BRCA carriers have similar reproductive potential at baseline to noncarriers: comparisons in cancer and cancer-free cohorts undergoing fertility preservation.

OBJECTIVE: To investigate whether BRCA carriers with and without malignancy have decreased ovarian reserve at baseline compared with BRCA noncarriers. DESIGN: Retrospective cohort study. SETTING: Academic medical center. PATIENT(S): Seven-hundred and ninety-five oocyte cryopreservation patients, comprising BRCA carriers with and without malignancy (n = 57) and BRCA noncarriers (n = 738). INTERVENTION(S): Fertility preservation with oocyte cryopreservation. MAIN OUTCOME MEASURE(S): Antral follicle count (AFC), antimüllerian hormone (AMH) concentration, day-3 follicle-stimulating hormone (FSH) level, number of harvested oocytes, and number of mature/cryopreserved oocytes. RESULT(S): In the cancer cohort we compared BRCA-positive breast cancer (n = 38) with BRCA-negative breast cancer (n = 53) and with non-breast-cancer malignancies (n = 85). In the cancer-free cohort we compared BRCA carriers (n = 19) with women undergoing elective egg freezing (n = 600). We also compared the BRCA1 (n = 31) versus the BRCA2 carriers (n = 18). The patients' mean ages were 32.4 ± 3.6 years and 35.5 ± 4.3 years in the BRCA carrier and noncarrier cohorts, respectively. BRCA status was associated with a higher day-3 FSH level in the cancer cohort, but we found no changes in the other outcomes compared with the BRCA-negative cancer groups. BRCA carriers without cancer exhibited a higher AFC and number of mature oocytes compared with the patients undergoing planned egg freezing. Overall (cancer and cancer-free cohorts), the BRCA carriers had an increased AFC (15.5 ± 4.6 vs. 12.6 ± 5.7) and number of mature/cryopreserved oocytes (14.0 ± 7.9 vs. 10.4 ± 6.9) compared with the BRCA noncarriers but had no differences in other outcomes. CONCLUSION(S): BRCA carriers with and without malignancy exhibit comparable ovarian reserve and responses to ovarian stimulation compared with women with BRCA-negative cancers and cancer-free controls.

High serum IGF-1 levels are associated with pregnancy loss following frozen-thawed euploid embryo transfer cycles.

An elevated level of insulin growth factor (IGF-1) in rat uterine fluid has been shown to exert detrimental effects of embryo development possibly leading to an increase in pregnancy loss. Interestingly, the administration of somatostatin to rats undergoing superovulation reduced IGF-1 levels in uterine luminal fluid and thus reversed its deleterious effects on embryo development and increased the number of normal embryos. Therefore, we investigated whether serum levels of IGF-1 correlate with the incidence of pregnancy loss following IVF. To account for aneuploidy and the effect of hormonal supplementation on serum IGF levels, we only included natural frozen-thawed euploid embryo transfer (N-FET) cycles. Sera collected in the follicular phase (cycle day 10) were tested for levels of IGF-1, IGF-2, and IGF-binding protein 1 (IGFBP-1) using quantitative ELISA. A total of 156 N-FET cycles were included: 120 resulted in a live birth whereas 36 led to a first trimester pregnancy loss. Women with a pregnancy loss had significantly higher serum IGF-1 levels compared to those who achieved a live birth (18.0 ±â€¯1.1 vs. 14.6 ±â€¯0.7 ng/mL, respectively). The two groups had comparable serum IGF-2 and IGFBP-1 levels. There was no significant difference in maternal age, body mass index, gravidity, parity, number of prior miscarriages, peak endometrial thickness, or infertility diagnosis between the two groups. In conclusion, women undergoing euploid blastocyst transfer with elevated serum IGF-1 concentrations may be at increased risk of pregnancy loss. This may constitute a novel molecular explanation of pregnancy loss of euploid conceptus.

Novel Fumarate Hydratase Mutation in Siblings With Early Onset Uterine Leiomyomas and Hereditary Leiomyomatosis and Renal Cell Cancer Syndrome.

Hereditary leiomyomatosis renal cell cancer syndrome is an autosomal dominant disorder characterized by uterine and cutaneous leiomyomas and increased predisposition to renal cell carcinoma, papillary type II. The syndrome is caused by heterozygous mutations to the fumarate hydratase (FH) gene located on chromosome 1. Affected females generally present with early onset, atypical uterine leiomyomas and cutaneous findings, however, delays in diagnosis are very common in patients with isolated uterine findings. We present a case series of 2 sisters in their 20s who presented with isolated uterine leiomyomas and were found to carry a novel mutation for the fumarate hydratase gene. One patient was referred for treatment of infertility and recurrent miscarriages and the other was referred for acute symptomatic anemia due to myomas. Prompt diagnosis of hereditary leiomyomatosis renal cell cancer was made due to a high index of clinical suspicion based on early onset disease and familial clustering as well as characteristic pathologic findings on uterine leiomyoma surgical specimen. Timely diagnosis not only allowed for genetic counseling and renal cancer surveillance, but also for fertility counseling given the increased morbidity associated with uterine leiomyoma due to hereditary leiomyomatosis and renal cell cancer syndrome.

Unilateral pleural effusion as the sole clinical presentation of severe ovarian hyperstimulation syndrome: a systematic review.

The pathophysiology of isolated pleural effusion in ovarian hyperstimulation syndrome (OHSS) is not well defined. The objective of the current review is to delineate the pathophysiology, risk factors, preventive measures, and therapeutic options of isolated pleural effusion in severe OHSS. Major databases were searched until June 2016. Studies evaluating women who presented with pleural effusion as the sole extra-ovarian manifestation of severe OHSS were included. Data were extracted from 24 articles encompassing 30 reported cases. Values were expressed as mean ± SEM. Patients were young (31.5 ± 0.8 years old) and 29.1% of them were diagnosed with polycystic ovary syndrome. All the patients received human chorionic gonadotropin to trigger oocyte maturation. Estradiol level was 3110 ± 330 pg/mL on the day of the ovulatory trigger. Dyspnea was the presenting symptom in 86.6% of the patients. Pleural effusion was predominantly on the right side (80%). Ninety percent of the patients underwent thoracentesis (4332 ± 769 mL): 66.7% exudate and 33.3% transudate. Fluid initially accumulates in the peritoneal cavity then enters the pleural space due to the pressure gradient through the thoracic duct and diaphragmatic defects, which are more common on the right side. The risk factors, prevention, and management, which are also discussed in this review, are similar to those of severe OHSS.

One thousand seventy-eight autologous IVF cycles in women 45 years and older: the largest single-center cohort to date.

PURPOSE: The purpose of this study was to determine IVF outcomes in women 45 years and older using autologous oocytes. METHODS: This is a retrospective cohort study reviewing all IVF cycles in women ≥ 45 years old from January 1995 to June 2015 that were conducted at one academic medical center. One thousand seventy-eight fresh, autologous IVF cycles met inclusion criteria. PGD/S, natural IVF, and donor egg cycles were excluded. Outcomes were analyzed for the different age groups (age 45, n = 773; age 46, n = 221; age 47, n = 57; age 48, n = 22; age 49, n = 5). Primary outcome measures included IVF cycle characteristics, total pregnancy loss, clinical pregnancy, and live birth rates, and were stratified according to patient age. RESULTS: Mean age of patients in the study cohort was 45.4 ± 0.72. 11.7% of patients did not start due to an elevated FSH or cyst and 28.5% of patients were canceled prior to oocyte retrieval. The overall pregnancy rate per transfer was 18.7% (117/626), of which 82.1% ended in a pregnancy loss. The overall clinical pregnancy and live birth rates per transfer were 9.6 and 3.4%, respectively, which did not differ between age groups. Per cycle start women aged 45 had significantly higher positive pregnancy rates compared to women aged 46 and 47 (14.1 vs. 8.6 vs. 5.9%, p = 0.04). For women 45 years old, the live birth rate was 2.9% per cycle start and was 4.4% per embryo transfer. Of the 21 live births, 20 were in women aged 45 and one live birth was in a 46-year-old woman. There were no live births in any patient with ≤ 4 oocytes retrieved. CONCLUSION: Autologous IVF in women aged 45 with acceptable ovarian reserve is not futile; however, it does carry very low prognosis. Patients aged 46 and older should be counseled appropriately that a live birth seems highly unlikely.

Optimal parameters for determining the LH surge in natural cycle frozen-thawed embryo transfers.

BACKGROUND: There is no consensus on the exact parameters that define the LH surge for natural cycle frozen-thawed embryo transfers (NC-FET). Accurately determining the LH surge would affect the timing, and subsequently the success rates, of embryo transfer. Therefore, the aim of this study was to delineate the optimal levels and relationship for luteinizing hormone (LH) and estradiol in an effort to optimally identify the LH surge in NC-FET. METHODS: It is a retrospective study that was performed in an academic medical center. Patients who underwent blastocyst NC-FET who either had preimplantation genetic screening (PGS) or were <35 years old but did not undergo PGS (non-PGS) were included in separate analyses. They were divided into two groups: Group A included patients whose LH surge was defined as the first attainment of LH ≥ 17 IU/L during the follicular phase with a ≥30% drop in estradiol levels the following day; group B encompassed patients whose LH level continued to rise and the surge was defined as the highest serum LH level occurring a day after LH ≥ 17 IU/L despite a ≥ 30% drop in estradiol levels. The main outcomes measures were implantation and live birth rates. RESULTS: Four hundred-seven non-PGS and 284 PGS NC-FET were included. Among non-PGS cycles, group A was associated with significantly higher implantation rates (48.7% vs. 38.1%) and live birth rates (52.9% vs. 40.1%) compared to group B. In contrast, group A and B had comparable live birth rates among PGS cycles. CONCLUSIONS: Among non-PGS cycles, measuring LH and estradiol levels the day after an LH ≥ 17 IU/L and defining the surge as the first day of LH ≥ 17 IU/L in the context of a ≥ 30% drop in estradiol the following day was associated with better NC-FET outcomes than defining the surge as the day representing the highest serum LH level despite a ≥30% drop in estradiol levels.

Sliding scale HCG trigger yields equivalent pregnancy outcomes and reduces ovarian hyperstimulation syndrome: Analysis of 10,427 IVF-ICSI cycles.

OBJECTIVE: To evaluate pregnancy outcomes and the incidence of ovarian hyperstimulation syndrome (OHSS) using a sliding scale hCG protocol to trigger oocyte maturity and establish a threshold level of serum b-hCG associated with optimal oocyte maturity. DESIGN: Retrospective cohort. SETTING: Academic medical center. PATIENTS: Fresh IVF cycles from 9/2004-12/2011. INTERVENTION: 10,427 fresh IVF-ICSI cycles met inclusion criteria. hCG was administered according to E2 level at trigger: 10,000IU vs. 5,000IU vs. 4,000IU vs. 3,300IU vs. dual trigger (2mg leuprolide acetate + 1,500IU hCG). Serum absorption of hCG was assessed according to dose and BMI. MAIN OUTCOME MEASURES: Oocyte maturity was analyzed according to post-trigger serum b-hCG. Fertilization, clinical pregnancy, live birth and OHSS rates were examined by hCG trigger dose. RESULTS: Post-trigger serum b-hCG 20-30, 30-40, and 40-50 mIU/mL was associated with reduced oocyte maturity as compared b-hCG >50 (67.8% vs. 71.4% vs. 73.3% vs. 78.9%, respectively, P<0.05). b-hCG 20-50 mIU/mL was associated with a 40.1% reduction in live birth (OR 0.59, 95% CI 0.41-0.87). No differences in IVF outcomes per retrieval were seen for varying doses of hCG or dual trigger when controlling for patient age. The incidence of moderate to severe OHSS was 0.13% (n = 14) and severe OHSS was 0.03% (n = 4) of cycles. CONCLUSIONS: Moderate stimulation with sliding scale hCG at trigger and fresh transfer is associated with low rates of OHSS and favorable pregnancy rates. Doses as low as 3,300IU alone or dual trigger with 1,500IU are sufficient to facilitate oocyte maturity.

Unilateral Salpingectomy and Methotrexate Are Associated With a Similar Recurrence Rate of Ectopic Pregnancy in Patients Undergoing In Vitro Fertilization.

STUDY OBJECTIVE: To determine whether different treatment approaches of ectopic pregnancy (EP), particularly unilateral salpingectomy and methotrexate, affect its recurrence rate in patients undergoing in vitro fertilization (IVF). DESIGN: A retrospective cohort study (Canadian Task Force classification II-2). SETTING: An academic medical center. PATIENTS: Patients with a history of a previous EP who achieved pregnancy after IVF cycles between January 2004 and August 2015 were included. The recurrence rate of EP was compared between patients who underwent different treatment approaches for a previous EP. INTERVENTIONS: IVF. MEASUREMENTS AND MAIN RESULTS: A total of 594 patients were included. Seventeen patients had a recurrence of EP (2.9%). Patients with a history of ≥2 EPs were associated with a significantly higher recurrence rate of EP than those with 1 previous EP (8.5% vs. 1.8%; p = .01; odds ratio [OR] = 2.2; 95% confidence interval [CI], 1.2-4.4). Patients who underwent unilateral salpingectomy (n = 245) had a comparable recurrence rate of EP after IVF with those who received methotrexate (n = 283) (3.6% vs. 2.8%; p = .5; OR = 1.3; 95% CI, 0.4-3.4). This OR remained unchanged after adjusting for patient's age, number of previous EPs, number of transferred embryos, and peak estradiol level during stimulation (adjusted OR = 1.4; 95% CI, 0.5-3.8). None of the patients who underwent bilateral salpingectomy (n = 45) or salpingostomy (n = 21) had a recurrence of EP after IVF. CONCLUSION: The recurrence rate of EP significantly correlates with the number of previous EPs. Treatment of EP with methotrexate has a comparable recurrence rate of EP after IVF with unilateral salpingectomy. Therefore, the risk of recurrence should not be a reason to favor salpingectomy over methotrexate in this population.

Oocyte vitrification for elective fertility preservation: the past, present, and future.

PURPOSE OF REVIEW: Oocyte cryopreservation is no longer experimental and one of its rapidly growing indications is elective fertility preservation. Currently there is no sufficient evidence to support its practice and therefore its place in IVF remains uncertain. RECENT FINDINGS: Vitrification has superior post-thaw survival and fertilization outcomes compared with oocytes that were frozen with the slow-freeze technique. Oocyte vitrification produces similar IVF outcomes compared with fresh oocytes and is not associated with further obstetrical or perinatal morbidity. Undergoing elective oocyte cryopreservation between ages 35 and 37 will optimize live birth rates as well as cost effectiveness from mathematical models. SUMMARY: In women who delay child bearing, elective oocyte cryopreservation in the mid 30s may be beneficial in terms of live birth rates and cost effectiveness. Prospective studies of women who have undergone oocyte cryopreservation and are now attempting conception are needed before official recommendations can be made regarding elective egg freezing.

Abdominal ectopic pregnancy with undetectable serum ß-human chorionic gonadotropin 9 days following blastocyst transfer.

With the availability of the highly sensitive ß-human chorionic gonadotropin (ß-hCG) assays, all pregnancies, including ectopic pregnancies (EP), are expected to have detectable serum ß-hCG at 4 weeks' gestation or 9 days following blastocyst transfer. To our knowledge, this is the first report of a woman who underwent in vitro fertilization, had undetectable serum ß-hCG 9 days after blastocyst transfer, and was then diagnosed with a ruptured abdominal EP and intra-abdominal bleeding 19 days later. This case highlights that the rise in serum ß-hCG might be delayed in abdominal EP compared to intrauterine pregnancy. This delay should raise the suspicion for EP, thus meriting close monitoring. Moreover, in the absence of menstruation, an undetectable serum ß-hCG 9 days post-blastocyst transfer should prompt ß-hCG measurement in 2-3 days to avoid the misdiagnosis of an EP.

Robot-Assisted Myomectomy for Large Uterine Myomas: A Single Center Experience.

Objective. To determine if robot-assisted myomectomy (RAM) is feasible for women with large uterine myomas. Methods. Retrospective review of one gynecologic surgeon's RAM cases between May 2010 and July 2013. Large uterine myomas, defined as the largest myoma ≥9 cm by preoperative magnetic resonance imaging, was age- and time-matched to controls with the largest myoma <9 cm. Primary surgical outcomes compared were operative time and estimated blood loss (EBL). Results. 207 patients were included: 66 (32%) patients were in the ≥9 cm group, while 141 (68%) patients were in the <9 cm group. There was a statistically significant increase in the operative time (130 min versus 92 min) and EBL (100 mL versus 25 mL) for the ≥9 cm group compared to the <9 cm group. Ten (4.8%) patients had the largest myoma measuring ≥15 cm, and 11 (5.3%) patients had a specimen weight >900 gm, of which no major adverse outcomes were observed. All patients in the study cohort were discharged on the same day after surgery. Conclusion. RAM is a feasible surgical approach for patients with myomas ≥9 cm. Patients with large myomas undergoing RAM are also candidates for same-day discharge after surgery.

Beyond the American Society for Reproductive Medicine transfer guidelines: how many cleavage-stage embryos are safe to transfer in women ≥43 years old?

OBJECTIVE: To determine the number of cleavage-stage embryos that can be safely transferred in women ≥43 years old. DESIGN: Retrospective cohort. SETTING: Academic medical center. PATIENT(S): All patients ≥43 years old undergoing transfer of five or more cleavage-stage embryos during the period from January 2004 through April 2012. INTERVENTION(S): In vitro fertilization. MAIN OUTCOME MEASURE(S): A total of 567 cycles in 464 patients aged 43-45 years, whose IVF cycles were characterized by transfer of five to eight cleavage-stage embryos were identified. Clinical outcomes and risk of multiples were analyzed, stratifying by age and number of embryos transferred. RESULT(S): Live birth rates per transfer were 14.4%, 9.4%, and 1.3% for women aged 43, 44, and 45 years, respectively. In 43-year-old women, 2.9% (2/69) of pregnancies were triplet gestations (one selective reduction and one spontaneous reduction). Twin birth rate was 16.3%, 6.7%, and 0 (of all live births) for ages 43, 44, and 45 years, respectively. There was no higher order multiple births. Women aged 43 and 44 years having five or more embryos transferred experienced higher clinical pregnancy rates (PRs) than those patients receiving a transfer of three or four embryos. Clinical outcomes for patients undergoing transfer with six or more embryos were not better than those undergoing transfer with five embryos. CONCLUSION(S): Transferring five or more day 3 embryos may be a safe option for patients ≥43 years of age, as it is associated with an overall low rate of multiple gestations. Having more than five embryos available for transfer on day 5 is associated with improved IVF outcomes. Whether this benefit is from the additional embryo(s) for transfer or the inherently better prognosis of such patients remains to be determined.

In vitro fertilization versus conversion to intrauterine insemination in the setting of three or fewer follicles: how should patients proceed when follicular response falls short of expectation?

OBJECTIVE: To determine whether in vitro fertilization (IVF) cycles with suboptimal response should be converted to intrauterine insemination (IUI) or proceed to oocyte retrieval (OR). DESIGN: Retrospective cohort. SETTING: Academic medical center. PATIENT(S): All patients initiating IVF from January 2004 through December 2011. INTERVENTION(S): OR versus conversion to IUI. MAIN OUTCOME MEASURE(S): A total of 1,098 patients were identified whose IVF cycles were characterized by recruitment of three or fewer follicles, excluding patients with bilateral tubal disease or severe male factor. Cycles with three follicles were defined as those with three follicles ≥ 14 mm with no fourth follicle ≥ 10 mm. Cycles with two or fewer follicles were similarly defined. Outcomes were compared for patients proceeding with OR (n = 624) versus converting to IUI (n = 474). Age-adjusted relative risks for pregnancy were calculated, stratifying for number of follicles. RESULT(S): The likelihood of retrieving at least one mature oocyte (82.9% vs. 94.8% vs. 96.2%), having at least one zygote (61.9% vs. 76.8% vs. 84.2%), and undergoing transfer (57.1% vs. 73.0% vs. 83.3%) increased significantly with increasing follicle number. Patients with three or fewer follicles were 2.6 times more likely to achieve a live birth with IVF versus IUI (9.3% vs. 3.4%). This benefit was only apparent when at least two follicles were present. No benefit was gained by performing OR in the setting of one follicle. CONCLUSION(S): IVF compared with IUI presents superior pregnancy rates in the setting of two or more follicles. Assisted reproduction programs may benefit their patients by pursuing IVF in this scenario.