Tubal Ectopic Pregnancy with Undetectable Initial Serum ß-Human Chorionic Gonadotropin Level.

We present a case of a tubal ectopic pregnancy (EP) in a patient with an initially undetectable serum ß-human chorionic gonadotropin (ß-hCG) level. A 33-year-old woman in a same-sex relationship underwent timed donor intrauterine insemination. Her serum ß-hCG level was <5 mIU/mL 14 days after the intrauterine insemination. She reported menstrual bleeding 3 days after her negative pregnancy test and returned to the office 10 days later to begin a new treatment cycle. Her serum levels of estradiol, progesterone, and ß-hCG were 119 pg/mL, 6.1 ng/mL and 1157 mIU/mL, respectively. Transvaginal ultrasonography did not show an intrauterine pregnancy. Her ß-hCG level increased to 1420 mIU/mL the next day. She was diagnosed with a pregnancy of unknown location and treated with methotrexate. Her ß-hCG levels continued to increase despite 3 methotrexate doses, necessitating laparoscopy. The diagnostic laparoscopy demonstrated approximately 100 mL of hemoperitoneum in the posterior cul-de-sac with an intact right fallopian tube that was dilated at its distal end by the EP. A total right salpingectomy was performed. Her ß-hCG level was <5 mIU/mL 3 weeks later. The current case supports that although rare, an undetectable serum ß-hCG level does not completely rule out the diagnosis of an EP.

Fertility preservation with random-start controlled ovarian stimulation and embryo cryopreservation for early pregnancy-associated breast cancer.

We report a case of fertility preservation using random-start controlled ovarian stimulation (COS), intracytoplasmic sperm injection (ICSI) and embryo cryopreservation in a patient with early pregnancy-associated breast cancer. A 34-year-old nulliparous woman at 5 weeks of gestation was diagnosed with estrogen receptor (ER) positive, progesterone receptor (PR) positive and human epidermal growth factor receptor-2 (HER-2) negative infiltrating intraductal carcinoma. Urgent neoadjuvant chemotherapy was deemed necessary and the patient decided to terminate the pregnancy. Random-start COS was initiated 5 days after pregnancy termination using a letrozole-based protocol. The beta human chorionic gonadotropin level on the day of COS start was 119.8 mIU/mL. Twenty-nine oocytes were retrieved after 11 days of COS. Seventeen oocytes underwent successful fertilization and 10 blastocysts were cryopreserved. The patient subsequently initiated neoadjuvant chemotherapy with her oncologist. The current case highlights the feasibility of random-start COS and embryo cryopreservation for fertility preservation immediately after the termination of an early pregnancy in a patient with pregnancy-associated breast cancer.

Risk factors and human chorionic gonadotropin trends in patients with ruptured tubal ectopic pregnancies despite methotrexate treatment.

This retrospective cohort study investigates the risk factors and beta-human chorionic gonadotropin (ß-hCG) trends in patients with ruptured tubal ectopic pregnancies (EPs) despite methotrexate (MTX) treatment. All patients receiving MTX for sonographically confirmed tubal EPs at our fertility center between 2004 and 2014 were included. Baseline demographics and ß-hCG trends of patients with EP rupture after MTX were compared to patients with resolved EPs after MTX. One-hundred-thirty-seven patients with EPs were treated with MTX during the study duration; 27 experienced EP rupture and 110 EP resolution. There was no difference in the baseline demographics or ß-hCG levels on the day of MTX between the groups. Patients with ruptured EPs after MTX had higher ß-hCG levels on day-4 (1223.9 ± 243.5 vs. 1111.2 ± 179.7 mIU/mL; p < .001) and day-7 (1156.9 ± 206.2 vs. 872.4 ± 690.2 mIU/mL; p < .001). The odds of EP rupture compared to EP resolution was 6.2 (95% CI 2.1-19.1), 13.7 (95% CI 4.8-38.9), and 3.0 (95% CI 1.2-7.2) times higher when the change in ß-hCG levels was <5% between day-7 vs. day of MTX, day-7 vs. day-4, and day-4 vs. day of MTX, respectively. Our results demonstrate that ruptured tubal EPs despite MTX have <5% change in ß-hCG levels between the day of MTX and day-4 or day-7 after MTX.

Contemporary Management of Polycystic Ovarian Syndrome.

PCOS remains one of the most intriguing endocrine disorders that physicians encounter even though it was first described over 80 years ago. Although the diagnostic criteria, nomenclature, and ideal therapeutic strategies are areas of active and ongoing debate, there is no doubt that we have made tremendous progress in improving the quality of life and reproductive outcomes of women who suffer from this wide-ranging disorder.

Contemporary Management of Unexplained Infertility.

Infertility is estimated to affect about 10% to 15% of couples. Most cases of infertility have etiologies that can be attributed to tubal factors, ovulatory dysfunction, endometriosis, uterine factor, male factor, or diminished ovarian reserve, while the remainder often do not have a known attributable cause, that is, unexplained infertility. The current manuscript summarizes the contemporary management of unexplained infertility.

Fresh or Frozen Embryo Transfer in In Vitro Fertilization: An Update.

The past decade has witnessed a rapid increase in the number of frozen-thawed embryo transfer (FET) cycles. Several factors have contributed to the increase in FET cycles, including improvement in culture media, vitrification, and an increase in preimplantation genetic testing of embryos. However, the accelerated trend in FET cycles also suggests that FET may be preferred over fresh embryo transfer. The current review explores the factors that have influenced this practice shift toward preferential FET and why this shift may be premature.

Expanded genetic carrier screening in clinical practice: a current survey of patient impressions and attitudes.

PURPOSE: Expanded genetic carrier screening (ECS) is an important part of gynecological practice and preconception planning. We evaluated the awareness and attitudes among women regarding ECS and factors that may influence decision-making in a family planning context. METHODS: A 32-question survey in an academic university practice was given to 521 women who were either currently pregnant (n = 108), undergoing gynecologic care who were considering future fertility (n = 308), and considering or receiving fertility treatment (n = 105). Data are reported descriptively. RESULTS: Forty-seven percent (n = 246) of patients were aware of ECS. Though most reported feeling positive or neutral towards ECS, 51% (n = 263) reported no desire for testing. Fifty-eight percent (n = 303) felt it beneficial to know their carrier status, and 55% (n = 257) said it was their responsibility to undergo testing. Those considering future fertility were found to have a more positive attitude towards ECS (51.4%) than those considering or receiving fertility treatment (34%). For positive carriers of a genetic disorder, 228 (49%) of patients would proceed with having their partner screened, 58 (13%) would undergo prenatal screening only and 12 (2.6%) would continue with vitro fertilization (IVF). Related to cost for ECS, 53.5% (n = 191) would be willing to pay at least $50-100 for testing, while 29% (n = 146) would not pay anything out of pocket. CONCLUSIONS: Despite patients' beliefs that it would be beneficial and their responsibility to undergo carrier status testing, the majority reported no desire for ECS and many were unwilling to pay out of pocket. Further education is necessary to reconcile the gap between technology and patient decision-making.

CGG repeat length and AGG interruptions as indicators of fragile X-associated diminished ovarian reserve.

PURPOSE: Fragile X premutation (PM) carriers may experience difficulties conceiving a child probably due to fragile X-associated diminished ovarian reserve (FXDOR). We investigated which subgroups of carriers with a PM are at higher risk of FXDOR, and whether the number of AGG interruptions within the repeat sequence further ameliorates the risk. METHODS: We compared markers of ovarian reserve, including anti-Müllerian hormone, antral follicle count, and number of oocytes retrieved between different subgroups of patients with a PM. RESULTS: We found that carriers with midrange repeats size (70-90 CGG) demonstrate significantly lower ovarian reserve. Additionally, the number of AGG interruptions directly correlated with parameters of ovarian reserve. Patients with longer uninterrupted CGG repeats post-AGG interruptions had the lowest ovarian reserve. CONCLUSION: This study connects AGG interruptions and certain CGG repeat length to reduced ovarian reserve in carriers with a PM. A possible explanation for our findings is the proposed gonadotoxicity of the FMR1 transcripts. Reduction of AGG interruptions could increase the likelihood that secondary RNA structures in the FMR1 messenger RNA are formed, which could cause cell dysfunction within the ovaries. These findings may provide women with guidance regarding their fertility potential and accordingly assist with their family planning.

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.

Impact of FMR1 Pre-Mutation Status on Blastocyst Development in Patients Undergoing Pre-Implantation Genetic Diagnosis.

BACKGROUND/AIMS: The study aimed to investigate the impact of fragile X mental retardation 1 (FMR1) pre-mutation status on blastocyst development in patients undergoing pre-implantation genetic diagnosis (PGD). METHODS: Case-control study of patients <40 years undergoing PGD at blastocyst stage for FMR1 pre-mutation status. Age-matched patients undergoing PGD for other single gene disorders were considered controls. Blastocyst development, calculated per metaphase II (MII) oocyte retrieved and per 2 pronuclear (2PN) embryos, was compared between the 2 groups. Pregnancy outcomes after embryo transfer were also compared. RESULTS: Eighty-one and 791 patients were included in the FMR1 and control groups, respectively. FMR1 pre-mutation carriers had lower indicators of ovarian reserve, required higher gonadotropin doses, and had fewer MII oocytes retrieved. Mean blastocyst development per MII oocyte (12.6 vs. 29.4%; p < 0.001) and per 2PN embryos (21.5 vs. 41.7%; p < 0.001) was lower in the FMR1 group. An inverse correlation between the number of FMR1 CGG repeats and blastocyst development per MII oocyte (ρ = -0.63; p < 0.001) was observed. There was no difference in the rates of clinical pregnancy, spontaneous abortion, or live birth among the groups. CONCLUSION: Our study suggests lower rates of blastocyst development in patients with FMR1 pre-mutation status and an inverse correlation between the number of FMR1 CGG repeats and blastocyst development.

Arabian Peninsula ethnicity is associated with lower ovarian reserve and ovarian response in women undergoing fresh ICSI cycles.

PURPOSE: Recent studies have demonstrated that ethnicity can be an independent determinant of assisted reproductive technology (ART) outcomes. In this context, we investigate whether ART outcomes differ between Arabian Peninsula and Caucasian women. METHODS: This is a retrospective cohort study of women undergoing fresh intracytoplasmic sperm injection (ICSI)-embryo transfer (ET) cycles for male factor infertility. The study cohort was divided into 2 groups based on ethnicity-Arabian Peninsula or Caucasian. Ovarian reserve, ovarian response, and pregnancy outcomes were compared between the groups. A sub-analysis was performed between individual Arabian Peninsula nationalities for the same outcomes. A multiple linear regression model was used to assess the independent effect of ethnicity on ovarian response. RESULTS: Seven hundred sixty-three patients were included-217 (28.4%) Arabian Peninsula and 546 (71.6%) Caucasian. There was no difference in the mean age of the two groups; however, the former had a higher body mass index (28.5 ± 7.5 vs. 23.3 ± 5.7; P < 0.001). Although follicle stimulating hormone (FSH) levels and antral follicle counts (AFC) were within the normal range in both groups, Arabian Peninsula women had higher FSH levels (5.7 ± 2.5 vs. 4.9 ± 2.8; P = 0.001) and lower AFC (13.9 ± 4.7 vs. 16.5 ± 4.3; P < 0.001) when compared to Caucasian women. Women from the Arabian Peninsula also had a statistically lower number of mature oocytes retrieved (15.6 ± 6.8 vs. 14.1 ± 8.4; P = 0.01), despite requiring higher gonadotropin doses. Multiple linear regression reveled that Arabian Peninsula women had 2.5 (95% CI 2.1-3.9) less mature oocytes, even after controlling for confounders. A sub-analysis within the Arab cohort demonstrated that Qatari women had a higher yield of mature oocytes when compared to Emirati, Kuwaiti, and Saudi women. There was no difference in the rates of implantation, clinical pregnancy, or live birth when comparing individual Arabian Peninsula nationalities with each other or to Caucasians. CONCLUSIONS: Arabian Peninsula ethnicity is associated with lower ovarian reserve and ovarian response parameters in women undergoing their first ICSI-ET cycle.

Expanded carrier screening: a current survey of physician utilization and attitudes.

PURPOSE: Expanded carrier screening (ECS) is an available component of preconception and prenatal care. There is complexity around offering, administering, and following-up test results. The goal of this study is to evaluate current physicians' utilization and attitudes towards ECS in current practice. METHODS: This was a prospective qualitative survey study. A 32-question electronic survey was distributed during a 1-year period to obstetricians-gynecologists who were identified using a Qualtrics listserv database. RESULTS: While more than 90% of physicians offered ethnic-based carrier screening (CS), ECS was offered significantly less (2010, 20.6%, and 2016, 27.1%). Physicians who were not fellowship-trained in reproductive endocrinology and infertility (REI) preferred ethnic-based carrier screening (95.9 vs 16.8%; P < 0.001). REI subspecialists were more likely to offer ECS (80%) compared to 70% of maternal fetal medicine physicians (MFM). Physicians were comfortable discussing negative results (53.6%) compared to positive results (48.4%). Most physicians (56%) believed that ECS should not be offered until the significance of each disease is understood; 52% believed that testing should be restricted to those conditions important to couples; while 26% felt that testing should be done regardless of the clinical significance. CONCLUSIONS: Discussion and application of ECS has increased in clinical practice. However, lack of comfort with counseling and varying beliefs surrounding ECS continue to hinder its utilization. Further education and training programs, and subsequent evaluation are warranted.

The pioneering of intracytoplasmic sperm injection: historical perspectives.

Intracytoplasmic sperm injection (ICSI) has often been heralded as a ground-breaking technique that has transformed the treatment of couples with infertility. By injecting a single spermatozoon into the cytoplasm of the oocyte, ICSI bypasses the zona pellucida and increases the chances of fertilization and subsequent embryo development, independent of semen parameters. Ever since the first live births using ICSI were reported in 1992, ICSI has become the mainstay of treating male factor infertility as well as overcoming fertilization failure associated with conventional in vitro insemination. Today, ICSI is utilized in nearly 66% of all assisted reproductive treatments worldwide and has resulted in the birth of millions of babies. The primary goal of this review is to provide historical perspectives about the pioneering of ICSI. We begin by highlighting the scientific work of early investigators who elucidated the mechanisms central to mammalian fertilization. Furthermore, we briefly discuss how these findings contributed to the development of IVF for the treatment of infertility. We then emphasize the shortcomings of IVF in treating severe forms of male factor infertility and enumerate the micromanipulation techniques that were developed to circumvent these shortcomings. Finally, we indicate how the inadequacies of these micromanipulation techniques lead to the inception, application and popularity of ICSI.