A Mitochondrial Progesterone Receptor Increases Cardiac Beta-Oxidation and Remodeling.

Progesterone is primarily a pregnancy-related hormone, produced in substantial quantities after ovulation and during gestation. Traditionally known to function via nuclear receptors for transcriptional regulation, there is also evidence of nonnuclear action. A previously identified mitochondrial progesterone receptor (PR-M) increases cellular respiration in cell models. In these studies, we demonstrated that expression of PR-M in rat H9c2 cardiomyocytes resulted in a ligand-dependent increase in oxidative cellular respiration and beta-oxidation. Cardiac expression in a TET-On transgenic mouse resulted in gene expression of myofibril proteins for remodeling and proteins involved in oxidative phosphorylation and fatty acid metabolism. In a model of increased afterload from constant transverse aortic constriction, mice expressing PR-M showed a ligand-dependent preservation of cardiac function. From these observations, we propose that PR-M is responsible for progesterone-induced increases in cellular energy production and cardiac remodeling to meet the physiological demands of pregnancy.

State Insurance Mandates and Multiple Birth Rates After In Vitro Fertilization.

OBJECTIVE: To examine the association between state-mandated insurance coverage for in vitro fertilization (IVF) and the incidence of multiple birth while controlling for differences in baseline patient characteristics. METHODS: We conducted a retrospective cohort study using the Society for Assisted Reproductive Technology Clinic Outcomes Reporting System from 2007 to 2011 to examine the association between state-mandated insurance coverage for IVF and the incidence of multiple birth while controlling for differences in baseline patient characteristics. Analyses were stratified according to patient age and day of embryo transfer (3 or 5). RESULTS: Of the 173,968 cycles included in the analysis, 45,011 (25.9%) were performed in mandated states and 128,957 (74.1%) in nonmandated states. The multiple birth rate was significantly lower in mandated states (29.0% compared with 32.8%, adjusted odds ratio [OR] 0.87, 99.95% confidence interval [CI] 0.80-0.94). After stratification, this association remained statistically significant only in women younger than 35 years old who underwent transfer on day 5 (33.1% compared with 38.6%, adjusted OR 0.81, 99.95% CI 0.71-0.92). Among women younger than 35 years with day 5 transfer, the elective single embryo transfer rate was significantly higher in mandated states (21.8% compared with 13.1%, adjusted OR 2.36, 99.95% CI 2.09-2.67). CONCLUSION: State-mandated insurance coverage for IVF is associated with decreased odds of multiple birth. This relationship is driven by increased use of elective single embryo transfer among young women undergoing day 5 transfer.

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.

Donor oocytes are associated with preterm birth when compared to fresh autologous in vitro fertilization cycles in singleton pregnancies.

OBJECTIVE: To use a national registry to examine the role of oocyte donation on pregnancy outcomes in singleton pregnancies. DESIGN: Retrospective cohort. SETTING: Not applicable. PATIENT(S): Women undergoing autologous cycles and donor oocyte recipients in the United States from 2008-2010. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Preterm delivery, birth weight <2,500 g, small for gestational age birthweight, perinatal death. RESULT(S): The rates of preterm delivery and low birthweight for all members of this cohort were higher than the US national average. Pregnancies resulting from oocyte donation were significantly more likely to end before 34 weeks' and 37 weeks' gestation (adjusted odds ratio [OR] = 1.30, 95% confidence interval [CI] = 1.03-1.64 for 34 weeks' gestation, adjusted OR = 1.28, 95% CI = 1.12-1.46 for 37 weeks' gestation), and to result in infants weighing <2,500 g (adjusted OR = 1.21, 95% CI = 1.02-1.44). However, once gestational age at delivery is accounted for, these infants are actually at decreased risk of having a small for gestational age birthweight (adjusted OR = 0.72, 95% CI = 0.58-0.89) and of perinatal death (adjusted OR = 0.29, 95% CI = 0.09-0.94). CONCLUSION(S): Data from a national cohort indicate that donor oocyte recipients are more likely to deliver preterm when compared with autologous patients. The effect of donor oocyte donation on birthweight is likely a function of an increased rate of preterm delivery among this population.

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.

Ectopic pregnancy rate increases with the number of retrieved oocytes in autologous in vitro fertilization with non-tubal infertility but not donor/recipient cycles: an analysis of 109,140 clinical pregnancies from the Society for Assisted Reproductive Technology registry.

OBJECTIVE: To study the impact of controlled ovarian stimulation on ectopic pregnancy (EP) rate as a function of the number of oocytes retrieved, using donor IVF cycles as a control. DESIGN: Retrospective cohort study using a large national database. SETTING: Not applicable. PATIENT(S): Data from 109,140 cycles from the 2008-2010 SART registry, including 91,504 autologous cycles and 17,636 donor cycles in patients with non-tubal infertility. INTERVENTION(S): Varying amounts of oocytes retrieved in autologous and donor IVF. MAIN OUTCOME MEASURE(S): Ectopic pregnancy rates. RESULT(S): In autologous cycles, the EP rate significantly increased as oocyte yield increased. This association was not found in oocyte recipients. CONCLUSION(S): In autologous IVF cycles, increasing oocyte yield is correlated with a significantly increased EP rate. This association is not found in oocyte recipients, indicating that the increased EP rate may be due to the supraphysiologic hormone levels achieved with controlled ovarian hyperstimulation.

High Peak Estradiol Predicts Higher Miscarriage and Lower Live Birth Rates in High Responders Triggered with a GnRH Agonist in IVF/ICSI Cycles.

OBJECTIVE: To investigate parameters predictive of pregnancy outcomes in high responders undergoing fresh, autologous, GnRH antagonist IVF/ICSI cycles using a GnRH agonist trigger. STUDY DESIGN: Retrospective cohort study of all patients deemed high-risk for ovarian hyperstimulation syndrome who underwent fresh, autologous IVF/ICSI using a GnRH agonist trigger at an academic fertility center from 2010-2012. RESULTS: A total of 71 first cycles were analyzed. Rates of clinical pregnancy, live birth (LB), and total (clinical plus biochemical) miscarriage (MC) were 52%, 38%, and 25%, respectively. Mean peak estradiol (E2) and the number of oocytes retrieved were 3,701 pg/mL and 15.2, respectively. Peak E2 was significantly higher in those cycles resulting in clinical MC (p = 0.003). After adjusting for age, basal follicle stimulating hormone, and the number of oocytes retrieved, elevated peak E2 remained associated with increased clinical MC (p = 0.029) and trended towards a relationship with higher total MC (p = 0.062). When peak E2 was treated as a binary variable based on the threshold value of > 5,000 pg/mL, peak E2 above this value was associated with a higher rate of clinical MC (OR = 16.14 with 95% CI 1.25-209.35, p = 0.033) and total MC (OR = 6.81 with 95% CI 1.12-41.54, p = 0.037), as well as a lower LB rate (OR = 0.095 with 95% CI 0.01-0.90, p = 0.041). CONCLUSION: Clinicians should recognize most IVF/ICSI patients triggered with a GnRH agonist as inherently in danger of excessively high serum E2 and avoid peak levels > 5,000 pg/mL in order to avoid higher MC and lower LB rates.

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.

Late ovarian hyperstimulation syndrome after controlled ovarian stimulation in a woman with systemic lupus erythematosus and lupus nephritis.

OBJECTIVE: To report a case of late ovarian hyperstimulation syndrome (OHSS) in a woman with lupus nephritis undergoing controlled ovarian stimulation and in vitro fertilization (IVF) with subsequent transfer into a gestational surrogate. DESIGN: A case report. SETTING: Academic reproductive medicine clinic. PATIENT(S): A 33-year-old woman who presented 10 days after recombinant human chorionic gonadotropin (hCG) injection with fatigue, abdominal pain, and bloating, diagnosed as OHSS. INTERVENTION(S): Patient admitted for intravenous fluid hydration, anticoagulation, and gonadotropin-releasing hormone (GnRH) antagonist therapy. MAIN OUTCOME MEASURE(S): Successful detection and management of severe OHSS in a patient with chronically impaired kidney function. RESULT(S): The patient has returned to her baseline condition, and the gestational carrier was noted to have a twin gestation. CONCLUSION(S): In patients with impaired renal function, final oocyte maturation should be triggered with a GnRH agonist rather than hCG.