The contradictive findings between ultrasound, hysteroscopy and cytokines in women with nonhormonal IUDs suffering from menorrhagia: a prospective study.

PURPOSE: The objective of this study is to assess the correlation between bleeding irregularities and the accurate placement of the intrauterine device (IUD) device in the uterine cavity, determined through transvaginal ultrasonography and hysteroscopy. In addition, the study aims to examine the cytokine profile in the uterine cavity and serum of patients experiencing bleeding irregularities after the insertion of nonhormonal IUDs. METHODS: A prospective cohort study was conducted at a single tertiary medical center, wherein patients experiencing intermenstrual bleeding and spotting after the insertion of nonhormonal IUDs were enrolled. The study involved hysteroscopic and sonographic assessments of the uterine cavity and IUD placement, along with the analysis of blood and uterine cavity cytokine profiles. RESULTS: During the period between July 2019 and February 2020, a total of eight patients who experienced intermenstrual bleeding and spotting after the insertion of nonhormonal IUDs were enrolled the study. One case was excluded since a progestative device was detected by ultrasound. Out of the five cases that underwent a thorough ultrasonographic assessment, three cases (60%) showed an embedded IUD. However, these findings were excluded by the hysteroscopic evaluation. CONCLUSION: The results suggest that ultrasonographic assessment may lead to an overdiagnosis of IUD mispositioning compared to hysteroscopy. In addition, both ultrasound and hysteroscopy have limitations in diagnosing the cause of bleeding in most cases. The role of local reactive inflammatory cytokines should be further studied.

Transplantation of small ovarian tissue fragments using pipelle device is effective: method evaluation and reproductive outcomes.

PURPOSE: To assess the feasibility, effectiveness, and reproductive outcomes of transplantation of tiny cryopreserved ovarian pieces through a pipelle cannula during laparoscopic surgery. METHODS: A retrospective study of patients who underwent ovarian tissue transplantation for fertility restoration between 2004 and 2022. The "pipelle group" had their ovarian cortex cut into tiny pieces of ~ 1-2 mm3 before cryopreservation. The pieces were too small to be handled and transplanted via standard laparoscopic tools. Transplantation was performed using a pipelle cannula during laparoscopic surgery. The "control group" underwent transplants of ovarian cortex pieces 1-2 mm thick, measuring approximately 25-50 mm2 pieces, using standard procedures. RESULTS: The pipelle group consisted of 4 patients aged 19, 21, 27, and 28 years old at ovarian tissue cryopreservation (OTC). The control group consisted of 14 patients aged 21-30 years old. All pipelle patients restored their endocrine activity, and all of them conceived. FSH levels dropped during the first 3 months following the pipelle transplant. IVF cycle outcomes were similar for both groups. All patients from the pipelle group conceived, resulting in 5 pregnancies and 4 live births (one patient had 2 deliveries, and one additional pregnancy is ongoing), compared to the control group, where 8 patients achieved a total of 20 pregnancies and 18 live births. CONCLUSION: Pipelle transplantation for tiny cryopreserved ovarian pieces is feasible and effective. This study opens a door for patients who had their ovaries cut into small pieces and may even simplify the procedure in some instances, making ovarian transplant more accessible. TRIAL REGISTRATION: (#6531-19-SMC) [18/09/2019].

Office Operative Hysteroscopy for the Management of Retained Products of Conception.

The aim of this study was to compare office to conventional operative hysteroscopy for the treatment of retained products of conception (RPOC). This retrospective cohort study included all women who underwent hysteroscopy due to RPOC between January 2018 and December 2019, in a single tertiary medical care center. Exclusion criteria for hysteroscopy included the following: (1) proximity to delivery (up to 3 weeks); (2) hemodynamic instability; (3) active massive bleeding; and (4) genital tract infection. See-and-treat hysteroscopy (study group) outcomes were compared to operative hysteroscopy (controls). Data were collected from women's medical records. Primary outcome was defined as successful removal of all suspected RPOC with no need for additional intervention. Data are presented as median and interquartile range. During the study period, 222 women underwent hysteroscopy due to RPOC. Of them, 138 (62%) and 84 (38%) underwent see-and-treat and operative hysteroscopy, respectively. Symptomatic women were more commonly referred to operative hysteroscopy (60 (71%) vs. 54 (39%); p = 0.001). Maximal diameter of the suspected finding was smaller both by ultrasound examination (13 (10-18) vs. 18 (13-32) mm; p = 0.001) and by surgeon estimation during diagnostic hysteroscopy (12 (8-20) vs. 20 (14-30) mm; p = 0.001), in the see-and-treat compared to the operative hysteroscopy group, respectively. While comparing success rate between groups, no difference was observed. Sub-analysis by the maximal diameter of RPOC findings revealed that see-and-treat success rate is reduced as the RPOC is larger. Success rate was high and comparable to operative hysteroscopy for findings ≤ 2 cm (102/117 (87%) vs. 49/54 (91%); p = 0.79). Nevertheless, for RPOC > 2 cm, success was significantly more frequent in the operative hysteroscopy group (28/30 (93%) vs. 9/16 (57%); p = 0.002). This finding was supported by logistic regression analysis that found maximal diameter of RPOC as the only parameter associated with success rate (B = 0.96; p = 0.03). Office operative hysteroscopy is a feasible treatment option for the removal of RPOC when maximal diameter is taken under consideration due to its association to success rate.Clinical trial registration: The study protocol was approved by the "Sheba Medical Center" Review Board (ID 5200-18 SMC) on June 24, 2018.

Placenta accreta spectrum in subsequent pregnancy following myomectomy.

PURPOSE: To compare the prevalence of placental abnormalities in pregnancy following different modes of operative myomectomy. METHODS: A retrospective cohort study, including all women after myomectomy that gave birth in a single tertiary care center from February 2011 to January 2019. Data was collected from the patients' medical files and completed by telephone questionnaire. Patients were stratified to 3 groups, according to the mode of operative myomectomy (laparotomy, laparoscopy, hysteroscopy). Groups were compared for women demographics, fibroid's characteristics, operative management, post-operative placental evaluation and delivery characteristics. Primary outcome was defined as the need for any intervention for placental separation during the third phase of the delivery. RESULTS: Two hundred forty one women met inclusion criteria. Complete follow-up was achieved in 199 (82.57%) women, of whom 82, 89, and 28 underwent laparoscopic, laparotomy and hysteroscopic myomectomy, respectively. There were no in-between groups differences in women's age, BMI, and gravidity. Disruption of the endometrial cavity during laparoscopy and laparotomy was reported in 3 (3.6%) and 7 (7.8%) cases, respectively (p = .21). During the subsequent pregnancy following myomectomy, placenta accreta spectrum disorder was suspected in only one woman in each of the study groups (p = .63). Placenta previa was low and comparable between groups. Vaginal delivery rate was significantly higher in the hysteroscopy group, as compared to the laparoscopy or the laparotomy groups [11 (36.3%) vs. 5 (6.1%) vs. 4 (4.5%); p = .001], with significantly lower need for manual lysis of the placenta [11(39.0%) vs. 51 (62.1%) vs. 62 (69.7%); p = .01] and further interventions for blood loss control. CONCLUSIONS: Subsequent pregnancy following surgical myomectomy was not found to be associated with higher prevalence placental abnormality. Furthermore, other than manual lysis, the different modes of myomectomy did not necessitate any further intervention for complications associated with abnormal placentation requiring intervention. KEY MESSAGE: Subsequent pregnancy following surgical myomectomy is not associated with higher prevalence of placental abnormality.

Does the time interval between the diagnosis to hysteroscopic evacuation of retained products of conception affect reproductive outcome?

BACKGROUND: Retained products of conception (RPOC) refer to the presence of placental and/or fetal tissue in the uterus following delivery, miscarriage, or termination of pregnancy. The presence of such tissue might lead to complications, which might be the culprit of secondary infertility. Although some studies have considered the management of symptomatic RPOC, there are no data regarding the management of asymptomatic, incidentally diagnosed RPOC, nor the optimal time for surgical intervention required to prevent adverse reproductive outcomes. OBJECTIVE: This study aimed to examine whether the time interval between the pregnancy termination to surgical evacuation of RPOC influences the reproductive outcome in asymptomatic women. DESIGN: This is a retrospective cohort study, which includes women who were admitted for an elective procedure in the gynecology day-care clinic due to suspected RPOC. The diagnosis was made during patients' routine examination following either delivery or miscarriage between the years 2010 and 2018. SETTING: Records of women who were admitted to the day-care gynecology department during the years 2010-2018 for hysteroscopic removal of RPOC. PATIENTS: The patients were divided into three groups, according to the time from desired pregnancy to conception following the procedure (> 6; 3-6 and < 3 months). Data regarding obstetric history prior to the procedure was retrieved from patients' clinical files, while data concerning reproductive outcome following the procedure was obtained by telephone questionnaires. INTERVENTION: Data regarding obstetric history prior to the procedure was retrieved from patients' clinical files, while data concerning reproductive outcome following the procedure was obtained by telephone questionnaires. MEASUREMENTS: 75 patients whose reproductive outcome could be analyzed were included in the study. The time interval between the end of pregnancy and surgical intervention was analyzed as a continuous variable and was compared between the three groups, together with parameters such as age and obstetric history. RESULTS: There were no significant differences between the groups. CONCLUSIONS: The main finding of the present study is that the time interval between the end of pregnancy and surgical evacuation of the asymptomatic, incidentally diagnosed RPOC, has no significant implication on patients' reproductive outcomes.

Microvesicle Proteomic Profiling of Uterine Liquid Biopsy for Ovarian Cancer Early Detection.

High-grade ovarian cancer (HGOC) is the leading cause of mortality from gynecological malignancies, because of diagnosis at a metastatic stage. Current screening options fail to improve mortality because of the absence of early-stage-specific biomarkers. We postulated that a liquid biopsy, such as utero-tubal lavage (UtL), may identify localized lesions better than systemic approaches of serum/plasma analysis. Further, while mutation-based assays are challenged by the rarity of tumor DNA within nonmutated DNA, analyzing the proteomic profile, is expected to enable earlier detection, as it reveals perturbations in both the tumor as well as in its microenvironment. To attain deep proteomic coverage and overcome the high dynamic range of this body fluid, we applied our method for microvesicle proteomics to the UtL samples. Liquid biopsies from HGOC patients (n = 49) and controls (n = 127) were divided into a discovery and validation sets. Data-dependent analysis of the samples on the Q-Exactive mass spectrometer provided depth of 8578 UtL proteins in total, and on average ∼3000 proteins per sample. We used support vector machine algorithms for sample classification, and crossed three feature-selection algorithms, to construct and validate a 9-protein classifier with 70% sensitivity and 76.2% specificity. The signature correctly identified all Stage I lesions. These results demonstrate the potential power of microvesicle-based proteomic biomarkers for early cancer diagnosis.

APOBEC3A Is Upregulated by Human Cytomegalovirus (HCMV) in the Maternal-Fetal Interface, Acting as an Innate Anti-HCMV Effector.

Human cytomegalovirus (HCMV) is the leading cause of congenital infection and is associated with a wide range of neurodevelopmental disabilities and intrauterine growth restriction. Yet our current understanding of the mechanisms modulating transplacental HCMV transmission is poor. The placenta, given its critical function in protecting the fetus, has evolved effective yet largely uncharacterized innate immune barriers against invading pathogens. Here we show that the intrinsic cellular restriction factor apolipoprotein B editing catalytic subunit-like 3A (APOBEC3A [A3A]) is profoundly upregulated following ex vivo HCMV infection in human decidual tissues-constituting the maternal aspect of the placenta. We directly demonstrated that A3A severely restricted HCMV replication upon controlled overexpression in epithelial cells, acting by a cytidine deamination mechanism to introduce hypermutations into the viral genome. Importantly, we further found that A3 editing of HCMV DNA occurs both ex vivo in HCMV-infected decidual organ cultures and in vivo in amniotic fluid samples obtained during natural congenital infection. Our results reveal a previously unexplored role for A3A as an innate anti-HCMV effector, activated by HCMV infection in the maternal-fetal interface. These findings pave the way to new insights into the potential impact of APOBEC proteins on HCMV pathogenesis.IMPORTANCE In view of the grave outcomes associated with congenital HCMV infection, there is an urgent need to better understand the innate mechanisms acting to limit transplacental viral transmission. Toward this goal, our findings reveal the role of the intrinsic cellular restriction factor A3A (which has never before been studied in the context of HCMV infection and vertical viral transmission) as a potent anti-HCMV innate barrier, activated by HCMV infection in the authentic tissues of the maternal-fetal interface. The detection of naturally occurring hypermutations in clinical amniotic fluid samples of congenitally infected fetuses further supports the idea of the occurrence of A3 editing of the viral genome in the setting of congenital HCMV infection. Given the widely differential tissue distribution characteristics and biological functions of the members of the A3 protein family, our findings should pave the way to future studies examining the potential impact of A3A as well as of other A3s on HCMV pathogenesis.

Zika Virus Infects Early- and Midgestation Human Maternal Decidual Tissues, Inducing Distinct Innate Tissue Responses in the Maternal-Fetal Interface.

Zika virus (ZIKV) has emerged as a cause of congenital brain anomalies and a range of placenta-related abnormalities, highlighting the need to unveil the modes of maternal-fetal transmission. The most likely route of vertical ZIKV transmission is via the placenta. The earliest events of ZIKV transmission in the maternal decidua, representing the maternal uterine aspect of the chimeric placenta, have remained unexplored. Here, we show that ZIKV replicates in first-trimester human maternal-decidual tissues grown ex vivo as three-dimensional (3D) organ cultures. An efficient viral spread in the decidual tissues was demonstrated by the rapid upsurge and continued increase of tissue-associated ZIKV load and titers of infectious cell-free virus progeny, released from the infected tissues. Notably, maternal decidual tissues obtained at midgestation remained similarly susceptible to ZIKV, whereas fetus-derived chorionic villi demonstrated reduced ZIKV replication with increasing gestational age. A genome-wide transcriptome analysis revealed that ZIKV substantially upregulated the decidual tissue innate immune responses. Further comparison of the innate tissue response patterns following parallel infections with ZIKV and human cytomegalovirus (HCMV) revealed that unlike HCMV, ZIKV did not induce immune cell activation or trafficking responses in the maternal-fetal interface but rather upregulated placental apoptosis and cell death molecular functions. The data identify the maternal uterine aspect of the human placenta as a likely site of ZIKV transmission to the fetus and further reveal distinct patterns of innate tissue responses to ZIKV. Our unique experimental model and findings could further serve to study the initial stages of congenital ZIKV transmission and pathogenesis and evaluate the effect of new therapeutic interventions. IMPORTANCE: In view of the rapid spread of the current ZIKV epidemic and the severe manifestations of congenital ZIKV infection, it is crucial to learn the fundamental mechanisms of viral transmission from the mother to the fetus. Our studies of ZIKV infection in the authentic tissues of the human maternal-fetal interface unveil a route of transmission whereby virus originating from the mother could reach the fetal compartment via efficient replication within the maternal decidual aspect of the placenta, coinhabited by maternal and fetal cells. The identified distinct placental tissue innate immune responses and damage pathways could provide a mechanistic basis for some of the placental developmental abnormalities associated with ZIKV infection. The findings in the unique model of the human decidua should pave the way to future studies examining the interaction of ZIKV with decidual immune cells and to evaluation of therapeutic interventions aimed at the earliest stages of transmission.

Delayed intra-abdominal bleeding following trans-vaginal ultrasonography guided oocyte retrieval for in vitro fertilization in patients at risk for thrombo-embolic events under anticoagulant therapy.

We report herein, two cases of massive delayed (2 and 4 days) intra abdominal hemorrhage following ovum pick-up (OPU), in patients at risk for thrombo-embolic events, who concomitantly used therapeutic doses of low molecular weight heparin (LMWH). We discuss the possible mechanisms involved in causing the aforementioned delayed bleeding, and call for re-evaluation of the presently accepted anticoagulant co-treatment regimen. These case reports should direct physicians' attention and keep them alert, while conducting IVF treatment to this subgroup of high risk patients.

Emergency laparoscopy for suspected ovarian torsion: are we too hasty to operate?

OBJECTIVE: To reevaluate the rate of correct diagnosis of ovarian torsion (OT) in our department. DESIGN: Retrospective computerized chart review. SETTING: Tertiary referral center. PATIENT(S): Seventy-eight women who underwent laparoscopy for suspected OT. INTERVENTION(S): Laparoscopy. MAIN OUTCOME MEASURE(S): Rate of true diagnosis of torsion, correlation with Doppler studies. RESULT(S): The preoperative diagnosis of OT was confirmed in only 36 (46.1%) of the patients. Immediate operation (<10 hours) after admission (n = 48) was associated with a statistically significantly higher likelihood of operatively confirming OT (56.2% vs. 28.6%). We found that the lack of ovarian blood flow on Doppler sonography was a good predictor of OT; women with pathologic flow were statistically significantly more likely to have OT (77% vs. 29%). The sensitivity and specificity of abnormal ovarian flow for OT were 43.8% and 91.7%, respectively, with a positive and negative predictive value of 78% and 71%, respectively. CONCLUSION(S): Despite 20 years of research, the accuracy of the preoperative diagnosis of OT remains low. The urge to operate can be attributed to the importance of preserving ovarian function in young women as well as to the availability and the low associated complication rate of laparoscopy.

Medical treatment with misoprostol for early failure of pregnancies after assisted reproductive technology: a promising treatment option.

OBJECTIVE: To assess the success rate of misoprostol to induce abortion in early pregnancy failure and to define the factors associated with success of treatment. DESIGN: Prospective study. SETTING: University-affiliated tertiary medical center. PATIENT(S): Two hundred twenty women with the diagnosis of blighted ovum or missed abortion with a crown-rump length (CRL) up to 25 mm (<9 w). INTERVENTION(S): Treatment protocol included two doses of 800 microg misoprostol given vaginally and orally in intervals of 24 to 72 hours. MAIN OUTCOME MEASURE(S): Failure was defined as surgical intervention because of retained gestational sac, severe pain or bleeding, or suspected retained products of gestation after menstruation. RESULT(S): The treatment was successful in 77.2% (170/220) of the patients. Success rate was 72.5% (121/167) for pregnancies achieved spontaneously and 92.4% (49/53) among women who conceived after assisted reproductive technology (relative risk = 3.65: 95% confidence interval 1.378 to 9.667). Multivariate analysis showed that the risk of failure of medical abortion increased significantly for patients who had had at least five previous pregnancies (of them, three or more abortions) as compared with patients with one or two previous pregnancies only, and for those who conceived spontaneously as compared with pregnancies after ovulation induction. CONCLUSION(S): Medical treatment in early missed abortion is recommended especially for women with low gravidity and for those who conceived after assisted reproductive technology.

A randomized prospective study of misoprostol or mifepristone followed by misoprostol when needed for the treatment of women with early pregnancy failure.

OBJECTIVE: To compare the effectiveness and safety of misoprostol and mifepristone, followed when needed by misoprostol, for the treatment of women with early pregnancy failure. DESIGN: Prospective randomized nonblinded controlled trial. SETTING: University-affiliated tertiary medical center. PATIENT(S): One hundred fifteen consecutive women diagnosed as having a blighted ovum or missed abortion of <9 weeks of gestation enrolled. INTERVENTION(S): The patients received orally 600 mg mifepristone (group I) or orally 800 microg misoprostol (group II). Most patients in both groups subsequently received 48 hours later orally 800 microg misoprostol. MAIN OUTCOME MEASURE(S): Failure was defined as surgical intervention due to retained gestational sac 48 hours after completion of the drug protocol, severe symptoms, or suspected retained products of conception after the menstrual period. RESULT(S): The success rate was similar in groups I and II: 38 of 58 patients (65.5%) versus 42 of 57 patients (73.6%), respectively. No cases of severe infection or bleeding necessitating blood transfusion occurred. CONCLUSION(S): Misoprostol is an effective and safe treatment for early pregnancy failure and could replace surgical curettage in over two-thirds of the patients. Mifepristone offers no advantage compared with misoprostol as initial treatment.

Transvaginal ultrasound and operative hysteroscopy in women undergoing medical termination of pregnancy as a part of routine follow-up.

Follow-up of the first cohort of 191 patients who underwent medical abortion in a tertiary medical center included postmenstruation transvaginal sonography (TVS), even in asymptomatic patients. Suspected products of gestation by TVS were found in 3.7% of the asymptomatic women, and residual products of gestation were diagnosed by hysteroscopy in 85.7% of such cases.

Cystectomy for immature teratoma of the ovary.

OBJECTIVES: Most patients with malignant ovarian germ cell tumors (MOGCT) of the ovary are in their reproductive years and wish to preserve fertility. Because of the excellent response to chemotherapy, the standard of care is unilateral salpingo-oophorectomy (USO), but some patients undergo cystectomy only before final pathology. In view of the lack of information concerning the outcome following cystectomy in germ cell tumors, we retrospectively evaluated the clinical outcome of patients who underwent cystectomy only as part of their surgical treatment. METHODS: The clinical and pathological records of 38 patients diagnosed with MOGCT, treated and followed in the department of gynecologic oncology were reviewed. Eight patients underwent cystectomy only at their initial surgery and are the subjects of this study. RESULTS: All the eight patients who underwent cystectomy were diagnosed with immature teratoma (three grade 1, four grade 2, and one grade 3) on final pathology following surgery. All except three patients (two with grade 1 and one with grade 2 disease) received adjuvant chemotherapy. Follow-up was available for all the patients, with a median duration of 4.7 years. No recurrences were observed during this period. Three patients delivered a total of seven babies. CONCLUSIONS: Cystectomy followed by adjuvant chemotherapy appeared satisfactory for apparent early-stage immature teratoma when close follow-up was carried out. It is still unclear whether cystectomy alone will also be safe. Further studies will need to address this issue.

Pregnancy outcome after laparoscopy or laparotomy in pregnancy.

STUDY OBJECTIVE: To assess obstetric performance and fetal outcomes after laparoscopy or laparotomy performed during pregnancy. DESIGN: Nationwide, multicenter, retrospective chart review (Canadian Task Force classification II-2). SETTING: Seventeen hospitals throughout Israel: 12 university or university-affiliated hospitals and 5 general hospitals. PATIENTS: Three hundred eighty-nine pregnant women. INTERVENTION: Laparoscopy or laparotomy for various indications. MEASUREMENTS AND MAIN RESULTS: Of 192 laparoscopies performed, 141 were during the first, 46 during the second, and 5 during the third trimester; respective figures for 197 laparotomies were 63, 110, and 24. No intraoperative complications were reported for either procedure. Six and 25 women had complications after laparoscopy and laparotomy, respectively. There was no significant difference in abortion rates between groups. Mean gestational age at delivery and mean birthweight were comparable between groups. No significant difference was found in frequency of fetal anomalies between groups or when compared with the Israel register of anomalies. CONCLUSION: Operative laparoscopy seems to be as safe as laparotomy in pregnancy.