Search

Objective Increased levels of soluble fms-like tyrosine kinase (sFlt-1) in Trisomy 13 pregnancies are thought to be mediated by the placenta. This study aimed to compare sFlt-1 expression in Trisomy 13 (n = 7) placentas with that in control placentas (Trisomy 21, n=11, and euploid, n=6). Study Design This was a retrospective case-control study analyzing paraffin-embedded placental blocks that were stained with hematoxylin and eosin and antibodies to sFlt-1. Their staining intensity was compared using a semiquantitative technique. The Kruskal-Wallis test and Wilcox rank sum test were used for statistical analysis. Results The median staining was significantly higher in Trisomy 13 compared with control specimens ( P = .008) (for Trisomy 13 vs Trisomy 21, P = .003, and Trisomy 13 vs euploid, P = .004). Conclusion Our study demonstrates that Trisomy 13 placentas express more sFlt-1 than control placentas. These results strengthen the hypothesis that the increased incidence of preeclampsia in Trisomy 13 pregnancies is secondary to placental up-regulation of sFlt-1.

Preeclampsia is a common complication of pregnancy with potentially devastating consequences to both the mother and the baby.It is the leading cause of maternal deaths in developing countries. In developed countries it is the major cause of iatrogenic premature delivery and contributes significantly to increasing health care cost associated with prematurity. There is currently no known treatment for preeclampsia; ultimate treatment involves delivery of the placenta. Although there are several risk factors (such as multiple gestation or chronic hypertension), most patients present with no obvious risk factors. The molecular pathogenesis of preeclampsia is just now being elucidated. It has been proposed that abnormal placentation and an imbalance in angiogenic factors lead to the clinical findings and complications seen in preeclampsia. Preeclampsia is characterized by high levels of circulating antiangiogenic factors such as soluble fms-like tyrosine kinase-1 and soluble endoglin, which induce maternal endothelial dysfunction. These soluble factors are altered not only at the time of clinical disease but also several weeks before the onset of clinical signs and symptoms. Many methods of prediction and surveillance have been proposed to identify women who will develop preeclampsia, but studies have been inconclusive. With the recent discovery of the role of angiogenic factors in preeclampsia, novel methods of prediction and diagnosis are being developed to aid obstetricians and midwives in clinical practice. This article discusses the role of angiogenic factors in the pathogenesis, prediction, diagnosis, and possible treatment of preeclampsia.

Preeclampsia, a systemic syndrome of pregnancy clinically characterized by new onset of proteinuria and hypertension, is associated with significant morbidity and mortality to both mothers and fetuses. The pathogenesis of preeclampsia has been enigmatic; this review will focus on understanding the origins of this disorder. Preeclampsia originates in the placenta, starting with inadequate cytotrophoblast invasion and ending with widespread maternal endothelial dysfunction. Production of placental anti-angiogenic factors, specifically soluble fms-related tyrosine kinase 1 and soluble endoglin, have been shown to be upregulated in preeclampsia. These placental anti-angiogenic factors are released into the maternal circulation; their actions disrupt the maternal endothelium and result in hypertension, proteinuria, and the other systemic manifestations of preeclampsia. The molecular basis for placental dysregulation of these pathogenic factors remains unknown, remains unknown. Hypoxia is likely an important regulator. Other factors such as alterations in the renin-angiotensin-aldosterone axis, immune maladaption, excessive shedding of trophoblast debris, oxidative stress, and genetic factors likely contribute to the pathogenesis of the abnormal placentation. As of 2009, the only successful treatment for preeclampsia is delivery. No definitive preventive strategies have been identified. However, several of the recent observations related to phenotypic causality provide stimuli for the development of novel therapies.

Objective Our objective was to investigate whether serum concentrations of a novel anti-angiogenic factor, soluble endoglin (sEng), could predict placental abruption. Methods In a nested case–control study of nulliparous pregnancies, we examined levels of sEng in serum collected prospectively from 31 women who later developed placental abruption and from 31 normal controls. All serum specimens were collected before the onset of hypertension or abruption and before labor or delivery. Serum sEng was compared within three gestational age intervals: early- (

Objectives Upregulation of placental soluble fms-like tyrosine kinase 1 (sFlt1) contributes to the pathogenesis of preeclampsia. Our aim was to evaluate novel upstream pathways that regulate placental sFlt1 production. Methods We screened a library of natural compounds ( N = 502) in primary cytotrophoblasts and placental villous cultures and characterized molecules that had biological activity in the nanomolar range. sFlt1 production was assayed by ELISA. Immunoblot analysis, Co-immunoprecipitation, RT-PCR were employed in Characterizing the sFlt1, HIF AND hsp27 proteins and RNA. Pregnancy-induced hypertension rats were used as animal models. Results Here we report three compounds in the cardiac glycoside family, ouabain, gitoxigenin and digitoxin that inhibited placental sFlt1 production at nanomolar concentrations in vitro. We further characterized ouabain and demonstrate that it inhibits sFlt1 mRNA and protein expression in human placental cytotrophoblasts and explant cultures in a dose and time dependent manner. Ouabain down-regulated sFlt1 production by inhibiting hypoxia inducible factor 1 (HIF-1 α ) protein expression in the placenta. Furthermore, we found that phosphorylation of heat shock protein 27 (HSP27) was necessary for ouabain to inhibit HIF-1 α translation. In a rat model of pregnancy-induced hypertension, ouabain reduced mean arterial pressure and enhanced placental HSP27 phosphorylation without any adverse effects on pups. Conclusions Collectively we show that ouabain inhibits placental sFlt1 production through a HIF-1 α / HSP27 dependent pathway. Further studies are needed to explore the usefulness of targeting HIF-1 α /HSP27 pathway in preeclampsia. Disclosures S. Rana: None. A. Rajakumar: None. C. Geahchan: None. S. Salahuddin: None. A. Cerdeira: None. S.D. Burke: None. E. George: None. J. Granger: None. S. Karumanchi: co-inventor on multiple patents for preeclampsia markers and reports service as a consultant to Siemens Diagnostics, and has financial interest in Aggamin LLC.

Objective The objective of the study was to evaluate neurocognitive function in preeclampsia and normal pregnancy. Study design Three groups (each n = 15) were studied before and after delivery using standard neurocognitive test techniques. Group A consisted of normal laboring patients; group B, preeclamptics receiving magnesium; and group C, women in preterm labor receiving MgSO4 tocolysis (Mg control). The tests, examining attention, working memory, explicit memory, auditory comprehension, and measures for emotional distress, pain, and fatigue were analyzed via 4-way multivariate analysis of variance and multiple t tests. Results Preeclamptics receiving MgSO4 had better attention and working memory (P = .05), compared with normal laboring women and the preterm patients. Explicit memory was impaired in all groups, and this could not be accounted for by pain or emotional distress. Conclusion We could detect no cognitive defects in preeclamptics, compared with normotensive gravidas, at least while the cerebral vasodilator MgSO4 is being infused.

Objective The purpose of this study was to assess sonographic fetal cheek-to-cheek diameter (CCD) in predicting mode of delivery. Study design Two hundred sixty-four patients were considered in 2 parts. First, a retrospective analysis of 214 patients entered into a birth weight (BW) study. Measurements of the CCD, biparietal diameter (BPD), and BW, as well as labor data, were collected. Then a prospective study of patients at ≥38 weeks gestational age was conducted. Fetal weight (EFW) was estimated by routine measurements. Information regarding CCD was withheld from the delivering caregiver. Labor records were reviewed for BW and complications, defined as: instrumental delivery, cesarean section (C/S) for nonprogress of labor or “CPD,” and “difficult” vaginal delivery. The CCD, BW (both parts), or EFW (prospective part) and mode of delivery were compared. Results Abnormal CCD (>2SD above previously published norms for each GA) was closely associated with cesarean delivery, regardless of EFW. At term, risk of C/S with a CCD >7.9 cm was 94%. Conclusion Within limits, EFW alone has weak correlation with cesarean delivery. CCD, as a reflector of fetal adipose tissue, performs as well as actual BW and demonstrates good prediction for delivery by C/S.

Background Small cell carcinoma of the ovary is an aggressive tumor primarily affecting young women. Despite adjuvant therapy, the majority of patients described in the literature have fared poorly, even when the disease is diagnosed at an early stage. Case A 19-year-old nulligravida with small cell carcinoma of the left ovary underwent conservative surgery with staging and was found to have stage IIIC disease. She received multiagent chemotherapy with vinblastine, cisplatin, cyclophosphamide, bleomycin, doxorubicin, and etoposide and is alive and doing well more than 2 years after completion of her therapy, with no evidence of disease. Conclusion In young patients who desire future fertility, conservative surgery followed by aggressive multiagent chemotherapy may be an effective treatment regimen and warrants further consideration.

Introduction Patients with preeclampsia are at risk for cardiovascular disease [1,2]. Changes in cardiac function are subtle in preeclampsia and are quantitatively difficult with conventional imaging. Strain measurements using speckle-tracking echocardiography have been used to sensitively quantifyabnormalities in other disease settings [3]. Objectives The objective of this study was to evaluate changes in myocardial strain using speckle tracking echocardiography in women with and without preeclampsia. We hypothesized that global left systolic strain measures would prove more sensitive than conventional left ventricular ejection fraction in detecting early changes in systolic LV function manifesting as subclinical disease prior to overt progression. Methods We evaluated the feasibility and sensitivity of strain imaging using speckle tracking echocardiography. Thirty-six women were enrolled in this pilot study; 28 were analyzed: 11 with preeclampsia and 17 without preeclampsia. Echocardiographic Ejection fraction and global peak longitudinal ,radial and circumferential strain were measured. Results Global Median longitudinal strain was significantly worsened in women with preeclampsia compared to women without preeclampsia ( P P =0.006) and circumferential strain ( P =0.03). There was no significant difference in ejection fraction between the groups ( P =0.52) (Table 1). Data are presented as median (interquartile range). Conclusion Myocardial strain imaging using speckle tracking is more sensitive than left ventricular ejection fraction to detect differences in left ventricular systolic function in women with and without preeclampsia.

Preeclampsia (PE) is a pregnancy specific hypertensive disorder with an overall incidence of 5-8% among all pregnancies.Incidence of PE in twins is about 2-4 fold higher compared to singletons.Angiogenic factors are implicated in pathogenesis of PE and related adverse outcomes.No studies exist evaluating angiogenic factor assessment in twin pregnancies complicated by PE or use of these proteins for prediction of PE-related adverse outcomes in twins.Our objective was to evaluate whether angiogenic factor levels correlate with the diagnosis of PE and predict adverse maternal and perinatal outcomes in women with twin pregnancy.This was a prospective cohort study of women with suspected PE and twin pregnancy from July 2009-August 2011.Antiangiogenic soluble fms-like tyrosine kinase 1 (sFlt1) and proangiogenic placental growth factor (PlGF) were measured at presentation on an automated platform.Diagnosis of hypertension PE during pregnancy was based on ACOG criteria.All diagnoses and outcomes were recorded 2 weeks later.An adverse outcome was defined as hemolysis elevated liver enzymes and low platelets (HELLP) syndrome; disseminated intravascular coagulation (DIC); abruption; pulmonary edema; cerebral hemorrhage; maternal, fetal and neonatal death; eclampsia; acute renal failure; small for gestational age; and indicated delivery.Data are presented as median (interquartile range).We computed the area under the curve (AUC) from the receiver operating characteristic curves to evaluate the ability of clinical values to discriminate between women who would and would not develop an adverse outcome within 2 weeks.There were 79 women with twin gestation who presented to triage for evaluation of PE. The median gestational age at enrollment was 33.9 (31.9-36.0) weeks.The incidence of PE was 58.2%, of which 60.9% was mild and 39.1% was severe.The median sFlt1/PlGF ratio was 72.2 (42.5-111.9) in women with PE compared to 47.4 (5.5-82.2) in women with no hypertensive disorder (P=0.052).Among the 52 (65.8%) women who experienced an adverse outcome within 2 weeks, the median sFlt1/PlGF ratio at presentation was elevated [74.2 (43.5-110.5)] compared to the 27 (34.2%) women without an adverse outcome [36.2 (7.1-71.3); P=0.0003].Among those presenting at34 weeks (n=40), the difference in sFlt1/PlGF ratio was more striking [97.7 (76.6-178.1) versus 31.7 (6.5-48.7); P=0.001].When using only the highest systolic blood pressure at presentation and proteinuria the AUC was 0.61.Adding the sFlt1/PlGF ratio significantly improved the AUC to 0.77 (P=0.01).When restricting to women who presented at34 weeks, a similar, although not statistically significant, improvement was seen when adding the sFlt1/PlGF ratio (AUC=0.85) compared with blood pressure and proteinuria alone(AUC=0.69;P=0.08).In women with twin pregnancy and suspected PE, the sFlt1/PlGF ratio at the time of initial evaluation is associated with subsequent diagnosis of PE and, more importantly, PE-related adverse maternal and perinatal outcomes. These findings are similar to singleton pregnancies and may implicate similar pathogenic pathways.

Background: The usual symptoms of endometriosis are secondary dysmenorrhea, dyspareunia, and infertility, but when located in the retroperitoneal space, it might have atypical symptoms that delay diagnosis and postpone therapy. Case: A young nulligravida presented with secondary dysmenorrhea and concurrent cyclic hip pain. Recent laparoscopy was reportedly normal. Computed tomography (CT)-directed percutaneous needle biopsy of a retroperitoneal mass showed endometriosis. Laparotomy with retroperitoneal dissection removed the endometriosis, and operative arthroscopy released strictured hip tendons improving her hip pain and limp. Conclusion: Retroperitoneal endometriosis presenting as hip pain was diagnosed by CT-guided percutaneous needle biopsy permitting removal by a multidisciplinary surgical approach.

Background The purpose of this study was to compare plasma soluble endoglin (sEng) levels with standard clinical evaluation or plasma levels of other angiogenic proteins [soluble fms-like tyrosine kinase 1 (sFlt1) and placental growth factor (PlGF)] in predicting short-term adverse maternal and perinatal outcomes in women with suspected preeclampsia presenting prior to 34 weeks. Methods and Findings Data from all women presenting at

Objective We sought to compare the risk of giving birth to large-for-gestational-age (LGA) infants in women with and without preeclampsia, after adjustment for obesity and glucose intolerance. Study Design We conducted secondary analysis of a prospective database of pregnant women with and without preeclampsia who delivered infants from 1998 through 2006 at Massachusetts General Hospital (n = 17,465). Results The risk of LGA was similar in women with and without preeclampsia (odds ratio, 0.81; 95% confidence interval, 0.59–1.14). After adjustment for body mass index, glucose intolerance, and other factors, the risk of LGA was significantly lower in women with preeclampsia compared to those without preeclampsia (odds ratio, 0.69; 95% confidence interval, 0.49–0.96). Stratified analysis in groups with a higher risk of LGA revealed that preeclampsia has a similar effect on the risk of LGA regardless of maternal obesity, glucose intolerance, parity, and race. Conclusion Preeclampsia appears to be characterized by reduced, and not increased, fetal growth.

Objective The purpose of this study was to describe relations among maternal demographic and lifestyle characteristics and midpregnancy levels of angiogenic markers (soluble Fms-like tyrosine kinase-1, placental growth factor, soluble endoglin). Study Design In a large pregnancy cohort, linear models were used to evaluate relations among maternal characteristics and midpregnancy angiogenic markers with and without covariate adjustment. Associations were examined in a subcohort that included term and preterm deliveries (n = 1302) and among “normal” term pregnancies (n = 668). Results Concentrations of all factors declined with increasing maternal body mass index. Multiparous women had lower soluble Fms-like tyrosine kinase-1 levels than primiparous women. Higher placental growth factor and slightly lower soluble endoglin levels were observed among women who smoked at enrollment, but not among those women who quit before enrollment. African American women had higher levels of all markers. Conclusion Understanding relations among maternal characteristics and levels of angiogenic factors may improve studies that use these markers to examine etiology and/or to predict adverse pregnancy outcome.

SAROSH RANA (F), HUILING JI, VIT LONG, EDWARD CHIEN, Brown University, Women and Infants Hospital of Rhode Island, Providence, Rhode Island, Brown University, Obstetrics and Gynecology, Providence, Rhode Island OBJECTIVE: The regulation of cervical remodeling during pregnancy is poorly understood but is thought to be regulated by steroid hormones. A number of model systems with androgen metabolism abnormalities have disturbances in cervical ripening. These models would suggest that nonaromatizable androgens directly control cervical ripening. 5a-reductase type II converts testosterone to DHT (Dihydrotestosterone), a non-aromatizable androgen. We hypothesize that cervical remodeling is mediated through androgens leading to decreased cervical tensile strength. STUDY DESIGN: Cervical creep (an assessment of tensile strength) was assessed in timed pregnant Sprague-Dawley rats at mid gestation. Treatment groups included three androgenic compounds: Androstenedione (20 mg), Testosterone (2 mg), and DHT (2 mg). Cervical creep was determined using the technique of Hollingsworth. Androgens were administered intravaginally on day 15. Tissue was harvested 16 hrs later. Groups were compared to control using t-test. RESULTS: A significant increase in cervical creep rates were seen after DHT (p = 0.01). No statistically significant difference was detected in rats treated with androstenedione or testosterone when compared to rats in the control group. The effect of testosterone had greater variability then androstenedione or DHT CONCLUSION: The non-aromatizable androgen, DHT, is an effective cervical ripening agent. The conversion of aromatizable androgens to DHT is necessary for androgen induced cervical ripening.