Efficacy and safety of hydroxychloroquine for treatment of mild SARS-CoV-2 infection and prevention of COVID-19 severity in pregnant and postpartum women: A randomized, double-blind, placebo-controlled trial.

INTRODUCTION: Pregnant women have an increased risk of severe COVID-19. Evaluation of drugs with a safety reproductive toxicity profile is a priority. At the beginning of the pandemic, hydroxychloroquine (HCQ) was recommended for COVID-19 treatment. MATERIAL AND METHODS: A randomized, double-blind, placebo-controlled clinical trial was conducted in eight teaching hospitals in Spain to evaluate the safety and efficacy of HCQ in reducing viral shedding and preventing COVID-19 progression. Pregnant and postpartum women with a positive SARS-CoV-2 PCR (with or without mild COVID-19 signs/symptoms) and a normal electrocardiogram were randomized to receive either HCQ orally (400 mg/day for 3 days and 200 mg/day for 11 days) or placebo. PCR and electrocardiogram were repeated at day 21 after treatment start. Enrollment was stopped before reaching the target sample due to low recruitment rate. Trial registration EudraCT #: 2020-001587-29, on April 2, 2020. CLINICAL TRIALS: gov # NCT04410562, registered on June 1, 2020. RESULTS: A total of 116 women (75 pregnant and 41 post-partum) were enrolled from May 2020 to June 2021. The proportion of women with a positive SARS-CoV-2 PCR at day 21 was lower in the HCQ group (21.8%, 12/55) than in the placebo group (31.6%, 18/57), although the difference was not statistically significant (P = 0.499). No differences were observed in COVID-19 progression, adverse events, median change in QTc, hospital admissions, preeclampsia or poor pregnancy and perinatal outcomes between groups. CONCLUSIONS: HCQ was found to be safe in pregnant and postpartum women with asymptomatic or mild SARS-CoV-2 infection. Although the prevalence of infection was decreased in the HCQ group, the statistical power was insufficient to confirm the potential beneficial effect of HCQ for COVID-19 treatment.

Glomerular diseases in pregnancy: pragmatic recommendations for clinical management.

Our understanding of the various aspects of pregnancy in women with kidney diseases has significantly improved in the last decades. Nevertheless, little is known about specific kidney diseases. Glomerular diseases are not only a frequent cause of chronic kidney disease in young women, but combine many challenges in pregnancy: immunologic diseases, hypertension, proteinuria, and kidney tissue damage. An international working group undertook the review of available current literature and elicited expert opinions on glomerular diseases in pregnancy with the aim to provide pragmatic information for nephrologists according to the present state-of-the-art knowledge. This work also highlights areas of clinical uncertainty and emphasizes the need for further collaborative studies to improve maternal and fetal health.

Dopamine receptors D1 and D2 show prognostic significance and potential therapeutic applications for endometrial cancer patients.

OBJECTIVE: Catecholaminergic signaling has been a target for therapy in different type of cancers. In this work, we characterized the ADRß2, DRD1 and DRD2 expression in healthy tissue and endometrial tumors to evaluate their prognostic significance in endometrial cancer (EC), unraveling their possible application as an antitumor therapy. METHODS: 109 EC patients were included. The expression of the ADRß2, DRD1 and DRD2 proteins was evaluated by immunohistochemistry and univariate and multivariate analysis to assess their association with clinic-pathological and outcome variables. Finally, HEC1A and AN3CA EC cell lines were exposed to different concentrations of selective dopaminergic agents alone or in combination to study their effects on cellular viability. RESULTS: ADRß2 protein expression was not associated with clinico-pathological parameters or prognosis. DRD1 protein expression was reduced in tumors samples but showed a significant inverse association with tumor size and stage. DRD2 protein expression was significantly associated with non-endometrioid EC, high grade tumors, tumor size, worse disease-free survival (HR = 3.47 (95%CI:1.35-8.88)) and overall survival (HR = 2.98 (95%CI:1.40-6.34)). The DRD1 agonist fenoldopam showed a reduction of cellular viability in HEC1A and AN3CA cells. The exposure to domperidone, a DRD2 antagonist, significantly reduced cell viability compared to the control. Finally, DRD1 agonism and DRD2 antagonism combination induced a significant reduction in cell viability of the AN3CA cells compared to monotherapy, close to being an additive response than a synergistic effect (CI of 1.1 at 0.5% Fa). CONCLUSION: DRD1 and DRD2 expression levels showed a significant association with clinico-pathological parameters. Both the combined activation of DRD1 and blockage of DRD2 may form an innovative strategy to inhibit tumor growth in EC.

Low-molecular-weight heparin for prevention of preeclampsia and other placenta-mediated complications: a systematic review and meta-analysis.

BACKGROUND: Evidence on the impact of low-molecular-weight heparin, alone or in combination with low-dose aspirin, for the prevention for preeclampsia in high-risk patients is conflicting. OBJECTIVE: We conducted a meta-analysis of studies published to assess the effectiveness of low-molecular-weight heparin for the prevention of preeclampsia and other placenta-related complications in high-risk women. DATA SOURCES: A systematic search was performed to identify relevant studies, using the databases PubMed and Cochrane Central Register of Controlled Trials, without publication time restrictions. STUDY ELIGIBILITY CRITERIA: Randomized controlled trials comparing treatment with low-molecular-weight heparin or unfractionated heparin (with or without low-dose aspirin), in high-risk women, defined as either history of preeclampsia, intrauterine growth restriction, fetal demise, or miscarriage or being at high risk after first-trimester screening of preeclampsia. STUDY APPRAISAL AND SYNTHESIS METHODS: The systematic review was conducted according to the Cochrane Handbook guidelines. The primary outcome was the development of preeclampsia. We performed prespecified subgroup analyses according to combination with low-dose aspirin, low-molecular-weight heparin type, gestational age when treatment was started, and study population (patients with thrombophilia, at high risk of preeclampsia or miscarriage). Secondary outcomes included small for gestational age, perinatal death, miscarriage, and placental abruption. Pooled odds ratios with 95% confidence intervals were calculated using a random-effects model. Quality of evidence was assessed using the grading of recommendations assessment, development, and evaluation methodology. RESULTS: A total of 15 studies (2795 participants) were included. In high-risk women, treatment with low-molecular-weight heparin was associated with a reduction in the development of preeclampsia (odds ratio, 0.62; 95% confidence interval, 0.43-0.90; P=.010); small for gestational age (odds ratio, 0.61; 95% confidence interval, 0.44-0.85; P=.003), and perinatal death (odds ratio, 0.49; 95% confidence interval, 0.25-0.94; P=.030). This reduction was stronger if low-molecular-weight heparin was started before 16 weeks' gestation (13 studies, 2474 participants) for preeclampsia (odds ratio, 0.55; 95% confidence interval, 0.39-0.76; P=.0004). When only studies including low-dose aspirin as an intervention were analyzed (6 randomized controlled trials, 920 participants), a significant reduction was observed in those with combined treatment (low-molecular-weight heparin plus low-dose aspirin) compared with low-dose aspirin alone (odds ratio, 0.62; 95% confidence interval, 0.41-0.95; P=.030). Overall, adverse events were neither serious nor significantly different. Quality of evidence ranged from very low to moderate, mostly because of the lack of blinding, imprecision, and inconsistency. CONCLUSION: Low-molecular-weight heparin use was associated with a significant reduction in the risk of preeclampsia and other placenta-mediated complications in high-risk women and when treatment was started before 16 weeks' gestation. Combined treatment with low-dose aspirin was associated with a significant reduction in the risk of preeclampsia compared with low-dose aspirin alone. However, there exists important clinical and statistical heterogeneity, and therefore, these results merit confirmation in large well-designed clinical trials.

A study on exposure to greenspace during pregnancy and lipid profile in cord blood samples.

Although evidence reporting the beneficial associations of prenatal greenspace exposure with pregnancy outcomes is increasing, there is still a lack of evidence on the potential association of such exposure to greenspace on fetal lipid profile. We aimed to first-time investigate the associations between prenatal exposure to greenspace and lipid levels in the cord blood. The present study was based on data from 150 expectant mothers, residents of Sabzevar city in Iran (2018). For each participant, we identified exposure to greenspace in residential surroundings, residential accessibility to green space, use of green spaces, and the number of plant pots inside the home. Measures of levels of triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and TC/HDL-C and TG/HDL-C ratios in samples of cord blood were applied to identify the lipid profile. We developed adjusted linear regression models to estimate the associations of each indicator of greenspace exposure with each cord blood lipid. We found increased greenspace in residential surroundings across a 100 m buffer, higher residential accessibility to green space, and more use of green spaces were associated with decreased cord blood lipid levels. The remainder findings regarding the greenspace in residential surroundings across 300 m and 500 m buffers and the number of plant pots were null. Some suggestions were observed for a potential mediatory role of air pollution. This study suggests that greenspace exposure during pregnancy may influence positively fetal lipid levels in the cord blood.

Longitudinal changes in fetal head biometry and fetoplacental circulation in fetuses with congenital heart defects.

INTRODUCTION: Objectives were to analyze changes in fetal cephalic biometry and fetoplacental circulation throughout pregnancy in fetuses with congenital heart defects. MATERIAL AND METHODS: Prospective study conducted on three university tertiary referral hospitals. Fetuses with the diagnosis of isolated congenital heart defects attending between 2014 and 2018 were included. Congenital heart defects were divided into two groups according to the oxygen supply to the central nervous system: group I (expected low placental blood content and low oxygen delivery to the brain) and group II (expected intermediate and high placental blood content). Fetal biometry and Doppler parameters were collected between 25-30 weeks of gestation and 34-40 weeks of gestation and transformed into Z scores. The results were compared with healthy controls. Finally, general linear modeling was performed to analyze repeated measurements. RESULTS: In all, 71 fetuses met the inclusion criteria. Fetuses with congenital heart defects had significantly smaller head (biparietal diameter [p < 0.001], head circumference [p = 0.001]) and abdominal circumference (p < 0.001), and lower estimated fetal weight (p < 0.001) than controls. When analyzing according to congenital heart defects type, head size was significantly smaller in group I compared with group II (p = 0.04). Regarding Doppler parameters, fetuses with congenital heart defects showed higher umbilical artery pulsatility index (p < 0.001) and lower cerebroplacental ratio (p = 0.044) than controls. In group I, umbilical artery pulsatility index was above the 95th centile in 15.4% of fetuses compared with 6.7% in group II and 1.9% in controls (p < 0.001); moreover, middle cerebral artery pulsatility index was below the 5th centile in 5.4% of group I fetuses compared with 0% in group II and 1.2% in controls (p = 0.011). General linear model for two measurements showed significant longitudinal changes in biometric parameters. Growth rate of fetal head through pregnancy (head circumference Z score) was lower in fetuses with congenital heart defects compared with controls (p = 0.043). In group I, the head circumference Z score longitudinal decrease was significantly higher than in group II (p < 0.001). CONCLUSIONS: Fetuses with congenital heart defects are at risk of smaller head size and Doppler changes. Growth rate of fetal head throughout pregnancy is also affected. These findings are mainly associated with cardiac defects with expected low oxygen supply to the central nervous system.

First-Trimester SARS-CoV-2 Infection: Clinical Presentation, Inflammatory Markers, and Obstetric Outcomes.

OBJECTIVE: Second- and third-trimester SARS-CoV-2 infections may have an increased risk of obstetric complications. However, data on first-trimester infections are scarce. We sought to characterize the clinical and inflammatory presentations and pregnancy outcomes of first-trimester infections. METHODS: A population-based multicenter study including 817 singleton pregnancies with SARS-CoV-2 serologic testing at 8-14 weeks between March and May 2020. Blood count, uterine artery Doppler, and pregnancy-associated plasma protein A (PAPP-A) were performed in all women. Placental growth factor (PlGF), soluble fms-like tyrosine kinase 1 (sFlt-1), IL-6, and ferritin were determined in positive women. Obstetric outcomes were evaluated. RESULTS: The prevalence of first-trimester infection was 15.2% (n = 124). 72.6% of positive women were asymptomatic. Symptomatic women had higher rates of lymphopenia (1.91 × 109/L vs. 2.16 × 109/L, p = 0.017) and increased levels of IL-6 (9.1% vs. 1.2%, p = 0.051), but lower rates of decreased ferritin (6.3% vs. 19.8%, p = 0.015). PAPP-A was higher in symptomatic women compared with asymptomatic and negative women (1.44 [IQR 0.90-1.82] vs. 1.08 [IQR 0.66-1.61] p = 0.014, vs. 1.08 [IQR 0.77-1.55] p = 0.019, respectively). Obstetric outcomes were not increased. CONCLUSIONS: First-trimester SARS-CoV-2 infections are mostly asymptomatic, with a mild increase of inflammatory markers in symptomatic women. Obstetric complications were not increased, but PAPP-A levels were higher in symptomatic women.

Gestational Age-Adjusted Reference Ranges for Fetal Left Ventricle Longitudinal Strain by Automated Cardiac Motion Quantification between 24 and 37 Weeks' Gestation.

INTRODUCTION: The objective of this study was to construct gestational age (GA) based reference values for left ventricle (LV) longitudinal strain in normal fetuses, between 24 and 37 weeks' gestation, assessing its feasibility and reproducibility with automated cardiac motion quantification software (aCMQ-QLab), which is widely used in postnatal echocardiography. METHODS: This prospective study included healthy gravid women with singleton pregnancies and no evidence of fetal structural cardiovascular disease. Fetal echocardiographies were performed between 24 and 37 GA. 2D four-chamber view clips were recorded and LV longitudinal strain was analyzed offline. Intra- and interobserver reproducibility between 2 independent observers was evaluated by intraclass correlation coefficients (ICC) and Bland-Altman scatterplots. Regression analysis was used to determine GA adjusted reference ranges and construct nomograms. RESULTS: LV longitudinal strain measurements were feasible in 95.4% of acquisitions. 435 clips were obtained. Intra- and interobserver ICC were 0.998 (95% CI 0.997-0.999) and 0.991 (95% CI 0.984-0.995), respectively. The global longitudinal strain and the middle and apical LV segments showed progressive decline as GA advanced, whereas the basal segments remained stable. CONCLUSIONS: Assessment of LV longitudinal strain by aCMQ-QLab is feasible, reproducible, and within normal ranges. Our results offer more information regarding fetal cardiac function assessment with 2D speckle tracking techniques, aiding in the introduction of this software into research practice, encouraging the realization of more studies, and probably helping in its future use in clinical practice, allowing longitudinal surveillance of strain without intervendor variability and aiding in follow-up of fetal cardiac conditions before and after birth, as it is the most commonly used software postnatally.

Impact of Severe Acute Respiratory Syndrome Coronavirus 2 Infection on Pregnancy Outcomes: A Population-based Study.

BACKGROUND: We performed a population-based study to describe the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on pregnancy outcomes. METHODS: This prospective, population-based study included pregnant women who consecutively presented at first/second trimester visits or at delivery at 3 hospitals in Barcelona, Spain. SARS-CoV-2 antibodies (immunoglobulin [Ig] G and IgM/IgA) were measured in all participants, and nasopharyngeal real-time polymerase chain reaction (RT-PCR) was performed at delivery. The primary outcome was a composite of pregnancy complications in SARS-CoV-2-positive vs negative women that included miscarriage, preeclampsia, preterm delivery, perinatal death, small-for-gestational-age newborn, or neonatal admission. Secondary outcomes were components of the primary outcome plus abnormal fetal growth, malformation, or intrapartum fetal distress. Outcomes were also compared between positive symptomatic and positive asymptomatic SARS-CoV-2 women. RESULTS: Of 2225 pregnant women, 317 (14.2%) were positive for SARS-CoV-2 antibodies (n = 314, 99.1%) and/or RT-PCR (n = 36, 11.4%). Among positive women, 217 (68.5%) were asymptomatic, 93 (29.3%) had mild coronavirus disease 2019 (COVID-19), and 7 (2.2%) had pneumonia, of whom 3 required intensive care unit admission. In women with and without SARS-CoV-2 infection, the primary outcome occurred in 43 (13.6%) and 268 (14%), respectively (risk difference, -0.4%; 95% confidence interval, -4.1% to 4.1). Compared with noninfected women, those with symptomatic COVID-19 had increased rates of preterm delivery (7.2% vs 16.9%, P = .003) and intrapartum fetal distress (9.1% vs 19.2%, P = .004), while asymptomatic women had rates that were similar to those of noninfected cases. Among 143 fetuses from infected mothers, none had anti-SARS-CoV-2 IgM/IgA in cord blood. CONCLUSIONS: The overall rate of pregnancy complications in women with SARS-CoV-2 infection was similar to that of noninfected women. However, symptomatic COVID-19 was associated with modest increases in preterm delivery and intrapartum fetal distress.

Cardiac dysfunction and remodeling regulated by anti-angiogenic environment in patients with preeclampsia: the ANGIOCOR prospective cohort study protocol.

BACKGROUND: Cardiovascular diseases (CVD) are cause of increased morbidity and mortality in spite of advances for diagnosis and treatment. Changes during pregnancy affect importantly the maternal CV system. Pregnant women that develop preeclampsia (PE) have higher risk (up to 4 times) of clinical CVD in the short- and long-term. Predominance of an anti-angiogenic environment during pregnancy is known as main cause of PE, but its relationship with CV complications is still under research. We hypothesize that angiogenic factors are associated to maternal cardiac dysfunction/remodeling and that these may be detected by new cardiac biomarkers and maternal echocardiography. METHODS: Prospective cohort study of pregnant women with high-risk of PE in first trimester screening, established diagnosis of PE during gestation, and healthy pregnant women (total intended sample size n = 440). Placental biochemical and biophysical cardiovascular markers will be assessed in the first and third trimesters of pregnancy, along with maternal echocardiographic parameters. Fetal cardiac function at third trimester of pregnancy will be also evaluated and correlated with maternal variables. Maternal cardiac function assessment will be determined 12 months after delivery, and correlation with CV and PE risk variables obtained during pregnancy will be evaluated. DISCUSSION: The study will contribute to characterize the relationship between anti-angiogenic environment and maternal CV dysfunction/remodeling, during and after pregnancy, as well as its impact on future CVD risk in patients with PE. The ultimate goal is to improve CV health of women with high-risk or previous PE, and thus, reduce the burden of the disease. TRIAL REGISTRATION: NCT04162236.

Bleeding and antithrombotic therapy during pregnancy in women with poor aPL-related obstetric outcomes: A survey of 1075 cases from EUROAPS registry∗.

BACKGROUND: The combination of low-dose aspirin (LDA) and low-molecular-weight heparin (LMWH) until the end of gestation are the currently the accepted standard of care for the treatment of antiphospholipid-related obstetric disorders. In refractory cases, hydroxychloroquine (HCQ) can be added to this standard of care. OBJECTIVE: To evaluate the haemostatic safety of LDA and LMWH (medium to high prophylactic doses) during pregnancy and the puerperium in women with both full-blown obstetric antiphospholipid syndrome (OAPS) (Sydney criteria) and noncriteria - incomplete - OAPS. STUDY DESIGN: Retrospective/prospective multicentre observational study. Obstetric background, laboratory categories, delivery mode, antithrombotic regimens and bleeding complications were compared. SETTING: A total of 30 tertiary European hospitals. PATIENTS: Mainly, Caucasian/Arian pregnant women were included. Other ethnicities were minimally present. Women were controlled throughout pregnancy and puerperium. MAIN OUTCOME MEASURES: The primary end-point was to evaluate the number of major and minor haemorrhagic complications in this cohort of women. Neuraxial anaesthetic bleeding complications were particularly assessed. Secondly, we aimed to compare local/general bleeding events between groups. RESULTS: We studied 1650 women, of whom 1000 fulfilled the Sydney criteria of the OAPS and 650 did not (noncriteria OAPS). Data on antithrombotic-related complications were available in 1075 cases (65.15%). Overall, 53 (4.93%) women had bleeding complications, with 34 being considered minor (3.16%) and 19 major (1.76%). Neither obstetric complications nor laboratory categories were bleeding-related. Assisted vaginal delivery and caesarean section were related to local haemorrhage. Heparin doses and platelet count were not associated with major bleeding. CONCLUSIONS: LDA and medium to high prophylactic LMWH during pregnancy in women with full-blown OAPS/noncriteria OAPS are safe. A slight increase in bleeding risk was noted in instrumental deliveries. No women who underwent spinal or epidural anaesthesia suffered bleeding complications. No haemorrhage was observed in cases where HCQ was added to standard therapy.

Gestational Age-Specific Reference Ranges for the sFlt-1/PlGF Immunoassay Ratio in Twin Pregnancies.

OBJECTIVE: Establish reference ranges for the Elecsys® soluble fms-like tyrosine kinase-1 (sFlt-1)/placental growth factor (PlGF) immunoassay ratio in twin pregnancies. METHODS: Data analyzed were from 3 prospective studies: Prediction of Short-Term Outcome in Pregnant Women with Suspected Preeclampsia (PE) (PROGNOSIS), Study of Early-onset PE in Spain (STEPS), and a multicenter case-control study. Median, 5th, and 95th percentiles for sFlt-1, PlGF, and the sFlt-1/PlGF ratios were determined for normal twin pregnancies for 7 gestational windows and compared with the previous data for singleton pregnancies. RESULTS: The reference range analysis included 269 women with normal twin pregnancies. Before 29 weeks' gestation, median, 5th, and 95th percentiles for sFlt-1/PlGF ratios did not differ between twin and singleton pregnancies. From 29 weeks' gestation to delivery, median, 5th, and 95th percentiles for sFlt-1/PlGF ratios were substantially higher in twin versus singleton pregnancies. sFlt-1 values were higher in women with twin pregnancies across all gestational windows. PlGF values were similar or higher in twin versus singleton pregnancies; PlGF concentrations increased from 10 weeks + 0 days to 28 weeks + 6 days' gestation. CONCLUSIONS: Reference ranges for the sFlt-1/PlGF ratio are similar in women with twin and singleton pregnancies until 29 weeks' gestation but appear higher in twin pregnancies thereafter.

Environmental Exposure during Pregnancy: Influence on Prenatal Development and Early Life: A Comprehensive Review.

Preconception and prenatal exposure to environmental contaminants may affect future health. Pregnancy and early life are critical sensitive windows of susceptibility. The aim of this review was to summarize current evidence on the toxic effects of environment exposure during pregnancy, the neonatal period, and childhood. Alcohol use is related to foetal alcohol spectrum disorders, foetal alcohol syndrome being its most extreme form. Smoking is associated with placental abnormalities, preterm birth, stillbirth, or impaired growth and development, as well as with intellectual impairment, obesity, and cardiovascular diseases later in life. Negative birth outcomes have been linked to the use of drugs of abuse. Pregnant and lactating women are exposed to endocrine-disrupting chemicals and heavy metals present in foodstuffs, which may alter hormones in the body. Prenatal exposure to these compounds has been associated with pre-eclampsia and intrauterine growth restriction, preterm birth, and thyroid function. Metals can accumulate in the placenta, causing foetal growth restriction. Evidence on the effects of air pollutants on pregnancy is constantly growing, for example, preterm birth, foetal growth restriction, increased uterine vascular resistance, impaired placental vascularization, increased gestational diabetes, and reduced telomere length. The advantages of breastfeeding outweigh any risks from contaminants. However, it is important to assess health outcomes of toxic exposures via breastfeeding. Initial studies suggest an association between pre-eclampsia and environmental noise, particularly with early-onset pre-eclampsia. There is rising evidence of the negative effects of environmental contaminants following exposure during pregnancy and breastfeeding, which should be considered a major public health issue.

Comparative study of obstetric antiphospholipid syndrome (OAPS) and non-criteria obstetric APS (NC-OAPS): report of 1640 cases from the EUROAPS registry.

OBJECTIVES: To compare clinical features, laboratory data and fetal-maternal outcomes between 1000 women with obstetric APS (OAPS) and 640 with aPL-related obstetric complications not fulfilling Sydney criteria (non-criteria OAPS, NC-OAPS). METHODS: This was a retrospective and prospective multicentre study from the European Registry on Obstetric Antiphospholipid Syndrome. RESULTS: A total of 1650 women with 5251 episodes, 3601 of which were historical and 1650 latest episodes, were included. Altogether, 1000 cases (OAPS group) fulfilled the Sydney classification criteria and 650 (NC-OAPS group) did not. Ten NC-OAPS cases were excluded for presenting thrombosis during follow-up. All cases were classified as category I (triple positivity or double positivity for aPL) or category II (simple positivity). Overall, aPL laboratory categories showed significant differences: 29.20% in OAPS vs 17.96% in NC-OAPS (P < 0.0001) for category I, and 70.8% in OAPS vs 82% in NC-OAPS (P < 0.0001) for category II. Significant differences were observed when current obstetric complications were compared (P < 0.001). However, major differences between groups were not observed in treatment rates, livebirths and thrombotic complications. In the NC-OAPS group, 176/640 (27.5%) did not fulfil Sydney clinical criteria (subgroup A), 175/640 (27.34%) had a low titre and/or non-persistent aPL positivity but did meet the clinical criteria (subgroup B) and 289/640 (45.15%) had a high aPL titre but did not fulfil Sydney clinical criteria (subgroup C). CONCLUSION: Significant clinical and laboratory differences were found between groups. Fetal-maternal outcomes were similar in both groups when treated. These results suggest that we could improve our clinical practice with better understanding of NC-OAPS patients.

Urban-Related Environmental Exposures during Pregnancy and Placental Development and Preeclampsia: a Review.

PURPOSE OF REVIEW: To summarize the current knowledge of the pathophysiological implications and the clinical role of urban-related environmental exposures in pregnancy. RECENT FINDINGS: The ongoing urbanization worldwide is leading to an increasing number of pregnant women being exposed to higher levels of urban-related environmental hazards such as air pollution and noise and, at the same time, having less contact with natural environments. Pregnancy represents a particular and vulnerable life period both for women and their children. Extensive physiological and metabolic changes, as well as changes to the cardiovascular and respiratory systems during pregnancy, could result in increased sensitivity to damage by environmental factors. Exposure to air pollution and noise is associated with placental dysfunction and damage, which, in turn, could lead to maternal complications such as preeclampsia. In contrast, more contact with greenspace during pregnancy seems to mitigate these adverse impacts. These findings open up new challenges for our understanding of the potential effect of urban living on placental function and preeclampsia, and offer new clinical and research opportunities.

Inter- and Intraobserver Agreement in First Trimester Ultrasound Evaluation of Placental Biometry.

OBJECTIVE: The aim of this study was to assess the clinical applicability of a new analytical software program by determining the inter- and intraobserver agreement for 2D placental biometry and three-dimensional (3D) placental volume (PV) in the first trimester. METHODS: A prospective study of 25 singleton pregnancies between 11 and 14 weeks was conducted. 3D datasets were captured, and PV was estimated using the Phillips QLAB GI3DQ ultrasound quantification software. The basal plate (BP), chorionic plate (CP), placental thickness (PT), and the free uterine surface (FUS) area not occupied by placenta were considered for 2D biometry evaluation. Each variable was measured in 2 orthogonal planes with mean values used for the analysis. Intra- and interobserver agreement was evaluated. RESULTS: Intraobserver agreement for both 2D and 3D measurements was high, particularly for the PV and PT (interclass correlation coefficient [ICC] 0.989 [95% confidence interval (CI) 0.97-0.99] and ICC 0.936 [95% CI 0.86-0.97], respectively). Interobserver agreement was good for the PV (ICC 0.963 [95% CI 0.91-0.98]), PT (ICC 0.822 [95% CI 0.63-0.91]), and CP (ICC 0.708 [95% CI 0.44-0.86]), but moderate for BP and FUS. CONCLUSIONS: PV, PT, and CP are reproducible measurements to evaluate first trimester placental biometry. Further research is needed to assess the clinical utility of these variables as predictors of poor obstetric outcomes.

Early Prophylactic Enoxaparin for the Prevention of Preeclampsia and Intrauterine Growth Restriction: A Randomized Trial.

BACKGROUND: Preeclampsia (PE) and intrauterine growth restriction (IUGR) are major causes of maternal and perinatal morbidity and mortality. Previous studies have shown that intervention with low-dose aspirin resulted in a reduction in the occurrence of preterm PE. However, no data are currently available on the effect of low-molecular-weight heparin (LMWH) for the prevention of pregnancy complications in women enrolled at first trimester screening. OBJECTIVE: We aimed to assess the effectiveness of LMWH in the prevention of PE, IUGR, fetal death, and abruptio placentae in women classified as high risk based on their medical history and in women selected by first trimester screening of PE. Study -Design: This was a multicenter, randomized, open-label, parallel controlled trial in women without thrombophilia between 6.0 and 15.6 weeks of gestation. Inclusion criteria were severe PE or IUGR before 34 weeks of gestation and/or abruptio placentae or unexplained intrauterine death in a previous pregnancy; uterine artery mean pulsatility index Doppler >95th percentile and/or positive first trimester screening for PE. Pregnant women were randomly assigned to receive no intervention or LMWH until the 36th week of gestation. The primary composite outcome consisted of 1 or more of the following: development of PE, IUGR, abruptio placentae, and intrauterine fetal death. RESULTS: A total of 278 pregnant women were randomly allocated to receive LMWH (n = 134) or no intervention (n = 144). Overall, 115 (41%) women experienced placental insufficiency complications, with no significant differences between the 2 arms: 50/144 (34.7%) in the LMWH arm and 43/134 (32%) in the control arm (p = 0.64, OR: 1.13, 95% CI: 0.68-1.85). CONCLUSION: LMWH did not reduce the incidence of placenta-mediated complications either in women with previous adverse obstetric history without thrombophilia or in women selected by first trimester screening for PE. Based on these results, we cannot recommend the use of LMWH alone in women at risk of placental complications.

Predictive Value of the sFlt-1:PlGF Ratio in Women with Suspected Preeclampsia.

BACKGROUND: The ratio of soluble fms-like tyrosine kinase 1 (sFlt-1) to placental growth factor (PlGF) is elevated in pregnant women before the clinical onset of preeclampsia, but its predictive value in women with suspected preeclampsia is unclear. METHODS: We performed a prospective, multicenter, observational study to derive and validate a ratio of serum sFlt-1 to PlGF that would be predictive of the absence or presence of preeclampsia in the short term in women with singleton pregnancies in whom preeclampsia was suspected (24 weeks 0 days to 36 weeks 6 days of gestation). Primary objectives were to assess whether low sFlt-1:PlGF ratios (at or below a derived cutoff) predict the absence of preeclampsia within 1 week after the first visit and whether high ratios (above the cutoff) predict the presence of preeclampsia within 4 weeks. RESULTS: In the development cohort (500 women), we identified an sFlt-1:PlGF ratio cutoff of 38 as having important predictive value. In a subsequent validation study among an additional 550 women, an sFlt-1:PlGF ratio of 38 or lower had a negative predictive value (i.e., no preeclampsia in the subsequent week) of 99.3% (95% confidence interval [CI], 97.9 to 99.9), with 80.0% sensitivity (95% CI, 51.9 to 95.7) and 78.3% specificity (95% CI, 74.6 to 81.7). The positive predictive value of an sFlt-1:PlGF ratio above 38 for a diagnosis of preeclampsia within 4 weeks was 36.7% (95% CI, 28.4 to 45.7), with 66.2% sensitivity (95% CI, 54.0 to 77.0) and 83.1% specificity (95% CI, 79.4 to 86.3). CONCLUSIONS: An sFlt-1:PlGF ratio of 38 or lower can be used to predict the short-term absence of preeclampsia in women in whom the syndrome is suspected clinically. (Funded by Roche Diagnostics.).

Cervical pessary for preventing preterm birth in twin pregnancies with maternal short cervix after an episode of threatened preterm labor: randomised controlled trial.

BACKGROUND: No intervention has proved effective to date in reducing the spontaneous preterm birth rate in twin pregnancies following an episode of threatened preterm labor and with a short cervix remaining. This study was designed to ascertain whether cervical pessaries are useful in preventing spontaneous preterm birth in women with twin pregnancies and a short cervix remaining after a threatened preterm labor episode. STUDY DESIGN: This open, randomized, controlled trial was conducted in 132 pregnant women who had not delivered 48 hours after a threatened preterm labor episode and had a short cervix remaining (≤20 mm between 240 and 296 weeks and ≤10 mm between 300 and 336 weeks). Patients were randomly assigned to cervical pessary (n = 67) or routine management (n = 65). The primary outcome was the spontaneous preterm birth rate before 34 weeks. Spontaneous preterm birth before 28 and 37 weeks and neonatal morbidity and mortality were also evaluated in an intention-to-treat analysis. RESULTS: Significant differences were observed in the spontaneous preterm birth rate before 34 weeks between the pessary and routine management groups (11 of 67 [16.4%] in the pessary group vs 21 of 65 [32.3%] in the control group; relative risk, 0.51 [confidence interval, 0.27-0.97]; P = .03). No significant differences were observed in the preterm birth rate < 28 weeks or < 37 weeks between groups. The pessary group less frequently required readmission for new threatened preterm labor episodes (4 of 67 [5.6%] vs 14 of 65 [21.5%]; relative risk, 0.28 [confidence interval, 0.10-0.80]; P = .009). Significant reduction was observed in the number of neonates weighing less than 2500 g (17.9% [24 of 134] vs 70.8% [92 of 130]; relative risk, 0.25 [confidence interval, 0.15-0.43]; P < .0001). CONCLUSION: Pessary use did significantly lower the spontaneous preterm birth rate before 34 weeks in twin pregnancies with maternal short cervix remaining after a threatened preterm labor episode. Pessary use also reduced the threatened preterm labor recurrence and neonates' weight less than 2500 g.

Cervical pessary to reduce preterm birth <34 weeks of gestation after an episode of preterm labor and a short cervix: a randomized controlled trial.

BACKGROUND: To date, no intervention has proved effective in reducing the spontaneous preterm birth rate in singleton pregnancies following an episode of threatened preterm labor and short cervix remaining. OBJECTIVE: This study was designed to ascertain whether cervical pessaries could be useful in preventing spontaneous preterm birth in women with singleton pregnancies and a short cervix after a threatened preterm labor episode. STUDY DESIGN: This open randomized controlled trial was conducted in 357 pregnant women (between 240-336 weeks) who had not delivered 48 hours after a threatened preterm labor episode and had a short cervix remaining (≤25 mm at 240-296 weeks; ≤15 mm at 300-336 weeks). Patients were randomly assigned to cervical pessary (179) or routine management (178). The primary outcome was the spontaneous preterm birth rate <34 weeks. Spontaneous preterm birth <28 and 37 weeks and neonatal morbidity and mortality were also evaluated in an intention-to-treat analysis. RESULTS: No significant differences between the pessary and routine management groups were observed in the spontaneous preterm birth rate <34 weeks (19/177 [10.7%] in the pessary group vs 24/175 [13.7%] in the control group; relative risk, 0.78; 95% confidence interval, 0.45-1.38). Spontaneous preterm birth <37 weeks occurred less frequently in the pessary group (26/175 [14.7%] vs 44/175 [25.1%]; relative risk, 0.58; 95% confidence interval, 0.38-0.90; P = .01). Preterm premature rupture of membranes rate was significantly lower in pessary carriers (4/177 [2.3%] vs 14/175 [8.0%]; relative risk, 0.28; 95% confidence interval, 0.09-0.84; P = .01). The pessary group less frequently required readmission for new threatened preterm labor episodes (8/177 [4.5%] vs 35/175 [20.0%]; relative risk, 0.23; 95% confidence interval, 0.11-0.47; P < .0001). No serious adverse maternal events occurred; neonatal morbidity and mortality were similar in both groups. CONCLUSION: Pessary use did not significantly lower the spontaneous preterm birth rate <34 weeks in women with a short cervix remaining after a threatened preterm labor episode but did significantly reduce the spontaneous preterm birth rate <37 weeks, threatened preterm labor recurrence, and the preterm premature rupture of membranes rate.