The window is wide: flexible timing for vitrified-warmed embryo transfer in natural cycles.

RESEARCH QUESTION: What is the optimal timing for transfer in natural cycle vitrified-warmed embryo transfers (NC-VET)? DESIGN: This retrospective cohort study uses data from a large university-affiliated IVF clinic. The study included 341 NC-VET cycles with autologous oocytes and non-preimplantation genetic testing, vitrified embryos from January 2013 to September 2017. Each cycle was classified by timing of embryo transfer in relation to LH surge ≥20 IU/l. Group 1: LH ≥20 IU/l one day and blastocyst was transferred 6 days later; Group 2: LH ≥20 IU/l two consecutive days and blastocyst was transferred 6 days after the initial surge; Group 3: LH ≥20 IU/l two consecutive days and blastocyst was transferred 7 days after the initial surge. The primary outcome was ongoing pregnancy rate (OPR). The secondary objective was to compare OPR in relation to serum oestradiol dynamics and progesterone concentration (according to threshold 1.0 ng/ml) 6 days prior to embryo transfer. RESULTS: OPR were similar for all three groups (66.8%, 65.0%, 62.9% for Groups 1, 2 and 3, respectively). When stratified according to oestradiol and progesterone, no significant differences were noted in OPR. CONCLUSIONS: The results suggest that the timing of blastocyst transfer in a natural cycle after LH surge is flexible within 24 h. Outcomes are equally good with day of embryo transfer 6 or 7 days after LH surge date. Oestradiol dynamics and progesterone concentration 6 days prior to NC-VET did not have a significant impact on OPR.

Correlation of normal-range FMR1 repeat length or genotypes and reproductive parameters.

PURPOSE: This study aims to ascertain whether the length of normal-ranged CGG repeats on the FMR1 gene correlates with abnormal reproductive parameters. METHODS: We performed a retrospective, cross-sectional study of all FMR1 carrier screening performed as part of routine care at a large university-based fertility center from January 2011 to March 2014. Correlations were performed between normal-range FMR1 length and baseline serum anti-Müllerian hormone (AMH), cycle day 3 follicle stimulating hormone (FSH), ovarian volumes (OV), antral follicle counts (AFC), and incidence of diminished ovarian reserve (DOR), while controlling for the effect of age. RESULTS: Six hundred three FMR1 screening results were collected. One subject was found to be a pre-mutation carrier and was excluded from the study. Baseline serum AMH, cycle day 3 FSH, OV, and AFC data were collected for the 602 subjects with normal-ranged CGG repeats. No significant difference in median age was noted amongst any of the FMR1 repeat genotypes. No significant correlation or association was found between any allele length or genotype, with any of the reproductive parameters or with incidence of DOR at any age (p > 0.05). However, subjects who were less than 35 years old with low/low genotype were significantly more likely to have below average AMH levels compared to those with normal/normal genotype (RR 3.82; 95 % CI 1.38-10.56). CONCLUSIONS: This large study did not demonstrate any substantial association between normal-range FMR1 repeat lengths and reproductive parameters.

Selection of first in vitro fertilization cycle stimulation protocol for good prognosis patients: gonadotropin releasing hormone antagonist versus agonist protocols.

OBJECTIVE: The objective of this study was to compare outcome parameters in patients anticipated to have a good response to stimulation based upon baseline characteristics using either a gonadotropin releasing hormone (GnRH) agonist or antagonist protocol in their first in vitro fertilization (IVF) cycle. STUDY DESIGN: A retrospective chart review of all first-time IVF cycles performed during the time period 2005 through 2007 in an academic teaching center. Patients <40 years of age with a normal baseline follicle stimulating hormone (<10 mIU/mL) and normal antral follicle counts (> or = 3 in each ovary) were included. All patients studied were undergoing their first IVF cycle. The main outcome measures were clinical pregnancy and live birth rates. RESULTS: Included in the study were 755 patients undergoing a GnRH agonist protocol and 378 patients undergoing a GnRH antagonist cycle. Implantation rates (39.4% vs. 39.5%), cancellation rates (22.4% vs. 19.2%), clinical pregnancy rates (43.6% vs. 48.6%) and live birth rates (34.9% vs. 40.1%) were similar between GnRH antagonist and GnRH agonist protocol groups, respectively. CONCLUSION: Clinical pregnancy and live birth rates are similar in good responders utilizing either a GnRH agonist or antagonist during their first cycle of IVF.

In vitro fertilization outcomes after preimplantation genetic testing for chromosomal structural rearrangements comparing fluorescence in-situ hybridization, microarray comparative genomic hybridization, and next-generation sequencing.

OBJECTIVE: To compare in vitro fertilization (IVF) outcomes for preimplantation genetic testing for chromosomal structural rearrangements (PGT-SR) using various testing platforms. DESIGN: Retrospective cohort. SETTING: Large academic IVF center. PATIENTS: Fifty-one balanced translocation carriers undergoing IVF with PGT-SR who completed a total of 91 cycles, including 31 fluorescence in-situ hybridization (FISH), 24 microarray comparative genomic hybridization (aCGH), and 36 next-generation sequencing (NGS) testing cycles. INTERVENTIONS: PGT-SR. MAIN OUTCOME MEASURES: Primary outcome of live-birth rate and secondary outcomes including implantation rate, clinical loss rate, and percentages of normal or balanced, unbalanced, and aneuploid embryos detected. RESULTS: There was no statistically significant difference in LBR, though there was a tendency toward a higher LBR for NGS testing (14 of 19, 73.7%) compared with FISH (8 of 18, 44.4%) and aCGH (10 of 20, 50.0%). The implantation rate was statistically significantly higher for NGS (16 of 20, 80.0%) compared with FISH (11 of 25, 44.0%) and aCGH (16 of 30, 53.3%). There was no statistically significant difference in clinical pregnancy losses. There was a lower percentage of normal or balanced embryos with FISH (12.5%) compared with aCGH (23.7%) and with NGS (20.7%). CONCLUSIONS: This is the first report of PGT-SR outcomes for translocation carriers directly comparing PGT-SR using FISH, aCGH, and NGS. Our findings suggest an improvement in pregnancy outcomes parallel to the advancement in technology and are reassuring for continued use of NGS for this population.

Reproductive efficiency of women over the age of 40 and the low risk of multiple pregnancies.

Infertile patients over the age of 40 are generally considered to have a low chance of success with assisted cycles despite high numbers of embryos transferred. The risk of multiple pregnancy in this group of patients is not well established. The present study determined the rate of embryos that fail to produce a live birth and the rate of multiple pregnancies in a cohort of women over the age of 40 undergoing IVF/intracytoplasmic sperm injection cycles, utilizing Society for Assisted Reproductive Technology reported cycle outcomes from national summaries as well as from two university-based IVF centres. The rate of embryo wastage for women over the age of 40 is approximately 95% and these women have a correspondingly low rate of multiple pregnancy per cycle started (2.5% and 1.6% for women aged 41-42 years and 43-44 years, respectively). These data underscore the low reproductive efficiency of oocytes in women over the age of 40 and the very low probability of a multiple-gestation live birth despite the high number of embryos transferred. This information is an important additional counselling tool at the time of embryo transfer in this group of patients.

Obstetrical complications in gestational carrier pregnancies.

OBJECTIVE: To report two cases of severe obstetrical complications in gestational carrier pregnancies and to review our clinical experience and compare our results with those reported in the literature. DESIGN: Retrospective analysis. SETTING: A university IVF program. PATIENT(S): Women without a functioning uterus or those whose pregnancy would exacerbate a medical condition were enrolled in the gestational carrier pregnancy program. INTERVENTION(S): IVF cycles using oocytes from genetic mothers (or oocyte donors) were performed, with ET to gestational carriers. MAIN OUTCOME MEASURE(S): Clinical pregnancy rates, obstetrical complications, and neonatal outcomes. RESULT(S): Ten couples underwent a total of 13 cycles using gestational carriers. A clinical pregnancy rate of 69% (9/13) was achieved. An intrapartum hysterectomy and a late puerperal hysterectomy were required because of severe obstetrical complications. The late puerperal hysterectomy was performed for placenta accreta in a triplet gestation. This carrier sustained multiple cerebral infarcts and blindness. One triplet infant died secondary to a hypoplastic left ventricle and complications of prematurity. A second gestational carrier with a singleton gestation underwent a hysterectomy for a uterine rupture, and the infant has cerebral palsy. CONCLUSION(S): The past medical and obstetrical histories of potential gestational carriers must be closely scrutinized, and candidates must be thoroughly counseled about the potential risks involved in the procedure.

Ovulation rate and cycle characteristics in a subsequent clomiphene citrate cycle after stair-step protocol.

OBJECTIVE: To determine the ovulation rate after ovulation induction with clomiphene citrate (CC) in women who had previously been ovulatory after a stair-step (CC-SS) ovulation induction. DESIGN: Retrospective cohort. SETTING: University-based tertiary fertility center. PATIENT(S): 61 anovulatory patients <40 years of age with polycystic ovary syndrome who underwent ovulation induction with a CC-SS protocol and a subsequent CC cycle. INTERVENTION(S): Ovulation induction with CC. MAIN OUTCOME MEASURE(S): Ovulation rates and cycle characteristics. RESULT(S): Of 61 patients who underwent a subsequent CC cycle, 15 (25%) failed to ovulate at the previously ovulatory dose. Of those 15 patients, 13 (86.7%) ovulated after an increase in dose. The total number of follicles ≥15 mm (2.8 ± 1.2 vs. 1.6 ± 0.7) and peak estradiol (E2) levels (604 ± 272 pg/mL vs. 447 ± 218 pg/mL) were statistically significantly higher in the CC-SS cycle compared with the subsequent CC cycle, respectively. The endometrial lining was statistically significantly thinner in the CC-SS than the CC cycle (7.8 ± 1.8 vs. 9.2 ± 2.7, respectively). CONCLUSION(S): The majority of patients who ovulate after a CC-SS protocol will ovulate after taking the previously ovulatory CC dose in a subsequent cycle. Those who do not ovulate will likely ovulate with a further increase in CC dose.

Reducing the dose of human chorionic gonadotropin in high responders does not affect the outcomes of in vitro fertilization.

OBJECTIVE: The lowest effective hCG dose in high responders during IVF-embryo transfer (ET) has not been established. This study was performed to confirm that a dose of 3,300 IU is sufficient to provide adequate oocyte maturation and fertilization. DESIGN: Retrospective review of IVF clinical data. SETTING: Infertility center at a tertiary care university. PATIENT(S): Ninety-four IVF cycles were analyzed from high responders based on peak E(2) levels. Demographics were compared including age, diagnosis, and stimulation protocol. INTERVENTION(S): On the day of hCG administration, if E(2) levels were >/=2,500 but <4,000 pg/mL, patients received 5,000 IU (group A). For levels between 4,000 pg/mL and 5,500 IU pg/mL, they received 3,300 IU (group B). MAIN OUTCOME MEASURE(S): Number of oocytes retrieved, proportion of mature oocytes, fertilization rates, chemical and clinical pregnancy rates (PR). The incidence and severity of ovarian hyperstimulation syndrome (OHSS) was also analyzed. RESULT(S): Mean ages were 35.4 +/- 0.7 and 33.2 +/- 0.7 for groups A and B, respectively. Peak E(2) levels differed significantly (2,907 +/- 76 vs. 4,260 +/- 129 pg/mL), as well as the mean number of eggs retrieved (15.9 +/- 0.9 vs. 20.3 +/- 1.2). Proportion of mature eggs (81.6% vs. 81.9%), fertilization rate (70.5% vs. 68.7%), chemical PR (58.7% vs. 58.7%), and clinical PR (50.0% vs. 43.5%) were similar. There was no difference in the incidence of mild, moderate, or severe OHSS. CONCLUSION(S): A reduced hCG dose of 3,300 IU results in a similar proportion of mature eggs, similar fertilization rates, and similar PRs compared to 5,000 IU. Reducing the dose of hCG does not eliminate the risk of OHSS in a high-risk group.

Maternal and neonatal outcomes after gonadotropin-releasing hormone agonist trigger for final oocyte maturation in patients undergoing in vitro fertilization.

OBJECTIVE: To compare the rate of congenital anomalies, obstetrical complications, and neonatal complications in antagonist cycles where either GnRH agonist (GnRHa) or hCG was used for final oocyte maturation. DESIGN: Retrospective cohort study. SETTING: University-based tertiary fertility center. PATIENT(S): Three hundred ninety-two women under 40 years of age who underwent controlled ovarian stimulation using a GnRH antagonist protocol and who had final oocyte maturation triggered with either a GnRHa or hCG that resulted in pregnancy and delivery after 16 weeks' gestation. INTERVENTION(S): GnRHa versus hCG trigger of final oocyte maturation. MAIN OUTCOME MEASURE(S): Congenital anomaly rates, obstetrical complications, and neonatal complications. RESULT(S): There were no significant differences in the rate of congenital anomalies between GnRHa and hCG trigger (6.6 vs. 9.2%). There were also no differences in the maternal complications (27.6 vs. 20.8%) or neonatal complications (19.7 vs. 20.0%) between the GnRHa trigger and hCG trigger groups. CONCLUSION(S): GnRHa trigger does not affect the rate of congenital anomalies or obstetrical or neonatal complications and remains a viable option in the prevention of ovarian hyperstimulation syndrome.

A randomized trial of microdose leuprolide acetate protocol versus luteal phase ganirelix protocol in predicted poor responders.

We performed a randomized trial to compare IVF outcomes in 54 poor responder patients undergoing a microdose leuprolide acetate (LA) protocol or a GnRH antagonist protocol incorporating a luteal phase E(2) patch and GnRH antagonist in the preceding menstrual cycle. Cancellation rates, number of oocytes retrieved, clinical pregnancy rates (PR), and ongoing PRs were similar between the two groups.

In vitro fertilization outcomes in patients experiencing a premature rise in luteinizing hormone during a gonadotropin-releasing hormone antagonist cycle.

Patients undergoing controlled ovarian hyperstimulation and pituitary suppression with a GnRH antagonist who experienced a transient premature rise in LH were compared with those who did not have an early surge. Those experiencing a premature LH surge had equivalent clinical and ongoing pregnancy rates per ET.

Endogenous gonadotropin flare following microdose leuprolide (MDL) stimulation protocol does not correlate with in vitro fertilization (IVF) outcome.

Patients undergoing first IVF cycle using MDL from October 2005 to November 2008 had serum FSH, LH, and estradiol (E2) levels measured prior to and 2 days after initiation of MDL; and evidence of a follicular flare, defined as a doubling in endogenous gonadotropins, was evaluated and correlated with clinical pregnancy, cancellation, implantation, spontaneous abortion, and ongoing pregnancy rate as well as cycle parameters. Although there was no difference in IVF outcomes, higher doses of exogeneous gonadotropins as well as greater days of stimulation were observed in patients with a documented FSH or LH flare.

Gonadotropin-releasing hormone agonist to induce final oocyte maturation prevents the development of ovarian hyperstimulation syndrome in high-risk patients and leads to improved clinical outcomes compared with coasting.

Ninety-four women undergoing IVF with peak E2 level>4000 pg/mL received leuprolide acetate (LA) trigger (LA trigger group) or had gonadotropins withheld for one or more days (coasting group) followed by hCG trigger, unless cycle cancellation occurred. There were no cases of ovarian hyperstimulation syndrome in either group, and the LA trigger group had significantly more oocytes retrieved (26.9+/-9.5 vs. 17.7+/-9.3) P<0.001, more normally fertilized oocytes (15.0+/-7.8 vs. 10.3+/-6.3) P=0.01, and higher clinical and ongoing pregnancy rates than the coasting group (52.5% vs. 27.2%; 49.2% vs. 24.2%, P=0.02 for both comparisons, respectively).

Transfer of two versus three embryos in women less than 40 years old undergoing frozen transfer cycles.

OBJECTIVE: To compare outcomes of frozen embryo transfer (FET) cycles when two or three embryos were transferred in women aged <40 years. DESIGN: Retrospective chart review. SETTING: A university-affiliated IVF program. PATIENT(S): Women undergoing FET cycles between January 2004 and December 2005. INTERVENTION(S): Transfer of two or three embryos. MAIN OUTCOME MEASURE(S): Clinical pregnancy rate (PR), multiple pregnancy rate (MPR), and live birth rate (LBR). RESULT(S): In patients aged <35 (n = 145), two versus three embryo group had similar PR and LBR, but the MPR was significantly higher in the three-embryo group (41% for three embryos vs. 9.4% for two embryos). Clinical pregnancy in the fresh cycle from which the frozen embryos were obtained did not affect the PR, and an increase in MPR was still observed. In patients aged 35 to 39 (n = 93), there were no differences in the PR, MPR, or LBR between the two groups. CONCLUSION(S): Transfer of two instead of three frozen embryos in patients <35 years old resulted in a significant decrease in MPR without compromising PR or LBR. Transferring additional embryos when a patient had an unsuccessful fresh cycle was not warranted. In the age group 35-39 years, transferring two instead of three embryos did not decrease PR or LBR, and had no effect on the risk of high-order multiples.

Chronic endometritis is a frequent finding in women with recurrent implantation failure after in vitro fertilization.

OBJECTIVE: To determine the role of endometrial sampling for identification and treatment of chronic endometritis (CE) in patients undergoing IVF-ET who repeatedly failed to conceive despite the transfer of good-quality embryos. DESIGN: Retrospective chart review. SETTING: University-based tertiary fertility center. PATIENT(S): Thirty-three patients with recurrent implantation failure (RIF) who underwent endometrial sampling and subsequent ET were analyzed based on immunohistochemically confirmed CE: CE present on biopsy (group 1; n = 10) and CE absent on biopsy (group 2; n = 23). Patients with RIF undergoing IVF cycles during the same time period who did not have endometrial sampling were used as controls (group 3; n = 485). INTERVENTION(S): Endometrial sampling for CE and subsequent antibiotic treatment in affected patients followed by another IVF-ET cycle. RESULT(S): Chronic endometritis was identified in 30.3% of patients with RIF. Group 1 had lower implantation rates (11.5%) in the IVF cycle following treatment than did group 2 and group 3 (32.7% and 20.3%, respectively). Clinical pregnancy and ongoing pregnancy rates were similar across groups. CONCLUSION(S): Recurrent implantation failure warrants investigation of CE as a contributing factor. Women demonstrating CE on endometrial sampling have lower implantation rates in a subsequent IVF-ET cycle; however, there were no differences in subsequent clinical pregnancy or ongoing pregnancy rates after successful antibiotic treatment.

Ruptured ectopic pregnancy with contralateral adnexal torsion after spontaneous conception.

OBJECTIVE: To describe a case of ruptured ectopic pregnancy and contralateral adnexal torsion after spontaneous conception. DESIGN: Case report. SETTING: Tertiary university medical center. PATIENT(S): A 23-year-old multiparous female with severe bilateral pelvic pain and a positive pregnancy test. INTERVENTION(S): Operative laparoscopy with detorsion of left adnexa, drainage of left ovarian hemorrhagic corpus luteum cyst, right salpingectomy, and dilation and curettage. MAIN OUTCOME MEASURE(S): Laparoscopy revealed a 5 cm hemorrhagic corpus luteum cyst of the left ovary, torsion of the left ovary and fallopian tube, and a ruptured right ampullary ectopic pregnancy. RESULT(S): Normal perfusion of left ovary and fallopian tube after detorsion, resolution of left ovarian hemorrhagic corpus luteum cyst, patent left fallopian tube with chromopertubation, and successful removal of ectopic pregnancy. CONCLUSION(S): This is a unique case of adnexal torsion and contralateral ectopic pregnancy occurring after spontaneous conception.

A randomized prospective study of microdose leuprolide versus ganirelix in in vitro fertilization cycles for poor responders.

Forty-eight patients who met the criteria of poor response during prior gonadotropin stimulation were enrolled in a randomized prospective study comparing a gonadotropin-releasing hormone (GnRH) antagonist protocol, using ganirelix acetate, with a microdose GnRH agonist protocol for in vitro fertilization-embryo transfer (IVF-ET). This pilot study contributes to the literature of poor response IVF treatment protocols because the use of ganirelix appears to be as effective as the microdose protocol and may be a superior choice in terms of cost and convenience for the patient.

Influence of embryo quality and number of previous cycles on pregnancy and multiple pregnancy rates in women aged 35 to 37 years who received two or three embryos.

Women aged 35-37 years undergoing IVF-ET with fresh embryos at a university infertility center were analyzed to evaluate factors useful in determining whether two or three embryos should be transferred in this age group. Embryo quality and number, but not number of previous failed cycles, were important in determining outcome, and all triplet pregnancies could have been avoided at our program in this age group by limiting the transfer to two good-quality embryos, without reducing pregnancy rates.