Sarah K. Darmon

Outcomes of Fresh and Cryopreserved Oocyte Donation

Outcomes of Fresh and Cryopreserved Oocyte Donation Use of oocytes donated for in vitro fertilization (IVF) has increased in recent years.1 Donated fresh oocytes traditionally have been used immediately, creating embryos for transfer into the uterus, with extra embryos being cryopreserved for later use. In January 2013, the American Society for Reproductive Medicine declared the technique of oocyte cryopreservation (egg freezing) no longer experimental, although it called for “more widespread clinic-specific data on the safety and efficacy of oocyte cryopreservation ... before universal donor oocyte banking can be recommended.”2 Based on data that IVF outcomes with cryopreserved and fresh donor oocytes are comparable,3 some IVF centers established frozen donor egg banks. However, data reflecting IVF outcomes in routine clinical practice with cryopreserved donor oocytes have not been published.

Systematic review of worldwide trends in assisted reproductive technology 2004–2013

BackgroundAssisted Reproductive Technology (ART) has undergone considerable changes over the last decade, with consequences on ART outcomes in different regions of the world being unknown.MethodsWe conducted a systematic review of published national and regional ART registry data to assess how changes in clinical practice between 2004 and 2013 have impacted outcomes in Australia and New Zealand, Canada, Continental Europe, the United Kingdom (U.K.), Japan, Latin America, and the United States (U.S.). The data reflect 7,079,145 total ART cycles utilizing both fresh and previously cryopreserved embryos from autologous oocytes that resulted in 1,454,724 live births. This review focused on the following measures: ART cycle volume, use of cryopreserved embryos, single embryo transfer (SET), live birth rates in fresh and frozen-thawed cycles, and perinatal outcomes in recent years.ResultsSETs and utilization of frozen-thawed embryos increased worldwide over the study period. In 2012 SET utilization in all ART cycles was highest in Japan and Australia/New Zealand (82.6% and 76.3% respectively) and lowest in Latin America (16.0%). While gradual improvements in live birth rates were observed in most regions, some demonstrated declines. By 2012–2013, fresh cycle live birth rates were highest in the U.S. (29%) and lowest in Japan (5%). In Japan, the observed decline in fresh cycle live birth rate coincided with transition to minimal stimulation protocols, transfer of frozen-thawed rather than fresh embryos, and implementation of an SET policy. Similarly, implementation of an SET policy in parts of Canada was followed by a decline in fresh cycle live birth rate. Increasing live birth rates in frozen-thawed embryo cycles, seen all over the world, partially compensated for declines in fresh ART cycles. During 2012–2013 Australia/New Zealand and Japan reported the lowest multiple delivery rates of 5.6 and 4% respectively while the US had the highest of 27%. In recent years, preterm delivery rates in all regions ranged between 9.0 to 16.6% for singletons, 53.9 to 67.3% for twins, and 91.4 to 100% for triplets and higher order multiples. Inconsistencies in the way perinatal outcome data are presented by various registries, made comparison between regions difficult.ConclusionsART practices are characterized by outcome differences between regions. International consensus on the definition of ART success, which accounts for perinatal outcomes, may help to standardize worldwide ART practice and improve outcomes.Trial registrationPROSPERO (CRD42016033011)

Live-birth rates in very poor prognosis patients, who are defined as poor responders under the Bologna criteria, with nonelective single embryo, two-embryo, and three or more embryos transferred.

OBJECTIVE To determine live-birth rates (LBRs) at various ages in very poor prognosis patients, who are defined as poor responders under the Bologna criteria. DESIGN Retrospective cohort study. SETTING Academically affiliated private fertility center. PATIENT(S) Among 483 patients, who under the Bologna criteria (three or fewer oocytes, >40 years of age, and/or antimüllerian hormone [AMH] <1.1 ng/mL [2/3 criteria minimum]) were poor responders, 278 (381 fresh IVF cycles) qualified for the study because they had at least one embryo on day 3 for transfer. INTERVENTION(S) IVF cycles in women with low functional ovarian reserve, involving androgen and CoQ10 supplementation and ovarian stimulation with daily gonadotropin dosages of 300-450 IU of FSH and 150 IU of hMG in microdose agonist cycles. MAIN OUTCOME MEASURE(S) Age-specific LBRs per ET. RESULT(S) Ages did not differ between nonelective (ne) single ET (SET), ne2-ET, and ne ≥ 3-ET cycles (41.3 ± 3.9, 41.7 ± 3.1, and 42.4 ± 2.1 years, respectively). Patients with neSETs demonstrated significantly lower AMH and higher FSH levels and required higher gonadotropin dosages than ne2-ET and ne ≥ 3-ET patients. LBRs declined with age. Above age 42, three or more embryos are required to achieve reasonable LBRs and two or more to avoid futility under American Society for Reproductive Medicine (ASRM) guidelines. CONCLUSION(S) Very poor prognosis patients can still achieve acceptable pregnancy rates at least till their mid-40s if they reach ET. The degree to which egg donation is emphasized as the only treatment option in such patients, therefore, requires reconsideration. Above age 42, at least two, and preferably three embryos, are however required to exceed futility, as defined by ASRM.

Systemic Inflammation and Autoimmunity in Women with Chronic Endometritis.

To determine in women with recurrent pregnancy loss (RPL) and/or implantation failure (RIF) the prevalence of chronic endometritis (CE), systemic inflammation and autoimmunity, and whether they relate.

Utilization of third-party in vitro fertilization in the United States

Background: The use of in vitro fertilization that includes third‐party in vitro fertilization is increasing. However, the relative contribution of third‐party in vitro fertilization that includes the use of donor oocytes, sperm, or embryo and a gestational carrier to the birth cohort after in vitro fertilization is unknown. Objective: The purpose of this study was to examine the contribution of third‐party in vitro fertilization to the in vitro fertilization birth cohort over the past decade. Study Design: This retrospective analysis investigated 1,349,874 in vitro fertilization cycles that resulted in 421,525 live births and 549,367 liveborn infants in the United States from 2004–2013. Cycles were self‐reported by fertility centers to a national registry: Society for Assisted Reproductive Technologies Clinic Outcome Reporting System. Results: Third‐party in vitro fertilization accounted for 217,030 (16.1%) of all in vitro fertilization cycles, 86,063 (20.4%) of all live births, and 115,024 (20.9%) of all liveborn infants. Overall, 39.7% of third‐party in vitro fertilization cycles resulted in a live birth, compared with 29.6% of autologous in vitro fertilization cycles. Use of third‐party in vitro fertilization increased with maternal age and accounted for 42.2% of all in vitro fertilization cycles and 75.3% of all liveborn infants among women >40 years old. Oocyte donation was the most common third‐party in vitro fertilization technique, followed by sperm donation. Over the study period, annual cycle volume and live birth rates gradually increased for both autologous in vitro fertilization and third‐party in vitro fertilization (P<.0001 for all). Live birth rates were the highest when multiple third‐party in vitro fertilization modalities were used, followed by oocyte donation. Conclusion: Third‐party in vitro fertilization use and efficacy have increased over the past decade, now comprising >20% of the total in vitro fertilization birth cohort. In women who are >40 years old, third‐party in vitro fertilization has become the dominant treatment.

Definition by FSH, AMH and embryo numbers of good-, intermediate- and poor-prognosis patients suggests previously unknown IVF outcome-determining factor associated with AMH

BackgroundThough outcome models have been proposed previously, it is unknown whether cutoffs in clinical pregnancy and live birth rates at all ages are able to classify in vitro fertilization (IVF) patients into good-, intermediate- and poor prognosis.MethodsWe here in 3 infertile patient cohorts, involving 1247, 1514 and 632 women, built logistic regression models based on 3 functional ovarian reserve (FOR) parameters, including (1) number of good quality embryos, (2) follicle stimulating hormone (FSH, mIU/mL) and (3) anti-Müllerian hormone (AMH, ng/mL), determining whether clinical pregnancy and live birth rates can discriminate between good, intermediate and poor prognosis patients.ResultsAll models, indeed, allowed at all ages for separation by prognosis, though cut offs changed with age. In the embryo model, increasing embryo production resulted in linear improvement of IVF outcomes despite transfer of similar embryo numbers; in the FSH model outcomes and FSH levels related inversely, while the association of AMH followed a bell-shaped polynomial pattern, demonstrating “best” outcomes at mid-ranges. All 3 models demonstrated increasingly poor outcomes with advancing ages, though “best” AMH even above age 43 was still associated with unexpectedly good pregnancy and delivery outcomes. Excessively high AMH, in contrast, was at all ages associated with spiking miscarriage rates.ConclusionsAt varying peripheral serum concentrations, AMH, thus, demonstrates hithero unknown and contradictory effects on IVF outcomes, deserving at different concentrations investigation as a potential therapeutic agent, with pregnancy-supporting and pregnancy-interrupting properties.

New PCOS-like phenotype in older infertile women of likely autoimmune adrenal etiology with high AMH but low androgens.

How anti-Müllerian hormone (AMH) and testosterone (T) interrelate in infertile women is currently largely unknown. We, therefore, in a retrospective cohort study investigated how infertile women with high-AMH (AMH ≥75th quantile; n=144) and with normal-AMH (25th-75th quantile; n=313), stratified for low-T (total testosterone ≤19.0ng/dL), normal-T (19.0-29.0ng/dL) and high-T (>29.0ng/dL) phenotypically behaved. Patient age, follicle stimulating hormone (FSH), dehyroepiandrosterone (DHEA), DHEA sulphate (DHEAS), cortisol (C), adrenocorticotrophic hormone (ACTH), IVF outcomes, as well as inflammatory and immune panels were then compared between groups, with AMH and T as variables. We identified a previously unknown infertile PCOS-like phenotype, characterized by high-AMH but, atypically, low-T, with predisposition toward autoimmunity. It presents with incompatible high-AMH and low-T (<19.0ng/dL), is restricted to lean PCOS-like patients, presenting delayed for tertiary fertility services. Since also characterized by low DHEAS, low-T is likely of adrenal origina, and consequence of autoimmune adrenal insufficiency since also accompanied by low-C and evidence of autoimmunity. DHEA supplementation in such patients equalizes low- to normal-T and normalizes IVF cycle outcomes. Once recognized, this high-AMH/low-T phenotype is surprisingly common in tertiary fertility centers but, currently, goes unrecognized. Its likely adrenal autoimmune etiology offers interesting new directions for investigations of adrenals control over ovarian function via adrenal androgen production.

Effect of Embryo Banking on U.S. National Assisted Reproductive Technology Live Birth Rates

Background Assisted Reproductive Technology (ART) reports generated by the Centers for Disease Control and Prevention (CDC) exclude embryo banking cycles from outcome calculations. Methods We examined data reported to the CDC in 2013 for the impact of embryo banking exclusion on national ART outcomes by recalculating autologous oocyte ART live birth rates. Inflation of reported fresh ART cycle live birth rates was assessed for all age groups of infertile women as the difference between fresh cycle live births with reference to number of initiated fresh cycles (excluding embryo banking cycles), as typically reported by the CDC, and fresh cycle live births with reference to total initiated fresh ART cycles (including embryo banking cycles). Results During 2013, out of 121,351 fresh non-donor ART cycles 27,564 (22.7%) involved embryo banking. The proportion of banking cycles increased with female age from 15.5% in women <35 years to 56.5% in women >44 years. Concomitantly, the proportion of thawed cycles decreased with advancing female age (P <0.0001). Exclusion of embryo banking cycles led to inflation of live birth rates in fresh ART cycles, increasing in size in parallel to advancing female age and utilization of embryo banking, reaching 56.3% in women age >44. The inflation of live birth rates in thawed cycles could not be calculated from the publically available CDC data but appears to be even greater. Conclusions Utilization of embryo banking increased during 2013 with advancing female age, suggesting a potential age selection bias. Exclusion of embryo banking cycles from national ART outcome reports significantly inflated national ART success rates, especially among older women. Précis Exclusion of embryo banking cycles from US National Assisted Reproductive Technology outcome reports significantly inflates reported success rates especially in older women.

Anti-mullerian hormone levels decline with the presence of antiphospholipid antibodies.

Autoimmunity is thought to be an important cause of premature ovarian senescence, characterized by abnormal ovarian reserve markers. Anti‐Mullerian hormone (AMH) has emerged as the most reliable marker for ovarian reserve. We here investigated whether non‐specific immune markers are associated with a low age‐specific AMH.

Degree of mosaicism in trophectoderm does not predict pregnancy potential: a corrected analysis of pregnancy outcomes following transfer of mosaic embryos

BackgroundPreimplantation genetic screening (PGS) is increasingly utilized as an adjunct procedure to IVF. Recently healthy euploid live birth were reported following transfer of mosaic embryos. Several recent publications have surmised that the degree of trophectoderm (TE) mosaicism in transferred embryos is predictive of ongoing pregnancy and miscarriage rates.MethodsThis is a corrected analysis of previously published retrospective data on vitro fertilization (IVF) cycle outcomes involving replacement of 143 mosaic and 1045 euploid embryos tested by PGS, utilizing high-resolution next-generation sequencing (NGS) of TE and determination of percentages of mosaicism. Receiver operating curves (ROCs) and measurement of area under the curve (AUC) were used to evaluated the accuracy of the predictor variable, proportion of aneuploid cells in a TE biopsy specimen, with IVF outcomes, ongoing pregnancy and miscarriage rates.ResultsConfirming findings of the previously published report we also found higher ongoing pregnancy rates (63.3% vs. 39.2%) and lower miscarriage rates (10.2% vs. 24.3%) with euploid embryo transfers than with mosaic embryo transfer. There, however, were no significant differences in ongoing pregnancy or miscarriage rates among mosaic embryo transfers at any threshold of aneuploidy. Based on AUC, TE biopsies predicted ongoing pregnancy for euploid, as well as mosaic embryos, in a range of 0.50 to 0.59 and miscarriage in a range from 0.50 to 0.66ConclusionsDegree of TE mosaicism was a poor predictor of ongoing pregnancy and miscarriage.