Black race associated with lower live birth rate in frozen-thawed blastocyst transfer cycles: an analysis of 7,002 Society for Assisted Reproductive Technology frozen-thawed blastocyst transfer cycles.

OBJECTIVE: To evaluate if racial/ethnic differences in pregnancy outcomes persisted in frozen-thawed embryo transfer (FET) cycles on a national level. DESIGN: Retrospective cohort study. SETTING: Clinic-based data. PATIENT(S): A total of 189,000 Society for Assisted Reproductive Technology FET cycles from 2014-2016 were screened, of which 12,000 cycles had available fresh cycle linkage information and ultimately, because of missing data, 7,002 FET cycles were included. Cycles were stratified by race (White, Black, Asian, and Hispanic). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The primary outcome was live birth rate. Secondary outcomes were implantation rate, clinical pregnancy rate, multiple pregnancy rate, and clinical loss rate (CLR). RESULT(S): Live birth rate was significantly lower in the Black vs. White and Asian, but not Hispanic group. Implantation rate was also significantly lower and CLR higher in the Black group compared with all other groups (all P<.01). Black women had a lower risk of live birth (adjusted risk ratio, 0.82; 95% confidence interval [CI], 0.73-0.92) and a higher risk of clinical loss (adjusted risk ratio, 1.59; 95% CI, 1.28-1.99) compared with White women. There was no significant difference between groups in clinical pregnancy rate or multiple pregnancy rate. When the analysis was limited to preimplantation genetic testing FET cycles, there remained a significantly lower implantation rate in the Black group compared with all other groups (all P<.01). CONCLUSION(S): Black race remains an independent predictor of reduced live birth rate in FET cycles, likely because of higher CLR.

Assessment of Anti-Mullerian Hormone and Anti-Mullerian Hormone Type II Receptor Variants in Women with Repeated Implantation Failures.

Repeated implantation failure (RIF) is a common endocrine disease that causes female infertility and the etiology is unknown. The abnormal expression of key proteins and hormones at the maternal-fetal interface affected the maternal-fetal communication and leads to adverse pregnancy outcomes. The expression of anti-Mullerian hormone (AMH) and AMH receptor II (AMHRII) was observed in the endometrium. This study aimed to investigate the expression of AMH and AMHRII at the human endometrium, decidual tissue, and blastocyst. Furthermore, the expression of AMH and AMHRII were examined in the RIF patients using immunohistochemistry and quantitative real-time PCR to test the AMHRII expression. The results demonstrated that AMH and AMHRII were present in healthy endometrium and AMHRII was highly expressed in mid-luteal phase. In addition, AMHRII expression was detected throughout the pregnancy and AMHRII's highest expression was in the second trimester. AMHRII was expressed in the blastocysts; however, AMH was not observed. The positive expression rate for AMHRII was significantly higher in the endometrium from RIF. Estrogen receptor (ER), insulin-like growth factor binding protein 1(IGFBP1), and prolactin (PRL) were significantly less expressed in RIF with high expression of AMHRII. The apoptosis was significantly higher in patients with high expression of AMHRII than in patients with normal expression of AMHRII. Our data suggests that AMHRII had an effect on RIF via the AMH and AMHRII signaling pathway. It participated in the development of RIF by interfering with endometrial decidualization and apoptosis.

Artificial Cycle with or without a Depot Gonadotropin-releasing Hormone Agonist for Frozen-thawed Embryo Transfer: An Assessment of Infertility Type that Is Most Suitable.

The clinical outcomes of five groups of infertility patients receiving frozen-thawed, cleavage-stage embryo transfers with exogenous hormone protocols with or without a depot gonadotropin-releasing hormone (GnRH) agonist were assessed. A retrospective cohort analysis was performed on 1003 cycles undergoing frozen-thawed, cleavage-stage embryo transfers from January 1, 2012 to June 31, 2015 in the Reproductive Medicine Center of Wuhan General Hospital of Guangzhou Military Region. Based on the infertility etiologies of the patients, the 1003 cycles were divided into five groups: tubal infertility, polycystic ovary syndrome (PCOS), endometriosis, male infertility, and unexplained infertility. The main outcome was the live birth rate. Two groups were set up based on the intervention: group A was given a GnRH agonist with exogenous estrogen and progesterone, and group B (control group) was given exogenous estrogen and progesterone only. The results showed that the baseline serum hormone levels and basic characteristics of the patients were not significantly different between groups A and B. The live birth rates in groups A and B were 41.67% and 29.29%, respectively (P<0.05). The live birth rates in patients with PCOS in groups A and B were 56.25% and 30.61%,respectively (P<0.05). The clinical pregnancy, implantation and on-going pregnancy rates showed the same trends as the live birth rates between groups A and B. The ectopic pregnancy rate was significantly lower in group A than in group B. We concluded that the live birth rate was higher and other clinical outcomes were more satisfactory with GnRH agonist cotreatment than without GnRH agonist co-treatment for frozen-thawed embryo transfer. The GnRH agonist combined with exogenous estrogen and progesterone worked for all types of infertility tested, especially for women with PCOS.

A 50% reduction in multiple live birth rate is associated with a 13% cost saving: a real-life retrospective cost analysis.

Belgian legislation limiting the number of embryos for transfer has been shown to result in a 50% reduction of the multiple live birth rate (MLBR) per cycle without having a negative impact on the cumulative delivery rate per patient within six cycles or 36 months. The objective of the current study was to evaluate the cost saving associated with a 50% reduction in MLBR. A retrospective cost analysis was performed of 213 couples, who became pregnant and had a live birth after one or more assisted reproductive technology treatment cycles, and their 254 children. The mean cost of a singleton (n = 172) and multiple (n = 41) birth was calculated based on individual hospital invoices. The cost analysis showed a significantly higher total cost (assisted reproductive technology treatment, pregnancy follow-up, delivery, child cost until the age of 2 years) for multiple births (both children: mean €43,397) than for singleton births (mean: €17,866) (Wilcoxon-Mann-Whitney P < 0.0001). A 50% reduction in MLBR resulted in a significant cost reduction related to hospital care of 13%.

What is a difficult transfer? Analysis of 7,714 embryo transfers: the impact of maneuvers during embryo transfers on pregnancy rate and a proposal of objective assessment.

OBJECTIVE: To establish the relationship between the degree of difficulty of ET and pregnancy rate (PR), with a view to proposing an algorithm for the objective assessment of ET. DESIGN: Retrospective, observational study. SETTING: In vitro fertilization unit. PATIENT(S): Women undergoing assisted reproductive technology (ART) with ET after IVF/intracytoplasmic sperm injection, in whom fresh embryo transfer or frozen-thawed embryo transfer was performed. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Clinical pregnancy rate (CPR). RESULT(S): A total of 7,714 ETs were analyzed. The CPR was significantly higher in the cases of easy ET compared with difficult ET (38.2% vs. 27.1%). Each instrumentation needed to successfully deposit the embryos in the fundus involves a progressive reduction in the CPR: use of outer catheter sheath (odds ratio [OR] 0.89; 95% confidence interval [CI] 0.79-1.01), use of Wallace stylet (OR 0.71; 95% CI 0.62-0.81), use of tenaculum (OR 0.54; 95% CI 0.36-0.79). Poor ultrasound visualization significantly diminish the CPR. CONCLUSION(S): The CPR decreases progressively with the use of additional maneuvers during ET. An objective classification of the instrumentation applied during ET is proposed.

Current regulatory arrangements for assisted conception treatment in European countries.

Infertility is a condition affecting an increasing number of individuals all over the world. In recent years, this phenomenon has spread across both western countries and developing countries, thus developing the features of a pandemic. For this reason, the World Health Organization (WHO) acknowledged that infertility should be considered a disease to all intents and purposes, as it diminishes the health and wellbeing of the individuals who suffers from it. At present, the most effective means to contain the spread of infertility are essentially prevention and Assisted Reproductive Technologies (ART). With reference to the latter, although most of these techniques are routinely used in the majority of countries, they are still subject to medical, ethical and political debates. There are huge variations noted when the regulatory legislation adopted by different countries to govern infertility treatment in various countries all over the world are reviewed. In fact, it has to be recognized that ART legislation depends on a variety of factors, such as social structure, political choices, ethical issues and religious beliefs. This makes it apparently impossible to create a standard regulation for different countries, especially in case of controversial issues like gamete and embryo donation, embryo cryopreservation or surrogacy.

Cleavage-stage or blastocyst transfer: what are the benefits and harms?

ET is a critical step in an assisted reproduction cycle. Over the past decade there has been an increasing trend to extending culture from cleavage-stage to blastocyst transfer. There has also been a trend to single ET and reporting the success of an assisted reproductive cycle as a cumulative live-birth rate after using both fresh and frozen embryos. There is low evidence that fresh blastocyst transfer is associated with improved live-birth rates compared with fresh cleavage-stage embryos. However, in the few studies that report cumulative pregnancy rates after fresh and frozen transfers, no significant difference was found. Cleavage-stage transfer is associated with greater numbers of embryos available for freezing, and blastocyst transfer is associated with increased number of cycles with no embryos to transfer. Further well-designed studies are warranted to evaluate the outcomes for blastocyst transfer including cumulative live-birth rate after fresh and frozen transfers, time to live birth, costs of the different transfer strategies, and perinatal mortality and severe perinatal morbidity.

Assisted reproduction with gametes and embryos: what research is needed and fundable?

Principles for selecting future research projects include interests of investigators, fundability, potential applications, ethical considerations, being able to formulate testable hypotheses and choosing the best models, including selection of the most appropriate species. The following 10 areas of assisted reproduction seem especially appropriate for further research: efficacious capacitation of bovine spermatozoa in vitro; improved in vitro bovine oocyte maturation; decreasing variability and increasing efficacy of bovine superovulation; improved fertility of sexed semen; improving equine IVF; improving cryopreservation of rooster spermatozoa; understanding differences between males in success of sperm cryopreservation and reasons for success in competitive fertilisation; mechanisms of reprogramming somatic cell nuclei after nuclear transfer; regulation of differentiation of ovarian primordial follicles; and means by which spermatozoa maintain fertility during storage in the epididymis. Issues are species specific for several of these topics, in most cases because the biology is species specific.

Economic implications of the Society for Assisted Reproductive Technology embryo transfer guidelines: healthcare dollars saved by reducing iatrogenic triplets.

OBJECTIVE: To estimate the national cost savings resulting from reductions in higher-order multiple (HOM) live births (defined as three or more fetuses), following the initial publication of the Society for Assisted Reproductive Technology (SART) guidelines on ET in 1998. DESIGN: Descriptive use and cost analysis. SETTING: Not applicable. PATIENT(S): Not applicable. INTERVENTION(S): Not applicable. MAIN OUTCOME MEASURE(S): Estimates of the total number of HOM deliveries prevented (from 1998-2012) following the publication of SART guidelines; the associated healthcare savings (2014 US dollars). RESULT(S): A singleton live birth was estimated to cost $17,100-$24,200. A twin live birth was estimated at $66,000-$117,500. A triplet live birth was estimated at $190,800-$456,300. The percentage of HOM gestations among all ART pregnancies decreased from 11.4% in 1997 to 2.0% in 2012, with the sharpest year-over-year decline of 20.3% occurring in the year following the publication of the guidelines. The number of prevented HOM deliveries from 1998 through 2012 was estimated to be between 13,500 and 16,300, corresponding to cost savings of $6.02B (billion) (range, $2.35B-$7.03B, 2014 US dollars). CONCLUSION(S): Iatrogenic HOM gestations represent a substantial economic burden to our healthcare system. The introduction of guidelines for ET in 1998 coincided with a dramatic decrease in the HOM rate in subsequent years and an associated cumulative cost savings of more than $6B. Further reductions in HOM gestations could save up to an additional $2B annually.

Cost Implications for Subsequent Perinatal Outcomes After IVF Stratified by Number of Embryos Transferred: A Five Year Analysis of Vermont Data.

BACKGROUND: In states in the USA without in vitro fertilzation coverage (IVF) insurance coverage, more embryos are transferred per cycle leading to higher risks of multi-fetal pregnancies and adverse pregnancy outcomes. OBJECTIVE: To determine frequency and cost of selected adverse perinatal complications based on number of embryos transferred during IVF, and calculate incremental cost per IVF live birth. METHODS: Medical records of patients who conceived with IVF (n = 116) and delivered at >20 weeks gestational age between 2007 and 2011 were evaluated. Gestational age at delivery, low birth weight (LBW) term births, and delivery mode were tabulated. Healthcare costs per cohort, extrapolated costs assuming 100 patients per cohort, and incremental costs per infant delivered were calculated. RESULTS: The highest prematurity and cesarean section rates were recorded after double embryo transfers (DET), while the lowest rates were found in single embryo transfers (SET). Premature singleton deliveries increased directly with number of transferred embryos [6.3 % (SET), 9.1 % (DET) and 10.0 % for ≥3 embryos transferred]. This trend was also noted for rate of cesarean delivery [26.7 % (SET), 36.6 % (DET), and 47.1 % for ≥3 embryos transferred]. The proportion of LBW infants among deliveries after DET and for ≥3 embryos transferred was 3.9 and 9.1 %, respectively. Extrapolated costs per cohort were US$718,616, US$1,713,470 and US$1,227,396 for SET, DET, and ≥3 embryos transferred, respectively. CONCLUSION: Attempting to improve IVF pregnancy rates by permitting multiple embryo transfers results in sharply increased rates of multiple gestation and preterm delivery. This practice yields a greater frequency of adverse perinatal outcomes and substantially increased healthcare spending. Better efforts to encourage SET are necessary to normalize healthcare expenditures considering the frequency of very high cost sequela associated with IVF where multiple embryo transfers occur.

[Association of fertilization strategy and embryo transfer time with the incidence of ectopic pregnancy].

OBJECTIVE: To investigate the correlation of the fertilization strategy and embryo transfer (ET) time with the incidence of ectopic pregnancy. METHODS: We selected 3,331 fresh and 2,706 frozen-thawed ET cycles for the patients undergoing in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI). The fresh transfers included 2 546 IVF-ET and 785 ICSI-ET cycles and 2,220 day-3 embryo and 1,111 day-5 blastocyst transfers, while the frozen-thawed transfers included 2,080 IVF-ET and 626 ICSI-ET cycles and 741 day-3 embryo and 1 965 day-5 or -6 blastocyst transfers. We compared the incidence rate of ectopic pregnancy associated with different fertilization strategies and ET time. RESULTS: The incidence rate of ectopic pregnancy was 1. 41% (36/2 546) in the IVF-ET cycles and 3.44% (27/785) in the ICSI-ET cycles of the fresh transfers, significantly lower in the IVF-ET than in the ICSI-ET cycles (P < 0.01), and it was 1.01% (21/2,080) in the IVF-ET cycles and 0.80% (5/626) in the ICSI-ET cycles of the frozen-thawed transfers, with no remarkable difference between the two groups (P > 0.05). The IVF-ET and ICSI-ET cycles included 2,220 fresh day-3 (F-D3) embryos, 1,111 F-D5 blastocysts, 741 frozen-thawed day-3 (T-D3) embryos, and 1,965 T-D5/6 blastocysts. The incidence rate of ectopic pregnancy was 1.71% (n = 38) in the F-D3, 2.25% (n = 25) in the F-D5, 1.35% (n = 10) in the T-D3, and 0.81% (n = 16) in the T-D5/6 group, respectively, significantly lower in the T-D5/6 than in the other three groups (P < 0.05). CONCLUSION: The incidence rate of ectopic pregnancy is associated with fertilization strategies, which is significantly lower in frozen-thawed than in fresh embryo transfers.

The oviduct: a neglected organ due for re-assessment in IVF.

The oviduct has long been considered a 'pipeline', a tube allowing transit of spermatozoa and embryos; this perspective has been reinforced by the success of human IVF. Evidence accumulated over several decades, however, indicates that embryos can modulate the metabolism of tubal cells in their environment. Human IVF culture media is based on formulations that pass mouse embryo assays as quality control: the requirements of mouse embryos differ from those of human embryos, and therefore conditions for human IVF are far removed from the natural environment of the oviduct. The preimplantation environment, both in vitro and in vivo, is known to affect the health of offspring through mechanisms that influence imprinting. Recent studies also show that male accessory glands act in synergy with the oviduct in providing an optimal environment, and this represents a further perspective on the oviduct's contribution to harmonious embryo development and subsequent long-term health. The metabolism of the human embryo is far from being understood, and a 'return' to in-vivo conditions for preimplantation development is worthy of consideration. Although results obtained in rodents must be interpreted with caution, lessons learned from animal embryo culture must not be neglected.

On the cost and prevention of iatrogenic multiple pregnancies.

Multiple pregnancies are an undesirable complication of IVF and of ovulation induction and/or ovulation enhancement without IVF. Studies based on published population data and data from the Centers for Disease Control and Prevention indicate that savings from the mitigation of iatrogenic multiples would save money in the billions (10(9)) of US dollars on a national basis. The aim of this study was to determine whether, using real data from a major regional insurance carrier for the interval 2005-2009 covering obstetric costs requiring hospitalization and neonatal costs through the first year, it was possible to show that the cost saved by eliminating iatrogenic multiple births would be adequate to fund a protocol to minimize iatrogenic multiple births. The net savings on an annual basis for the study group of 13,478 was about US$4.4 million. Applying the regional findings to national data suggests savings of approximately US$6.3 billion if national iatrogenic multiples were eliminated. These findings indicate that the health insurance industry should be able to offer infertility coverage at a lower rate by requiring a treatment algorithm designed to essentially eliminate iatrogenic multiple pregnancies. It is concluded that efforts should be made to assure a singleton birth when treating infertility.

Cryo-thawed embryo transfer: natural versus artificial cycle. A non-inferiority trial. (ANTARCTICA trial).

BACKGROUND: Frozen thawed embryo transfer (FET) is a cost-effective adjunct to IVF or IVF-ICSI treatment. In order to optimize treatment outcome, FET should be carried out during a period of optimal endometrial receptivity. To optimize implantation several methods for endometrium preparation have been proposed. In natural cycle FET (NC-FET), the endometrium develops under endogenous hormonal stimulation. The development of the dominant follicle and endometrium is monitored by ultrasound and FET is timed after triggering ovulation induction or determination of the spontaneous LH surge. In an artificial cycle FET (AC-FET) estrogens and progesterone are administered to prepare the endometrium for implantation. While the currently available data show no significant difference in pregnancy rates between these methods, well designed randomized controlled trials are lacking. Moreover there is little literature on difference in cancellation rates, cost-efficiency and adverse events. METHODS AND DESIGN: In this randomized, multi-centre, non-inferiority trial we aim to test the hypothesis that there is no significant difference in live birth rates between patients undergoing NC-FET versus AC-FET. The primary outcome will be live birth rate per embryo transfer procedure. Secondary outcomes will be ongoing and clinical pregnancy rate, cancellation rate, (serious) adverse events and cost-efficiency. Based on a live birth rate of 20% and a minimal clinical important difference of 7.5% (one-sided alpha 2.5%, beta 20%) a total of 1150 patients will be needed. Analyzes will be performed using both per protocol as well as intention to treat analyses. DISCUSSION: This prospective, randomized, non-inferiority trial aims to address the hypothesis that there is no significant difference in live birth rates between patients undergoing NC-FET versus patients undergoing AC-FET. Moreover it addresses cost-efficiency as well as the perceived burden of both treatments. TRIAL REGISTER: Netherlands trial register (NTR): 1586.

Damages claim for wrongful birth due to a systems failure.

Health professionals are well versed in the need to have systems in place which avoid mishaps happening to patients due to human error or breakdown in communications: for example, legal actions for damages for operations wrongfully performed on patients due to a failure in the identification process; surgery involving the wrong limb or organ; medications being given to the wrong patient. Hospitals set in place systems by which a patient's name and procedures to be performed are checked multiple times throughout the patient's stay. This process is particularly vital when a patient is undergoing a surgical procedure which will be performed under anaesthesia. Nevertheless, systems failures continue to occur resulting in claims for damages by affected patients.

Embryo transfer: a comparative biosecurity advantage in international movements of germplasm.

This paper uses cattle as a model to provide an overview of the hazards involved in the transfer of in vivo-derived and in vitro-produced embryos. While scientific studies in recent decades have led to the identification of pathogens that may be associated with both in vivo- and in vitro-derived embryos, those studies have also been the basis of appropriate disease control measures to reduce the risks to a negligible level. These disease control measures have been identified and assessed by the International Embryo Transfer Society's (lETS) Health and Safety Advisory Committee, the expert body that advises the World Organisation for Animal Health (OIE) on matters related to the safety of embryo transfer. Through the OIE's processes for developing and adopting international standards, the disease control measures identified by the IETS have been incorporated into the Terrestrial Animal Health Code. The basic principles rely on the crucial ethical roles of the embryo collection team and embryo transfer team, under the leadership of approved veterinarians. Decades of experience, with nearly 10 million embryos transferred, have demonstrated the very significant biosecurity advantage that embryo transfer technology has when moving germplasm internationally, provided that the international standards developed by the IETS and adopted by the OIE are strictly followed.

Initial experience with a risk-sharing in vitro fertilization-embryo transfer program with novel features.

OBJECTIVE: To describe outcomes of the first 100 consecutive infertility patients participating in a risk-sharing program with uncomplicated eligibility requirements. The program included the costs of FSH-containing gonadotropin preparations and provided a full payment refund if no birth occurred that resulted in a normal infant surviving to an age of 1 month. DESIGN: Retrospective cohort study. SETTING: Private IVF center. PATIENT(S): Infertility patients<35 years of age, considered to be good autologous oocyte IVF candidates at time of program enrollment. INTERVENTION(S): Retrospective analysis of outcomes of fresh IVF-ET and frozen embryo transfer cycles involving conventional treatment protocols. MAIN OUTCOME MEASURE(S): Cumulative successful pregnancy rate. RESULT(S): Of the first 100 patients enrolled in the program, 82 have had a delivery of a normal infant surviving to an age of 1 month, and another 6 have undelivered ongoing pregnancies at 20+ weeks. Nine participants completed the program without completing a successful treatment cycle, and another three remain enrolled. CONCLUSION(S): Infertility patients<35 years of age participating in a risk-sharing program with uncomplicated eligibility requirements are very likely to have a successful pregnancy. Other centers may wish to incorporate some of the described program's features into their own risk-sharing IVF programs.

Coming soon to your clinic: patient-friendly ART.

The current practice in medically assisted reproduction is still too exclusively focused on effectiveness and success rates. This has a number of considerable, and more importantly, avoidable drawbacks. Single embryo transfer was an important move away from this model to include safety and welfare of mother and child. Patient-friendly ART goes one big step further. It is composed of a mix of four criteria: cost-effectiveness, equity of access, minimal risk for mother and child and minimal burden for patients. All four components have a strong normative ethical basis: cost-effectiveness relies on the optimal use of community resources to maximise well-being; equity of access is based on justice, minimal risk is founded on the fundamental non-maleficence rule and minimal burden is largely based on the autonomy principle. The inclusion of the four criteria in decision-making about treatment would express these values in clinical practice.