Intrauterine human chorionic gonadotropin infusion in oocyte donors promotes endometrial synchrony and induction of early decidual markers for stromal survival: a randomized clinical trial.

STUDY QUESTION: Does a single intrauterine infusion of human chorionic gonadotropin (hCG) at the time corresponding to a Day 3 embryo transfer in oocyte donors induce favorable molecular changes in the endometrium for embryo implantation? SUMMARY ANSWER: Intrauterine hCG was associated with endometrial synchronization between endometrial glands and stroma following ovarian stimulation and the induction of early decidual markers associated with stromal cell survival. WHAT IS KNOWN ALREADY: The clinical potential for increasing IVF success rates using an intrauterine hCG infusion prior to embryo transfer remains unclear based on previously reported positive and non-significant findings. However, infusion of CG in the non-human primate increases the expression of pro-survival early decidual markers important for endometrial receptivity, including α-smooth muscle actin (α-SMA) and NOTCH1. STUDY DESIGN, SIZE, DURATION: Oocyte donors (n=15) were randomly assigned to receive an intrauterine infusion of 500 IU hCG (n=7) or embryo culture media vehicle (n=8) 3 days following oocyte retrieval during their donor stimulation cycle. Endometrial biopsies were performed 2 days later, followed by either RNA isolation or tissue fixation in formalin and paraffin embedding. PARTICIPANTS/MATERIALS, SETTING, METHODS: Reverse transcription of total RNA from endometrial biopsies generated cDNA, which was used for analysis in the endometrial receptivity array (ERA; n = 5/group) or quantitative RT-PCR to determine relative expression of ESR1, PGR, C3 and NOTCH1. Tissue sections were stained with hematoxylin and eosin followed by blinded staging analysis for dating of endometrial glands and stroma. Immunostaining for ESR1, PGR, α-SMA, C3 and NOTCH1 was performed to determine their tissue localization. MAIN RESULTS AND THE ROLE OF CHANCE: Intrauterine hCG infusion was associated with endometrial synchrony and reprograming of stromal development following ovarian stimulation. ESR1 and PGR were significantly elevated in the endometrium of hCG-treated patients, consistent with earlier staging. The ERA did not predict an overall positive impact of intrauterine hCG on endometrial receptivity. However, ACTA2, encoding α-SMA was significantly increased in response to intrauterine hCG. Similar to the hCG-treated non-human primate, sub-epithelial and peri-vascular α-SMA expression was induced in women following hCG infusion. Other known targets of hCG in the baboon were also found to be increased, including C3 and NOTCH1, which have known roles in endometrial receptivity. LIMITATIONS, REASONS FOR CAUTION: This study differs from our previous work in the hCG-treated non-human primate along with clinical studies in infertile patients. Specifically, we performed a single intrauterine infusion in oocyte donors instead of either continuous hCG via an osmotic mini-pump in the baboon or infusion followed by blastocyst-derived hCG in infertile women undergoing embryo transfer. Therefore, the full impact of intrauterine hCG in promoting endometrial receptivity may not have been evident. WIDER IMPLICATIONS OF THE FINDINGS: Our findings suggest a potential clinical benefit for intrauterine hCG prior to embryo transfer on Day 3 in counteracting endometrial dyssynchrony from ovarian stimulation and promoting expression of markers important for stromal survival. Finally, there were no obvious negative effects of intrauterine hCG treatment. STUDY FUNDING/COMPETING INTERESTS: Funding for this work was provided by NICHD R01 HD042280 (A.T.F.) and NICHD F30 HD082951 (M.R.S.). C.S. and P.D.-G are co-inventors of the patented ERA, which is owned by IGENOMIX SL and was used in this study, and C.S. is a shareholder in IGENOMIX SL. M.R.-A. is employed by IGENOMIX SL. No other authors have any conflicts of interest to report. TRIAL REGISTRATION NUMBER: This study was registered with ClinicalTrials.gov (NCT01786252). TRIAL REGISTRATION DATE: 5 February 2013. DATE OF FIRST PATIENT'S ENROLLMENT: 10 May 2013.

Analysis of adverse events with Essure hysteroscopic sterilization reported to the Manufacturer and User Facility Device Experience database.

STUDY OBJECTIVE: The Manufacturer and User Facility Device Experience database may be useful for clinicians using a Food and Drug Administration-approved medical device to identify the occurrence of adverse events and complications. We sought to analyze and investigate reports associated with the Essure hysteroscopic sterilization system (Conceptus Inc., Mountain View, CA) using this database. DESIGN: Retrospective review of the Manufacturer and User Facility Device Experience database for events related to Essure hysteroscopic sterilization from November 2002 to February 2012 (Canadian Task Force Classification III). SETTING: Online retrospective review. PATIENTS: Online reports of patients who underwent Essure tubal sterilization. INTERVENTION: Essure tubal sterilization. MEASUREMENTS AND MAIN RESULTS: Four hundred fifty-seven adverse events were reported in the study period. Pain was the most frequently reported event (217 events [47.5%]) followed by delivery catheter malfunction (121 events [26.4%]). Poststerilization pregnancy was reported in 61 events (13.3%), of which 29 were ectopic pregnancies. Other reported events included perforation (90 events [19.7%]), abnormal bleeding (44 events [9.6%]), and microinsert malposition (33 events [7.2%]). The evaluation and management of these events resulted in an additional surgical procedure in 270 cases (59.1%), of which 44 were hysterectomies. CONCLUSION: Sixty-one unintended poststerilization pregnancies were reported in the study period, of which 29 (47.5%) were ectopic gestations. Thus, ectopic pregnancy must be considered if a woman becomes pregnant after Essure hysteroscopic sterilization. Additionally, 44 women underwent hysterectomy after an adverse event reported to be associated with the use of the device.

Influenza immunization in pregnancy: overcoming patient and health care provider barriers.

Seasonal influenza imparts disproportionate morbidity and death to pregnant women. Immunization against influenza is the most effective intervention to mitigate the burden of influenza disease during pregnancy; nevertheless, immunization rates remain suboptimal in this patient population. Therefore, there is a clear need for strategies to optimize influenza vaccination among pregnant women. We reviewed potential patient and health care provider barriers to influenza immunization and propose effective strategies for overcoming them.

Hysterectomy subsequent to endometrial ablation.

STUDY OBJECTIVE: To estimate the incidence of and factors associated with hysterectomy subsequent to endometrial ablation. DESIGN: Retrospective cohort study (Canadian Task Force classification II-2). SETTING: Gynecology practice. PATIENTS: Women who underwent endometrial ablation from January 2003 to June 2010, with a minimum follow-up of 9 months. INTERVENTIONS: Endometrial ablation and hysterectomy. MEASUREMENTS AND MAIN RESULTS: Of 1169 women, 157 (13.4%) underwent hysterectomy subsequent to endometrial ablation. Women who underwent subsequent hysterectomy were significantly younger at ablation (mean [SD; 95% CI] 39.0 [6.8; 38.0-40.1] years vs 41.4 [7.0; 41.0-41.9] years; p < .001) and were more likely to have previously delivered via cesarean section (26.3 vs 18.1%; p = .02). The rate of hysterectomy was significantly associated with the type of ablation performed: 33.0% for rollerball vs 16.5% for thermal balloon (p = .003), 11.0% for radiofrequency (p < .001), and 9.8% for cryoablation (p < .001). Time to hysterectomy also differed significantly based on the type of ablation performed (p = .006). Adenomyosis was present in 44.4% of hysterectomy specimens. CONCLUSION: With a mean follow-up of 39 months, 13.4% of women underwent hysterectomy subsequent to ablation. Women who were younger at ablation had an increased likelihood of hysterectomy. Rate and time to hysterectomy were associated with the type of ablation performed.

Misdiagnosis of cervical ectopic pregnancy.

PURPOSE: To determine the presenting symptoms as well as the frequency and reasons for the delayed diagnosis of cervical ectopic pregnancy (CEP) in order to increase detection and prevent treatment delay. METHODS: Retrospective case series of 15 women treated for CEP from January 1997 through December 2008 at a university teaching hospital. RESULTS: Fifteen patients were treated for CEP during the study period. Eight patients presented to the emergency department, of which 6 (75%) were initially misdiagnosed. The most common misdiagnosis was threatened miscarriage (n = 5). All patients with accurately diagnosed CEP presented with heavy vaginal bleeding; those misdiagnosed reported mild to moderate vaginal bleeding. Three of six patients misdiagnosed did not have an ultrasound performed upon presentation, and three patients had an ultrasound report not suggestive of CEP. CEP was diagnosed on follow-up ultrasound, delaying treatment 1-4 days. CONCLUSIONS: Misdiagnosis of CEP upon initial presentation is a common occurrence. Transvaginal ultrasound performed by a qualified practitioner may increase detection and prevent treatment delay.

Uncoupling oxidative phosphorylation with 2,4-dinitrophenol promotes development of the adhesion phenotype.

OBJECTIVE: To determine the effect of uncoupling oxidative phosphorylation with 2,4-dinitrophenol (DNP) on adhesion phenotype development. DESIGN: Prospective experimental study. SETTING: Academic medical center. PATIENT(S): Women undergoing laparotomy for pelvic pain from whom normal peritoneum and adhesions were excised to create primary cultures of normal peritoneal and adhesion fibroblasts. INTERVENTION(S): Treatment of normal peritoneal and adhesion fibroblasts isolated from the same patient(s) with or without 0.2 mM DNP for 24 hours. MAIN OUTCOME MEASURE(S): Evaluation of adhesion phenotype markers type I collagen, vascular endothelial growth factor (VEGF), and hypoxia-inducible factor (HIF)-1α. RESULT(S): In agreement with prior findings, adhesion fibroblasts exhibited significantly higher basal levels of type I collagen, VEGF, and HIF-1α compared with normal peritoneal fibroblasts. Treatment of normal peritoneal fibroblasts with DNP resulted in significant increases in type I collagen (10.2 ± 1.4 vs. 18.4 ± 1.9 fg/µg RNA) and VEGF (8.2 ± 1.1 vs. 13.7 ± 0.4 fg/µg RNA) over baseline. HIF-1α levels did not increase when normal peritoneal fibroblasts were treated with DNP. CONCLUSION(S): The adhesion phenotype, which is normally expressed in response to hypoxia, is reproduced in a normoxic environment by uncoupling oxidative phosphorylation with DNP, as evidenced by an increase in type I collagen and VEGF. Acquisition of the adhesion phenotype was via a mechanism distinct from up-regulation of HIF-1α. These observations are consistent with the hypothesis that the adhesion phenotype represents a state of intracellular metabolic depletion.

Adverse obstetric outcomes associated with sonographically identified large uterine fibroids.

STUDY OBJECTIVE: To determine the impact of sonographically identified large uterine fibroids (>5 cm in diameter) on obstetric outcomes. DESIGN: Retrospective cohort study. SETTING: University teaching hospital. PATIENT(S): Women with singleton gestations (n = 95) noted to have uterine fibroids on obstetric ultrasonography from September 2009 through April 2010 and age-matched controls (n = 95). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Obstetric outcomes including short cervix, preterm premature rupture of membranes, and preterm delivery. RESULT(S): Compared to women with no fibroids or small fibroids (≤5 cm), women with large fibroids (>5 cm) delivered at a significantly earlier gestational age (38.6 vs. 38.4 vs. 36.5 weeks). Short cervix, preterm premature rupture of membranes, and preterm delivery were also significantly more frequent in the large fibroid group, and were associated with number of fibroids >5 cm in diameter. Blood loss at delivery was significantly higher in the large fibroid group (486.8 vs. 535.6 vs. 645.1 mL), as was need for postpartum blood transfusion (1.1 vs. 0.0 vs. 12.2%). CONCLUSION(S): Women with large uterine fibroids in pregnancy are at significantly increased risk for delivery at an earlier gestational age compared to women with small or no fibroids, as well as obstetric complications including excess blood loss and increased frequency of postpartum blood transfusion.

Small bowel obstruction subsequent to Essure microinsert sterilization: a case report.

OBJECTIVE: To report a case of small bowel obstruction (SBO) subsequent to Essure microinsert sterilization. DESIGN: Case report. SETTING: University teaching hospital. PATIENT(S): A 38-year-old woman, gravida 1, para 1, with a history of pelvic pain, vaginal spotting, nausea, vomiting, and constipation 1 month after Essure hysteroscopic sterilization. INTERVENTION(S): Radiologic investigation, including a computed tomography scan of the abdomen and pelvis, followed by operative laparoscopy. MAIN OUTCOME MEASURE(S): Alleviation of the SBO. RESULT(S): Radiologic investigation suggested a distal SBO, with the left Essure microinsert noted in the left lower pelvis. These findings, including an inflamed appendix, were confirmed at operative laparoscopy. Lysis of adhesions, removal of the Essure microinsert, appendectomy, and left salpingectomy were performed. CONCLUSION(S): This case is reported to increase awareness that SBO is a potential complication of Essure microinsert placement.

Conservative management of cervical ectopic pregnancy: utility of uterine artery embolization.

OBJECTIVE: To evaluate the use of uterine artery embolization (UAE) in conjunction with methotrexate in the conservative treatment of cervical ectopic pregnancy (CEP). DESIGN: Case series. SETTING: Tertiary-care university hospital. PATIENT(S): Cases of CEP treated at Hutzel Women's Hospital between January 1997 and December 2008. INTERVENTION(S): Multidose methotrexate treatment with or without UAE and intra-amniotic potassium chloride injection (KCl). MAIN OUTCOME MEASURE(S): Beta-human chorionic gonadotropin level, vaginal bleeding, length of hospital stay, and future fecundity. RESULT(S): A retrospective analysis of 15 patients with CEP treated conservatively using methotrexate with leucovorin rescue (MTx/Leu) alone (group 1, five cases), with UAE as an adjunctive therapy (group 2, six cases), or also having received intra-amniotic KCl before UAE (group 3, four cases) is reported. There was no significant difference in age, parity, or gestational age among treatment groups. The median ß-hCG level on presentation was 9,606 mIU/mL for group 1, 26,516 mIU/mL for group 2, and 130,464 mIU/mL for group 3. The difference was found to be statistically significant. No patients developed complications from UAE. Of the 10 patients who underwent UAE, 2 subsequently had confirmed viable pregnancies. CONCLUSION(S): Uterine artery embolization with methotrexate is an option for minimally invasive intervention in the treatment of CEP.

Nickel hypersensitivity associated with an intratubal microinsert system.

BACKGROUND: Although known nickel hypersensitivity is a contraindication to intratubal microinsert placement in the United States, this case demonstrates that nickel hypersensitivity to intratubal microinserts can occur. CASE: A young woman developed an allergic reaction after placement of intratubal microinserts. Nickel hypersensitivity was confirmed with skin patch testing. The microinserts were removed hysteroscopically, and the patient improved. CONCLUSION: If a patient experiences symptoms of an allergic reaction after hysteroscopic sterilization, referral to an allergy specialist is recommended. If nickel hypersensitivity is confirmed, the microinserts should be removed; this may be performed under hysteroscopic guidance.

Appendectomy in the gynecological setting: intraoperative findings and corresponding histopathology.

BACKGROUND/AIMS: To evaluate the intraoperative findings and corresponding histopathology associated with appendectomies performed during benign gynecological surgery. METHODS: Retrospective case series. RESULTS: Twenty-two appendectomies were performed from 2002 through 2008 at Hutzel Women's Hospital due to intraoperative findings of inflammation or erythema (n = 8), periappendiceal adhesions (n = 5), injury to the appendix or mesoappendix (n = 2), fecalith (n = 2), dilation of the appendix (n = 1), adnexal mass involving the appendix (n = 1), and suspected lipoma (n = 1). Final pathology was consistent with significant findings such as acute inflammation, periappendicitis, and adhesions or endometriosis involving the appendix in 68.2% of cases. CONCLUSION: In the benign gynecological setting, appendectomies were primarily performed due to inflammation or erythema. In the majority of cases, significant appendiceal pathology was confirmed.

Vaccination in pregnancy.

Vaccination is one of the most effective strategies employed to prevent morbidity and mortality from infectious diseases. Pregnancy is considered to be a time when women have consistent contact with their healthcare providers and it presents an opportunity for providers to review their immunization status and to advocate for appropriate vaccination antepartum and in the immediate postpartum period. All forms of immunization, with the exception of live viral or live bacterial vaccines are generally considered to be safe for administration during pregnancy. It is important that healthcare providers counsel pregnant women about the benefits of receiving the vaccines that are recommended during pregnancy as well as the potential risks to the developing fetus. It is imperative that obstetricians and primary care providers are aware of and implement the vaccination guidelines for women, both during pregnancy and in the postpartum period.

Pathogenesis of benign metastasizing leiomyoma: a review.

UNLABELLED: 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.

Early demonstration of postoperative adhesions in a rodent model.

OBJECTIVE: To assess the cellular and molecular mechanisms of postoperative adhesion development in a rodent model. DESIGN: Prospective randomized controlled study. SETTING: Research laboratory. PATIENTS: Thirty sexually mature female Sprague-Dawley rats. INTERVENTIONS: Cecal abrasion. MAIN OUTCOME MEASURE(S): At 0, 2, 4, 8, 16, 24, 48, 72, 96, 168, 336, and 504 hours after cecal abrasion, one to three rats were sacrificed (n = 26). Four nonabraded rats served as controls. Peritoneal adhesion status was evaluated and tissue was collected for histologic and immunohistochemical investigation. RESULTS: Postoperative tissue attachments were identified as early as 2 hours after cecal abrasion. Significant local edema and vessel congestion appeared within 2 hours, and cellular proliferation was observed at 24 hours; angiogenesis and tissue proliferation remained present at 2 weeks. beta1 integrin was highly expressed early and was thereafter decreased. Cellular fibronectin was not detectable until 1 week after cecal abrasion. CONCLUSIONS: Postoperative adhesions are initiated as rapidly as 2 hours after surgical intervention in this rodent model.

Reasons for poststerilization hysterosalpingography noncompliance in a clinic population.

OBJECTIVE: Although hysterosalpingography (HSG) is required 12 weeks after hysteroscopic sterilization, HSG compliance in our clinic population is remarkably low. We were interested in determining the reason(s) for HSG noncompliance in this urban-based patient population. STUDY DESIGN: University Health Center patients who underwent hysteroscopic sterilization between January 1, 2006, and December 31, 2007, and who did not complete HSG were contacted by telephone to elicit the reason(s) for lack of follow-up. RESULTS: Fifty-two patients qualified for inclusion in this study. Consent was obtained from all 14 patients accessible by telephone. Of note, 63.5% of patient-provided phone numbers were not in service at the time contact was attempted (n = 33). Patient-reported reasons for HSG noncompliance included insurance issues (n = 5), failure to remember to schedule HSG (n = 4), HSG scheduling difficulties (n = 2),failure to be informed about the need for HSG (n = 2), and prolonged postoperative vaginal bleeding (n =1). CONCLUSION: Reasons for poststerilization HSG noncompliance varied. However, an insurance issue was the most frequently reported reason for noncompliance. not recalling the need to schedule HSG was another common reason for noncompliance. Approaches to increase compliance with poststerilization HSG are needed, particularly in an urban-based, clinic population.

Failed female sterilization: a review of pathogenesis and subsequent contraceptive options.

OBJECTIVE: To review the published literature, outline the pathogenesis of failed sterilization and discuss the currently available contraceptive options once sterilization fails. STUDY DESIGN: Publications from January 1966 to October 2008 and indexed in the MEDLINE/PubMed database were reviewed. Medical search heading words sterilization, sterilization failure, sterilization methods and contraception were used to identify relevant articles. In addition, references were obtained through cross-referencing the bibliography cited in each work. RESULTS: Available evidence suggests that sterilization fails in 0.13-1.3% of sterilization procedures and of these, 15-33% will be ectopic pregnancies. Tubal recanalization and cornual and tuboperitoneal fistula formation are the main causes; their occurrence can be reduced by proper training and use of appropriate sterilization techniques. Following sterilization failure, hysterosalpingography can provide valuable information about the patency of the fallopian tubes. CONCLUSION: Tubal sterilization is highly effective but can fail. There is a paucity of information in the literature as to what is best or most appropriate for patients when sterilization fails. Patients should be counseled at the outset about the contraceptive options that are available should sterilization fail.

Tuboovarian abscess after saline infusion sonohysterography: an unusual complication.

A 45-year-old woman, nulligravida, who underwent saline infusion sonohysterography for infertility evaluation experienced fever and pelvic pain 7 days after the procedure. Transvaginal ultrasonography and computed tomography of the abdomen and pelvis revealed bilateral tuboovarian abscesses (TOA). Because of persistent febrile morbidity despite treatment with broad-spectrum parenteral antibiotics, the TOA were drained under computed tomography guidance. We believe is the first reported case of TOA after saline infusion sonohysterography.

Placement of a permanent birth control device at a university medical center.

OBJECTIVE: To determine the Essure placement failure rate and analyze factors associated with failure in an urban, nonstudy population at a university medical center. STUDY DESIGN: A retrospective study was conducted of women who underwent attempted Essure hysteroscopic sterilization at the Detroit Medical Center (DMC) from January 1, 2003, to June 30, 2007. RESULTS: There were 316 Essure procedures attempted at the DMC from January 2003 through June 2007. Of the 316 attempted procedures, there were 22 device placement failures and 3 documented post-Essure pregnancies. Of the 22 placement failures, 11 were attributed to difficulty visualizing the tubal ostia. Other causes of failure included device malfunction, uterine perforation, tubal perforation, expulsion of the device, tubal spasm, tubal ostia too large for the device and unspecified. Difficulty visualizing the ostia (p < 0.001) and a longer procedure time (p = 0.008) were significantly associated with failure. CONCLUSION: The rate of successful placement of the Essure permanent birth control device at the DMC is 92.1%, with a post-Essure pregnancy rate of 0.95%. The majority of placement failures may be attributed to difficulty visualizing the tubal ostia.

Review: cellular metabolism: contribution to postoperative adhesion development.

Postoperative adhesions are a significant source of morbidity, including contributions to pelvic pain, bowel obstruction, and infertility. While the mechanisms of postoperative adhesion development are complex and incompletely understood, hypoxia appears to trigger a cascade of intracellular responses involving hypoxia-inducible factors, lactate, reactive oxygen species, reactive nitrogen species, and insulin-like growth factors that results in manifestation of the adhesion phenotype. Thus, substantial evidence exists to implicate the direct role of cellular metabolism in wound repair and adhesion development.

Complete septate uterus, obstructed hemivagina, and ipsilateral renal anomaly: pregnancy course complicated by a rare urogenital anomaly.

BACKGROUND: Abnormalities of the female reproductive tract are associated with a multitude of intrapartum complications. In the case that follows, we report the complicated pregnancy course of a woman diagnosed postpartum with the uncommon syndrome of obstructed hemivagina and ipsilateral renal anomaly (OHVIRA) associated with a complete septate uterus. CASE: A 19-year-old nulliparous woman with a history of a right nephrectomy secondary to multicystic dysplastic kidney disease presented with premature rupture of membranes at 30 weeks' gestation. After failed induction of labor at 34 weeks' gestation, a uterine anomaly was discovered at the time of cesarean section. Magnetic resonance imaging performed postpartum revealed a complete septate uterus, longitudinal vaginal septum, and obstructed right hemivagina. CONCLUSION: The OHVIRA syndrome is classically associated with uterus didelphys, not complete septate uterus as in this woman. This case illustrates the potential for intrapartum complications in women with abnormalities of the urogenital tract.