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].

Predictive value of new onset versus primary meconium-stained amniotic fluid.

BACKGROUND: Transition of clear amniotic fluid to meconium-stained fluid is a relatively common occurrence during labor. However, data regarding the clinical significance and the prognostic value of the presence of meconium-stained amnionic fluid (MSAF) are scarce. This study aimed to investigate delivery and neonatal outcomes according to the presence of MSAF and the timing of the meconium passage. METHODS: We used an historical cohort study at a single tertiary medical center in Israel between the years 2011 and 2018. Women were divided into two groups according to timing of meconium passage: primary MSAF (MSAF present at membrane rupture) and secondary MSAF (clear amnionic fluid that transitioned to MSAF during labor). Neonatal complication rates were compared between groups. Composite adverse neonatal outcome was defined as arterial cord blood pH <7.1, 5 min Apgar score ≤7, and/or neonatal intensive care unit admission. RESULTS: The study cohort included 56 863 singleton term births. Of these, 9043 (15.9%) were to women who had primary MSAF, and 1484 (2.6%) to those with secondary MSAF. Secondary MSAF compared with primary MSAF increased the risks of cesarean birth and operative vaginal delivery, increased the risks of low one- and five-minute Apgar scores and low arterial cord blood pH, and increased hospital stay duration. Multivariate analysis revealed that secondary MSAF was independently associated with an increased risk of composite adverse neonatal outcome (OR1.68, 95% CI 1.25-2.24, p < 0.001) compared with primary MSAF. CONCLUSIONS: In this sample, secondary MSAF was associated with more adverse neonatal outcomes than primary MSAF. Closer monitoring of fetal well-being may be prudent in these cases.

Neonatal and maternal outcome of small-for-gestational-age neonates delivered by vacuum-assisted delivery.

OBJECTIVE: To evaluate the association between neonatal weight centile and neonatal and maternal morbidity following vacuum-assisted delivery (VAD) among term nulliparous women. METHODS: A retrospective cohort study of all nulliparous women who delivered at term by VAD between 2011 and 2019. Deliveries were allocated into two groups and compared: (1) delivery of an small-for-gestational-age (SGA) neonate, and (2) delivery of an appropriate-for-gestational-age (AGA) neonate. RESULTS: Overall, 3116 women were included in the study; 2878 (92.4%) were AGA and 163 (5.2%) were SGA and comprised the study groups. Neonatal and maternal adverse outcomes did not vary between groups. Rates of composite neonatal adverse outcome for SGA and AGA neonates were 26 (16.0%) versus 462 (16.1%), respectively (P = 0.972). Duration of the second stage of labor and rate of prolonged second stage were significantly lower among the SGA group compared with the AGA group (P < 0.001 for both comparisons). Maternal rates of anal sphincter injury and postpartum hemorrhage did not differ between groups. CONCLUSION: Neonatal outcomes among SGA neonates delivered by VAD at term did not differ from those of AGA neonates. Maternal outcome did not differ. These data provide reassurance for practitioners to perform VAD in SGA neonates at term.

Prediction of adverse neonatal outcome among newborns born through meconium-stained amniotic fluid.

OBJECTIVE: To study maternal and intrapartum factors associated with adverse neonatal outcome in deliveries complicated by meconium-stained amniotic fluid (MSAF). METHODS: A retrospective cohort study of all women with singleton gestations undergoing trial of labor with MSAF during 2011-2020. Deliveries with adverse neonatal outcome were compared with deliveries without. RESULTS: Overall, 11 329 were included; 376 (3.3%) neonates were diagnosed with adverse neonatal outcomes. Multivariable regression analysis underlined the following factors as independently associated with composite adverse neonatal outcome: pregestational diabetes (odds ratio [OR] 3.21, 95% confidence interval [CI] 1.09-9.43, P = 0.031), polyhydramnios (OR 2.14, 95% CI 1.33-3.44, P = 0.002), fever (OR 2.52, 95% CI 1.67-3.80, P < 0.001), and amnioinfusion (OR 1.73, 95% CI 1.24-2.2438, P = 0.003). When 0, 1, 2, and 3 of the independent risk factors identified were present, the rates of adverse neonatal outcome were 2.9%, 5.5%, 10.0%, and 100%, respectively. CONCLUSION: The current study's results suggest that special attention should be payed to deliveries complicated by MSAF and with any of the following factors-polyhydramnios, intrapartum fever, amnioinfusion, and pregestational diabetes.

Ovaries of patients recently treated with alkylating agent chemotherapy indicate the presence of acute follicle activation, elucidating its role among other proposed mechanisms of follicle loss.

OBJECTIVE: To investigate mechanisms of primordial follicle (PMF) loss in vivo in human ovaries shortly after alkylating agent (AA) chemotherapy. DESIGN: Cohort study. SETTING: Tertiary university medical center. PATIENT(S): Ninety-six women aged 15-39 years who underwent ovarian tissue cryopreservation for fertility preservation. INTERVENTION(S): Fresh ovarian tissue samples were harvested from women treated with AA (n = 24) or non-AA (n = 24) chemotherapy <6 months after treatment and age-matched untreated women (n = 48). MAIN OUTCOME MEASURE(S): Differential follicle counts, time from chemotherapy exposure, immunostaining for apoptosis (cleaved caspase-3) and FOXO3A on tissue harvested within ultrashort time intervals (4-12 days), collagen (Sirius red) and neovascularization (CD34). RESULT(S): AA-treated ovaries had significant loss of PMFs, and significant increase in absolute numbers of growing follicles compared with untreated control ovaries. The number of growing follicles was inversely correlated with time from chemotherapy. Representative staining for FOXO3A observed decreased nuclear localization in PMF oocytes in AA-treated ovaries removed within the ultrashort time interval compared with untreated ovaries. Neither significant loss of PMFs, increase in growing follicles, nor decrease in nuclear FOXO3A were observed in non-AA-treated ovaries. No increased expression of cleaved caspase-3 was seen in PMFs within the ultrashort time interval after AA or non-AA chemotherapy. Significant stromal fibrosis and neovascularization were observed in AA-treated ovaries only after follicle loss had already occurred (4-6 months). CONCLUSION(S): Follicle activation occurs in vivo in ovaries of patients treated with AA, indicating a pathologic mechanism which may contribute to chemotherapy-induced follicle loss.

The effect of polyhydramnios on the success of trial of labor after cesarean delivery (TOLAC): A retrospective cohort.

OBJECTIVE: Prediction of success of trial of labor after cesarean delivery (TOLAC) is of major importance. We investigated the impact of polyhydramnios on the success rate of TOLAC. STUDY DESIGN: A retrospective cohort study of all women with singleton pregnancies ≥ 34th weeks of gestation who underwent TOLAC after one previous cesarean delivery, between 2011 and 2016 in a single tertiary care center. Polyhydramnios was defined as amniotic fluid index ≥ 240 mm. Primary outcome was defined as the rate of successful TOLAC. RESULTS: 31,245 women gave birth during the study period, of them 1637 (5.3 %) women underwent TOLAC and met inclusion criteria. 39 (2.4 %) women with polyhydramnios were compared to a control group of 1598 (97.6 %) women with amniotic fluid index < 240 mm. Polyhydramnios significantly reduced the rate of successful TOLAC: 69.2 % (27/39) in the study group compared to 85.8 % (1371/1598) in the control group (P = 0.009). In a subgroup analysis based on amniotic fluid index, women with AFI > 270 mm had substantially lower TOLAC success rate [9/19 (47.4 %) vs 18/20 (90 %); P = 0.006]. There was no difference in the rate of uterine rupture between the groups (0/39 (o%) vs 9/1598 (0.56 %); P = 0.64). Logistic regression analysis revealed that polyhydramnios remained significantly associated with higher rates of cesarean delivery [OR 3.09 (95 % CI, 1.37-6.98)] after adjustment for confounding factors. CONCLUSION: Polyhydramnios was associated with significantly reduced TOLAC success rate with no statistical difference in the rate of uterine rupture. This information should be considered in physician counseling.

Evaluation of ovarian tissue transplantation: results from three clinical centers.

OBJECTIVE: To report ovarian tissue autotransplantation (AT) results and describe the relationship between technical and clinical factors and outcomes. DESIGN: Multicenter retrospective cohort study. SETTING: Tertiary medical centers. PATIENT(S): Infertile patients who had stored ovarian tissue before sterilizing treatment and returned for AT with the aim of conceiving. INTERVENTIONS(S): Ovarian tissue cryopreservation (OTC) and AT, endocrine monitoring, in vitro fertilization. MAIN OUTCOME MEASURE(S): Endocrine performance, pregnancy and live-birth rates. RESULT(S): From 2004 to 2018, 70 patients underwent 87 ATs. Sixty patients undergoing 70 ATs met the inclusion criteria. After AT, menses returned in 94% of patients and median FSH dropped from 68 to 19 IU/mL. Fifty pregnancies and 44 deliveries were attained, with 50% of women achieving at least one pregnancy and 41.6% at least one delivery. Twelve patients underwent AT more than once and had their endocrine activity restored in case menses recurred after the first transplantation. Repeated transplantations yielded five live births in three patients, two of whom had already given birth after the first transplantation. Preharvesting chemotherapy was not associated with inferior outcomes. Of seven patients whose pelvis was exposed to radiation before AT, four conceived and delivered. Neither tissue dimensions nor surgical approach affected fertility outcomes. CONCLUSION(S): OTC is highly effective at restoring fertility in sterilized patients, and prior exposure to chemotherapy should not be considered a contraindication. Repeated AT should be contemplated in case of graft malfunction, especially if previous transplantation was successful. In selected cases, conception and delivery may be feasible after pelvic exposure to radiation.

Does daily co administration of gonadotropins and letrozole during the ovarian stimulation improve IVF outcome for poor and sub optimal responders?

BACKGROUND: Co-administration of letrozole during the first 5 days of ovarian stimulation was suggested to improve IVF outcomes in poor responders. We aimed to determine whether poor/sub-optimal responders might benefit from Letrozole co-treatment throughout the entire stimulation course. METHODS: We retrospectively reviewed the medical files of women who demonstrated poor (oocyte yield ≤3) and sub-optimal (4 ≤ oocyte yield ≤9) ovarian response during conventional multiple-dose antagonist stimulation protocols and were co-treated in a subsequent cycle with 5 mg Letrozole from the first day of stimulation until trigger day. A self-paired comparison between gonadotropins-only and gonadotropins-letrozole cycles was performed. RESULTS: Twenty-four patients were included. Mean patients' age was 39.83 ± 4.60 and mean day-3-FSH was 12.77 ± 4.49 IU/m. Duration of stimulation and total gonadotropins dose were comparable between the two cycle groups. Peak estradiol levels were significantly lower in gonadotropins-letrozole cycles (2786.74 ± 2118.53 vs 1200.13 ± 535.98, p < 0.05). Number of retrieved oocytes (3.29 ± 2.15 vs 6.46 ± 3.20, p < 0.05), MII-oocytes (2.47 ± 1.65 vs 5.59 ± 3.20, p < 0.05), 2PN-embryos (1.78 ± 1.50, 4.04 ± 2.74, p < 0.05) and top-quality embryos (0.91 ± 0.97 vs. 2.35 ± 1.66, p < 0.05) were significantly higher in the gonadotropins-letrozole cycles. Clinical pregnancy rate in gonadotropins-letrozole cycles was 31.5%. CONCLUSION: Letrozole co-treatment during the entire stimulation course improves ovarian response and IVF outcomes in poor/sub-optimal responders.

The role of fetal head circumference in the formation of obstetric anal sphincter injuries following vacuum deliveries among primiparous women.

PURPOSE: To evaluate the association of sonographic fetal head circumference (HC) with obstetric anal sphincter injury (OASIS) occurrence among primiparous women who underwent vacuum-assisted delivery (VAD). METHODS: A retrospective study of all primiparous women who delivered at term by VAD between 2011 and 2019 and underwent ultrasound with fetal biometry within 1 week prior to delivery. Women who suffered OASIS were compared to women without OASIS. RESULTS: Overall, 74 of 3222 (2.3%) primiparous women suffered an OASIS. As compared with control, women with OASIS were younger (median 28 vs. 30 years, p = 0.001), had higher BMI (median 28.2 vs. 26.9 kg/m2, p = 0.03), and had a longer second stage of labor (median 190 vs. 168 min, p = 0.01). Fetal head circumference was larger in the OASIS group (mean 334 vs. 330 mm, p = 0.03), occiput posterior fetal head position was more prevalent (12 (16%) vs. 232 (7.4%), OR [95% CI]: 2.43 (1.29-4.57), p = 0.004), and the rate of mediolateral episiotomy performed was lower (58 (78.0%) vs. 2777 (88.2%), OR [95% CI]: 0.48 (0.27-0.85), p = 0.01). Multivariate regression modeling identified higher fetal HC (aOR [95% CI] 1.03 (1.001-1.06), p = 0.04) and occiput posterior (aOR [95% CI] 2.5 (1.16-5.71), p = 0.01) as independently positively associated with OASIS. Mediolateral episiotomy and maternal age were independently negatively associated with an OASIS (aOR [95% CI] 0.39 (0.18-0.85), p = 0.01); aOR [95% CI] 0.4 (0.17-0.60), p = 0.001). CONCLUSIONS: Sonographic large fetal HC is associated with OASIS occurrence during VAD. The only modifiable predictor of OASIS detected was mediolateral episiotomy, found to be protective against OASIS.

Clinical Success Rate of Extensive Hysteroscopic Cesarean Scar Defect Excision and Correlation to Histologic Findings.

STUDY OBJECTIVE: Cesarean scar defect (CSD) is often associated with postmenstrual bleeding, infertility, and pain. Hysteroscopic CSD repair was described in the past, mainly as excision of the proximal edge of the defect to allow continuous blood flow during menstruation. In this study we aimed to evaluate the efficacy of extensive hysteroscopic cesarean scar niche excision in symptomatic patients. DESIGN: A retrospective cohort study. PATIENTS: Symptomatic patients treated with hysteroscopic CSD excision who were considered eligible for the procedure when myometrial thickness of 2 mm or more was observed on sonohysterography. SETTING: Tertiary referral center. INTERVENTIONS: Extensive CSD excision was performed using a cutting loop and pure cutting current. The proximal and distal edges of the defect were resected. This was followed by resection of tissue at the base of the niche, until underling muscular tissue was evident. Tissue sampled from the base of the CSD was collected for histologic examination. Patients were followed for a minimum of 1 year after hysteroscopic CSD excision. Clinical information obtained included detailed obstetric history and preoperative and postoperative menstruation pattern. MEASUREMENTS AND MAIN RESULTS: Between 2011 and 2016, 95 patients underwent extensive hysteroscopic niche excision; 67 were included in the study, whereas the remaining were lost to follow-up. Patient mean age at the time of the procedure was 38 ± 5.5 years. Twenty-nine patients (43%) had a history of high-order repeat cesarean surgeries. Sixty-six patients (98.5%) presented with postmenstrual bleeding, 26 with secondary infertility (38.8%), and 2 with pelvic pain (2.9%). After hysteroscopic niche excision, 63.4% of patients reported significant improvement or resolution of postmenstrual bleeding. A statistically significant reduction in number of bleeding days per cycle (15.5 ± 4.8 vs 9.8 ± 4.7, p < .001) was also noted. Histologic evidence for myometrial tissue within the obtained samples was associated with better outcomes. A histologic specimen from patients who experienced significant improvement or resolution of postmenstrual bleeding was more likely to reveal myometrial tissue (p = .04). Of the 26 patients who suffered from infertility, 19 attempted to conceive spontaneously after CSD excision. Of those, 10 patients (52.6%) conceived and 9 delivered at least once (47.36%). CONCLUSION: Extensive hysteroscopic surgical excision of cesarean scar niche should be considered in symptomatic patients suffering from irregular menstrual bleeding. The quality of the excision at the apex of the niche could be associated with a higher success rate. The role of niche excision to overcome secondary infertility should be further evaluated.

Prenatal diagnosis of congenital head, face, and neck malformations-Is complementary fetal MRI of value?

OBJECTIVES: The aim of this study was to evaluate the role of fetal magnetic resonance imaging (MRI) as a complement to ultrasound (US) in the prenatal diagnosis of craniofacial anomalies. METHODS: A historical cohort study including all pregnant women who were referred for fetal MRI because of antenatal diagnosis of craniofacial anomalies on screening US. Prenatal diagnostic US, MRI, and postnatal diagnosis were compared for consistencies and discrepancies. RESULTS: Forty-five pregnant women with 73 suspected fetal craniofacial anomalies diagnosed by US underwent MRI. In 40 out of 73 anomalies (54.8%), US and MRI findings were in complete agreement with postnatal diagnoses. MRI correctly ruled out the diagnosis of 24 anomalies suspected on US and diagnosed four additional pathologies that were not demonstrated by US. Out of the 85 anomalies (suspected by imaging or confirmed postnatally), confident diagnosis could be made by MRI in 68 anomalies (80%), not diagnosed in 10 (11.8%), and over-diagnosed in seven (8.2%). By US, confident diagnosis could be made in 44 anomalies (51.8%), not diagnosed in 11 (12.9%), and over-diagnosed in 30 (35.3%). CONCLUSION: MRI is valuable in the antenatal evaluation of fetal craniofacial anomalies and may be useful as an adjunct to US in the prenatal work-up of craniofacial anomalies.

Urgent Laparoscopic Surgeries during the Third Trimester of Pregnancy: A Case Series.

STUDY OBJECTIVE: Laparoscopic management of nonobstetric acute abdominal pain in the third trimester of pregnancy remains controversial with limited data regarding procedure safety and feasibility. This study aimed to investigate the feasibility, immediate complications, and short-term outcomes of laparoscopic surgery at an advanced gestational age. DESIGN: Case-series. SETTING: Sheba Medical Center, a tertiary referral center. PATIENTS: Pregnant women who underwent urgent laparoscopic surgery at 27 weeks of gestation and above. INTERVENTION: Emergent laparoscopic surgery. MEASUREMENTS AND MAIN RESULTS: Clinical data were retrospectively collected and analyzed. A telephone questionnaire was administered in cases of missing data. Clinical information obtained included detailed medical and obstetric history; preoperative, intraoperative, and postoperative data; complications; and pregnancy outcomes. Between January 2010 and July 2017, 12 patients underwent emergent laparoscopic surgeries during the third trimester of pregnancy. The gestational age at the time of the surgery ranged between 27 and 38 weeks. All women had singleton pregnancies. Laparoscopic surgeries included 7 appendectomies, 4 adnexal surgeries, and 1 diagnostic laparoscopy. No complications related to the access route for any of the 12 laparoscopic surgeries occurred. The laparoscopic surgical procedure was successfully completed in 11 patients; only 1 laparoscopic appendectomy for perforated acute appendicitis with purulent peritonitis at 30 weeks of gestation was converted to laparotomy because of a limited operative field. Two patients had preterm labor at 35 and 36 weeks of gestation, respectively. None of the women was complicated with intrauterine fetal demise or low Apgar scores. CONCLUSION: Our results demonstrate that urgent laparoscopic surgeries in the third trimester of pregnancy are feasible and can be safely performed with minimal risk for the patient and fetus. Larger prospective studies are required to validate these recommendations.

The safety of early pregnancy exposure to granisetron.

OBJECTIVE: Current guidelines suggest that granisetron is an optional treatment for nausea and vomiting in pregnancy (NVP) despite lack of evidence to support fetal safety. We aimed to determine the association between early pregnancy exposure to granisetron and fetal/neonatal outcomes. DESIGN: Medical records of patients treated for NVP during the first and second trimester between June 2013 to September 2015 were reviewed. Patients were asked to participate in the study by answering a detailed questionnaire regarding newborn's health and complementary data. Pregnancy outcomes of patients exposed to granisetron were compared with those of patients who were not exposed to granisetron. RESULTS: 100 Granisetron exposed pregnancies were compared with 108 granisetron unexposed pregnancies. Exposure to granisetron occurred in the first trimester in 88 patients (94 fetuses). Maternal characteristics, history of anomalies in first degree relatives, co-exposure to other substances and extent of prenatal sonographic surveillance were comparable between both groups. Miscarriage rate was significantly lower among granisetron exposed patients compared to controls (0 vs 5.5 %, respectively, p = 0.03). Three major malformations were identified prenatally or postnatally in each of the groups (2.77 % Vs 2.83 %, p = 1). The rate of major malformations was similar between exposed and unexposed fetuses even after excluding second trimester exposure (3.2 % vs. 2.83 %, respectively p = 1). Mean gestational age at delivery, mean newborn weight and incidence of small for gestation age, were not significantly different between the groups. CONCLUSION: Granisetron exposure was not associated with increased risk for minor or major fetal anomalies. This study provides preliminary reassurance regarding the safety of in-utero exposure to granisetron.

Long-term follow-up on fetuses with isolated sonographic finding of short long bones: a cohort study.

PURPOSE: To evaluate the long-term outcome of fetuses with a diagnosis of isolated short long bones. METHODS: A retrospective review was conducted of all cases diagnosed with short long bones above 20 weeks of gestation during 2010-2017 in a single tertiary center. Exclusion criteria included abnormal sonographic findings other than short long bones, suspected genetic syndromes, chromosomal abnormalities, and abnormal Doppler flow indices. Follow-up was carried out by telephone questionnaire. RESULTS: During the study period, 54 (24.32%) women met inclusion criteria. Mean gestational age at delivery was 38.05 years (± 2.42 SD). Mean birth weight was 12-19th percentile according to the local fetal growth charts [2645 g (± 684 SD) 95% CI 2173-2980]. Median time for post-natal follow-up was 9.3 years (IQR 6.6-10.75). Growth below the 10th percentile was demonstrated in 27 (50%) children. 11 (20.37%) children were followed up by endocrinological clinics, of them 7 (12.96%) were treated with growth hormone. Three (5.6%) of the children were diagnosed with attention deficit hyperactivity disorder, an incidence that is considered lower than that of the general population (± 9%). CONCLUSIONS: Prenatal fetal isolated short long bones diagnosed during the late second and third trimester is associated with short stature. No neurodevelopmental impact was observed in our study group.

Challenges of fertility preservation in leukemia patients.

An ongoing increase in survival rates among young leukemia patients is accompanied by a growing attention to possible long-term complications such as chemotherapy induced ovarian insufficiency and infertility. Therefore, an important element of the management of these patients is fertility preservation, which is challenged by considerations specific for leukemia. Such considerations include prepuberty, poor medical condition on presentation and the need for urgent chemotherapy, all of which may preclude the use of conventional assisted reproductive technologies. A restrictive approach towards utilizing cryopreserved ovarian tissue due to the risk for malignancy reintroduction on transplantation, further minimize the options that currently exist for these patients. This paper aims to provide up-to-date knowledge on gonadotoxicity associated with therapy regimens currently used in the treatment of leukemia. Different fertility preservation techniques are discussed, with an emphasis on efficacy, applicability and limitations in the context of leukemia.

First delivery in a leukemia survivor after transplantation of cryopreserved ovarian tissue, evaluated for leukemia cells contamination.

OBJECTIVE: To describe a successful autologous ovarian tissue re-transplantation in a sterile leukemia survivor after evaluation for minimal residual disease and provide a review of the current literature. DESIGN: Presentation of a carefully designed workup taken to evaluate tissue for minimal residual disease, its limitations, and applicability to other patients. To date, there have not been any publications of auto-transplantations in leukemia survivors, owing to an estimated high risk for malignancy induction. SETTING: Large tertiary hospital. PATIENT(S): A 19-year-old acute myeloid leukemia patient underwent ovarian tissue cryopreservation during complete remission before bone marrow transplantation. After prolonged amenorrhea, the patient desired pregnancy. Laboratory tests showed antimüllerian hormone <0.1 ng/mL and FSH 116 mIU/mL. Ultrasound revealed no ovarian follicles. INTERVENTION(S): Ovarian tissue cryopreservation and auto-transplantation. Histology, immunohistochemistry, FISH, next-generation sequencing, and xenotransplantation were done to evaluate thawed tissue samples for the presence of leukemia cells. MAIN OUTCOME MEASURE(S): Evidence for leukemia cells in thawed ovarian tissue, reproductive outcomes and live birth after transplantation, and leukemia-free survival. RESULT(S): Histology was negative for leukemia cells. Three severe combined immunodeficiency mice, grafted with tissue fragments, were followed for 6 months and showed no macroscopic/microscopic signs for leukemia. Fluorescence in situ hybridization for disease-specific gene rearrangement resulted in a read below the probe's cut-off. A next-generation sequencing panel of genes implicated in myeloproliferative disorders did not reveal any significant molecular event. Transplantation was performed, followed by ovarian stimulation and IVF, resulting in the delivery of healthy newborn. More than 2 years have elapsed since transplantation, and the patient is leukemia free. CONCLUSION(S): Harvesting during complete remission, combined with intense tissue evaluation before transplantation, allowed a safe, successful transplantation in an acute myeloid leukemia survivor.

Transplantations of frozen-thawed ovarian tissue demonstrate high reproductive performance and the need to revise restrictive criteria.

OBJECTIVE: To report the single-center results of orthotopic retransplantations of cryopreserved ovarian tissue in cancer survivors and evaluate the validity of commonly accepted procedure limitations. DESIGN: Prospective cohort study. SETTING: Tertiary university-affiliated assisted reproduction technology (ART) and oncology centers. PATIENT(S): Twenty cancer survivors who underwent ovarian transplantation of frozen-thawed ovarian tissue with the aim to conceive. INTERVENTION(S): Ovarian tissue cryopreservation (OTCP) and transplantation, endocrine monitoring, in vitro fertilization (IVF). MAIN OUTCOME MEASURE(S): Endocrine profile, IVF, pregnancies, live births. RESULT(S): The patient ages at tissue harvesting ranged from 14 to 39 years. Fifteen women had hematologic malignancies, and two had leukemia (chronic myelogenous leukemia and acute myelogenous leukemia). Ten patients were exposed to nonsterilizing chemotherapy before OTCP. After transplantation, the endocrine recovery rate was 93%. Fourteen patients underwent IVF treatments with a fertilization rate of 58%. Sixteen pregnancies were achieved (10 after IVF, 6 spontaneous), resulting in 10 live births, two (twins) after harvesting from the mother at the age of 37. Two pregnancies are currently ongoing. After transplantation, 53% of patients conceived, and 32% delivered at least once. One patient conceived four times. Preharversting chemotherapy exposure was not associated with inferior outcomes. All patients, including two leukemia survivors, remained cancer free. CONCLUSION(S): Orthotopic transplantation of thawed ovarian tissue is a highly effective measure to restore fertility in sterilized cancer patients. Chemotherapy exposure before harvesting and age >35 is a realistic option in selected patients. Retransplantation in leukemic patients is possible after application of maximal safety measures. These results have led the national ethical and professional authorities to decide for the first time not to consider OTCP as an experimental modality for fertility preservation. CLINICAL TRIAL REGISTRATION NUMBER: NCT02659592.

BRCA mutation carriers show normal ovarian response in in vitro fertilization cycles.

OBJECTIVE: To evaluate the association between carriage of BRCA1/2 mutations and ovarian performance, as demonstrated by in vitro fertilization (IVF) outcomes. DESIGN: Retrospective cohort study. SETTING: Two tertiary IVF centers. PATIENT(S): BRCA mutation carriers undergoing IVF for preimplantation genetic diagnosis (PGD) or fertility preservation were compared with non-BRCA PGD or fertility preservation patients, matched by age, IVF protocol, IVF center, and cancer disease status. INTERVENTION(S): In vitro fertilization cycles for PGD and fertility preservation. MAIN OUTCOME MEASURE(S): Outcome of IVF: oocyte yield, poor response rate, number of zygotes, pregnancy rates. RESULT(S): A total of 62 BRCA mutation carriers and 62 matched noncarriers were included; 42 were fertility preservation breast cancer patients, and 82 were PGD non-cancer patients. Mean (± SD) age of patients was 32 ± 3.58 years. Number of stimulation days and total stimulation dose were comparable between carriers and noncarriers. Their cycles resulted in comparable oocyte yield (13.75 vs. 14.75) and low response rates (8.06% vs. 6.45%). Number of zygotes, fertilization rates, and conception rates were also comparable. CONCLUSION(S): Both healthy and cancer-affected BRCA mutation carriers demonstrated normal ovarian response in IVF cycles.

GSK-3ß Inhibition Affects Singing Behavior and Neurogenesis in Adult Songbirds.

GSK-3 (glycogen synthase kinase-3) is a serine/threonine kinase which is a critical regulator in neuronal signaling, cognition, and behavior. We have previously shown that unlike other vertebrates that harbor both α and ß GSK-3 genes, the α gene is missing in birds. Therefore, birds can be used as a new animal model to study the roles of GSK-3ß in behavior and in regulating adult neurogenesis. In the present study, we inhibited GSK-3ß in brains of adult male zebra finches (Taeniopygia guttata) and accordingly investigated how this inhibition affects behavior and cell proliferation. Our results show that GSK-3 inhibition: (1) affects specific aspects of singing behavior, which might be related to social interactions in birds, and (2) differentially affects cell proliferation in various parts of the ventricular zone. Taken together, our study demonstrates a role of GSK-3ß in regulating singing behavior and neuronal proliferation in birds and highlights the importance of GSK-3ß in modulating cognitive abilities as well as social behavior.