Augmented Placental Protein 13 in Placental-Associated Extracellular Vesicles in Term and Preterm Preeclampsia Is Further Elevated by Corticosteroids.

Placental protein 13 (PP13) is a regulatory protein involved in remodeling the vascular system of the pregnancy and extending the immune tolerance of the mother to the growing fetus. PP13 is localized on the surface of the syncytiotrophoblast. An ex vivo placental model shows that the PP13 is released via placental-associated extracellular vesicles (PEVs) to the maternal uterine vein. This exploratory study aimed to determine PEV-associated PP13 in the maternal circulation as compared to the known soluble fraction since each has a specific communication pathway. Patients admitted to Bnai Zion Medical Center for delivery were recruited, and included 19 preeclampsia (PE) patients (7 preterm PE gestational age < 37 weeks' gestation), 16 preterm delivery (PTD, delivery at GA < 37 weeks' gestation), and 15 matched term delivery controls. Treatment by corticosteroids (Celestone), which is often given to patients with suspected preterm PE and PTD, was recorded. The PEV proteome was purified from the patients' plasma by size exclusion chromatography (SEC) to separate the soluble and PEV-associated PP13. The total level of PP13 (soluble and PEV-associated) was determined using mild detergent that depleted the PEV proteome. PP13 fractions were determined by ELISA with PP13 specific antibodies. ELISA with alkaline phosphatase (PLAP)- and cluster differentiation 63 (CD63)-specific antibodies served to verify the placental origin of the PEVs. SPSS was used for statistical analysis. The patients' medical, pregnancy, and delivery records in all groups were similar except, as expected, that a larger number of PE and PTD patients had smaller babies who were delivered earlier, and the PE patients had hypertension and proteinuria. The SEC analysis detected the presence of PP13 in the cargo of the PEVs and on their surface, in addition to the known soluble fraction. The median soluble PP13 was not significantly different across the PE, PTD, and term delivery control groups. However, after depleting the PEV of their proteome, the total PP13 (soluble and PEV-associated) was augmented in the cases of preterm PE, reaching 2153 pg/mL [IQR 1866-2838] but not in cases of PTD reaching 1576 pg/mL [1011-2014] or term delivery groups reaching 964 pg/mL [875-1636]), p < 0.01. On the surface of the circulating PEV from PTD patients, there was a decrease in PP13. Corticosteroid treatment was accompanied by a massive depletion of PP13 from the PEV, especially in preterm PE patients. This exploratory study is, thus, the first to determine PEV-associated PP13 in maternal circulation, providing a quantitative determination of the soluble and the PEV-associated fractions, and it shows that the latter is the larger. We found an increase in the amount of PP13 carried via the PEV-associated pathway in PE and PTD patients compared to term delivery cases, which was further augmented when the patients were treated with corticosteroids, especially in preterm PE. The signal conveyed by this novel communication pathway warrants further research to investigate these two differential pathways for the liberation of PP13.

[ISOLATED OLIGOHYDRAMNIOS - THE DILEMMA OF PROPER MANAGEMENT].

INTRODUCTION: There are two methods to diagnose oligohydramnios: maximal vertical pocket (MVP) and amniotic fluid index (AFI). Following a recent large Cochrane review and other studies, MVP is being recommended as the method of choice by professional societies, after it was shown to result in fewer inductions of labor and C-sections (CS), without compromising neonatal outcome. There is controversy regarding the management of isolated oligohydramnios (IO). It is unclear whether this finding reflects an underlying pathological process, and therefore management protocols differ between different institutions. Studies have shown a higher rate of CS (RR of >2) in IO. Whether this is a true complication of IO or is a result of different confounders like labor inductions and primigravidity is unclear. The effects on neonatal outcomes are also unclear; whereas some authors did not show any adverse effects, others have shown higher rates of neonatal intensive care unit (NICU) admissions, lower Apgar scores and higher rate of Meconium aspiration syndrome. Some studies have shown a higher rate of undiagnosed small for gestational age (SGA) in IO pregnancies. There is no consensus regarding the optimal management and time of delivery. Until now, common practice was to induce labor at term, and some advocate induction in late preterm. Recently, the growing awareness to early term morbidity has led practitioners to question the benefit of early induction. There are several studies that have shown maternal hydration to improve AFI, but there is insufficient data to show the effect on outcomes. In conclusion, many questions regarding IO are still unanswered, and further research, specifically RCT studies, is needed.

Prediction of neonatal respiratory distress in pregnancies complicated by fetal lung masses.

OBJECTIVE: The objective of this article is to evaluate the utility of fetal lung mass imaging for predicting neonatal respiratory distress. METHOD: Pregnancies with fetal lung masses between 2009 and 2014 at a single center were analyzed. Neonatal respiratory distress was defined as intubation and mechanical ventilation at birth, surgery before discharge, or extracorporeal membrane oxygenation (ECMO). The predictive utility of the initial as well as maximal lung mass volume and congenital pulmonary airway malformation volume ratio by ultrasound (US) and magnetic resonance imaging (MRI) was analyzed. RESULTS: Forty-seven fetal lung mass cases were included; of those, eight (17%) had respiratory distress. The initial US was performed at similar gestational ages in pregnancies with and without respiratory distress (26.4 ± 5.6 vs 22.3 ± 3 weeks, p = 0.09); however, those with respiratory distress had higher congenital volume ratio at that time (1.0 vs 0.3, p = 0.01). The strongest predictors of respiratory distress were maximal volume >24.0 cm3 by MRI (100% sensitivity, 91% specificity, 60% positive predictive value, and 100% negative predictive value) and maximal volume >34.0 cm3 by US (100% sensitivity, 85% specificity, 54% positive predictive value, and 100% negative predictive value). CONCLUSION: Ultrasound and MRI parameters can predict neonatal respiratory distress, even when obtained before 24 weeks. Third trimester parameters demonstrated the best positive predictive value. © 2017 John Wiley & Sons, Ltd.

Time matters: Cervical ripening balloon for 6 versus 12 h-Retrospective comparison between two protocols.

OBJECTIVE: Recently, two randomized controlled trials compared removal of cervical ripening balloon (CRB) after 6 versus 12 h. Their results showed similar Bishop score changes in both groups and a shorter time to delivery in the 6-h group. Neither of the studies was powered to show difference in mode of delivery. The aim of this study was to compare mode of delivery when the CRB was removed after 6 versus 12 h. METHODS: A historical control study comparing induction of labor with a CRB between two time periods, one in which the CRB was removed after 12 h (12-h group), and the other in which it was removed after 6 h (6-h group). We included term pregnancies with a singleton fetus in vertex presentation. We excluded patients with a previous cesarean delivery, failed ripening with prostaglandins prior to CRB insertion, and any contraindication for vaginal delivery. The primary outcome was mode of delivery. Secondary outcomes included delivery within 24 h and other maternal and neonatal outcomes. RESULTS: We included 1704 patients, 914 in the 12-h group, and 717 in the 6-h group. Removal after 6 h was associated with a lower rate of cesarean and instrumental deliveries (28.6% vs 22.5%, and 12% vs 6.2%, respectively) and a higher rate of vaginal delivery within 24 h. All differences were statistically significant. CONCLUSION: Removing a cervical ripening balloon after 6 rather than 12 h is associated with reduced cesarean and instrumental delivery rates, and should be considered as a reasonable, and potentially superior alternative in labor induction protocols with intracervical ripening balloon.

Comparison between the modified French AmbUlatory Cesarean Section and standard cesarean technique-a randomized double-blind controlled trial.

BACKGROUND: The French AmbUlatory Cesarean Section is a cesarean delivery technique, which includes a vertical fascial incision to the left of the linea alba and an extraperitoneal approach to the uterus. The presumed benefits of this technique are decreased postoperative pain and accelerated recovery. However, evidence supporting these impressions is scarce. OBJECTIVE: This study aimed to compare maternal recovery after French AmbUlatory Cesarean Section vs standard cesarean delivery technique. STUDY DESIGN: In this double-blind randomized controlled trial, women undergoing elective cesarean delivery at term were allocated into French AmbUlatory Cesarean Section vs standard cesarean delivery technique. A modified French AmbUlatory Cesarean Section technique was used, adhering to all French AmbUlatory Cesarean Section operative steps except for the extraperitoneal approach. In both groups, the use of intravenous hydration, intrathecal morphine, and bladder catheter was avoided, and all women were encouraged to stand and walk 3 to 4 hours after the operation. The primary adverse composite outcome included either of the following: a visual analog scale score of >6 at 3 to 4 hours after the operation, an inability to stand up and walk to the restroom 3 to 4 hours after the operation, and a 15-Item Quality of Recovery (QoR) questionnaire score of <90 at 24 hours after the operation. The women were followed up for 6 weeks. RESULTS: Overall, 116 women were included in the trial (58 in each group). The adverse composite outcome did not differ between the 2 groups (38.9% for the French AmbUlatory Cesarean Section group vs 53.8% for the regular cesarean delivery group; P=.172). In both groups, more than 90% of the women were able to get up and walk 3 to 4 hours after the operation. Compared with the standard cesarean delivery group, the French AmbUlatory Cesarean Section group had a longer duration of the operation (43.7±11.2 vs 54.4±11.3 minutes; P<.001), a higher rate of intraoperative complications (0.0% vs 13.8%; P=.006), and a higher rate of umbilical cord pH level of <7.2 (3.4% vs 17.2%; P=.029) were noted. Evaluation via phone call 1 week after the operation showed better quality of recovery scores in the French AmbUlatory Cesarean Section group than in the standard cesarean delivery group (27.1±8.4 vs 24.6±8.0; P=.043). Other secondary outcomes did not differ between the 2 groups. CONCLUSION: As excellent maternal recovery was noted in both groups, we believe that the main factor affecting this recovery is the perioperative management (including avoidance of the use of intraoperative intravenous hydration, intrathecal morphine, and bladder catheter, with early postoperative mobilization). The maternal and neonatal safety outcomes of the French AmbUlatory Cesarean Section technique remain to be proven by larger-scale high-quality randomized controlled trials.

Double-Balloon Device for 6 Compared With 12 Hours for Cervical Ripening: A Randomized Controlled Trial.

OBJECTIVE: To evaluate whether removal of a double-balloon device for cervical ripening for 6 compared with 12 hours in women with an unfavorable cervix will result in a shorter time to delivery, similar cervical ripening, and without affecting cesarean delivery rate. METHODS: In a prospective randomized trial, cervical ripening was performed using a double-balloon device. Women were randomized to removal of the device after 6 compared with 12 hours. Primary outcome was time to delivery. Secondary outcomes included mode of delivery, Bishop score, and maternal and neonatal adverse outcomes. A sample size of 100 nulliparous and 100 parous women was required assuming a 95% CI, power of 80%, and mean decrease of 6 hours to delivery between the groups. RESULTS: From March 2017 through February 2019, 688 women were screened, 243 were found eligible, and 197 were randomized as follows: nulliparous cohort (n=101): removal after 6 hours (n=48) compared with removal after 12 hours (n=53); parous cohort (n=96): removal after 6 hours (n=49) compared with removal after 12 hours (n=47). Insertion-to-delivery interval was significantly shorter in the 6-hour group for both nulliparous (25.6±12.8 hours vs 31.4±15.2 hours, P<.04; mean difference 5.8, 95% CI 0.2-11.3), and parous cohorts (18.0±6.8 hours vs 22.6±8.2 hours, P=.003; mean difference 4.7, 95% CI 1.6-7.7). Bishop score change and cesarean delivery rate were similar between groups regardless of parity. The 12-hour group in the combined cohort was associated with higher rates of maternal intrapartum fever (2% vs 10%, P=.02; odds ratio 5.3, 95% CI 1.1-24.8). CONCLUSION: Insertion-to-delivery interval is shorter after 6 compared with 12 hours for both nulliparous and parous women. Cervical ripening with a double-balloon device may be achieved in 6 hours. The longer time was associated with a higher rate of intrapartum fever. Six hours should be considered as standard placement time for double-balloon catheters. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT03045939.

A novel extended prophylactic antibiotic regimen in preterm pre-labor rupture of membranes: A randomized trial.

OBJECTIVES: Prophylactic antibiotic use in preterm pre-labor rupture of membranes (PPROM) is associated with a significant reduction in intra-amniotic infection and improved neonatal outcome. However, data is insufficient to determine the optimal antibiotic regimen. Considering the rise in Escherichia coli and Klebsiella pneumonia early-onset sepsis rate and the emergence of ampicillin resistance, our aim is to compare the efficiency of two antibiotic regimens in prolonging pregnancy and reducing infectious morbidity. DESIGN: This multicenter randomized unblinded controlled prospective trial compared two antibiotic prophylactic protocols in PPROM: ampicillin + roxithromycin vs. cefuroxime + roxithromycin in 84 women with PPROM, from 12/2015-12/2019. RESULTS: The median latency period was significantly longer (p = 0.039) in the cefuroxime + roxithromycin group (4.63 [0.59-50.18] days) than in the ampicillin + roxithromycin group (2.3 [0.15-58.3] days). Neonatal admission to neonatal intensive care unit rate, hospitalization length, neonatal respiratory distress syndrome, neonatal fever, and need for respiratory support or mechanical ventilation, were similar between the groups. K. pneumonia cultures were significantly more frequent in the ampicillin + roxithromycin group. None of the cultures were group B Streptococcus positive. CONCLUSIONS: To prolong latency period and reduce gram-negative early-onset sepsis, cefuroxime + roxithromycin is recommended as the first-line protocol in PPROM. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02819570.

Pregnancy exacerbating hepatopulmonary syndrome.

BACKGROUND: Hepatopulmonary syndrome is an uncommon complication of liver cirrhosis. The natural history of this condition and its optimal management during pregnancy are not yet known. CASE: We present the case of a 35-year-old woman with liver cirrhosis who developed severe dyspnea in the 25th week of gestation and was diagnosed as suffering from hepatopulmonary syndrome. She was managed conservatively until 35 weeks of gestation, when she was delivered by cesarean. CONCLUSION: The natural history, in this case, indicates that pregnancy may induce hepatopulmonary syndrome in an otherwise asymptomatic cirrhotic patient. Oxygen supplementation was the cornerstone of treatment and resulted in a favorable outcome.

Selenium concentrations in maternal and umbilical cord blood at 24-42 weeks of gestation: basis for optimization of selenium supplementation to premature infants.

BACKGROUND & AIMS: Selenium (Se) deficiency may have deleterious effects on premature infants. Umbilical cord (UC) Se concentrations presumably reflect fetal Se concentrations and represent reference values that should be achieved in premature infants. We aimed to establish reference data of Se serum concentrations in parturient women and their neonates across gestation. SUBJECTS AND METHODS: Parturient mothers and their newborn infants born after 24-42 weeks of gestation were enrolled. Only appropriate for gestational age (GA) singleton infants were included. Se serum concentrations were measured by atomic absorption spectrometry, in blood samples from parturient mothers and their infants (umbilical blood). Demographic, perinatal and labor data were obtained, and their correlations with umbilical Se serum concentrations, maternal Se serum concentrations, and the maternal-umbilical Se difference were examined. RESULTS: UC Se serum concentrations increased as gestation progressed (P<0.01). A statistically significant linear relationship was found between UC Se serum concentrations and GA (R=0.341, P<0.0001), birth weight (R=0.237, P=0.002), and 5-min Apgar score (R=0.202, P<0.01). Using multiple regression analysis, only GA was significantly associated with UC serum Se concentration (P=0.012). Maternal Se serum concentration were stable throughout gestation, and maternal-umbilical Se difference was negatively correlated with GA (R=-0.337, P<0.0001) and birth weight (R=-0.369, P<0.0001). CONCLUSIONS: UC Se serum concentration increases and the maternal-umbilical Se difference declines with gestation progression, probably reflecting fetal accretion of Se. With the current Se supplementation in premature infants, Se concentrations are lower than those measured in our study. We, therefore, suggest a two-fold increase or more in the recommended Se dosage.

Microvesicles of women with gestational hypertension and preeclampsia affect human trophoblast fate and endothelial function.

Microvesicles shedding from cell membrane affect inflammation, apoptosis, and angiogenesis. We hypothesize that microvesicles of women with gestational vascular complications reflect pathophysiological state of the patients and affect their endothelial and trophoblast cell function. Microvesicles of healthy pregnant women, women with gestational hypertension, mild, or severe preeclampsia/toxemia, were characterized, and their effects on early-stage or term trophoblasts and endothelial cells were evaluated using apoptosis, migration, and tube formation assays. Patient subgroups differed significantly only in proteinuria levels, therefore their microvesicles were assessed as 1 group, demonstrating higher levels of inflammatory and angiogenic proteins compared with those of healthy pregnant women. In endothelial cells, microvesicles of healthy pregnant women reduced caspase 3/7 activity, increased migration, and induced tube formation. These processes were suppressed by microvesicles of women with gestational vascular complications. In early-stage trophoblasts, microvesicles of healthy pregnant women decreased apoptosis compared with untreated cells (6±5% versus 13.8±5.8%; P<0.001) and caspase 3/7 activity and induced higher migration (39.7±10.1 versus 20.3±8.3 mm2; P<0.001). This effect was mediated through extracellular signal-regulated kinase pathway. Conversely, microvesicles of women with gestational vascular complications increased term trophoblast apoptosis compared with cells exposed to microvesicles of healthy pregnant women (15.1±3.3% versus 6.5±2.1%; P<0.001) and inhibited early-stage trophoblasts migration (21.4±18.5 versus 39.7±10.1 mm2; P<0.001). In conclusion, microvesicle content and effects on endothelial and trophoblast cells vary according to the physiological/pathological state of a pregnant woman. Microvesicles seem to play a pivotal role in the course of pregnancy, which could potentially result in gestational vascular complications.

Pregnancy course and outcome in women traveling to developing countries.

BACKGROUND: The issue of travel to developing countries during pregnancy has not been sufficiently studied. The aim of this study is to investigate the rate, course, and outcome of pregnancies in women who traveled to developing countries while pregnant, or became pregnant during such travel. METHODS: Women visiting two major travel clinics in Israel for consultation within the years 2004 to 2009, who were pregnant or declared an intention of becoming pregnant during travel were contacted. This was followed by a telephone interview by an obstetrician with those women who were actually pregnant. Background characteristics, morbidity during travel, and pregnancy course and outcome were collected. RESULTS: Overall 52,430 travelers' records had been screened. Of these, we identified 49 women who were pregnant during their trip, but 3 declined participation. Of the remaining 46 women, 33 were pregnant at departure, and 13 conceived during travel. The incidence of pregnancy during travel was thus 0.93/1000 travelers. Thirty-three women traveled to East Asia, 8 to South and Central America, 5 to Africa. More than two thirds of women received pretravel vaccinations. Adherence to the World Health Organization recommendations regarding food and drink was high (87%) and travelers' diarrhea occurred in only 11% of women. Five of 22 women traveling to malarious areas had taken antimalarial prophylaxis. Six women required medical therapy during travel. Pregnancy outcome was not different from the normal population except for an unusually low rate of preterm delivery. CONCLUSIONS: In this cohort, travel to developing countries was not associated with adverse pregnancy outcome. Larger studies are needed to support these findings.

Adrenalectomy for adrenocortical adenoma causing Cushing's syndrome in pregnancy: a case report and review of literature.

We present a case of adrenocorticotropic hormone (ACTH)-independent Cushing's syndrome diagnosed in a patient in the third trimester of her pregnancy, with an adrenal mass observed on imaging studies. Laparoscopic adrenalectomy was performed successfully at 32 weeks. To the best of our knowledge, this is the latest gestational age at which laparoscopic adrenalectomy has been reported. We present the various considerations for determining the surgical approach and the optimal timing for surgery. Adrenalectomy during pregnancy for the treatment of Cushing's syndrome caused by adrenocortical adenoma has been reported in 23 patients in the English-language medical literature to date and seems safe and beneficial. According to the data, surgical treatment has led to a reduction in perinatal mortality and maternal morbidity rates, but has not affected the occurrence of preterm birth and intrauterine growth restriction. The best outcome can be achieved by a multidisciplinary approach, with a team comprising a maternal-fetal medicine specialist, an endocrinologist and a surgeon. The timing of surgery and the surgical approach need to be determined according to the surgeon's expertise, the severity of the condition, the patient's preferences, and gestational age. Laparoscopy may prove to be the preferred surgical approach. The small number of cases precludes providing evidence-based recommendations.

Oral naproxen versus oral tramadol for analgesia after cesarean delivery.

OBJECTIVE: To compare the efficacies of oral naproxen and oral tramadol for pain relief after cesarean delivery, and to evaluate administration at fixed intervals versus on request. METHODS: In a prospective study, 120 women were randomized into 4 groups receiving either oral naproxen or oral tramadol at fixed intervals or on request. Pain was assessed at 6, 12, 24, and 48hours after delivery, and adverse effects, mobility, breastfeeding, and the need for additional drugs for breakthrough pain were recorded. RESULTS: No difference in pain scores was observed at 6, 12, 24, or 48hours among the 4 groups, between the 2 drugs, or between the 2 methods of administration. Women randomized to receive oral tramadol requested additional drugs for breakthrough pain more frequently. In addition, adverse effects were twice as common in the tramadol group as in the naproxen group, and more women in the tramadol group abandoned the study. CONCLUSION: Although similar in terms of pain scores, oral naproxen might be more effective than oral tramadol for pain relief after cesarean delivery. Naproxen seemed to have a better adverse-effects profile, and therefore might be more suitable for mothers. Administration at fixed intervals might be more efficacious than administration on request.

Haptoglobin phenotype in women with preeclampsia.

In pre-eclampsia, poor placentation causes both oxidative and endoplasmic reticulum stress of the placenta. The anti-oxidative protein Haptoglobin has three phenotypes: 1-1, 1-2, and 2-2. Haptoglobin 1-1 is a more potent antioxidant. Our objective was to determine whether haptoglobin 1-1 was less common in women with preeclampsia which is a disease with an oxidatives-stress component, compared to the healthy population. Haptoglobin phenotype was compared in 240 healthy and 120 preeclamptic gravida in a case-control study. Statistical analysis was performed using Chi square test. The prevalence of haptoglobin 1-1 was 13% among healthy women and 6% among preeclamptic women (P=0.049). Secondary analysis was also performed. The prevalence of haptoglobin 1-1 is higher in healthy compared to preeclamptic subjects, a finding compatible with a protective role. Haptoglobin 1-1 might have a protective role in preeclampsia. Further work is needed with more Hp 1-1 subjects before we can conclude on the possible use of Haptoglobin phenotype to assess the risk of preeclampsia.

Decidualization of ovarian endometriosis during pregnancy mimicking malignancy.

OBJECTIVE: The purpose of this series is to present deciduosis (the formation of extrauterine decidua) as one of the differential diagnoses of a malignant tumor during pregnancy. METHODS: Two cases are described in which pregnant patients had a pelvic tumor. The lesions, which were diagnosed in the early second trimester, consisted of complex masses with an extensive blood supply and had a sonographic appearance of a malignant tumor. The high suspicion for malignancy necessitated surgical intervention. RESULTS: During surgery, the lesions were observed to be of an ovarian origin with papillary excrescences covering their exterior. The lesions were excised and sent for histologic examination. The results showed a markedly decidualized endometriotic cyst in both cases. CONCLUSIONS: This phenomenon is a diagnostic challenge and should be considered in the differential diagnosis of a malignant mass during pregnancy.