The use of GnRH-agonist trigger for the final maturation of oocytes in normal and low responders undergoing planned oocyte cryopreservation.

STUDY QUESTION: Does GnRH-agonist trigger offer similar maturity rate (MR) in low and normal responders compared to high responders in women undergoing planned oocyte cryopreservation, for whom even a small risk of ovarian hyperstimulation syndrome (OHSS) may not be acceptable? SUMMARY ANSWER: GnRH-agonist is an appropriate choice for final maturation of oocytes in planned oocyte cryopreservation, regardless of response to stimulation or risk of ovarian hyperstimulation syndrome. WHAT IS KNOWN ALREADY: Numerous studies have demonstrated the utility of GnRH-agonist trigger for the prevention of ovarian hyperstimulation in high-responder in vitro fertilization cycles. Limited data exist supporting its use in normal or low responders, or in non-infertile women undergoing planned oocyte cryopreservation. STUDY DESIGN, SIZE, DURATION: Retrospective cohort study of 1189 subjects including all planned oocyte cryopreservation cycles performed at a large, single center, oocyte cryopreservation program from April 2016 to December 2018. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 1680 cycles were included in the study. A total of 57.1% (959/1680) utilized GnRH-agonist for trigger. Demographic and clinical data were collected from the medical record. Maturation rate was calculated for the entire cohort, and by trigger type, using the quotient of Metaphase II (MII) oocytes and retrieved oocytes. A sub-cohort of GnRH-agonist trigger cycles were categorized by peak estradiol (E2) levels and maturation rates compared between groups. Associations were made using Student's t test, ANOVA, Mann-Whitney U and Kruskal-Wallis, where appropriate. A sample size calculation for 90% power with a significance of 5% to detect non-inferiority of <0.05 from a 0.75 maturity rate between subjects with E2 > 3000 pg/mL and E2 < 3000 pg/mL demonstrated the need for at least 116 cycles per group. MAIN RESULTS AND THE ROLE OF CHANCE: Mean MR was 0.71 ± 0.19 overall, and 0.73 ± 0.18 in the sub-cohort of GnRH-agonist trigger cycles. A total of 611 cycles (63.7%) had peak E2 < 3000, and 331 (34.5%) had E2 > 3000. No significant difference in maturity rate was noted between cycles with E2 levels >3000 pg/mL and <3000 pg/mL (0.72 ± 0.19 vs. 0.74 ± 0.14, P = 0.18), confirming the non-inferiority of maturity rates with GnRH-agonist triggers in cycles with peak E2 < 3000 pg/mL. While lower mean oocytes retrieved and mean MII oocytes were associated with lower peak E2 levels, maturity rate did not significantly differ amongst E2 level groups. Cycles with E2 < 1000 pg/mL had lower MR irrespective of trigger type. LIMITATIONS, REASONS FOR CAUTION: The retrospective nature cannot entirely exclude selection biases, confounding factors or additional variables that could not be accounted for or were not collected by the electronic medical record. Given the nature of planned oocyte cryopreservation, studies of ongoing pregnancy rates and birth outcomes will naturally be delayed. Lastly, the study population was limited to women undergoing planned oocyte cryopreservation; therefore, the results may not be generalizable to women undergoing in vitro fertilization. WIDER IMPLICATIONS OF THE FINDINGS: This is the first study specifically comparing the efficacy of GnRH-agonist in patients at lower risk for OHSS to those at high risk, as well the first study evaluating GnRH-agonist's efficacy specifically in planned oocyte cryopreservation cycles. STUDY FUNDING/COMPETING INTEREST(S): Study support provided by departmental funds from the Center for Fertility Research and Education-Extend Fertility Medical Practice. BLM discloses personal fees from Ferring Pharmaceuticals and Merck KgAA, unrelated to the submitted work. C.S., M.G., L.R. and J.K. have nothing to disclose. TRIAL REGISTRATION NUMBER: N/A.

Likelihood of achieving a 50%, 60%, or 70% estimated live birth rate threshold with 1 or 2 cycles of planned oocyte cryopreservation.

PURPOSE: To characterize the likelihood of cryopreserving enough oocytes for 50%, 60%, or 70% estimated live birth rate (eLBR) with 1-2 planned oocyte cryopreservation (Pl-OC) cycles. METHODS: We performed a retrospective cohort study utilizing all patients completing ≥ 1 Pl-OC cycle from 2016 to 2018 at a large single-center OC program. Subjects were categorized by age at retrieval and number of cycles. We extrapolated age-based oocyte thresholds for 50%, 60%, or 70% eLBR from previously published data. We calculated the proportion of subjects overall, and for each age group, whose number of frozen oocytes was greater than or equal to their age-based threshold for a 50%, 60%, or 70% eLBR after 1 and 2 cycles. OR for 60% eLBR with one cycle was calculated for age and AMH cutoff values and corroborated with logistic regression. RESULTS: A total of 1241 subjects, completing 1799 Pl-OC cycles, were included. With one cycle, 66% (819/1241) achieved ≥ 50% eLBR and 51% (634/1241) achieved 70% eLBR. With two cycles, 79.6% (988/1241) attained ≥ 50% eLBR and 65.5% (813/1241) achieved 70% eLBR. Achieving 50%, 60%, or 70% eLBR with 1-2 cycles was significantly associated with both age (p < 0.001) and AMH (p < 0.001). Age < 37.5 and AMH > 1.995 were independently associated with attaining 60% eLBR with one cycle (age: OR 13.73; 95%CI 9.16-20.57, p < 0.001; AMH: OR 7.32; 95% CI 5.50-9.76, p < 0.001). CONCLUSIONS: Younger age and higher AMH were associated with achieving 50%, 60%, or 70% eLBR thresholds with Pl-OC. Nevertheless, almost all subjects were successfully able to preserve enough oocytes for ≥ 50% eLBR in 1-2 cycles.

Anti-Müllerian hormone testing is useful for individualization of stimulation protocols in oocyte donors.

While the age of a donor is a fundamental factor to the success of donor IVF, no serum markers have been demonstrated to be useful in predicting variability of ovarian response in individual donors. Anti-Müllerian hormone (AMH) has been described as an accurate marker of ovarian response in patients undergoing IVF, but has not been applied to oocyte donors. AMH concentrations from 104 anonymous oocyte donors between the ages of 21-32 years were studied and IVF outcome parameters compared. AMH was correlated with several parameters including the number of oocytes retrieved (r = 0.232, P = 0.024), the peak oestradiol concentrations (r = 0.235, P = 0.024) and the need to decrease gonadotrophin dose in order to avoid ovarian hyperstimulation syndrome (r = 0.274, P = 0.007). Receiver operating curve analysis was able to identify an AMH threshold that rendered about 70% sensitivity and 70% specificity for predicting the need to decrease gonadotrophin dosing. The clinical pregnancy rate was 77% per recipient and was not related to the donors' AMH concentrations. For oocyte donors, measurement of AMH appears most useful for determining gonadotrophin sensitivity in order to mitigate symptoms consistent with ovarian hyperstimulation.

Does the addition of clomiphene citrate or letrazole to gonadotropin treatment enhance the oocyte yield in poor responders undergoing IVF?

PURPOSE: To evaluate the effect of adjunctive letrazole or clomiphene in IVF stimulation protocols. METHODS: A retrospective analysis of high dose GnRH antagonist IVF cycles (450-600 IU of gonadotropins) that have met poor responder criteria. Selected consecutive cycles in same patients differed solely in presence or absence of adjunctive clomiphene or letrazole. RESULTS: Supplementation with clomiphene citrate in poor responders showed significant improvements (p < 0.05) in estradiol levels (1506 vs. 1044 pg/ml), number of dominant follicles (5.6 vs. 3.9), oocytes retrieved (5.2 vs. 3.4) and number of transferred embryos (1.7 vs. 1.1). It significantly improved biochemical pregnancy rates (18.1% vs. 5.9%) while reducing cycle cancellations (11.7% vs. 32.6%). Letrozole supplementation showed similar effects. CONCLUSION: Both Clomiphene and Letrazole performed similarly and showed significant effects. However, despite increasing oocyte yield and embryo transfer rates, the overall clinical and live birth rate in this population remained low and showed no measurable increase.

Anti-Müllerian hormone testing is useful for individualization of stimulation protocols in oocyte donors.

While the age of a donor is a fundamental factor to the success of donor IVF, no serum markers have been demonstrated to be useful in predicting variability of ovarian response in individual donors. Anti-Müllerian hormone (AMH) has been described as an accurate marker of ovarian response in patients undergoing IVF, but has not been applied to oocyte donors. AMH concentrations from 104 anonymous oocyte donors between the ages of 21-32 years were studied and IVF outcome parameters compared. AMH was correlated with several parameters including the number of oocytes retrieved (r=0.232, P=0.024), the peak oestradiol concentrations (r=0.235, P=0.024) and the need to decrease gonadotrophin dose in order to avoid ovarian hyperstimulation syndrome (r=0.274, P=0.007). Receiver operating curve analysis was able to identify an AMH threshold that rendered about 70% sensitivity and 70% specificity for predicting the need to decrease gonadotrophin dosing. The clinical pregnancy rate was 77% per recipient and was not related to the donors' AMH concentrations. For oocyte donors, measurement of AMH appears most useful for determining gonadotrophin sensitivity in order to mitigate symptoms consistent with ovarian hyperstimulation.

The association between anti-Müllerian hormone and IVF pregnancy outcomes is influenced by age.

The conflicting results from studies on the predictive capabilities of serum anti-Müllerian hormone (AMH) for IVF pregnancy outcomes may be attributed to small sample sizes and disparities in the age of the study populations. The relationship between AMH and IVF pregnancy outcomes was clarified with retrospective cross-tabulation analyses (n=1558) stratified by age to control for its confounding effects. Serum AMH concentrations were divided into tertiles (≤ 0.29, 0.30-1.20, ≥ 1.21 ng/ml) and ages into four groups (<34, 34-37, 38-41, ≥ 42 years). For women <34, having serum AMH in the lowest tertile did not reduce the chance of IVF pregnancy/live birth compared with those with higher AMH concentrations. For women 34-41, a significant positive relationship existed between serum AMH and pregnancy rates. For women ≥ 42, serum AMH concentrations ≤ 0.29 ng/ml were associated with a 3% chance of pregnancy, and women with AMH ≥ 1.21 ng/ml had the same pregnancy rate as women with concentrations 0.30-1.20 ng/ml. In conclusion, AMH has limited predictive value for IVF outcomes in the two extremes of female reproductive age; however, for women between 34 and 41, higher serum AMH concentrations are associated with significantly greater chances of pregnancy (P<0.01).

Bilateral megaureters may masquerade as hydrosalpinges on ultrasound.

Gynaecologists are familiar with occluded Fallopian tubes presenting as pelvic masses on ultrasound. However, it is important to also consider anomalies of the urinary collecting system when presented with a pelvic mass, some of which do not necessitate surgical therapy. This report describes the case of a woman with unknown and asymptomatic bilateral megaureters who presented for evaluation of infertility. Initially, it was presumed that she had tubal disease and the possibility of a laparoscopy to remove her hydrosalpinges was entertained.

A systematic, multidisciplinary approach to address the reproductive needs of HIV-seropositive women.

Nearly 130,000 American women are human immunodeficiency virus (HIV) seropositive. The present study sought to establish a comprehensive programme to address their fertility needs in order to minimize infectious, medical and reproductive risks to prospective patients. Forty women, aged 27-42 years, were evaluated. HIV was diagnosed 7.2 +/- 0.7 years prior to their seeking care, and most women (n = 38) were on highly active antiretroviral therapy. Their prenatal CD4 counts were 712.2 +/- 56 cells/mm(3) (range 327-1881) and HIV-1 concentrations were undetectable in all cases prior to initiating treatment. HIV-seropositive women were statistically identical to their age-matched HIV-seronegative counterparts with respect to the IVF clinical outcome parameters measured. Throughout the pregnancies, maternal HIV-1 RNA concentrations remained undetectable and CD4 counts were stable. All infants, tested at birth and at 3 and 6 months of age, remained HIV negative. This is the first report of an institutional paradigm in the USA dedicated to evaluate and treat HIV-seropositive women. Using a multidisciplinary approach to care, HIV-seropositive women may be successfully managed in a programme of assisted reproduction.

Hysterosalpingography with selective salpingography.

OBJECTIVE: To evaluate the use of selective salpingography to achieve tubal patency in patients with proximal fallopian tube occlusion on hysterosalpingography (HSG). STUDY DESIGN: We performed a retrospective cohort study on 116 infertile women (age 37.7 +/- 4.6 years) with proximal tubal obstruction treated with selective salpingography. Success was defined as opening at least 1 fallopian tube. Pregnancy was defined as having a positive beta-hCG level. RESULTS: A total of 151 tubes were blocked on HSG before tubal catheterization; 103 tubes were opened by selective salpingography. Of 116 patients, 84 (72.4%) had successful procedures with at least 1 tube opened by catheterization. Of the 116, 32 (27.6%) had failed procedures with no tubes opened. Of 83 patients, 30 (36.1%) with successful procedures achieved pregnancy. Of these pregnancies, 16 occurred spontaneously or following ovulation induction and 5 pregnancies occurred in the failure group, allfollowing in vitro fertilization. CONCLUSION: Selective salpingography is useful in demonstrating tubal patency, reducing the diagnosis of tubal disease and potentially minimizing surgery in infertile patients.

Uterine artery embolization as an adjunctive measure to decrease blood loss prior to evacuating a cervical pregnancy.

BACKGROUND: Cervical ectopic pregnancy accounts for less than 1% of all ectopic gestations. The most effective, fertility sparing treatment of a cervical ectopic pregnancy is still unclear due to limited reported experience. CASE: The diagnosis and management of a 32-year-old with a cervical ectopic pregnancy after in vitro fertilization and embryo transfer is described. The patient had multiple risk factors, including Asherman's syndrome following an abdominal myomectomy and three uterine curettages, for a cervical ectopic pregnancy. Due to her desire for future childbearing, conservative management strategies were chosen. This patient was successfully treated with uterine artery embolization followed by immediate dilation and evacuation of the pregnancy. CONCLUSIONS: This report demonstrates that UAE followed by immediate evacuation of a cervical ectopic pregnancy effectively terminates a viable gestation with minimal blood loss while maintaining fertility capacity.

Müllerian inhibiting substance and disrupted folliculogenesis in polycystic ovary syndrome.

OBJECTIVE: This study determines whether pretreatment levels of müllerian inhibiting substance/antimüllerian hormone (MIS/AMH) would reflect ovarian response to exogenous gonadotropin in women with polycystic ovary syndrome (PCOS) and ovulatory controls matched by age and weight. STUDY DESIGN: Case-control study of 20 women with PCOS and 10 normoovulatory women undergoing controlled ovarian hyperstimulation (COH) for in vitro fertilization (IVF) at an academic medical center. RESULTS: Baseline serum MIS/AMH levels in PCOS were higher than those of normoovulatory women (P < .001). MIS/AMH levels increased after gonadotropin-releasing hormone (GnRH) agonist pituitary suppression; 0.5 ng/mL in PCOS (P = .12) and 0.7 ng/mL in controls (P < .02). In normoovulatory women, MIS/AMH at baseline, after pituitary suppression, and the interval change after pituitary suppression all correlated closely to the number of mature oocytes retrieved (P < .005). In PCOS, however, levels of MIS/AMH at baseline and after pituitary suppression did not show this correlation, whereas only the interval change correlated with the number of mature oocytes retrieved. CONCLUSION: Baseline MIS/AMH is a good predictor of the ovarian response to COH in normoovulatory women but not in PCOS.

Reproductive outcomes of HIV seropositive women treated by assisted reproduction.

BACKGROUND: Over one million Americans are infected with HIV, and approximately 300,000 are women. Overall health in HIV infected persons has improved, and many seropositive women desire children. This study describes the reproductive outcomes of HIV seropositive women treated by assisted reproduction at our center and compares their clinical results with age-matched HIV seronegative controls. METHODS: From January 1, 1998 to December 31, 2011, 36 HIV seropositive women received treatment with in vitro fertilization (IVF) at a single center. The mean age at start of fertility treatment was 37.7±4.8 years. At presentation, 92% of seropositive women were using antiretrovirals and all had undetectable viral loads at time of cycle initiation. Clinical outcomes of seropositive women were compared in a one-to-one ratio to those of randomly selected age-matched seronegative controls undergoing treatment for male factor infertility during the same time period. Comparisons were stratified by age--women less than 35 and greater than 35 years of age. RESULTS: Fifteen treatment cycles resulted in live births (21 infants born without HIV infection). HIV seropositive and seronegative women < 35 years of age had nearly identical IVF clinical outcome parameters, including clinical pregnancy rates and live birth rates. For women 35 years of age or older, baseline serum estradiol levels and live birth rates were significantly lower in HIV seropositive women. CONCLUSIONS: This study demonstrates that the presence of well-controlled HIV infection does not impair fertility treatment in women undergoing IVF. Virally infected women should be encouraged to seek treatment in appropriate cases.

Preimplantation genetic diagnosis for stargardt disease.

PURPOSE: To report the first use of in vitro fertilization (IVF) and preimplantation genetic diagnosis to achieve an unaffected pregnancy in an autosomal-recessive retinal dystrophy. DESIGN: Case report. METHODS: An affected male with Stargardt disease and his carrier wife underwent IVF. Embryos obtained by intracytoplasmic sperm injection underwent single-cell DNA testing via polymerase chain reaction and restriction enzyme analysis to detect the presence of ABCA4 mutant alleles. Embryos were diagnosed as being either affected by or carriers for Stargardt disease. A single carrier embryo was implanted. RESULTS: Chorionic villus sampling performed during the first trimester verified that the fetus possessed only 1 mutant paternal allele and 1 normal maternal allele, thus making her an unaffected carrier of the disease. A healthy, live-born female was delivered. CONCLUSION: IVF and preimplantation genetic diagnosis can assist couples with an affected spouse and a carrier spouse with recessive retinal dystrophies to have an unaffected child.

Providing fertility care to men seropositive for human immunodeficiency virus: reviewing 10 years of experience and 420 consecutive cycles of in vitro fertilization and intracytoplasmic sperm injection.

OBJECTIVE: To review 10 years of experience providing fertility care to men seropositive for human immunodeficiency virus (HIV) using sperm washing and in vitro fertilization with intracytoplasmic sperm injection (IVF-ICSI). DESIGN: Retrospective study. SETTING: University-based practice. PATIENT(S): HIV-seropositive men with HIV-seronegative partners. INTERVENTION(S): IVF-ICSI, HIV testing of females and infants. MAIN OUTCOME MEASURE(S): IVF performance, pregnancy rates, obstetrical outcomes, infection rates. RESULT(S): We initiated 420 cycles (355 fresh and 65 frozen cycles) in 181 couples. Due to poor ovarian response, 16% of stimulations were canceled. The number of oocytes collected per retrieval was 15.0 +/- 0.5, providing 12.1 +/- 0.5 mature oocytes suitable for ICSI, yielding 9.0 +/- 0.3 embryos per couple. The overall clinical pregnancy rate/embryo transfer was 45%; ongoing/delivered pregnancy rate/embryo transfer was 37%. The most frequent obstetric complication was multiple gestation (41%), with 5% experiencing high order multiple birth. An attendant high rate of preterm delivery was noted, as 43% of infants were born premature. No maternal or neonatal HIV infections or deaths occurred. CONCLUSION(S): We have found IVF-ICSI to be an expeditious and safe means for HIV-serodiscordant couples to achieve pregnancy with minimal risk of viral infection. Risks and liabilities of IVF-ICSI relate to multiple gestations and will occur in a significant number of participants.

Cryopreservation of supernumerary high quality embryos predicts favorable outcomes for patients undergoing repeated cycles of in vitro fertilization.

OBJECTIVE: To determine whether the decline in pregnancy and implantation rates in repeated fresh IVF cycles is associated with the availability of embryo cryopreservation. DESIGN: Retrospective study. SETTING: Assisted reproductive unit at an academic institution. PATIENT(S): Women <38 years old (1,037), undergoing nondonor fresh or frozen embryo transfer (FET) cycles between January 1, 2000 and December 31, 2005. INTERVENTION(S): In fresh cycles, women used either pituitary desensitization or GnRH antagonists in combination with gonadotropin stimulation protocols before oocyte retrieval. In FET cycles, endometrial development was achieved by oral E(2) and vaginal P after pituitary desensitization. Embryo transfer occurred either on day 3 or on day 5. MAIN OUTCOME MEASURE(S): Implantation and pregnancy rates (PR). RESULT(S): Excluding FET cycles, implantation rates and PRs declined significantly in repeated cycles compared to the initial one. However, women with supernumerary embryos for cryopreservation appeared to produce embryos with higher implantation potential but were excluded from the analysis. When FET cycles were included, there were no significant declines in PRs for at least three repeated cycles. CONCLUSION(S): Embryo cryopreservation stratifies women with high quality embryos from those with low quality embryos who require repeat fresh attempts, resulting in an accelerated decline in observed PRs and implantation rates.

Triplet pregnancy after ovulation induction with an aromatase inhibitor.

OBJECTIVE: To describe the first reported case of a triplet pregnancy subsequent to the use of an aromatase inhibitor for ovulation induction. DESIGN: Case report. SETTING: Academic medical center. PATIENT(S): A 32-year-old female with polycystic ovary syndrome and primary infertility. INTERVENTION(S): Letrozole, 5 mg/day, on cycle days 2 to 6 for ovulation induction. MAIN OUTCOME MEASURE(S): Clinical pregnancy. RESULT(S): Viable triplet gestation. CONCLUSION(S): Use of an aromatase inhibitor for ovulation induction does not eliminate the risk for higher order multiple pregnancy.

The effect of cinnamon extract on insulin resistance parameters in polycystic ovary syndrome: a pilot study.

Cinnamon extract has been shown to reduce insulin resistance in in vitro and in vivo studies by increasing phosphatidylinositol 3-kinase activity in the insulin signaling pathway and thus potentiating insulin action. Fifteen women with polycystic ovary syndrome (PCOS) were randomized to daily oral cinnamon and placebo for 8 weeks. Comparisons of post-treatment to baseline insulin sensitivity indices using fasting and 2-hour oral glucose tolerance tests showed significant reductions in insulin resistance in the cinnamon group but not in the placebo group. A larger trial is needed to confirm the findings of this pilot study and to evaluate the effect of cinnamon extract on menstrual cyclicity.

Initial presentation of undiagnosed acute intermittent porphyria as a rare complication of ovulation induction.

OBJECTIVE: To discuss the diagnosis and management of acute intermittent porphyria following ovulation induction. DESIGN: Case report. SETTING: Academic IVF center. PATIENT(S): A patient with polycystic ovary syndrome and primary infertility undergoing ovulation induction with clomiphene citrate. INTERVENTION(S): Serial phlebotomy, IV fluid, inpatient observation. MAIN OUTCOME MEASURE(S): Condition at discharge. RESULT(S): The patient was diagnosed with severe hyponatremia caused by acute volume depletion and possible syndrome of inappropriate antidiuretic hormone secretion, secondary to acute intermittent prophyria, and was successfully managed with supportive measures. Neurovisceral symptoms resolved, and severe hyponatremia was corrected with IV saline solution without complications. CONCLUSION(S): Acute intermittent porphyrias are rare complications of ovulation induction, but should be considered in patients who develop unexplained hyponatremia or neurovisceral symptoms.