Maternal and fetal outcomes in multiparous women with Cystic Fibrosis.

BACKGROUND: Quality of life and survival in Cystic Fibrosis (CF) have improved dramatically, making family planning a feasible option. Maternal and perinatal outcomes in women with CF (wwCF) are similar to those seen in the general population. However, the effect of undergoing multiple pregnancies is unknown. METHODS: A multinational-multicenter retrospective cohort study. Data was obtained from 18 centers worldwide, anonymously, on wwCF 18-45 years old, including disease severity and outcome, as well as obstetric and newborn complications. Data were analyzed, within each individual patient to compare the outcomes of an initial pregnancy (1st or 2nd) with a multigravid pregnancy (≥3) as well as secondary analysis of grouped data to identify risk factors for disease progression or adverse neonatal outcomes. Three time periods were assessed - before, during, and after pregnancy. RESULTS: The study population included 141 wwCF of whom 41 (29%) had ≥3 pregnancies, "multiparous". Data were collected on 246 pregnancies, between 1973 and 2020, 69 (28%) were multiparous. A greater decline in ppFEV1 was seen in multiparous women, primarily in pancreatic insufficient (PI) wwCF and those with two severe (class I-III) mutations. Multigravid pregnancies were shorter, especially in wwCF over 30 years old, who had high rates of prematurity and newborn complications. There was no effect on pulmonary exacerbations or disease-related complications. CONCLUSIONS: Multiple pregnancies in wwCF are associated with accelerated respiratory deterioration and higher rates of preterm births. Therefore, strict follow-up by a multidisciplinary CF and obstetric team is needed in women who desire to carry multiple pregnancies.

Baseline Cystic fibrosis disease severity has an adverse impact on pregnancy and infant outcomes, but does not impact disease progression.

BACKGROUND: With increasing longevity and quality of life in adults with Cystic fibrosis (CF), growing maternity rates are reported. Women with severe CF are becoming pregnant, with unpredictable maternal and fetal outcomes. AIM: To determine how baseline disease severity, pancreatic insufficiency (PI) and Pseudomonas aeruginosa (PA) infection affect fertility, the pregnancy course, delivery, neonatal outcome, and subsequent disease progression. METHODS: A multicenter-retrospective cohort study. Data on patients that had been pregnant between 1986-2018 was collected from ten CF centers worldwide. Disease severity [mild or moderate-severe (mod-sev)] was defined according to forced expiratory volume % predicted in 1 second (FEV1) and body mass index (BMI). Three time periods were compared, 12 months prior to conception, the pregnancy itself and the 12 months thereafter. RESULTS: Data was available on 171 pregnancies in 128 patients aged 18-45 years; 55.1% with mod-sev disease, 43.1% with PI and 40.3% with PA. Women with mod-sev disease had more CF-related complications during and after pregnancy and delivered more preterm newborns. However, FEV1 and BMI decline were no different between the mild and mod-sev groups. A more rapid decline in FEV1 was observed during pregnancy in PI and PA infected patients, though stabilizing thereafter. PI was associated with increased risk for small for gestational age infants. CONCLUSION: Baseline disease severity, PA infection and PI have an adverse impact on infant outcomes, but do not impact significantly on disease progression during and after pregnancy. Consequently, pregnancies in severe CF patients can have a good prognosis.

The course of acquired von Willebrand syndrome during pregnancy among patients with essential thrombocytosis.

To investigate the course of acquired type 2A von Willebrand syndrome (AVWS) in relation to patient management and outcomes among pregnant patients with essential thrombocytosis (ET). A review of pregnant women with ET evaluated for AVWS at the beginning of pregnancy and at the third trimester. Eighteen women with 24 pregnancies were included in this study. A history of bleeding was noted in 8 (44%) patients. In 20 (83%) pregnancies AVWS was evident at the initial testing. Following initial testing, antithrombotic therapy was administered in 22 (92%) pregnancies (aspirin, n = 20 and low-molecular-weight heparin, n = 2). In the remaining two pregnancies, VWF:RCo levels were below 30%; thus, aspirin was given only after repeat testing at 14-16 weeks. At third trimester testing, median VWF:RCo levels were significantly higher than at the initial testing (86 vs. 48%, P < 0.001), with no evidence of AVWS in any of the patients. Significant increases were also observed in the VWF:Ag level (127 vs. 84%, P < 0.001), the VWF:RCo/VWF:Ag ratio (0.75 vs. 0.54, P < 0.001) and the FVIII level (103 vs. 68%, P < 0.001); while platelet count (359 vs. 701 × 109/l, P < 0.001) and hemoglobin level (11.6 vs. 13.4 g/dl, P < 0.001) decreased. Neuraxial anesthesia was safely performed in 17 (71%) pregnancies. No significant bleeding events occurred during pregnancy and delivery. AVWS-related abnormalities in women with ET mostly improved during pregnancy, with favorable maternal and fetal outcomes. VWF parameters should be tested at early pregnancy and repeated at the third trimester, to guide pregnancy and delivery management.

Pregnancy and non-pregnancy related ovarian vein thrombosis: Clinical course and outcome.

OBJECTIVE: To collect and summarize demographic, clinical, laboratory and radiologic characteristics, as well as management and follow-up data, of patients diagnosed with ovarian vein thrombosis. METHODS: A multicenter retrospective review of all patients diagnosed with ovarian vein thrombosis between January 2000 and May 2015 at three university hospitals. RESULTS: Data of 74 women were analyzed. Mean age was 31±9years. Sixty (81.1%) cases were pregnancy-related. The presence of at least one underlying risk factor (most commonly active infection or surgery) was more common among pregnancy than non-pregnancy related cases (61.7% vs. 14.3%, P=0.002). Anticoagulation therapy was administered in 98.6% of patients and adjunctive antibiotic therapy in 39 (52.7%). At a median follow-up of 40±38months, only one recurrent thrombotic event was observed, and no events of death. Median duration of anticoagulation treatment tended to be longer among patients with non-pregnancy related OVT (6months [3-14] vs. 3months [3-6], P=0.1). Thrombophilic evaluation detected any thrombophilic risk factor in 12 (20%) and 6 (42.9%) women with pregnancy and non-pregnancy related ovarian vein thrombosis, respectively (P=0.09). CONCLUSION: Pregnancy-related ovarian vein thrombosis is characterized by a provoked nature and a high rate of resolution after short term treatment. Treatment of three months duration of anticoagulation following this condition appeared in this study to be safe, with no recurrences encountered during a median follow up of 40months. Thrombophilia seems to have an important role in ovarian vein thrombosis and should be evaluated in non-pregnancy related cases.

Re-laparotomy following cesarean delivery - risk factors and outcomes.

INTRODUCTION: Re-laparotomy following caesarean delivery (CD) is a rare yet serious complication. The aim of this study was to identify risk factors, diagnostic features and outcomes following re-laparotomy. MATERIALS AND METHODS: This retrospective cohort study reviewed cases of re-laparotomy following CD performed at Hadassah-Hebrew University Medical Center. Occurrences were identified via the electronic medical record database. RESULTS: During the study period, 17,213 women underwent CD, of which 55 (0.3%) underwent re-laparotomy during the same hospitalization. Main indications for re-laparotomy were intra-peritoneal bleeding (62%) and wound infection/dehiscence (22%). During re-laparotomy, the bleeding source was found and ligated in 85% of the cases. Age, parity, previous CD, induction of labor, anesthesia type and operative duration were significant risk factors for re-laparotomy. In a selected group of patients, trial of conservative treatment was made. However, in 76% of these women a re-laparotomy was required. DISCUSSION: Risk factors for re-laparotomy following CD should be identified, thus enabling more intensified monitoring of patients considered at risk for this complication. When intra-peritoneal bleeding following CD is suspected, conservative management has a high failure rate and should be reserved for a selected group of stable patients.

Characterization of tumor infiltrating natural killer cell subset.

The presence of tumor-infiltrating Natural Killer (NK) within a tumor bed may be indicative of an ongoing immune response toward the tumor. However, many studies have shown that an intense NK infiltration, is associated with advanced disease and may even facilitate cancer development. The exact role of the tumor infiltrating NK cells and the correlation between their presence and poor prognosis remains unclear. Interestingly, during pregnancy high numbers of a specific NK subset, CD56(bright)CD16(dim), are accumulated within first trimester deciduas. These decidual NK (dNK) cells are unique in their gene expression pattern secret angiogenic factors that induce vascular growth. In the present study we demonstrate a significant enrichment of a CD56(brigh)CD16(dim) NK cells within tumors. These NK cells express several dNK markers including VEGF. Hence, this study adds new insights into the identity of tumor residual NK cells, which has clear implications for the treatment of human cancer.

Detailed transabdominal fetal anatomic scanning in the late first trimester versus the early second trimester of pregnancy.

OBJECTIVES: To compare visualization rates for early targeted organ scanning at gestational ages ranging from 11 weeks 3 days to 13 weeks 2 days versus 14 weeks 3 days to 16 weeks 2 days. METHODS: We conducted a prospective longitudinal study of patients who presented for nuchal translucency (NT) screening and targeted organ scanning. Extended targeted organ scanning, including the central nervous system, face and neck, chest, heart (including complete echocardiography), digestive system, abdominal wall, urinary system, skeleton, and umbilical cord with its insertion and placenta, was performed on gravidas in 2 age ranges. Uterine artery Doppler mapping was performed during the second scan. All cases were examined twice: once at NT screening (up to 13 weeks 2 days) and again in the early second trimester. RESULTS: A total of 408 women were recruited and scanned twice. Three abnormalities were diagnosed in the second scan that were not seen in the first: dysplastic long bones, tricuspid stenosis, and cleft lip (without palate involvement). None had chromosomal anomalies. Successful visualization rates in all organ systems exceeded 94% in the second trimester. At the first-trimester scan, some systems had high success rates, whereas others were very low; eg, in the brain, the cerebellum and posterior fossa were visualized successfully approximately 50% of the time and the upper lip only approximately 10%. On fetal echocardiography, the 4-chamber view and outflow tracts were imaged successfully approximately 40% of the time, and the kidneys approximately 35%. Uterine artery Doppler mapping was possible in all patients on at least one side. On third-trimester follow-up, we diagnosed 1 mild pulmonary stenosis, 1 autosomal recessive polycystic kidney disease, and 1 ventricular septal defect. CONCLUSIONS: The early second-trimester scan was much more productive than targeted organ scanning performed during the NT window. When counseling women regarding the optimal time for early transabdominal targeted organ scanning, successful visualization rates for various organ systems should be considered.

Identification of a novel neutrophil population: proangiogenic granulocytes in second-trimester human decidua.

The maternal leukocytes of the first-trimester decidua play a fundamental role in implantation and early development of the fetus and placenta, yet little is known regarding the second-trimester decidual environment. Our multicolor flow cytometric analyses of human decidual leukocytes detected an elevation in tissue resident neutrophils in the second trimester. These cells in both human and murine samples were spatially restricted to decidua basalis. In comparison with peripheral blood neutrophils (PMNs), the decidual neutrophils expressed high levels of neutrophil activation markers and the angiogenesis-related proteins: vascular endothelial growth factor-A, Arginase-1, and CCL2, similarly shown in tumor-associated neutrophils. Functional in vitro assays showed that second-trimester human decidua conditioned medium stimulated transendothelial PMN invasion, upregulated VEGFA, ARG1, CCL2, and ICAM1 mRNA levels, and increased PMN-driven in vitro angiogenesis in a CXCL8-dependent manner. This study identified a novel neutrophil population with a physiological, angiogenic role in human decidua.

Planned caesarean hysterectomy versus "conserving" caesarean section in patients with placenta accreta.

OBJECTIVES: Invasive placentation (placenta accreta, increta, or percreta) presents significant challenges at Caesarean section. Caesarean hysterectomy in such circumstances may result in massive blood loss despite surgical expertise. We reviewed two divergent surgical approaches: planned Caesarean hysterectomy versus a "conserving surgery" in which the placenta is left in situ after Caesarean section. METHODS: We conducted a single-centre retrospective review of all patients who delivered with invasive placentation between 2000 and 2009. We included only patients with antenatally diagnosed invasive placentation and planned mode of delivery. RESULTS: Twenty-six patients met the inclusion criteria. Caesarean hysterectomy was planned in 16 patients and conserving surgery in 10. Intraoperative and postoperative complications were comparable in the two groups. Four of 10 patients initially treated by conservative surgery required a subsequent hysterectomy for severe vaginal bleeding, coagulopathy, or sepsis. No pregnancies were subsequently reported in the conserving surgery group. CONCLUSION: An initial conserving surgical procedure is an option in patients with extensive invasive placentation, but it requires further monitoring for potential complications and carries a high subsequent hysterectomy rate.

Fetal cardiac tumors: a single-center experience of 40 cases.

OBJECTIVE: To determine the natural history and outcome of fetal cardiac tumors. METHODS: This was a retrospective cohort study of all prenatally detected cases of cardiac tumors at a tertiary cardiac care center. RESULTS: Forty fetuses were identified to have one or several cardiac tumors in association with fetal hydrops (18%), ventricular obstruction (30%) and/or arrhythmia (13%). Of 33 cases with rhabdomyoma, three patients elected to terminate the pregnancy, four offspring died at birth and 26 (79%) survived. On follow-up, 95% of all live-born cases with rhabdomyomas were free of cardiac symptoms but 88% had tuberous sclerosis. All three fetuses with teratoma presented with hydrops and none of them survived. In contrast, all three fetuses with cardiac fibroma are alive and have a biventricular physiology. One fetus with a large atrial hemangioendothelioma died in early infancy. Fetal or neonatal death was associated with an earlier cardiac anomaly diagnosis, earlier delivery, larger tumor size and fetal hydrops at presentation. CONCLUSIONS: The outcome of fetal cardiac tumors was predicted by the etiology and size of the cardiac mass and the presence of hydrops. Although most cardiac rhabdomyomas have a relatively benign perinatal course, the long-term prognosis is determined by the neurological manifestations associated with tuberous sclerosis.

Characterization of a lymphocyte subset displaying a unique regulatory activity in human decidua.

One of the most intriguing mechanisms of early pregnancy is the maternal immune tolerance toward her semi-allogeneic fetus, specifically in face of the accumulation of lymphocytes to high numbers at implantation sites. Here, we propose that a regulatory decidual lymphocyte (dL) population prevent the activation of reactive T cells and by that may maintain immune tolerance in the decidua. dLs were isolated from first trimester decidua and were then co-cultured with PBMC that were stimulated with anti-CD3 mAbs. Cytokine secretion to the media as well as the proliferative response were tested. The data demonstrate that dLs inhibit the production of IFN-gamma, tumor necrosis factor-alpha (TNF-alpha) and IL-5 but not CD25 expression, IL-2 production or proliferation in the responder PBMC. Suppression is mediated by a cell contact-dependent mechanism, was not restricted by the MHC and was not reversed by the addition of exogenous IL-2 although the inhibitory sub-population was identified as CD3+CD4+CD25+Foxp3+ natural regulatory T cells (Treg). Interestingly, suppression can also be overcome by the addition the endotoxin LPS, suggesting a mechanism for preterm labor triggered by chorioamnionitis. While these characteristics are in contrast to known peripheral CD4+CD25+ Treg activity, we identified these cells as the cellular subset responsible for the regulatory activity, suggesting that in decidua a functionally unique regulatory lymphocyte subset exist. These findings suggest the existence of a dynamic regulatory system in human decidua that is highly responsive to environmental factors.