Awoniyi O. Awonuga

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.

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.

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.

Cellular stress causes reversible, PRKAA1/2-, and proteasome-dependent ID2 protein loss in trophoblast stem cells

Stress reduces fertility, but the mechanisms mediating this are not understood. For a successful pregnancy, placental trophoblast stem cells (TSCs) in the implanting embryo proliferate and then a subpopulation differentiates to produce hormones. Normally, differentiation occurs when inhibitor of differentiation 2 (ID2) protein is lost in human and mouse placental stem cells. We hypothesize that stress enzyme-dependent differentiation occurs in association with insufficient TSC accumulation. We studied a well-defined model where TSC differentiation requires ID2 loss. The loss of ID2 derepresses the promoter of chorionic somatomammotropin hormone 1 (CSH1), the first hormone after implantation. Csh1 mRNA is known to be induced in stressed TSCs. In this study, we demonstrate that AMP-activated protein kinase (PRKAA1/2, aka AMPK) mediates the stress-induced proteasome-dependent loss of ID2 at high stress levels. At very low stress levels, PRKAA1/2 mediates metabolic adaptation exemplified by the inactivation of acetyl coA carboxylase by phosphorylation without ID2 loss. At the highest stress levels, irreversible TSC differentiation as defined by ID2 loss and slower cell accumulation occurs. However, lower stress levels lead to reversible differentiation accompanied by metabolic adaptation. These data support the hypothesis that PRKAA1/2 mediates preparation for differentiation that is induced by stress at levels where a significant decrease in cell accumulation occurs. This supports the interpretation that enzyme-mediated increases in differentiation may compensate when insufficient numbers of stem cells accumulate.

Second-trimester rudimentary uterine horn pregnancy: rupture after labor induction with misoprostol.

BACKGROUND: Uterine anomalies are often first suspected after bimanual or ultrasonographic examination. Currently there are no specific recommendations for further evaluation of asymptomatic women with suspected uterine anomalies in pregnancy. CASE: A young primigravida with a history of an ultrasound diagnosis of bicornuate uterus presented with mild abdominal pain. An ultrasound examination showed a viable 18-week fetus with anhydramnios in the left uterine horn. Labor induction with misoprostol culminated in uterine rupture. At laparotomy, a ruptured left noncommunicating rudimentary uterine horn of a unicornuate uterus was noted. CONCLUSION: Pregnancies within noncommunicating uterine horns significantly increase the risk of potentially catastrophic outcome, therefore, consideration should be given to performing 3-dimensonal ultrasonography and/or magnetic resonance imaging examinations to determine the nature of uterine anomalies. Caution should be exercised if prostaglandins are considered for use in this setting.

Postoperative Adhesion Development Following Cesarean and Open Intra-Abdominal Gynecological Operations: A Review

In this review, we discuss the pathophysiology of adhesion development, the impact of physiological changes associated with pregnancy on markers of adhesion development, and the clinical implications of adhesion development following cesarean delivery (CD). Although peritoneal adhesions develop after the overwhelming majority of intra-abdominal and pelvic surgery, there is evidence in the literature that suggests that patients having CD may develop adhesions less frequently. However, adhesions continue to be a concern after CD, and are likely significant, albeit on average less than after gynecological operations, but with potential to cause significant delay in the delivery of the baby with serious, lifelong consequences. Appreciation of the pathophysiology of adhesion development described herein should allow a more informed approach to the rapidly evolving field of intra-abdominal adhesions and should serve as a reference for an evidence-based approach to consideration for the prevention and treatment of adhesions.

Benzo(a)pyrene causes PRKAA1/2‐dependent ID2 loss in trophoblast stem cells

Benzo(a)pyrene (BaP), a cigarette smoke component, is metabolized to diol esters (BPDE) that bind to DNA and form mutagenic BPDE‐DNA adducts. BaP activates stress enzymes including stress‐activated protein kinase/jun kinase (MAPK8/9) in embryos, AMP‐activated protein kinase alpha1/2 subunits (PRKAA1/2) in somatic cells, and inhibits the proliferation of trophoblast cell lineages. The loss of transcription factor inhibitor of differentiation (ID)2 is required for the initial differentiation of mouse trophoblast stem cells (TSC) in implanting mouse embryo to produce the first placental hormone, chorionic sommatomammotropin (CSH)1. Here we demonstrate that BaP activates PRKAA1/2 and causes ID2 protein loss in TSC in a time‐ and dose‐dependent manner. Although PRKAA1/2 was activated at low BaP doses, PRKAA1/2‐dependent ID2 protein loss occurred at a dose that was similar to the threshold that results in a significant decrease in TSC accumulation and decreased fraction of proliferating TSC. This suggests a possible relationship between stress‐induced declines in cell accumulation and stem cell differentiation when BaP levels are high. The threshold BaP dose that induces significant ID2 loss is in the range of a 2–3 pack/day habit, suggesting that this mechanism may be involved with implantation failure in smoking women. Mol. Reprod. Dev. 77: 533–539, 2010.

The role of uterine fundal pressure in the management of the second stage of labor: A reappraisal

Among the maneuvers that are used in the second stage of labor, uterine fundal pressure is one of the most controversial. The prevalence of its use is unknown. We reviewed the existing literature to assess whether there is justification for the use of fundal pressure in the contemporary management of the second stage of labor. Only one randomized, controlled study and a few prospective studies, review articles, and case reports have been published. No confirmed benefit of the procedure has been documented and a few adverse events have been reported in association with its use. Alternative management strategies in the second stage of labor exist and should be considered whenever possible. In conclusion, the role of fundal pressure is understudied and remains controversial in the management of the second stage of labor. We believe that caution should be exercised using this maneuver until it is proven to be safe and effective. Target Audience: Obstetricians & Gynecologists, Family Physicians Learning Objectives: After completion of this article, the reader should be able to recall that there is a scarcity of literature related to the efficacy and safety of using fundal pressure during the second stage of labor, state that there is no confirmed benefit of the procedure and there may be some adverse maternal/fetal effects, and explain that there are alternative strategies for management of the second stage of labor.

Benzopyrene and Experimental Stressors Cause Compensatory Differentiation in Placental Trophoblast Stem Cells

Stress causes decreased cell accumulation in early periimplantation embryos and the placental trophoblast stem cells derived from them. Benzopyrene and many other stressors activate stress enzymes that lead to suppressed stem cell accumulation through diminished proliferation and increased apoptosis. Trophoblast stem cells proliferate and a subpopulation of early postimplantation trophoblast cells differentiate to produce the first placental hormones that arise in the implanting conceptus. These hormones mediate antiluteolytic effects that enable the continuation of a successful implantation. The normal determination and differentiation of placental trophoblast stem cells is dependent upon a series of transcription factors. But, these transcription factors can also be modulated by stress through the activity of stress enzymes. This review enumerates and analyzes recent reports on the effects of benzopyrene on placental function in terms of the emerging paradigm that placental differentiation from stem cells can be regulated when insufficient production of stem cells is caused by stress. In addition, we review the other effects caused by benzopyrene throughout placental development.