies are key issues for the adequate management of twin pregnancies. Pathologic placental examination after delivery can help in assessing the presence of placental and umbilical cord abnormalities, as well as providing information about chorionicity and gaining insight into the potential mechanisms of disease affecting twin gestations.
Preeclampsia is one of the leading causes of maternal mortality worldwide and is strongly associated with long-term morbidity in mothers and newborns. Referred to as one of the deep placentation ...disorders, insufficient remodeling of the spiral arteries during the first trimester remains a major cause of placental dysfunction. Persisting pulsatile uterine blood flow causes abnormal ischemia/reoxygenation phenomenon in the placenta and stabilizes the HIF-2α (hypoxia-inducible factor-2α) in the cytotrophoblasts. HIF-2α signaling impairs trophoblast differentiation and increases sFLT-1 (soluble fms-like tyrosine kinase-1) secretion, which reduces fetal growth and causes maternal symptoms. This study aims to evaluate the benefits of using PT2385-an oral specific HIF-2α inhibitor-to treat severe placental dysfunction.
To evaluate its therapeutic potential, PT2385 was first studied in primary human cytotrophoblasts isolated from term placenta and exposed to 2.5% O
to stabilize HIF-2α. Viability and luciferase assays, RNA sequencing, and immunostaining were used to analyze differentiation and angiogenic factor balance. The ability of PT2385 to mitigate maternal manifestations of preeclampsia was studied in the selective reduced uterine perfusion pressure model performed in Sprague-Dawley rats.
In vitro, RNA sequencing analysis and conventional techniques showed that treated cytotrophoblast displayed an enhanced differentiation into syncytiotrophoblasts and normalized angiogenic factor secretion compared with vehicle-treated cells. In the selective reduced uterine perfusion pressure model, PT2385 efficiently decreased sFLT-1 production, thus preventing the onset of hypertension and proteinuria in pregnant dams.
These results highlight HIF-2α as a new player in our understanding of placental dysfunction and support the use of PT2385 to treat severe preeclampsia in humans.
Objective
The Euro‐Lupus regimen of low‐dose intravenous cyclophosphamide (IV CYC) (cumulative dose of 3 gm) was developed to reduce gonadal toxicity. To address the possibility of a marginal effect ...on the ovarian reserve, we measured serum titers of anti–Müllerian hormone (AMH) in patients with systemic lupus erythematosus (SLE) treated with the Euro‐Lupus regimen and compared them with those measured in patients who were treated with higher doses of IV CYC or were never treated with IV CYC.
Methods
Serum AMH levels were measured by enzyme‐linked immunosorbent assay in a cohort of 155 premenopausal SLE patients; 30 of these patients had been treated with the Euro‐Lupus regimen, and 24 had received higher doses of IV CYC. None had received oral CYC. AMH levels were age‐adjusted using a slope computed from levels measured across the group of SLE patients who had not been treated with IV CYC. Demographic and clinical data were collected.
Results
Serum titers of AMH measured in SLE patients treated with the Euro‐Lupus IV CYC regimen (median dose 1.46 ng/ml) did not differ from those measured in patients never treated with the cytotoxic drug (median 1.85 ng/ml). As expected, patients given >6 gm of IV CYC had significantly lower serum titers of AMH (median 0.83 ng/ml) compared with those never treated with IV CYC (P = 0.047). Median serum AMH titers did not change before (1.24 ng/ml) and after (2.50 ng/ml) treatment with the Euro‐Lupus IV CYC regimen in the subset of patients for whom paired samples could be tested (P = 0.43).
Conclusion
The Euro‐Lupus regimen of low‐dose IV CYC does not impact the ovarian reserve of SLE patients and can therefore be proposed as treatment in patients seeking to become pregnant.
Pregnancy in women with paroxysmal nocturnal hemoglobinuria (PNH) is associated with increased maternal and fetal complications, to such an extent that PNH has for long been considered a relative ...contraindication for pregnancy. The most serious life-threatening complications are venous thromboembolic events, the risk of which is increased by the hypercoagulable state related to pregnancy. Eculizumab, a C5 complement inhibitor, has revolutionized the treatment of PNH. However, there are no published trials evaluating its use in pregnancy. Most recommendations are based on expert opinions and case reports. We report on the favorable outcome of a PNH patient who became pregnant while under eculizumab, suggesting that this drug can be given from conception to delivery.
Chemotherapy and especially anthracyclines are associated to cardiotoxicity. To assess this potential risk during pregnancy a clinical case–control trial was conducted. Maternal cardiac function, ...fetal Doppler and fetal cardiac function were evaluated before and after chemotherapy. Maternal cardiac function was assessed by echocardiography before and after the third cycle of anthracyclines and compared with a control group of 10 non‐pregnant women matched for age, type of cancer and anthracycline treatment. Ten fetuses exposed to chemotherapy were compared with 10 control fetuses matched for gestational age and gender. Biometry, amniotic fluid index, fetal Doppler and cardiac function were assessed before and after each cycle of chemotherapy. In all, 108 fetal ultrasounds scans were performed before and after 36 cycles of chemotherapy. Anthracycline exposure did not result in acute maternal and fetal cardiac dysfunction in this small cohort study.
The placenta is the functional interface between the mother and the fetus during pregnancy, and a critical determinant of fetal growth and life-long health. In the first trimester, it develops under ...a low-oxygen environment, which is essential for the conceptus who has little defense against reactive oxygen species produced during oxidative metabolism. However, failure of invasive trophoblasts to sufficiently remodel uterine arteries toward dilated vessels by the end of the first trimester can lead to reduced/intermittent blood flow, persistent hypoxia and oxidative stress in the placenta with consequences for fetal growth. Fetal growth restriction (FGR) is observed in ∼10% of pregnancies and is frequently seen in association with other pregnancy complications, such as preeclampsia (PE). FGR is one of the main challenges for obstetricians and pediatricians, as smaller fetuses have greater perinatal risks of morbidity and mortality and postnatal risks of neurodevelopmental and cardio-metabolic disorders.
The aim of this review was to examine the importance of placental responses to changing oxygen environments during abnormal pregnancy in terms of cellular, molecular and functional changes in order to highlight new therapeutic pathways, and to pinpoint approaches aimed at enhancing oxygen supply and/or mitigating oxidative stress in the placenta as a mean of optimizing fetal growth.
An extensive online search of peer-reviewed articles using PubMed was performed with combinations of search terms including pregnancy, placenta, trophoblast, oxygen, hypoxia, high altitude, FGR and PE (last updated in May 2020).
Trophoblast differentiation and placental establishment are governed by oxygen availability/hypoxia in early pregnancy. The placental response to late gestational hypoxia includes changes in syncytialization, mitochondrial functions, endoplasmic reticulum stress, hormone production, nutrient handling and angiogenic factor secretion. The nature of these changes depends on the extent of hypoxia, with some responses appearing adaptive and others appearing detrimental to the placental support of fetal growth. Emerging approaches that aim to increase placental oxygen supply and/or reduce the impacts of excessive oxidative stress are promising for their potential to prevent/treat FGR.
There are many risks and challenges of intervening during pregnancy that must be considered. The establishment of human trophoblast stem cell lines and organoids will allow further mechanistic studies of the effects of hypoxia and may lead to advanced screening of drugs for use in pregnancies complicated by placental insufficiency/hypoxia. Since no treatments are currently available, a better understanding of placental adaptations to hypoxia would help to develop therapies or repurpose drugs to optimize placental function and fetal growth, with life-long benefits to human health.
Advances in managing adult congenital heart disease (ACHD) have led to an increased number of women with CHD reaching childbearing age. This demographic shift underscores the need for improved ...understanding and prediction of complications during pregnancy in this specific ACHD population. Despite progress in maternal cardiac risk assessment, the prediction of neonatal outcomes for ACHD pregnancies remains underdeveloped. Therefore, the aims of this study are to assess neonatal outcomes in a CHD women population, to identify their predictive factors and to propose a new risk score for predicting neonatal complications.
This registry study included all women born between 1975 and 1996 diagnosed with ACHD who underwent at least one cardiology consultation for ACHD in Cliniques Universitaires Saint-Luc. A multivariate analysis was performed to identify predictors of neonatal complications and these were incorporated into a new risk index. Its validity was assessed using bootstrap method. This score was then compared with scores adapted from the ZAHARA and CARPREG studies for offspring events prediction.
Analysis of 491 pregnancies revealed 31.4% of neonatal complications. Four significant predictors of adverse neonatal outcomes were identified: cardiac treatment during pregnancy (OR 14.8, 95%CI 3.4-66), hypertensive disorders of pregnancy (OR 11.4, 95%CI 3.4-39.0), smoking during pregnancy (OR 10.6, 95%CI 2.8-40.6), and pre-pregnancy BMI <18.5 kg/m² (OR 6.5, 95%CI 2.5-16.5). The risk model demonstrated an AUC of 0.70 (95%CI 0.65-0.75), which remained stable after bootstrap validation. This model significantly outperformed the scores adapted from ZAHARA and CARPREG data. Based on the regression coefficients, a risk score was subsequently developed comprising five risk categories.
One third of ACHD pregnancies are complicated by poor neonatal outcome. These complications are determined by four independent factors relating to the cardiac and non-cardiac status of the patients, which have been incorporated into a risk score. Our study is one of the first to propose a predictive risk score of neonatal outcomes in ACHD pregancies, and paves the way for other validation and confirmation studies.
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