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.

Gonadotropin-releasing hormone agonist trigger increases the number of oocytes and embryos available for cryopreservation in cancer patients undergoing ovarian stimulation for fertility preservation.

OBJECTIVE: To compare the oocyte and embryo yield associated with GnRH-agonist triggers vs. hCG triggers in cancer patients undergoing controlled ovarian stimulation (COS) for fertilization preservation. DESIGN: Retrospective cohort study. SETTING: Academic center. PATIENT(S): Cancer patients undergoing COS with letrozole and gonadotropins or gonadotropin-only protocols for oocyte or embryo cryopreservation. INTERVENTION(S): Gonadotropin-releasing hormone agonist or hCG trigger. MAIN OUTCOME MEASURE(S): Number of metaphase II (MII) oocytes or two-pronuclei (2PN) embryos available for cryopreservation were primary outcomes. Separate multivariate linear regression models were used to assess the effect of trigger type on the primary outcomes, after controlling for confounders of interest. RESULT(S): A total of 341 patients were included, 99 (29.0%) in the GnRH-agonist group and 242 (71%) in the hCG group. There was no difference in the baseline demographics of patients receiving GnRH-agonist or hCG triggers. Within the letrozole and gonadotropins group (n = 269), the number (mean ± SD, 11.8 ± 5.8 vs. 9.9 ± 6.0) and percentage of MII oocytes (89.6% vs. 73.0%) available for cryopreservation was higher with GnRH-agonist triggers compared with hCG triggers. Similar results were noted with GnRH-agonist triggers in the gonadotropin-only group (n = 72) (i.e., a higher number [13.3 ± 7.9 vs. 9.3 ± 6.0] and percentage of MII oocytes [85.7% vs. 72.8%] available for cryopreservation). Multivariate linear regression demonstrated approximately three more MII oocytes and 2PN embryos available for cryopreservation in the GnRH-agonist trigger group, irrespective of cancer and COS protocol type. CONCLUSION(S): Utilization of a GnRH-agonist trigger increases the number of MII oocytes and 2PN embryos available for cryopreservation in cancer patients undergoing COS for fertility preservation.

Association between ABO blood type and live-birth outcomes in single-embryo transfer cycles.

OBJECTIVE: To investigate the association between ABO blood type and live-birth outcomes in patients undergoing IVF with day 5 single-embryo transfer (SET). DESIGN: Retrospective cohort study. SETTING: University-affiliated center. PATIENT(S): Normal responders, <40 years old, undergoing their first IVF cycle with fresh SET. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Live-birth rate was the primary outcome. Secondary outcomes were birth weight and gestational age at delivery. Univariate and multivariable logistic regression was used to examine the association between blood type and live birth, while controlling for confounders. Odds ratios (OR) with 95% confidence intervals (CI) for live birth were estimated. RESULT(S): A total of 2,329 patients were included. The mean age of the study cohort was 34.6 ± 4.78 years. The distribution of blood types was as follows: A = 897 (38.5%); B = 397 (17.0%); AB = 120 (5.2%); and, O = 1,915 (39.3%) patients. There was no difference in the baseline demographics, ovarian stimulation, or embryo quality parameters between the blood types. The unadjusted ORs for live birth when comparing blood type A (referent) with blood types B, AB, and O were 0.96 (95% CI, 0.6-1.7), 0.72 (95% CI, 0.4-1.2), and 0.96 (95% CI. 0.6-1.7), respectively. The adjusted ORs for live birth remained not significant when comparing blood type A to blood types B, AB, and O individually. No difference in birth weight or gestational age at delivery was noted among the four blood types. CONCLUSION(S): Our findings suggest that ABO blood type is not associated with live-birth rate, birth weight, or gestational age at delivery in patients undergoing IVF with day 5 SET.

Random Start Ovarian Stimulation for Oocyte or Embryo Cryopreservation in Women Desiring Fertility Preservation Prior to Gonadotoxic Cancer Therapy.

BACKGROUND: Women of reproductive age diagnosed with cancer are often interested in preserving gametes or reproductive tissue that would allow for future genetic parenthood. Preservation of fertility is often accomplished in young cancer patients via ovarian stimulation followed by oocyte or embryo cryopreservation. Conventional stimulation protocols, however, require 2-4 weeks to complete ovarian stimulation, oocyte retrieval and possible fertilization. Such a strategy may not be feasible in patients requiring urgent cancer treatment. Recent studies have highlighted that random start ovarian stimulation can be initiated irrespective of the phase of the menstrual cycle and is an attractive alternative to conventional ovarian stimulation. The primary aim of the current review is to discuss the feasibility and success of random start ovarian stimulation for oocyte or embryo cryopreservation in women desiring fertility preservation prior to gonadotoxic cancer therapy. METHOD: We performed a systematic review of medical literature published between January 2000 to June 2017 reporting the utility of random start ovarian stimulation for fertility preservation. Search terms included "fertility preservation," "cancer," "ovarian stimulation," "random-start ovarian stimulation," "embryo cryopreservation, and" "oocyte cryopreservation." Publications were included in this review only if patients underwent random start ovarian stimulation prior to cancer therapy. RESULTS: Nineteen publications were identified and perused by the authors. Most publications described the utility of random start ovarian stimulation in the setting of breast cancer. Radom-start stimulation was associated with a reduced time interval between ovarian stimulation initiation and oocyte or embryo cryopreservation. The yield of mature oocytes and their developmental potential into embryos was comparable between conventional and random-start protocols, albeit with higher gonadotropin doses in the latter. CONCLUSION: The current review suggests that random start ovarian stimulation can shorten the interval between ovarian stimulation and oocyte retrieval, with the yield of oocytes and embryos being comparable to conventional stimulation protocols. Thus, random start ovarian stimulation may serve as a better option for fertility preservation in patients requiring urgent cancer treatment.

Combined GnRH-agonist and human chorionic gonadotropin trigger improves ICSI cycle outcomes in patients with history of poor fertilization.

PURPOSE: The purpose of this study was to investigate the utility of a combined GnRH-agonist (GnRH-a) and human chorionic gonadotropin (hCG) trigger in improving ICSI cycle outcomes in patients with poor fertilization history after standard hCG trigger in prior ICSI cycles. METHODS: Retrospective cohort study. Patients with a fertilization rate of <20% in at least two prior ICSI cycles who subsequently underwent another ICSI cycle with hCG trigger were compared to those who underwent another ICSI cycle with a combined GnRH-a and hCG trigger. Oocyte maturity, fertilization, clinical pregnancy, and live birth rates were compared. A multiple linear regression model was used to explore the association between combined GnRH-a and hCG trigger (vs hCG trigger alone) and fertilization rate. RESULTS: A total of 427 patients with mean age of 37.3 ± 1.94 years and mean baseline fertilization rate of 17.9 ± 2.03% were included, of which 318 (74.5%) and 109 (25.5%) patients underwent a subsequent ICSI cycle with hCG and combined GnRH-a and hCG trigger, respectively. The baseline parameters of the male and female partner were similar. The mean fertilization rate in the combined trigger group was 16.4% (95% CI: 7.58-25.2%) higher than the hCG trigger group, even after adjustment for confounders. Patients in the combined trigger group had higher oocyte maturity (82.1 vs 69.8%), higher clinical pregnancy (27.5 vs 5.67%), and higher live birth rates (20.2 vs 3.46%) compared to the hCG trigger group. CONCLUSIONS: Combined GnRH-a and hCG trigger in ICSI cycles increase oocyte maturity, fertilization, clinical pregnancy, and live birth rates in patients with a history of poor fertilization after standard hCG trigger alone.

Temporal trends in minimally invasive myomectomy before and after the US Food and Drug Administration recommendation against electric morcellation.

OBJECTIVE: To investigate the temporal trends in minimally invasive myomectomy at one reproductive medicine center before and after the US Food and Drug Administration (FDA) recommendation against electric morcellation. METHODS: A retrospective chart review was undertaken of patients undergoing minimally invasive myomectomy between April 1, 2012, and April 30, 2016, at a center in New York. Temporal trends in laparoscopic myomectomy (LM), robot-assisted laparoscopic myomectomy (RAM), and laparoscopically assisted myomectomy (LAM), and intraoperative and postoperative outcomes before and after the April 2014 recommendation were compared. RESULTS: Minimally invasive myomectomy was performed in 73 patients. No difference was noted in the rates of minimally invasive myomectomy 2 years before (35/74 [47.3%]) and after (38/79 [48.1%]) the FDA's recommendation. The ratio of abdominal to minimally invasive myomectomy remained relatively constant before (68/59=1.15) and during the study period (80/73=1.10). There was a significant decrease in LM and RAM and a corresponding rise in LAM immediately after the recommendation (P<0.001). CONCLUSION: The rates of minimally invasive myomectomy before and after the FDA's recommendation did not differ, indicating that technical modifications to laparoscopic technique can allow surgeons to offer minimally invasive myomectomy to patients with symptomatic leiomyomas.

Ovarian Response and in Vitro Fertilization Outcomes After Salpingectomy: Does Salpingectomy Indication Matter?

STUDY OBJECTIVE: To investigate whether the ovarian response and pregnancy outcomes of patients undergoing in vitro fertilization (IVF) after salpingectomy are affected by the underlying indication for salpingectomy. DESIGN: Retrospective cohort study (Canadian Task Force classification II-3). SETTING: University-affiliated fertility center. PATIENTS: All patients age <37 years undergoing IVF within 12 months of laparoscopic salpingectomy. The underlying indication for laparoscopic salpingectomy in the study cohort was tubal ectopic pregnancy, unilateral or bilateral hydrosalpinx, or other reason (hematosalpinx or pyosalpinx), as confirmed by histopathology. INTERVENTIONS: IVF and embryo transfer (ET). MEASUREMENTS AND MAIN RESULTS: Surgical characteristics, demographics, ovarian stimulation parameters, total oocytes retrieved, fertilization rates, implantation rates, and clinical pregnancy rates were compared among the salpingectomy groups. Age- and time-matched patients undergoing their first IVF-ET cycle for male factor infertility, with no previous history of laparoscopy, served as controls. RESULTS: Of the 996 patients who underwent a laparoscopic procedure during the study period, 136 patients underwent unilateral salpingectomy for the following indications: 39 for ectopic pregnancy, 81 for unilateral hydrosalpinx, and 16 for other indications. Among these 136 patients, 29 in the ectopic pregnancy group, 75 in the unilateral hydrosalpinx group, and 10 in the "other" group underwent subsequent IVF-ET. Thirty-one patients underwent both bilateral salpingectomy and subsequent IVF-ET. There was no difference in the antral follicle counts before and after salpingectomy in all groups. There was a statistically significant difference in the mean duration of ovarian stimulation in the salpingectomy groups: ectopic pregnancy, 10.9 ± 2.15 days; unilateral hydrosalpinx, 9.56 ± 1.95 days; bilateral hydrosalpinx, 9.51 ± 2.01 days; "other", 9.89 ± 2.20 days; control, 9.76 ± 1.99 days. Similar trends were noted for total gonadotropins administered when comparing the ectopic pregnancy group (3375.9 ± 931.0 IU) with the remaining groups (unilateral hydrosalpinx, 2841.3 ± 1160.9 IU; bilateral hydrosalpinx, 2519.3 ± 1004.7 IU; "other", 2808.6 ± 990.1 IU; control, 2726.1 ± 1129.8 IU). There were no significant differences in the total number of oocytes retrieved, fertilization rate, implantation rate, or clinical pregnancy rate in the salpingectomy groups compared with controls. CONCLUSION: Although our findings indicate that patients undergoing IVF after salpingectomy for an ectopic pregnancy have a statistically significantly longer duration of stimulation and require higher gonadotropin doses compared with patients undergoing IVF after salpingectomy for other indications, these differences are of limited clinical significance, given that the total number of oocytes retrieved, implantation rate, and clinical pregnancy rate among the different salpingectomy groups are comparable to those in controls.

Increased odds of live birth in fresh in vitro fertilization cycles with shorter ovarian stimulation.

OBJECTIVE: To investigate the impact of prolonged ovarian stimulation on pregnancy outcomes in IVF cycles with fresh day 3 ET. DESIGN: Retrospective cohort study. SETTING: University-affiliated center. PATIENT(S): All patients initiating their first IVF cycle with fresh day 3 ET. Prolonged ovarian stimulation was defined as a duration of more than two standard deviations (95th percentile) for the study cohort (i.e., >13 days). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Live birth rate was considered the primary outcome and was compared between patients undergoing ovarian stimulation for ≤13 days and >13 days. Odds ratios (OR) with 95% confidence intervals (CI) for all pregnancy outcomes after day 3 ET were calculated. The OR for live birth was adjusted using logistic regression. RESULT(S): A total of 6,410 and 339 patients underwent ovarian stimulation for ≤13 days and >13 days, respectively. There were no differences in the demographics or mean number of day 3 embryos transferred between the two groups. Ovarian stimulation ≤13 days was associated with increased odds of clinical pregnancy (OR 2.15, 95% CI 1.19-3.89) and live birth (OR 2.35, 95% CI 1.25-4.43). The increased odds for live birth in the ≤13-day group remained unchanged after logistic regression. Patients with clinical pregnancies in the >13-day group were younger (34.6 ± 4.91 years) compared with those who did not conceive (38.2 ± 4.72 years). CONCLUSION(S): Our findings suggest that ovarian stimulation ≤13 days is associated with increased odds of clinical pregnancy and live birth. In patients undergoing ovarian stimulation >13 days, younger age is associated with live birth.

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.

Early spontaneous multiple fetal pregnancy reduction is associated with adverse perinatal outcomes in in vitro fertilization cycles.

The primary objective of this study is to investigate whether early spontaneous multiple fetal pregnancy reduction, also known as vanishing twin syndrome, is associated with adverse perinatal outcomes in fresh in vitro fertilization cycles. This is a retrospective cohort study of women with live singleton births with and without an early vanishing twin after fresh in vitro fertilization. Characteristics compared included incidence of preterm birth, overall birth weight, overall low birth weight, overall very low birth weight, and term low birth weight. In all, 4049 patients with live singleton births were included-853 and 3196 with and without a vanishing twin, respectively. The vanishing twin group had a lower overall birth weight compared to those without (3279.5 ± 369.9 vs 3368.6 ± 567.5 g; p < 0.01). Early vanishing twin was also associated with an increased odds of overall low birth weight (odds ratio: 1.75; 95% confidence interval: 1.36-2.25; p < 0.01) and increased odds of term low birth weight (odds ratio: 3.44; 95% confidence interval: 2.14-5.53; p < 0.01). Our study suggests that early vanishing twin is associated with lower overall birth weight and higher odds of overall low birth weight and term low birth weight in live singleton births after fresh in vitro fertilization.

Adjuvant gonadotrophin-releasing hormone agonist trigger with human chorionic gonadotrophin to enhance ooplasmic maturity.

This study investigates whether an adjuvant gonadotrophin-releasing hormone agonist (GnRHa) trigger with human chorionic gonadotrophin (HCG) improves fresh intracytoplasmic sperm injection (ICSI) cycle outcomes in patients with poor fertilization history after standard HCG trigger alone. This study compared 156 patients with <40% fertilization rate in a prior ICSI cycle with standard HCG trigger who underwent another ICSI cycle with a combined 2 mg GnRHa and 1500 IU HCG ovulatory trigger. There was no difference in the baseline demographics, ovarian stimulation outcomes or sperm parameters of the groups. More mature oocytes were retrieved in the combined trigger group compared with the HCG trigger group: 12 (9-14) versus 10 (7-12); P = 0.01. The fertilization rate in the combined trigger group (59.2%) was higher than the HCG group (35.3%); P = 0.01. The odds of clinical pregnancy and live birth were 1.8 and 1.7 times higher, respectively, when comparing the former group to the latter; P = 0.03. The results suggest that combined GnRHa and HCG trigger in ICSI cycles is a reasonable approach to increase oocyte maturity, specifically ooplasmic maturity, thereby increasing fertilization and improving ICSI cycle outcomes in patients with a history of poor fertilization after standard HCG trigger alone.

Antibiotic Prophylaxis for Gynecologic Procedures prior to and during the Utilization of Assisted Reproductive Technologies: A Systematic Review.

The use of assisted reproductive technologies (ART) has increased steadily. There has been a corresponding increase in the number of ART-related procedures such as hysterosalpingography (HSG), saline infusion sonography (SIS), hysteroscopy, laparoscopy, oocyte retrieval, and embryo transfer (ET). While performing these procedures, the abdomen, upper vagina, and endocervix are breached, leading to the possibility of seeding pelvic structures with microorganisms. Antibiotic prophylaxis is therefore important to prevent or treat any procedure-related infections. After careful review of the published literature, it is evident that routine antibiotic prophylaxis is generally not recommended for the majority of ART-related procedures. For transcervical procedures such as HSG, SIS, hysteroscopy, ET, and chromotubation, patients at risk for pelvic infections should be screened and treated prior to the procedure. Patients with a history of pelvic inflammatory disease (PID) or dilated fallopian tubes are at high risk for postprocedural infections and should be given antibiotic prophylaxis during procedures such as HSG, SIS, or chromotubation. Antibiotic prophylaxis is recommended prior to oocyte retrieval in patients with a history of endometriosis, PID, ruptured appendicitis, or multiple prior pelvic surgeries.

Is anti-Müllerian hormone associated with IVF outcomes in young patients with diminished ovarian reserve?

AIM: To investigate whether anti-Müllerian hormone (AMH) is associated with IVF cycle outcomes in young patients with diminished ovarian reserve. MATERIALS & METHODS: Retrospective study of patients <35 years of age undergoing fresh IVF who had at least two 8-cell, day-3 embryos transferred with grades 1, 1.5 or 2. Patients were subgrouped, a priori, based on serum AMH levels: <1 or >1 ng/ml and <0.5 or >0.5 ng/ml. RESULTS: In total, 1005 patients were included. Patients in the >1 ng/ml group required lesser gonadotropins compared with the <1 ng/ml and the <0.5 ng/ml group. More oocytes were retrieved from the same group compared with the latter two (p < 0.001). Despite these differences, the overall rates of clinical pregnancy, spontaneous abortion and live birth were comparable between the two groups. CONCLUSION: In patients with diminished ovarian reserve who have good quality embryos, AMH is not associated with clinical pregnancy, spontaneous miscarriage or live birth rates.