Superovulation with human chorionic gonadotropin (hCG) trigger and gonadotropin releasing hormone agonist (GnRHa) trigger differentially alter essential angiogenic factors in the endometrium in a mouse ART model†.

Gonadotropin-releasing hormone agonists (GnRHa) are used as an alternative to human chorionic gonadotropin (hCG) to trigger ovulation and decrease the risk of ovarian hyperstimulation syndrome. GnRHa is less potent at inducing ovarian vascular endothelial growth factor (VEGF), but may also affect endometrial angiogenesis and early placental development. In this study, we explore the effect of superovulation on endometrial angiogenesis during critical periods of gestation in a mouse model. We assigned female mice to three groups: natural mating or mating following injection with equine chorionic gonadotropin and trigger with GnRHa or hCG trigger. Females were killed prior to implantation (E3.5), post-implantation (E7.5), and at midgestation (E10.5), and maternal serum, uterus, and ovaries were collected. During peri-implantation, endometrial Vegfr1 and Vegfr2 mRNA were significantly increased in the GnRHa trigger group (P < 0.02) relative to the hCG group. Vegfr1 is highly expressed in the endometrial lining and secretory glands immediately prior to implantation. At E7.5, the ectoplacental cone expression of Vegfa and its receptor, Vegfr2, was significantly higher in the hCG trigger group compared to the GnRHa group (P < 0.05). Soluble VEGFR1 and free VEGFA were much higher in the serum of mice exposed to the hCG trigger compared to GnRHa group. At midgestation, there was significantly more local Vegfa expression in the placenta of mice triggered with hCG. GnRHa and hCG triggers differentially disrupt the endometrial expression of key angiogenic factors during critical periods of mouse gestation. These results may have significant implications for placental development and neonatal outcomes following human in vitro fertilization.

How much does the uterus matter? Perinatal outcomes are improved when donor oocyte embryos are transferred to gestational carriers compared to intended parent recipients.

OBJECTIVE: To assess the reproductive and neonatal outcomes of cycles in which donor oocyte embryos were transferred to gestational carriers compared to intended parent recipients. DESIGN: Retrospective cohort study. SETTING: Not applicable. PATIENT(S): Intended parent recipients and gestational carriers receiving donor oocyte embryos in 2014 in the United States. INTERVENTIONS(S): None. MAIN OUTCOMES MEASURE(S): Clinical pregnancy, live birth, miscarriage, plurality, prematurity, and birth weight from pregnancies conceived with donor oocyte embryos transferred to either a gestational carrier or an intended parent recipient. RESULT(S): The mean ages of intended parent recipients (N=18,317) and gestational carriers (N=1,927) were 41.6 and 31.6 years, respectively. Compared to an intended parent recipient, patients using a gestational carrier had significantly higher odds of a clinical pregnancy (65.2% vs. 56.3%, adjusted odds ratio (aOR) 1.33, 95% confidence interval (CI) 1.17-1.51) and live birth (57.1% vs. 46.4%, aOR 1.37, 95% CI 1.21-1.55) using fresh or frozen donor-oocyte embryos. Of the singletons born (n=716 using a gestational carrier and n=5,632 in intended parent recipients), the incidence of prematurity was significantly lower in gestational carriers compared to intended parent recipients (17.5% vs. 25.4%, aOR 0.78, 95% CI 0.61-0.99). The incidence of low birthweight among singletons was significantly reduced in gestational carrier cycles (6.4% vs. 12.1%, aOR 0.62, 95% CI 0.44-0.89). CONCLUSION: Intended parent recipients had decreased pregnancy rates and poorer neonatal outcomes compared to a gestational carrier. This suggests that a history of infertility adversely affects the uterine microenvironment, independent of the oocyte.

Forty years of IVF.

This monograph, written by the pioneers of IVF and reproductive medicine, celebrates the history, achievements, and medical advancements made over the last 40 years in this rapidly growing field.

How compliant are in vitro fertilization member clinics in following embryo transfer guidelines? An analysis of 59,689 fresh first in vitro fertilization autologous cycles from 2011 to 2012.

OBJECTIVE: To determine whether IVF clinics are compliant with American Society for Reproductive Medicine (ASRM) and Society for Assisted Reproductive Technology (SART) (ASRM/SART) guidelines and assess the multiple pregnancy outcomes according to the number of embryos transferred. DESIGN: Retrospective cohort study. SETTING: Not applicable. PATIENT(S): Data from 59,689 fresh first autologous IVF cycles from the 2011-2012 SART registry. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Percentage of compliant cycles, multiple pregnancy rate (PR). RESULT(S): Between 2011 and 2012, a total of 59,689 fresh first autologous cycles were analyzed. Among cleavage-stage ET cycles, the noncompliance rate ranged from 10%-27.4% depending on the age group. The multiple PR was significantly increased in noncompliant cycles involving patients <35 years (38.1% vs. 28.7%) and 35-37 years (35.4% vs. 24.5%) compared with compliant cycles. Among blastocyst-stage ET cycles, the highest rate of noncompliance was seen in patients <35 years old (71%), which resulted in a statistically higher multiple PR (48.3% vs. 2.8%) compared with compliant cycles. Far fewer cycles were noncompliant in patients 35-40 years of age. In a subanalysis of compliant cycles, transferring two blastocyst embryos in patients 35-37 years and 38-40 years resulted in a higher live birth rate compared with the transfer of one embryo (50.4% vs. 40.9% and 42.1% vs. 30.0%, respectively) but the multiple PR was also significantly higher (40.5% vs. 1.7% and 34.0% vs. 2.0%, respectively). CONCLUSION(S): Most first fresh autologous IVF cycles performed from 2011-2012 were compliant with ASRM/SART guidelines, except those that involved a blastocyst ET in patients <35 years. Despite compliance, cycles that involved the transfer of >1 embryo resulted in a high multiple PR, whereas noncompliant cycles resulted in an even more remarkable multiple PR for both cleavage and blastocyst-stage embryos. Clinics need to be more compliant with ET limits and ASRM/SART need to consider revising their guidelines to limit the number of blastocyst transfer to one in patients ≤40 years of age undergoing their first IVF cycle. Furthermore, decreasing the number of cleavage-stage embryos transferred in patients ≤40 years of age should also be considered.

Do donor oocyte cycles comply with ASRM/SART embryo transfer guidelines? An analysis of 13,393 donor cycles from the SART registry.

OBJECTIVE: To analyze donor oocyte cycles in the Society for Assisted Reproductive Technology (SART) registry to determine: 1) how many cycles complied with the 2009 American Society for Reproductive Medicine/SART embryo transfer guidelines; and 2) cycle outcomes according to the number of embryos transferred. For donor oocyte IVF with donor age <35 years, the consideration of single-embryo transfer was strongly recommended. DESIGN: Retrospective cohort study of United States national registry information. SETTING: Not applicable. PATIENT(S): A total of 13,393 donor-recipient cycles from 2011 to 2012. INTERVENTION(S): Embryos transferred in donor IVF cycles. MAIN OUTCOME MEASURE(S): Percentage of compliant cycles, multiple pregnancy rate. RESULT(S): There were 3,157 donor cleavage-stage transfers and 10,236 donor blastocyst transfers. In the cleavage-stage cycles, 88% met compliance criteria. The multiple pregnancy rate (MPR) was significantly higher in the noncompliant cycles. In a subanalysis of compliant cleavage-stage cycles, 91% transferred two embryos and only 9% single embryos. In those patients transferring two embryos, the MPR was significantly higher (33% vs. 1%). In blastocyst transfers, only 28% of the cycles met compliance criteria. The MPR was significantly higher in the noncompliant blastocyst cohort at 53% (compared with 2% in compliant cycles). CONCLUSION(S): The majority of donor cleavage-stage transfers are compliant with current guidelines, but the transfer of two embryos results in a significantly higher MPR compared with single-embryo transfer. The majority of donor blastocyst cycles are noncompliant, which appears to be driving an unacceptably high MPR in these cycles.

Pregnancy outcomes decline with increasing recipient body mass index: an analysis of 22,317 fresh donor/recipient cycles from the 2008-2010 Society for Assisted Reproductive Technology Clinic Outcome Reporting System registry.

OBJECTIVE: To examine the effect of recipient body mass index (BMI) on IVF outcomes in fresh donor oocyte cycles. DESIGN: Retrospective cohort study. SETTING: Not applicable. PATIENT(S): A total of 22,317 donor oocyte cycles from the 2008-2010 Society for Assisted Reproductive Technology Clinic Outcome Reporting System registry were stratified into cohorts based on World Health Organization BMI guidelines. Cycles reporting normal recipient BMI (18.5-24.9) were used as the reference group. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Implantation rate, clinical pregnancy rate (PR), pregnancy loss rate, live birth rate. RESULT(S): Success rates and adjusted odds ratios with 95% confidence intervals for all pregnancy outcomes were most favorable in cohorts of recipients with low and normal BMI, but progressively worsened as BMI increased. CONCLUSION(S): Success rates in recipient cycles are highest in those with low and normal BMI. Furthermore, there is a progressive and statistically significant worsening of outcomes in groups with higher BMI with respect to clinical pregnancy and live birth rate.

Pregnancy outcomes decline with increasing body mass index: analysis of 239,127 fresh autologous in vitro fertilization cycles from the 2008-2010 Society for Assisted Reproductive Technology registry.

OBJECTIVE: To examine the effect of body mass index (BMI) on IVF outcomes in fresh autologous cycles. DESIGN: Retrospective cohort study. SETTING: Not applicable. PATIENT(S): A total of 239,127 fresh IVF cycles from the 2008-2010 Society for Assisted Reproductive Technology registry were stratified into cohorts based on World Health Organization BMI guidelines. Cycles reporting normal BMI (18.5-24.9 kg/m(2)) were used as the reference group (REF). Subanalyses were performed on cycles reporting purely polycystic ovary syndrome (PCOS)-related infertility and those with purely male-factor infertility (34,137 and 89,354 cycles, respectively). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Implantation rate, clinical pregnancy rate, pregnancy loss rate, and live birth rate. RESULT(S): Success rates and adjusted odds ratios (ORs) with 95% confidence intervals (CIs) for all pregnancy outcomes were most favorable in cohorts with low and normal BMIs and progressively worsened as BMI increased. Obesity also had a negative impact on IVF outcomes in cycles performed for PCOS and male-factor infertility, although it did not always reach statistical significance. CONCLUSION(S): Success rates in fresh autologous cycles, including those done for specifically PCOS or male-factor infertility, are highest in those with low and normal BMIs. Furthermore, there is a progressive and statistically significant worsening of outcomes in groups with higher BMIs. More research is needed to determine the causes and extent of the influence of BMI on IVF success rates in other patient populations.

Pregnancy rates in donor oocyte cycles compared to similar autologous in vitro fertilization cycles: an analysis of 26,457 fresh cycles from the Society for Assisted Reproductive Technology.

OBJECTIVE: To use a large US IVF database and compare pregnancy outcomes in fresh donor oocyte versus autologous IVF cycles in women age 20-30 years. DESIGN: Retrospective cohort study. SETTING: Not applicable. PATIENT(S): Women undergoing fresh autologous ovarian stimulation, and oocyte donors and recipients in the United States between 2008 and 2010. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Implantation, clinical pregnancy (CP), and live birth (LB) rates. RESULT(S): Despite similar demographics, stimulation, and embryo parameters, donor oocyte recipients had significantly higher rates of implantation, CP, and LB compared to those undergoing fresh autologous cycles. Odds ratios for implantation, CP, and LB significantly favored the donor oocyte group in all comparisons, including those limited to intracytoplasmic sperm injection cycles, intracytoplasmic sperm injection with male factor, unexplained infertility, cleavage stage embryo transfer, blastocyst transfer, elective single blastocyst transfer, and autologous patients with prior tubal ligation. CONCLUSION(S): Recent US data suggest that the hormonal environment resulting from autologous ovarian stimulation lowers IVF success rates. Further research is needed to determine when to avoid fresh embryo transfer in autologous patients.

Pregnancy outcomes decline in recipients over age 44: an analysis of 27,959 fresh donor oocyte in vitro fertilization cycles from the Society for Assisted Reproductive Technology.

OBJECTIVE: To use a large and recent national registry to provide an updated report on the effect of recipient age on the outcome of donor oocyte in vitro fertilization (IVF) cycles. DESIGN: Retrospective cohort study. SETTING: United States national registry for assisted reproductive technology. PATIENT(S): Recipients of donor oocyte treatment cycles between 2008 and 2010, with cycles segregated into five age cohorts: ≤34, 35 to 39, 40 to 44, 45 to 49, and ≥50 years. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Implantation, clinical pregnancy, live-birth, and miscarriage rates. RESULT(S): In donor oocyte IVF cycles, all age cohorts ≤39 years had similar rates of implantation, clinical pregnancy, and live birth when compared with the 40- to 44-year-old reference group. Patients in the two oldest age groups (45 to 49, ≥50 years) experienced statistically significantly lower rates of implantation, clinical pregnancy, and live birth compared with the reference group. Additionally, all outcomes in the ≥50-year-old group were statistically significantly worse than the 45- to 49-year-old group, demonstrating progressive decline with advancing age. CONCLUSION(S): Recent national registry data suggest that donor oocyte recipients have stable rates of pregnancy outcomes before age 45, after which there is a small but steady and significant decline.

Oocyte number as a predictor for ovarian hyperstimulation syndrome and live birth: an analysis of 256,381 in vitro fertilization cycles.

OBJECTIVE: To investigate the association between oocyte number and the rates of ovarian hyperstimulation syndrome (OHSS) and live birth (LB) in fresh autologous in vitro fertilization (IVF) cycles. DESIGN: Retrospective cohort study. SETTING: An academic reproductive medicine practice. PATIENT(S): We analyzed data from 256,381 IVF cycles using the 2008-2010 Society for Assisted Reproductive Technology national registry. Patients were divided into five groups based on retrieved oocyte number. MAIN OUTCOME MEASURE(S): Rates of OHSS and LB were calculated for each group. A generalized estimating equation (GEE) was used to assess differences in OHSS and LB between groups. Receiver operating characteristic (ROC) curves were used to evaluate oocyte number as a predictor of OHSS and LB. INTERVENTION(S): None. RESULT(S): The LB rate increased up to 15 oocytes, then plateaued (0-5: 17%, 6-10: 31.7%; 11-15: 39.3%; 16-20: 42.7%; 21-25: 43.8%; and >25 oocytes: 41.8%). However, the rate of OHSS became much more clinically significant after 15 oocytes (0-5: 0.09%; 6-10: 0.37%; 11-15: 0.93%; 16-20: 1.67%; 21-25: 3.03%; and >25 oocytes: 6.34%). These trends remained after adjustment with the use of GEE. ROC curves revealed that although oocyte number is not useful in the prediction of LB, 15 retrieved oocytes is the number that best predicts OHSS risk. CONCLUSION(S): Retrieval of >15 oocytes significantly increases OHSS risk without improving LB rate in fresh autologous IVF cycles. In general, less aggressive stimulation protocols should be considered, especially in high-responders, to optimize outcomes.

Partnership for Families Program: philanthropy for in vitro fertilization patients.

OBJECTIVE: To describe our Partnership for Families Program, which was established to provide second in vitro fertilization (IVF) cycles for couples who pay for one IVF cycle, do not get pregnant and cannot afford a second IVF cycle. In addition, this program provides funding for fertility-sparing procedures for financially needy cancer patients. STUDY DESIGN: Retrospective description of the Partnership for Families' first 5 years of operation. RESULTS: In its 5 years of operation, the Partnership for Families Program has provided 137 infertile couples with a second IVF cycle, resulting in 68 ongoing or delivered pregnancies. It has also provided funding for 19 fertility-sparing procedures for cancer patients. CONCLUSION: Because of the high costs of IVF, alternative funding sources, specifically philanthropy, must be explored to provide increased access to IVF. The Partnership for Families Program, started by patients in a single practice, has in 5 years provided over 151 infertile and cancer patients IVF or egg-freezing cycles that they otherwise could not have afforded. This is a program that can be emulated by other fertility centers.

Follitropin-alpha versus human menopausal gonadotropin in an in vitro fertilization program.

OBJECTIVE: To compare the efficacy of recombinant FSH and urinary-derived hMG for ovarian stimulation during IVF. DESIGN: Retrospective analysis of data from IVF cycles conducted over 15 months. SETTING: University hospital IVF unit. PATIENT(S): Three hundred twenty-four women undergoing their first to sixth IVF cycle. INTERVENTION(S): After pituitary down-regulation, patients received recombinant FSH or hMG, according to personal choice. After hCG administration, patients underwent oocyte retrieval, oocyte fertilization, and embryo transfer. MAIN OUTCOME MEASURE(S): Implantation rate and clinical ongoing pregnancy rate per oocyte retrieval. RESULT(S): Patients who chose recombinant FSH were slightly younger than those who chose hMG (34.1 vs. 35.1 years, respectively). Although more embryos were transferred in the hMG group (3.6 vs. 3.2), the ongoing pregnancy and implantation rates were significantly higher in the recombinant FSH group (ongoing pregnancy rate, 50.0% vs. 36.2%). CONCLUSION(S): Recombinant FSH is more effective than hMG for ovarian stimulation in IVF cycles. This increased efficacy, which is achieved with fewer ampoules, is likely to offset the higher acquisition costs of recombinant FSH.