Economic evaluations of assisted reproductive technologies in high-income countries: a systematic review.

STUDY QUESTION: Which assited reproductive technology (ART) interventions in high-income countries are cost-effective and which are not? SUMMARY ANSWER: Among all ART interventions assessed in economic evaluations, most high-cost interventions, including preimplantation genetic testing for aneuploidy (PGT-A) for a general population and ICSI for unexplained infertility, are unlikely to be cost-effective owing to minimal or no increase in effectiveness. WHAT IS KNOWN ALREADY: Approaches to reduce costs in order to increase access have been identified as a research priority for future infertility research. There has been an increasing number of ART interventions implemented in routine clinical practice globally, before robust assessments of evidence on economic evaluations. The extent of clinical effectiveness of some studied comparisons has been evaluated in high-quality research, allowing more informative decision making around cost-effectiveness. STUDY DESIGN, SIZE, DURATION: We performed a systematic review and searched seven databases (MEDLINE, PUBMED, EMBASE, COCHRANE, ECONLIT, SCOPUS, and CINAHL) for studies examining ART interventions for infertility together with an economic evaluation component (cost-effectiveness, cost-benefit, cost-utility, or cost-minimization assessment), in high-income countries, published since January 2011. The last search was 22 June 2022. PARTICIPANTS/MATERIALS, SETTING, METHODS: Two independent reviewers assessed publications and included those fulfilling the eligibility criteria. Studies were examined to assess the cost-effectiveness of the studied intervention, as well as the reporting quality of the study. The chosen outcome measure and payer perspective were also noted. Completeness of reporting was assessed against the Consolidated Health Economic Evaluation Reporting Standard. Results are presented and summarized based on the intervention studied. MAIN RESULTS AND THE ROLE OF CHANCE: The review included 40 studies which were conducted in 11 high-income countries. Most studies (n = 34) included a cost-effectiveness analysis. ART interventions included medication or strategies for controlled ovarian stimulation (n = 15), IVF (n = 9), PGT-A (n = 7), single embryo transfer (n = 5), ICSI (n = 3), and freeze-all embryo transfer (n = 1). Live birth was the mostly commonly reported primary outcome (n = 27), and quality-adjusted life years was reported in three studies. The health funder perspective was used in 85% (n = 34) of studies. None of the included studies measured patient preference for treatment. It remains uncertain whether PGT-A improves pregnancy rates compared to IVF cycles managed without PGT-A, and therefore cost-effectiveness could not be demonstrated for this intervention. Similarly, ICSI in non-male factor infertility appears not to be clinically effective compared to standard fertilization in an IVF cycle and is therefore not cost-effective. Interventions such as use of biosimilars or HMG for ovarian stimulation are cheaper but compromise clinical effectiveness. LIMITATIONS, REASONS FOR CAUTION: Lack of both preference-based and standardized outcomes limits the comparability of results across studies. The selection of efficacy evidence offered for some interventions for economic evaluations is not always based on high-quality randomized trials and systematic reviews. In addition, there is insufficient knowledge of the willingness to pay thresholds of individuals and state funders for treatment of infertility. There is variable quality of reporting scores, which might increase uncertainty around the cost-effectiveness results. WIDER IMPLICATIONS OF THE FINDINGS: Investment in strategies to help infertile people who utilize ART is justifiable at both personal and population levels. This systematic review may assist ART funders decide how to best invest to maximize the likelihood of delivery of a healthy child. STUDY FUNDING/COMPETING INTEREST(S): There was no funding for this study. E.C. and R.W. receive salary support from the National Health and Medical Research Council (NHMRC) through their fellowship scheme (EC GNT1159536, RW 2021/GNT2009767). M.D.-T. reports consulting fees from King Fahad Medical School. All other authors have no competing interests to declare. REGISTRATION NUMBER: Prospero CRD42021261537.

Potential Costs and Benefits of Incorporating PGT-A Across Age Groups: A Canadian Clinic Perspective.

OBJECTIVE: To assess the potential costs and benefits of preimplantation genetic testing for aneuploidy (PGT-A) across age groups, considering financial costs, total euploidy rates and the potential for morphology grading to predict a euploid embryo. METHODS: This study is a blinded retrospective chart review of patients who incorporated PGT-A as part of their in vitro fertilization (IVF) treatment cycle at a university-affiliated fertility clinic. Patients between 25-44 years of age undergoing IVF with intracytoplasmic sperm injection and PGT-A with autologous oocytes (n = 220) were included in this study. Number of blastocysts achieved, euploidy rates and PGT-A costs were compared between 3 age groups: <35 years, 35-37, and ≥38. Additionally, agreement on the top-quality embryo based on morphology assessment alone versus PGT-A selection was analyzed and further compared based on the number of blastocysts achieved. RESULTS: A significant negative correlation between patient age and number of embryos produced, PGT-A costs, and euploidy rates (P < 0.001) was observed. Additionally, morphology alone ratings were able to predict the top-quality euploid embryo 78% of the time in the <35 age group, but only 32% of the time in the ≥38 age group (P < 0.05), with a trend toward even lower agreement when 3 or fewer blastocysts were produced. CONCLUSION: Based on our cost analysis, it may be advantageous to incorporate PGT-A when maternal age is ≥38, given the lower financial costs associated with each cycle and the low likelihood of transferring a euploid embryo on the first attempt for this age group. Nevertheless, we acknowledge that PGT-A remains a complex decision influenced by a multitude of factors.

Strong social disparities in access to IVF/ICSI despite free cost of treatment: a French population-based nationwide cohort study.

BACKGROUND: Access to IVF/ICSI is facilitated when the financial barrier is removed. In a national context where in vitro fertilisation (IVF)/intracytoplasmic sperm Injection (ICSI) treatment is cost-free, how many women do not access IVF/ICSI and what are the factors associated with non-access? METHODS: Using French national health insurance databases, the cohort included 20,240 women aged 18-43 years living in France who underwent unsuccessful treatment (no pregnancy) with clomiphene citrate (CC) and/or gonadotropins with treatment started between January and August 2016. The outcome measure was non-access to IVF/ICSI during the 24-month following start of infertility care. Factors associated with non-access to IVF/ICSI were explored using mixed effects logistic regression. RESULTS: In the cohort, 65.4% of women did not access IVF/ICSI. In multivariable analysis, non-access to IVF/ICSI was higher in younger women (18-25 years: (OR 2.17, 95% CI: 1.85-2.54) and in older women (40-43 years: (OR=3.60, 95% CI: 3.25-3.98)). Non-access was higher among women below the poverty line (OR=3.76, 95% CI: 3.34-4.23) and showed a significant upward trend with increasing deprivation of place of residence. Distance to the nearest fertility centre was not significantly associated with non-access to IVF/ICSI. CONCLUSIONS: In a national context of cost-free ART treatment, a large proportion of women did not access treatment, with a strong social gradient that raises important issues. We need to understand the underlying social mechanisms to develop an efficient and equitable health policy regarding infertility care.

Protocol for improving the costs and outcomes of assistive reproductive technology fertility care pathways: a study using cost measurement and process mining.

INTRODUCTION: Value-based healthcare suggests that care outcomes should be evaluated in relation to the costs of delivering that care from the perspective of the provider. However, few providers achieve this because measuring cost is considered complex and elaborate and, further, studies routinely omit cost estimates from 'value' assessments due to lacking data. Consequently, providers are currently unable to steer towards increased value despite financial and performance pressures. This protocol describes the design, methodology and data collection process of a value measurement and process improvement study in fertility care featuring complex care paths with both long and non-linear patient journeys. METHODS AND ANALYSIS: We employ a sequential study design to calculate total costs of care for patients undergoing non-surgical fertility care treatments. In doing so, we identify process improvement opportunities and cost predictors and will reflect on the benefits of the information generated for medical leaders. Time-to-pregnancy will be viewed in relation to total costs to determine value. By combining time-driven, activity-based costing with observations and process mining, we trial a method for measuring care costs for large cohorts using electronic health record data. To support this method, we create activity and process maps for all relevant treatments: ovulation induction, intrauterine insemination, in vitro fertilisation (IVF), IVF with intracytoplasmic sperm injection and frozen embryo transfer after IVF. Our study design, by showing how different sources of data can be combined to enable cost and outcome measurements, can be of value to researchers and practitioners looking to measure costs for care paths or entire patient journeys in complex care settings. ETHICS AND DISSEMINATION: This study was approved by the ESHPM Research Ethics Review Committee (ETH122-0355) and the Reinier de Graaf Hospital (2022-032). Results will be disseminated through seminars, conferences and peer-reviewed publications.

Assessment of cell-free DNA and apoptosis in an oocyte microenvironment: promising biomarkers to predict intracytoplasmic sperm injection outcomes.

Cell-free DNA (cf-DNA) is defined as DNA fragments that are released into the body fluids from apoptosis or necrosis cells, including follicular fluid (FF), which can affect the microenvironment of the oocyte associated with infertility. We aimed to investigate a relationship between apoptosis of cumulus cells (CCs) and cf-DNA levels in FF and clinical outcomes of women undergoing intracytoplasmic sperm injection (ICSI). Therefore, 82 FF samples were collected, and the corresponding CCs were isolated for ICSI procedures. FF cf-DNA concentration was quantified using ALU-quantitative polymerase chain reaction (PCR), and CCs DNA fragmentation index (DFI) was evaluated by the terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labelling (TUNEL) method. We found that cf-DNA and DFI levels were significantly higher in FF and CCs samples related to the age of women ≥37 years compared with the age of women < 37 years. Moreover, in older and younger women, FF cf-DNA and CCs DFI levels were significantly lower when the anti-Müllerian hormone (AMH) level was > 1.1 ng/ml compared with when AMH ≤ 1.1 ng/ml. In addition, patients with a low number of retrieved oocytes ≤ 6 had significantly higher levels of CCs DFI and FF cf-DNA than women with a higher number of retrieved oocytes > 6. Additionally, we observed that higher levels of cf-DNA and DFI were associated with poor oocyte maturity and poor embryo quality. Finally, cf-DNA and DFI levels were significantly lower in pregnant women than in non-pregnant ones. We conclude that DFI and cf-DNA levels in the oocyte microenvironment could have potential use in evaluating oocyte and embryo developmental competence.

The homeostasis model assessment of insulin resistance is a judgment criterion for metformin pre-treatment before IVF/ICSI and embryo transfer cycles in patients with polycystic ovarian syndrome.

Purpose: The aim of this study was to explore the value of the homeostasis model assessment of IR (HOMA-IR) as a judgment criterion for metformin pre-treatment before in vitro fertilization/intracellular sperm injection (IVF/ICSI) and embryo transfer (ET) for polycystic ovarian syndrome (PCOS) patients. Materials and methods: The clinical and laboratory information of PCOS patients who received IVF/ICSI-ET from January 2017 to September 2021 was retrospectively analyzed. We compared the clinical pregnancy rate (primary outcome) and controlled ovarian stimulation (COS)-related parameters (secondary outcomes) between patients with and without metformin pre-treatment for all PCOS patients not grouped by HOMA-IR, PCOS patients with HOMA-IR < 2.71, and PCOS patients with HOMA-IR ≥ 2.71. Results: A total of 969 PCOS patients who received the GnRH-antagonist protocol were included in this study. For all PCOS patients, the metformin group showed comparable clinical pregnancy rates in fresh ET cycles and frozen ET cycles compared with the control group (55.9% vs. 57.1%, p = 0.821 and 63.8% vs. 60.9%, p = 0.497). For PCOS patients with HOMA-IR < 2.71, the clinical pregnancy rates in both fresh ET cycles and frozen ET cycles were statistically similar between the two groups (61.5% vs. 57.6%, p = 0.658 and 70.6% vs. 66.7%, p = 0.535). For PCOS patients with HOMA-IR ≥ 2.71, the clinical pregnancy rate in fresh ET cycles was comparable between the two groups (51.5% vs. 56.3, p = 0.590), but it was statistically higher in the metformin group than in the control group in frozen ET cycles (57.1% vs. 40.0%, p = 0.023). The metformin group had less oocytes retrieved, a lower cleaved oocyte rate, a lower available D3 embryo rate, a lower blastocyst formation rate, and a lower available blastocyst rate than the control group. Conclusion: HOMA-IR is a judgment criterion for metformin pre-treatment before IVF/ICSI-ET in patients with PCOS. Metformin pre-treatment could be added for PCOS patients with HOMA-IR ≥ 2.71 during frozen IVF/ICSI-ET cycles to improve the clinical pregnancy rate.

Homeostatic Model Assessment for Insulin Resistance Is Associated With Late Miscarriage in Non-Dyslipidemic Women Undergoing Fresh IVF/ICSI Embryo Transfer.

Objective: To evaluate the associations between homeostatic model assessment for insulin resistance (HOMA-IR) and pregnancy outcomes in non-dyslipidemic infertile women undergoing in vitro fertilization/intracytoplasmic sperm injection-embryo transfer (IVF/ICSI-ET). Materials and Methods: This is a retrospective study involving 3,615 non-dyslipidemic infertile women who attend to the Reproductive Medicine Center of Xiangya Hospital, Central South University (CSU) between January 2014 and October 2021. Eligible participants were divided into three groups according to the quartiles of HOMA-IR: Group 1 (HOMA-IR <1.46), Group 2 (1.46 to <2.71) and Group 3 (HOMA-IR ≥2.71). Baseline data, clinical characteristics during the assisted reproductive technology (ART) procedure, pregnancy, and neonatal outcomes were compared among the three groups. Subgroup analysis based on presence or absence of the polycystic ovary syndrome (PCOS) status was also performed to analyze the effects of HOMA-IR among non-PCOS populations. Results: The late miscarriage rate and percentage of macrosomia increased with the HOMA-IR group (for late miscarriage rate: 2.23% vs. 3.04% vs. 7.35%, P<0.001; for macrosomia: 0.21% vs. 1.70% vs. 3.23%, P=0.002). Increased HOMA-IR (HOMA-IR≥2.71) was positively associated with late miscarriage (crude OR 3.50, 95% CI 1.64-7.47, P=0.001; adjusted OR 3.56, 95% CI 1.56-8.15, P=0.003). In the subgroup analysis, there were 3,165 participants in the non-PCOS group and 450 were assigned to the PCOS group. Late miscarriage rate increased with the HOMA-IR group among non-PCOS populations (2.20% vs. 3.03% vs. 7.67%, P<0.001). Late miscarriage rate of PCOS women were comparable among the three HOMA-IR groups (2.50% vs. 3.06% vs. 5.71%, P=0.634). Among non-PCOS women, increased HOMA-IR (HOMA-IR≥2.71) was positively associated with late miscarriage (crude OR 3.71, 95% CI 1.66-8.30, P=0.001; adjusted OR 3.82, 95% CI 1.59-9.17, P=0.003). Conclusions: Late miscarriage rate and prevalence of macrosomia increased with the HOMA-IR index. Preconception HOMA-IR is an independent risk factor for late miscarriage in normolipidemic women undergoing IVF/ICSI-ET. Controlling insulin resistance before ART might prevent the occurrence of late miscarriage and macrosomia.

Noninvasive embryo evaluation and selection by time-lapse monitoring vs. conventional morphologic assessment in women undergoing in vitro fertilization/intracytoplasmic sperm injection: a single-center randomized controlled study.

OBJECTIVE: To determine whether time-lapse monitoring (TLM) for cleavage-stage embryo selection improves reproductive outcomes in comparison with conventional morphological assessment (CMA) selection. DESIGN: Prospective randomized controlled trial. SETTING: Single academic center. PATIENTS: We randomly assigned 139 women who were undergoing their first in vitro fertilization or intracytoplasmic sperm injection cycle to undergo either fresh embryo transfer or first frozen embryo transfer (FET). Only 1 cleavage-stage embryo was transferred to each participant. INTERVENTIONS: The patients were randomly assigned to either the CMA or the TLM group. In the CMA group, day 2 and day 3 embryos were observed. A good-quality cleavage-stage embryo was selected for transfer or freezing in both groups. MAIN OUTCOME MEASURES: The primary and secondary outcomes were the clinical pregnancy rate (CPR) and the live birth rate (LBR), respectively, after the first embryo transfer (fresh embryo transfer or FET). RESULTS: The CPR and LBR were significantly lower in the TLM group than in the CMA group (CPR: 49.18% vs. 70.42%; relative risk, 0.70; 95% confidence interval [CI], 0.52-0.94; LBR: 45.90% vs. 64.79%; relative risk, 0.71; 95% CI, 0.51-0.98). The CPR with fresh embryo transfer or FET did not significantly differ between the TLM and the CMA groups (fresh embryo transfer: 44.44% vs. 70.0%, relative risk, 0.63, 95% CI, 0.39-1.03; FET: 52.94% vs. 70.73%, relative risk, 0.75, 95% CI, 0.52-1.09). There was a significant difference in the LBR with fresh embryo transfer between the TLM and the CMA groups (40.74% vs. 66.67%; relative risk, 0.61; 95% CI, 0.36-1.03). The LBRs with FET were similar in the TLM and the CMA groups (50.0% vs. 63.41%; relative risk, 0.79; 95% CI, 0.52-1.19). The rates of early spontaneous abortion and ectopic pregnancy did not differ between the TLM and the CMA groups. CONCLUSIONS: Elective single cleavage-stage embryo transfer with TLM-based selection did not have any advantages over CMA when day 2 and day 3 embryo morphology was combined in young women with a good ovarian reserve. Because of these results, we conclude that TLM remains an investigational procedure for in vitro fertilization practice. CLINICAL TRIAL REGISTRATION NUMBER: ChiCTR1900021981.

Secondary male infertility: the importance of the urological assessment for couples who desire children in later life.

Amongst 942 out-patients who consulted our male infertility division between 2016 to 2020, 85 (9.0%) patients suffered from secondary infertility. Of these, in 59 (69.4%) subjects, the first pregnancy was achieved by natural conception. 81 subjects were evaluated for semen quality except for two subjects who at the time were undergoing cancer treatment and another of two ejaculatory dysfunction (EjD). Semen analysis revealed 16 subjects (19.8%) were azoospermic, whereas 9 (11.1%) were cryptozoospermic at median three years of infertility. Left varicocelectomy had been undertaken in a total of 17 oligoasthenozoospermic and cryptozoospermic cases in order to improve semen quality. For achieving natural pregnancy, microscopic vasoepididymostomy was performed in 3 subjects of obstructive azoospemia and patency was achieved in two of three. 11 azoospermic subjects and two of the EjD underwent sperm retrieval surgery for intracytoplasmic sperm injection (ICSI). Motile sperm recovery was obtained by microscopic epididymal sperm aspiration (5/5=100%), microscopic testicular sperm extraction (micro-TESE, 2/6=33.3%), and retrograde vasal sperm aspiration (2/2=100%). Natural pregnancy was obtained in two subjects following varicocelectomy, and in one following vasoepididymostomy. Seven pregnancies were achieved by ICSI using cryopreserved sperm and surgically retrieved sperm. Even if the first pregnancy occurred naturally, 30.9% subjects showed azoospermia or cryptozoospermia at median duration of three years. We would like to emphasize that earlier urological assessment especially semen analysis is necessary if pregnancy later in life is desired.

Economic evaluation of endometrial scratching before the second IVF/ICSI treatment: a cost-effectiveness analysis of a randomized controlled trial (SCRaTCH trial).

STUDY QUESTION: Is a single endometrial scratch prior to the second fresh IVF/ICSI treatment cost-effective compared to no scratch, when evaluated over a 12-month follow-up period? SUMMARY ANSWER: The incremental cost-effectiveness ratio (ICER) for an endometrial scratch was €6524 per additional live birth, but due to uncertainty regarding the increase in live birth rate this has to be interpreted with caution. WHAT IS KNOWN ALREADY: Endometrial scratching is thought to improve the chances of success in couples with previously failed embryo implantation in IVF/ICSI treatment. It has been widely implemented in daily practice, despite the lack of conclusive evidence of its effectiveness and without investigating whether scratching allows for a cost-effective method to reduce the number of IVF/ICSI cycles needed to achieve a live birth. STUDY DESIGN, SIZE, DURATION: This economic evaluation is based on a multicentre randomized controlled trial carried out in the Netherlands (SCRaTCH trial) that compared a single scratch prior to the second IVF/ICSI treatment with no scratch in couples with a failed full first IVF/ICSI cycle. Follow-up was 12 months after randomization.Economic evaluation was performed from a healthcare and societal perspective by taking both direct medical costs and lost productivity costs into account. It was performed for the primary outcome of biochemical pregnancy leading to live birth after 12 months of follow-up as well as the secondary outcome of live birth after the second fresh IVF/ICSI treatment (i.e. the first after randomization). To allow for worldwide interpretation of the data, cost level scenario analysis and sensitivity analysis was performed. PARTICIPANTS/MATERIALS, SETTING, METHODS: From January 2016 until July 2018, 933 women with a failed first IVF/ICSI cycle were included in the trial. Data on treatment and pregnancy were recorded up until 12 months after randomization, and the resulting live birth outcomes (even if after 12 months) were also recorded.Total costs were calculated for the second fresh IVF/ICSI treatment and for the full 12 month period for each participant. We included costs of all treatments, medication, complications and lost productivity costs. Cost-effectiveness analysis was carried out by calculating ICERs for scratch compared to control. Bootstrap resampling was used to estimate the uncertainty around cost and effect differences and ICERs. In the sensitivity and scenario analyses, various unit costs for a single scratch were introduced, amongst them, unit costs as they apply for the United Kingdom (UK). MAIN RESULTS AND THE ROLE OF CHANCE: More live births occurred in the scratch group, but this also came with increased costs over a 12-month period. The estimated chance of a live birth after 12 months of follow-up was 44.1% in the scratch group compared to 39.3% in the control group (risk difference 4.8%, 95% CI -1.6% to +11.2%). The mean costs were on average €283 (95% CI: -€299 to €810) higher in the scratch group so that the point average ICER was €5846 per additional live birth. The ICER estimate was surrounded with a high level of uncertainty, as indicated by the fact that the cost-effectiveness acceptability curve (CEAC) showed that there is an 80% chance that endometrial scratching is cost-effective if society is willing to pay ∼€17 500 for each additional live birth. LIMITATIONS, REASONS FOR CAUTION: There was a high uncertainty surrounding the effects, mainly in the clinical effect, i.e. the difference in the chance of live birth, which meant that a single straightforward conclusion could not be ascertained as for now. WIDER IMPLICATIONS OF THE FINDINGS: This is the first formal cost-effectiveness analysis of endometrial scratching in women undergoing IVF/ICSI treatment. The results presented in this manuscript cannot provide a clear-cut expenditure for one additional birth, but they do allow for estimating costs per additional live birth in different scenarios once the clinical effectiveness of scratching is known. As the SCRaTCH trial was the only trial with a follow-up of 12 months, it allows for the most complete estimation of costs to date. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by ZonMW, the Dutch organization for funding healthcare research. A.E.P.C., F.J.M.B., E.R.G. and C.B. L. reported having received fees or grants during, but outside of, this trial. TRIAL REGISTRATION NUMBER: Netherlands Trial Register (NL5193/NTR 5342).

Differences in ICSI utilization rates among states with insurance mandates for ART coverage.

BACKGROUND: Assisted reproductive technology (ART) insurance mandates promote more selective utilization of ART clinic resources including intracytoplasmic sperm injection (ICSI). Our objective was to examine whether ICSI utilization differs by state insurance mandates for ART coverage and assess if such a difference is associated with male factor, preimplantation genetic testing (PGT), and/or live birth rates. METHODS: In this retrospective analysis of the Centers for Disease Control (CDC) data from 2018, ART clinics in ART-mandated states (n = 8, AR, CT, HI, IL, MD, MA, NJ, RI) were compared individually to one another and with non-mandated states in aggregate (n = 42) for use of ICSI, male factor, PGT, and live birth rates. ANOVA was used to evaluate differences between ART-mandated states and non-mandated states. Individual ART-mandated states were compared using Welch t-tests. Statistical significance was determined by Bonferroni Correction. RESULTS: There were significant differences in ICSI rates (%, mean ± SD) between MA (53.3 ± 21.3) and HI (90.7 ± 19.6), p = 0.028; IL (86.5 ± 18.7) and MA, p = 0.002; IL and MD (57.2 ± 30.8), p = 0.039; IL and NJ (62.0 ± 26.8), p = 0.007; between non-mandated states in aggregate (79.9 ± 19.9) and MA, p = 0.006, and NJ (62.0 ± 26.8), p = 0.02. Male factor rates of HI (65.8 ± 16.0) were significantly greater compared to CT (18.8 ± 8.7), IL (26.0 ± 11.9), MA (26.9 ± 6.6), MD (29.3 ± 9.9), NJ (30.6 ± 17.9), and non-mandated states in aggregate (29.7 ± 13.7), all p < 0.0001. No significant differences were reported for use of PGT and/or live birth rates across all age groups regardless of mandate status. CONCLUSIONS: ICSI use varied significantly among ART-mandated states while demonstrating no differences in live birth rates. These data suggest that the prevalence of male factor and the presence of a state insurance mandate are not the only factors influencing ICSI use. It is suggested that other non-clinical factors may impact the rate of ICSI utilization in a given state.

Core Histones Are Constituents of the Perinuclear Theca of Murid Spermatozoa: An Assessment of Their Synthesis and Assembly during Spermiogenesis and Function after Gametic Fusion.

The perinuclear theca (PT) of the eutherian sperm head is a cytoskeletal-like structure that houses proteins involved in important cellular processes during spermiogenesis and fertilization. Building upon our novel discovery of non-nuclear histones in the bovine PT, we sought to investigate whether this PT localization was a conserved feature of eutherian sperm. Employing cell fractionation, immunodetection, mass spectrometry, qPCR, and intracytoplasmic sperm injections (ICSI), we examined the localization, developmental origin, and functional potential of histones from the murid PT. Immunodetection localized histones to the post-acrosomal sheath (PAS) and the perforatorium (PERF) of the PT but showed an absence in the sperm nucleus. MS/MS analysis of selectively extracted PT histones indicated that predominately core histones (i.e., H3, H3.3, H2B, H2A, H2AX, and H4) populate the murid PT. These core histones appear to be de novo-synthesized in round spermatids and assembled via the manchette during spermatid elongation. Mouse ICSI results suggest that early embryonic development is delayed in the absence of PT-derived core histones. Here, we provide evidence that core histones are de novo-synthesized prior to PT assembly and deposited in PT sub-compartments for subsequent involvement in chromatin remodeling of the male pronucleus post-fertilization.

A randomised controlled trial to assess the clinical effectiveness and safety of the endometrial scratch procedure prior to first-time IVF, with or without ICSI.

STUDY QUESTION: What is the clinical-effectiveness and safety of the endometrial scratch (ES) procedure compared to no ES, prior to usual first time in vitro fertilisation (IVF) treatment? SUMMARY ANSWER: ES was safe but did not improve pregnancy outcomes when performed in the mid-luteal phase prior to the first IVF cycle, with or without intracytoplasmic sperm injection (ICSI). WHAT IS KNOWN ALREADY: ES is an 'add-on' treatment that is available to women undergoing a first cycle of IVF, with or without ICSI, despite a lack of evidence to support its use. STUDY DESIGN, SIZE, DURATION: This pragmatic, superiority, open-label, multi-centre, parallel-group randomised controlled trial involving 1048 women assessed the clinical effectiveness and safety of the ES procedure prior to first time IVF, with or without ICSI, between July 2016 and October 2019. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants aged 18-37 years undergoing their first cycle of IVF, with or without ICSI, were recruited from 16 UK fertility clinics and randomised (1:1) by a web-based system with restricted access rights that concealed allocation. Stratified block randomisation was used to allocate participants to TAU or ES in the mid-luteal phase followed by usual IVF with or without ICSI treatment. The primary outcome was live birth after completing 24 weeks gestation within 10.5 months of egg collection. MAIN RESULTS AND THE ROLE OF CHANCE: In total, 1048 women randomised to TAU (n = 525) and ES (n = 523) were available for intention to treat analysis. In the ES group, 453 (86.6%) received the ES procedure. IVF, with or without ICSI, was received in 494 (94.1%) and 497 (95.0%) of ES and TAU participants respectively. Live birth rate was 37.1% (195/525) in the TAU and 38.6% (202/523) in the ES: an unadjusted absolute difference of 1.5% (95% CI -4.4% to 7.4%, P = 0.621). There were no statistical differences in secondary outcomes. Adverse events were comparable across groups. LIMITATIONS, REASONS FOR CAUTION: A sham ES procedure was not undertaken in the control group, however, we do not believe this would have influenced the results as objective fertility outcomes were used. WIDER IMPLICATIONS OF THE FINDINGS: This is the largest trial that is adequately powered to assess the impact of ES on women undergoing their first cycle of IVF. ES was safe, but did not significantly improve pregnancy outcomes when performed in the mid-luteal phase prior to the first IVF or ICSI cycle. We recommend that ES is not undertaken in this population. STUDY FUNDING/COMPETING INTEREST(S): Funded by the National Institute of Health Research. Stephen Walters is an National Institute for Health Research (NIHR) Senior Investigator (2018 to present) and was a member of the following during the project: National Institute for Health Research (NIHR) Health Technology Assessment (HTA) Clinical Trials and Evaluation Committee (2011-2017), NIHR HTA Commissioning Strategy Group (2012 to 2017); NIHR Programme Grants for Applied Research Committee (2020 to present); NIHR Pre doctoral Fellowship Committee (2019 to present). Dr. Martins da Silva reports grants from AstraZeneca, during the conduct of the study; and is Associate editor of Human Reproduction and Editorial Board member of Reproduction and Fertility. Dr. Bhide reports grants from Bart's Charity and grants and non-financial support from Pharmasure Pharmaceuticals outside the submitted work. TRIAL REGISTRATION NUMBER: ISRCTN number: ISRCTN23800982. TRIAL REGISTRATION DATE: 31 May 2016. DATE OF FIRST PATIENT'S ENROLMENT: 04 July 2016.

Outcome of in vitro fertilization cycles with automatic time-lapse instrumentation combined with the early embryo viability assessment score.

AIM: To evaluate whether embryo selection using the early embryo viability assessment (EEVA) score increases the ongoing pregnancy rate of in vitro fertilization and intracytoplasmic sperm injection patients. METHODS: One hundred eighty-one patients whose serum anti mullerian hormone (AMH) level was greater than 0.5 ng/µL were enrolled in the study. All patients received oocyte retrieval repeatedly from June 2017 to January 2019. Transferred embryos were selected using the EEVA score and Veeck's criteria. We investigated the blastocyst rate according to the EEVA score and Veeck's criteria and also evaluated the clinical outcome following embryo transfer of the blastocysts. RESULTS: Blastocyst development rate (48.7%) and high-quality blastocyst (42.4%) of Veeck 1 was statistically higher than others. The blastocyst rate (71.4%) and high-quality blastocyst rate (60.0%) for EEVA 1 was the highest, and a correlation between the EEVA score and the blastocyst rate was also identified in cases younger than 40 years. Blastocyst rate of EEVA 1 + 2 (69.8% 208/298) was statistically higher than that of Veeck 1 + 2 (40.1% 317/791) (p < 0.05) and high-quality blastocyst rate of EEVA 1 + 2 (50.0% 104/208) was also higher than that of Veeck 1 + 2 (36.6% 117/320) (p < 0.05). However, there was a significant correlation between EEVA and the pregnancy rate and pregnancy rate of EEVA 1 + 2 showed no statistical difference compared with Veeck 1 + 2. CONCLUSIONS: Although it remains to be answered whether a computer can substitute Veeck's classification, the EEVA score could be a viable alternative to predict the blastocyst rate and to select those high-potential embryos that improve the pregnancy rate.

Monitoring of stimulated cycles in assisted reproduction (IVF and ICSI).

BACKGROUND: Monitoring of in vitro fertilisation (IVF) and intra-cytoplasmic sperm injection (ICSI) is necessary to detect as well as reduce the incidence and severity of ovarian hyperstimulation syndrome (OHSS) whilst achieving the optimal ovarian response needed for assisted reproduction treatment. Traditional monitoring of ovarian hyperstimulation during in vitro fertilisation IVF and ICSI treatment has included transvaginal ultrasonography (TVUS) plus serum estradiol levels. The need for combined monitoring (using TVUS and serum estradiol) during ovarian stimulation in assisted reproduction is controversial. It has been suggested that combined monitoring is time consuming, expensive and inconvenient for women and that simplification of IVF and ICSI therapy by using TVUS only should be considered.  OBJECTIVES: To assess the effect of monitoring controlled ovarian hyperstimulation (COH) in IVF and ICSI cycles in subfertile couples with TVUS only versus TVUS plus serum estradiol concentration, with respect to rates of live birth, pregnancy and OHSS. SEARCH METHODS: In this update conducted in March 2020, two review authors searched the Cochrane Gynaecology and Fertility Group's Specialised Register, CENTRAL, MEDLINE, Embase, CINAHL, PsycINFO, the National Research Register, and web-based trial registers. There was no language restriction applied. All references in the identified trials and background papers were checked and authors were contacted to identify relevant published and unpublished data. SELECTION CRITERIA: Only randomised controlled trials that compared monitoring with TVUS only versus TVUS plus serum estradiol concentrations in women undergoing COH for IVF and ICSI treatment were included. DATA COLLECTION AND ANALYSIS: Two review authors (IK, AW) independently selected the studies, extracted data and assessed risk of bias. We resolved disagreements by discussion. Outcomes data were pooled and summary statistics were presented when appropriate. The quality of the evidence was rated using the GRADE methods. MAIN RESULTS: We did not identify any new eligible studies in this update in 2020. The evidence based on the six trials identified in 2014 remained unchanged. They included 781 women undergoing monitoring of COH with either TVUS alone or a combination of TVUS and serum estradiol concentration during IVF or ICSI treatment. None of the six studies reported our primary outcome of live birth rate. Two studies presented pregnancy rate per initiated cycle and per embryo transfer, respectively. Four studies reported pregnancy rate per woman with pooled data; we are uncertain of the effect of monitoring with TVUS only versus combined monitoring on clinical pregnancy rate per woman (odds ratio (OR) 1.10; 95% confidence interval (CI) 0.79 to 1.54; four studies; N = 617; I² = 5%; low quality evidence). This suggests in women with a 36% chance of clinical pregnancy using monitoring with TVUS plus serum estradiol, the clinical pregnancy rate using TVUS only would be between 31% and 46%. We are uncertain of any effect in the mean number of oocytes retrieved per woman (mean difference (MD) 0.32; 95% CI -0.60 to 1.24; five studies; N = 596; I² = 17%; low quality evidence).  We are uncertain whether monitoring with TVUS only versus combined monitoring affected the incidence of OHSS (OR 1.03; 95% CI 0.48 to 2.20; six studies; N = 781; I² = 0%; low quality evidence), suggesting that in women with a 4% chance of OHSS using monitoring with TVUS plus serum estradiol, the OHSS rate monitored by TVUS only would be between 2% and 8%. The cycle cancellation rate was similar in both arms of two studies (0/34 versus 1/31, 1/25 versus 1/25; OR 0.57; 95% CI 0.07 to 4.39; N = 115; I² = 0%; low quality evidence).  The evidence was low quality for all comparisons. Limitations included imprecision and potential bias due to unclear randomisation methods, allocation concealment and blinding, as well as differences in treatment protocols. Quality assessment was hampered by the lack of methodological descriptions in several studies. AUTHORS' CONCLUSIONS: This review update found no new randomised trials. Evidence from the six studies previously identified did not suggest that combined monitoring by TVUS and serum estradiol is more efficacious than monitoring by TVUS alone with regard to clinical pregnancy rates and the incidence of OHSS. The number of oocytes retrieved appeared similar for both monitoring protocols. The data suggest that both these monitoring methods are safe and reliable. However, these results should be interpreted with caution because the overall quality of the evidence was low. Results were compromised by imprecision and poor reporting of study methodology. The choice of one or the other method may depend upon the convenience of its use, and the associated costs. An economic evaluation of the costs involved with the two methods and the views of the women undergoing cycle monitoring would be welcome.

Impact of Nonylphenols and Polyhalogenated Compounds in Follicular Fluid on the Outcome of Intracytoplasmic Sperm Injection.

Endocrine-disrupting chemicals (EDCs) interfere with the mammalian hormone system and alter its endo- and paracrine regulation. The goal of the present study was to examine the presence of 14 EDCs, including the technical mixture of nonylphenols and Mirex, in human follicular fluid (FF) and to find a potential correlation between endocrine active substances and a possible impact on female fertility. Furthermore, potential sources of EDC exposition regarding patients' lifestyle and socioeconomic factors were investigated. Human FF was collected from a total of 210 women undergoing intracytoplasmic sperm injection-treatment cycles because of male subfertility. The presence of EDCs was analyzed using gas chromatography coupled with mass spectrometry. Thirteen of the 14 investigated EDCs were present in every FF sample; compounds with the highest concentrations in FF were nonylphenol and Mirex. Nearly all kinds of EDCs led to significantly reduced maturation and fertilization rate. No significant influence of EDC concentration on the clinical pregnancy rate was observed for neither of the analyzed EDCs. Patients who obtained their clothes and textiles at fashion discounters displayed a higher amount of EDCs in their FF. In contrast, patients' residential area, source of food products, and nicotine or caffeine consumed were not associated with EDC accumulation. Clinicaltrials.gov NCT01385605 (11 July 2011).

Cost-effectiveness of freeze-all policy - A retrospective study based upon the outcome of cumulative live births.

OBJECT: We have previously reported that cumulative live birth rates (CLBRs) are higher in the freeze-all group compared with controls (64.3% vs. 45.8%, p = 0.001). Here, we aim to determine if the freeze-all policy is more cost-effective than fresh embryo transfer followed by frozen-thawed embryo transfer (FET). MATERIALS AND METHODS: The analysis consisted of 704 ART (Assisted reproductive technology) cycles, which included in IVF (In vitro fertilisation) and ICSI (Intra Cytoplasmic Sperm Injection) cycles performed in Taichung Veterans General Hospital, Taiwan between January 2012 and June 2014. The freeze-all group involved 84 patients and the fresh Group 625 patients. Patients were followed up until all embryos obtained from a single controlled ovarian hyper-stimulation cycle were used up, or a live birth had been achieved. The total cost related to treatment of each patient was recorded. The incremental cost-effectiveness ratio (ICER) was based on the incremental cost per couple and the incremental live birth rate of the freeze-all strategy compared with the fresh ET strategy. Probabilistic sensitivity analysis (PSA) and a cost-effectiveness acceptability curve (CEAC) were performed. RESULTS: The total treatment cost per patient was significantly higher for the freeze-all group than in the fresh group (USD 3419.93 ± 638.13 vs. $2920.59 ± 711.08 p < 0.001). However, the total treatment cost per live birth in the freeze-all group was US $5319.89, vs. US $6382.42 in the fresh group. CEAC show that the freeze-all policy was a cost-effective treatment at a threshold of US $2703.57 for one additional live birth. Considering the Willingness-to-pay threshold per live birth, the probability was 60.1% at the threshold of US $2896.5, with the freeze-all group being more cost-effective than the fresh-ET group; or 90.1% at the threshold of $4183.8. CONCLUSION: The freeze-all policy is a cost-effective treatment, as long as the additional cost of US $2703.57 per additional live birth is financially acceptable for the subjects.

Cost-effectiveness of prenatal screening methods for congenital heart defects in pregnancies conceived by in-vitro fertilization.

OBJECTIVES: To determine if a policy of universal fetal echocardiography (echo) in pregnancies conceived by in-vitro fertilization (IVF) is cost-effective as a screening strategy for congenital heart defects (CHDs) and to examine the cost-effectiveness of various other CHD screening strategies in IVF pregnancies. METHODS: A decision-analysis model was designed from a societal perspective with respect to the obstetric patient, to compare the cost-effectiveness of three screening strategies: (1) anatomic ultrasound (US): selective fetal echo following abnormal cardiac findings on detailed anatomic survey; (2) intracytoplasmic sperm injection (ICSI) only: fetal echo for all pregnancies following IVF with ICSI; (3) all IVF: fetal echo for all IVF pregnancies. The model initiated at conception and had a time horizon of 1 year post-delivery. The sensitivities and specificities for each strategy, the probabilities of major and minor CHDs and all other clinical estimates were derived from the literature. Costs, including imaging, consults, surgeries and caregiver productivity losses, were derived from the literature and Medicare databases, and are expressed in USA dollars ($). Effectiveness was quantified as quality-adjusted life years (QALYs), based on how the strategies would affect the quality of life of the obstetric patient. Secondary effectiveness was quantified as number of cases of CHD and, specifically, cases of major CHD, detected. RESULTS: The average base-case cost of each strategy was as follows: anatomic US, $8119; ICSI only, $8408; and all IVF, $8560. The effectiveness of each strategy was as follows: anatomic US, 1.74487 QALYs; ICSI only, 1.74497 QALYs; and all IVF, 1.74499 QALYs. The ICSI-only strategy had an incremental cost-effectiveness ratio (ICER) of $2 840 494 per additional QALY gained when compared to the anatomic-US strategy, and the all-IVF strategy had an ICER of $5 692 457 per additional QALY when compared with the ICSI-only strategy. Both ICERs exceeded considerably the standard willingness-to-pay threshold of $50 000-$100 000 per QALY. In a secondary analysis, the ICSI-only strategy had an ICER of $527 562 per additional case of major CHD detected when compared to the anatomic-US strategy. All IVF had an ICER of $790 510 per case of major CHD detected when compared with ICSI only. It was determined that it would cost society five times more to detect one additional major CHD through intensive screening of all IVF pregnancies than it would cost to pay for the neonate's first year of care. CONCLUSION: The most cost-effective method of screening for CHDs in pregnancies following IVF, either with or without ICSI, is to perform a fetal echo only when abnormal cardiac findings are noted on the detailed anatomy scan. Performing routine fetal echo for all IVF pregnancies is not cost-effective. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.