Anthony N. Imudia

Peak serum estradiol level during controlled ovarian hyperstimulation is associated with increased risk of small for gestational age and preeclampsia in singleton pregnancies after in vitro fertilization.

OBJECTIVE To assess the impact of elevated peak serum E(2) levels (EPE(2); defined as levels >90th percentile) on the day of hCG administration during controlled ovarian hyperstimulation (COH) for IVF on the likelihood for small for gestational age (SGA), preeclampsia (PreE), and preterm delivery (PTD) in singleton pregnancies. DESIGN Retrospective cohort study. SETTING Tertiary-care academic medical center. PATIENT(S) Singleton live-birth pregnancies conceived after fresh IVF-ET. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) The delivery rate of SGA infants and the development of PreE and PTD in patients with and without EPE(2). RESULT(S) Patients with EPE(2) during COH were more likely to deliver SGA infants (7 [26.9%] vs. 10 [3.8%]; odds ratio [OR], 95% confidence interval [CI] {9.40, 3.22-27.46}) and develop PreE (5 [18.5%] vs. 12 [4.5%]; adjusted OR, 95% CI {4.79, 1.55-14.84}). No association was found between EPE(2) and the likelihood for delivery before 37 weeks, 35 weeks, or 32 weeks of gestation. Receiver operating characteristic analysis revealed that EPE(2) level predicted adverse obstetrical outcome (SGA + PreE) with 38.5% and 91.7% sensitivity and specificity, respectively. Using a serum peak E(2) cutoff value of 3,450 pg/mL (>90th percentile level), the positive predictive value was 37%, while the negative predictive value was 92%. CONCLUSION(S) EPE(2) level (>3,450 pg/mL) on the day of hCG administration during COH is associated with greater odds of developing PreE and delivery of an SGA infant in singleton pregnancies resulting from IVF cycles.

Pathogenesis of intra-abdominal and pelvic adhesion development

Abdominal and pelvic adhesions are a frequent occurrence and are responsible for significant morbidity resulting in abdominal and pelvic pain, infertility, and small bowel obstruction. The process of adhesion development begins when damage to peritoneal surfaces from any source (operative trauma, infection, foreign bodies, desiccation, irradiation, allergic reaction, or chemical injury) induces a series of biochemical/molecular biologic cascades involving different elements. These elements include peritoneal fluid, neutrophils, leukocytes, macrophages, cytokines, mesothelial cells, and tissue and coagulation factors, which teleologically have the intention of peritoneal repair; however, these processes also result in adhesion development. Major pathways that play significant roles in the healing process of peritoneal damage leading to adhesion development are the fibrinolytic system, extracellular matrix deposition, growth factor and cytokines, cell adhesion molecules, angiogenesis, apoptosis and proliferation, and remesothelialization. Greater understanding of the regulation and interaction of these processes provides the potential for reduction of postoperative adhesion development.

Delayed postpartum preeclampsia and eclampsia: Demographics, clinical course, and complications

OBJECTIVE: To estimate and evaluate the demographics, clinical course, and complications of delayed postpartum preeclampsia in patients with and without eclampsia. METHODS: We conducted a retrospective cohort study of patients who were discharged and later readmitted with the diagnosis of delayed postpartum preeclampsia more than 2 days to 6 weeks or less after delivery between January 2003 and August 2009. RESULTS: One hundred fifty-two patients met criteria for the diagnosis of delayed postpartum preeclampsia. Of these, 96 (63.2%) patients had no antecedent diagnosis of hypertensive disease in the current pregnancy, whereas seven (4.6%), 14 (9.2%), 28 (18.4%), and seven (4.6%) patients had gestational hypertension, chronic hypertension, preeclampsia, and preeclampsia superimposed on chronic hypertension, respectively, during the peripartum period. Twenty-two patients (14.5%) developed postpartum eclampsia, and more than 90% of these patients presented within 7 days after discharge from the hospital. The most common presenting symptom was headache in 105 (69.1%) patients. Patients who developed eclampsia were significantly younger than those who did not (mean±standard deviation, 23.2±6.2 compared with 28.3±6.7 years; adjusted odds ratio [OR] 1.13, 95% confidence interval [CI] 1.02–1.26, P=.03), and other demographic variables were no different. A lower readmission hemoglobin was associated with a lower odds of progression to eclampsia (10.7±1.7 compared with 11.6±2.2 g/dL, adjusted OR 0.75, 95% CI 0.57–0.98, P=.04). CONCLUSION: One week after discharge appears to be a critical period for the development of postpartum eclampsia. Education about the possibility of delayed postpartum preeclampsia and eclampsia should occur after delivery, whether or not patients develop hypertensive disease before discharge from the hospital. LEVEL OF EVIDENCE: III

Pathogenesis of benign metastasizing leiomyoma: A review

Uterine leiomyomas are benign tumors of smooth muscle origin with protean symptomatology, and are the most common gynecological tumor in women of reproductive age. Very rarely, benign uterine leiomyomas display bizarre growth patterns with associated extrauterine benign-appearing smooth muscle tumors, similar to the smooth muscle cells found in a uterine fibroid, and are given the name benign metastasizing leiomyoma (BML). We reviewed the published literature to outline the possible etiology of benign metastasizing leiomyoma (BML), and explored the similarities between BML and endometriosis. Several observations and animal experiments support the findings that BML may evolve from lymphatic and hematological spread, coelomic metaplasia and intraperitoneal seeding. The weight of available evidence support the conclusion that the mechanism used to explain the pathogenesis of endometriosis can also be used to explain BML. However, in making a diagnosis of BML, meticulous sampling of the pathology specimen should be undertaken to exclude leiomyosarcoma, which unlike BML, has an aggressive course. It is hoped that analyses of the etiology and features of this disorder will facilitate a better understanding of its pathogenesis and treatment. Target Audience: Obstetricians & Gynecologists, Family Physicians Learning Objectives: After completion of this article, the reader will be able to asses the clinical characteristics of Benign Metastasizing Leiomyoma. Compare the potential pathophysiology with endometriosis and differentiate benign metastasizing Leiomyoma from Leiomyosarcoma.

The prevalence and prognostic impact of lymph node metastasis in malignant germ cell tumors of the ovary

BACKGROUND The purpose of this study is to report the prevalence and prognostic importance of lymph node metastasis in malignant germ cell tumors of the ovary (OGCT). METHODS Demographic and clinicopathologic information were abstracted from the Surveillance, Epidemiology, and End Results Program (SEER) from 1988 to 2004. Patients with a histologic diagnosis of OGCT after surgical resection were included. The study population was divided into Cohort A (lymph node metastasis absent) and Cohort B (lymph node metastasis present). Statistical analysis using Fishers Exact Test, Kaplan-Meier survival methods, and Cox regression proportional hazards were performed. RESULTS In 613 patients with lymphadenectomy, the prevalence of lymphnode metastasis was 18.1% (111/613). In dysgerminoma, malignant teratoma and mixed germ cell tumors including pure non-dysgerminoma histology, the lymphnode metastasis was present in 28%, 8% and 16% patients respectively (p<0.05). Age, race, grade and extent of lymph node dissection influenced lymph node involvement but this was statistically not significant. Five year survival in Cohort A was 95.7% compared to 82.8% in Cohort B (p<0.001). After controlling for age, race, stage, grade and histology, multivariate analysis revealed the presence of lymph node involvement as an independent predictor of poor survival with a hazards ratio of 2.87 (95% CI 1.439-5.725; p<0.05). CONCLUSIONS Prevalence of lymph node metastasis varies according to histology in OGCT and is an independent predictor of poor survival in these patients. These findings highlight the value of lymphadenectomy and may be helpful in creating risk stratification models for individualization of adjuvant therapies.

Elective cryopreservation of all embryos with subsequent cryothaw embryo transfer in patients at risk for ovarian hyperstimulation syndrome reduces the risk of adverse obstetric outcomes: a preliminary study.

OBJECTIVE To test the hypothesis that patients who undergo elective cryopreservation of all embryos, due to risk of ovarian hyperstimulation syndrome and elevated peak serum estradiol (E(2)), previously defined as level >3,450 pg/mL (90th percentile) during in vitro fertilization (IVF), will be less likely to have small for gestational age (SGA) infants and preeclampsia as compared with patients with elevated peak serum E(2) who undergo fresh embryo transfer (ET). DESIGN Cohort study. SETTING Tertiary care academic medical center. PATIENT(S) Twenty women who underwent elective cryopreservation of all embryos with subsequent cryothaw ET and 32 similar women with elevated peak E(2) during controlled ovarian hyperstimulation for IVF who underwent a fresh ET. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Prevalence of SGA infants and development of preeclampsia in patients with cryothaw ET or fresh ET in the setting of elevated peak E(2). RESULT(S) After adjusting for confounders (body mass index, antral follicle count, peak serum E(2) level) using forward stepwise logistic regression, the patients who elected cryopreservation of all embryos and subsequent cryothaw ET were statistically significantly less likely to deliver SGA infants as compared with the patients who had fresh ET in the setting of elevated peak E(2). In the entire cohort, a total of seven women had preeclampsia, all of whom had had fresh ET in the setting of elevated peak serum E(2): 7 (21.9%) in the fresh ET group versus 0 women in the elective cryopreservation group. CONCLUSION(S) This preliminary study suggests that elective cryopreservation of all embryos in patients with elevated peak serum E(2) for subsequent cryothaw ET in cycles with a better physiologic hormonal milieu may reduce the odds of SGA and preeclampsia in IVF singleton deliveries.

A comparison of younger vs older women with vulvar cancer in the United States.

OBJECTIVE The purpose of this study was to compare the prognostic variables and survival of younger (< 50 years) to that of older (> or = 50 years) women with vulvar cancer. STUDY DESIGN Subjects with invasive squamous cell carcinoma of the vulva were identified from the limited use Surveillance, Epidemiology, and End Results (SEER) Program 1988-2005. Comparisons between younger and older women were accomplished with chi(2) and t-tests. Survival analysis was accomplished with Kaplan-Meier for univariate analysis and Cox proportional hazards model for multivariate analysis. RESULTS A total of 6965 patients met inclusion criteria, of whom 1345 patients (19.3%) were younger and 5620 patients (80.7%) were older. The 5-year survival was 87.5% for younger women and 52.5% for older women (P < .001). After data were controlled for race, stage, grade, and surgical treatment, older patients had a hazard ratio of 3.9 (95% CI, 3.2-4.7) for death. CONCLUSION A striking survival difference exists between younger and older women with squamous cell vulvar cancer, which supports the view that etiopathogenesis of this disease may vary between age groups.

National trends of adnexal surgeries at the time of hysterectomy for benign indication, United States, 1998-2011

OBJECTIVE We sought to investigate the most recent national trends of bilateral salpingectomy (BS) and bilateral salpingo-oophorectomy (BSO) at the time of hysterectomy performed for benign indications. STUDY DESIGN We conducted a national cross-sectional analysis of all inpatient discharges for women aged ≥18 years who underwent a hysterectomy for benign indications from 1998 through 2011 using the largest publicly available all-payer inpatient database in the United States. We scanned International Classification of Diseases, Ninth Revision codes for an indication of specific bilateral adnexal surgeries, including BSO and BS. Joinpoint regression was used to characterize and estimate 14-year national trends in performing BSO and BS at the time of hysterectomy for benign indications, overall and in population subgroups. RESULTS During the study period, there were approximately 428,523 inpatient hysterectomy procedures performed annually for benign indications. Of these, >53% had no adnexal surgery performed during the same hospitalization, whereas 43.7% and 1.3% of those discharges had BSO and BS procedures, respectively. The rate of BSO was directly correlated with increasing age for patients <65 years. Conversely, we observed an inverse relationship between BS and patient age, with the BS rate among women aged <25 years twice that of women aged ≥45 years. From 1998 through 2001, there was a 2.2% increase in the rate of BSO per year (95% confidence interval, 0.4-4.0); however, this was followed by a consistent 3.6% (95% confidence interval, -4.0 to -3.3) annual decline in the BSO rate, from 49.7% in 2001 to 33.4% in 2011. National rates of BS among women undergoing hysterectomy for benign indications increased significantly throughout the study period, with an estimated 8% annual increase from 1998 through 2008, followed by a sharp 24% increase annually during the last 4 years of the study period. The BS rate nearly quadrupled in 14 years. CONCLUSION The type of adnexal surgery performed concomitantly with hysterectomy for benign indications has undergone a significant shift since 2001. Significantly more BS and less BSO procedures are being performed among gynecologic surgeons in the United States.

Incidence, trends, risk factors, indications for, and complications associated with cesarean hysterectomy: a 17-year experience from a single institution.

PurposeTo review the incidence, trends, risk factors, indications for, and complications associated with cesarean hysterectomy (CH) in our institution.Materials and methodsRetrospective study of 158 women who had CH at the Detroit Medical Center during a 17 period.ResultsDuring the study period, 158 of 202,356 deliveries were CH, giving an overall incidence of 0.78 per 1,000 deliveries. Of the 158 cases, 14 were elective while 144 were emergently performed due to complications encountered at cesarean section. Analysis of the eligible 144 cases showed that the commonest risk factors were previous cesarean delivery (76%) and placenta previa (35%). Abnormal placenta adherence was the indication for CH in 50.7%, followed by uterine atony in 34.7% and uterine rupture in 16.7% of the cases. Febrile morbidity (44.4%) and disseminated intravascular coagulopathy (22.9%) were the most common postoperative complications. Most complications occurred in patients with parity greater than two. Compared to the last decade, CH performed more recently were less likely to be complicated by bowel injury or disseminated intravascular coagulopathy.ConclusionMorbidly adherent placenta has replaced uterine atony as the leading indication for emergent CH in our institution. High parity remains a risk factor for complications; however, we recorded a reduction in bowel injury and disseminated intravascular coagulopathy in recent years.

Expression of Heparin-binding EGF-like Growth Factor in Term Chorionic Villous Explants and Its Role in Trophoblast Survival

Heparin-binding EGF-like growth factor (HBEGF) induces trophoblast extravillous differentiation and prevents apoptosis. These functions are compromised in preeclampsia. Because HBEGF is downregulated in placentas delivered by women with preeclampsia, we have examined its expression and cytoprotective activity in term villous explants. Chorionic villous explants prepared from non-pathological placentas collected by cesarean section at term were cultured at either 20% or 2% O2 and treated with the HBEGF antagonist CRM197 or recombinant HBEGF. Paraffin sections were assayed for trophoblast death, proliferation and HBEGF expression using the TUNEL method, immunohistochemistry for nuclear Ki67 expression and semi-quantitative immunohistochemistry with image analysis, respectively. Trophoblast cell death was increased significantly after 8h of culture with CRM197 or by culture for 2h at 2% O2. Exogenous HBEGF prevented cell death due to hypoxia. Proliferative capacity was not affected by culture at either 20% or 2% O2. Contrary to first trimester placenta, term trophoblasts do not elevate HBEGF expression in response to hypoxia. However, low endogenous levels of HBEGF are required to maintain survival. Therefore, HBEGF-mediated signaling significantly reduces trophoblast cell death at term and its deficiency in preeclampsia could negatively impact trophoblast survival.