Economic Evaluation of Medically Assisted Reproduction: A Methodological Systematic Review.

BACKGROUND: Medically assisted reproduction (MAR) is a challenging application area for health economic evaluations, entailing a broad range of costs and outcomes, stretching out long-term and accruing to several parties. PURPOSE: To systematically review which costs and outcomes are included in published economic evaluations of MAR and to compare these with health technology assessment (HTA) prescriptions about which cost and outcomes should be considered for different evaluation objectives. DATA SOURCES: HTA guidelines and systematic searches of PubMed Central, Embase, WOS CC, CINAHL, Cochrane (CENTRAL), HTA, and NHS EED. STUDY SELECTION: All economic evaluations of MAR published from 2010 to 2022. DATA EXTRACTION: A predetermined data collection form summarized study characteristics. Essential costs and outcomes of MAR were listed based on HTA and treatment guidelines for different evaluation objectives. For each study, included costs and outcomes were reviewed. DATA SYNTHESIS: The review identified 93 cost-effectiveness estimates, of which 57% were expressed as cost-per-(healthy)-live-birth, 19% as cost-per-pregnancy, and 47% adopted a clinic perspective. Few adopted societal perspectives and only 2% used quality-adjusted life-years (QALYs). Broader evaluations omitted various relevant costs and outcomes related to MAR. There are several cost and outcome categories for which available HTA guidelines do not provide conclusive directions regarding inclusion or exclusion. LIMITATIONS: Studies published before 2010 and of interventions not clearly labeled as MAR were excluded. We focus on methods rather than which MAR treatments are cost-effective. CONCLUSIONS: Economic evaluations of MAR typically calculate a short-term cost-per-live-birth from a clinic perspective. Broader analyses, using cost-per-QALY or BCRs from societal perspectives, considering the full scope of reproduction-related costs and outcomes, are scarce and often incomplete. We provide a summary of costs and outcomes for future research guidance and identify areas requiring HTA methodological development. HIGHLIGHTS: The cost-effectiveness of MAR procedures can be exceptionally complex to estimate as there is a broad range of costs and outcomes involved, in principle stretching out over multiple generations and over many stakeholders.We list 21 key areas of costs and outcomes of MAR. Which of these needs to be accounted for alters for different evaluation objectives (determined by the type of economic evaluation, time horizon considered, and perspective).Published studies mostly investigate cost-effectiveness in the very short-term, from a clinic perspective, expressed as cost-per-live-birth. There is a lack of comprehensive economic evaluations that adopt a broader perspective with a longer time horizon. The broader the evaluation objective, the more relevant costs and outcomes were excluded.For several costs and outcomes, particularly those relevant for broader, societal evaluations of MAR, the inclusion or exclusion is theoretically ambiguous, and HTA guidelines do not offer sufficient guidance.

The value of treatment for infertility: A systematic literature review of willingness-to-pay thresholds and approaches for determining the cost effectiveness of fertility therapies.

Willingness to pay (WTP) for an infertility treatment is the maximum amount of money a patient is willing to pay per treatment, or to achieve a live birth or pregnancy. Such thresholds are important to determine the cost effectiveness of a treatment. A systematic review was conducted to identify and explore the studies that attempt to ascertain WTP for infertility and compare them with the cost-effectiveness studies that claimed to use WTP thresholds. For comparison, all the costs were converted and inflated to 2021 euros. The results demonstrated that there were no standard outcomes or WTP thresholds for an outcome/treatment, and the methodologies used vary. Cost-effectiveness studies either used the incremental cost-effectiveness ratio to imply a WTP threshold, or used thresholds that were previously accepted for a quality-adjusted life year outcome converted, inappropriately, to an infertility outcome. There is a need for further research by health economists to develop a consensus for the meaningful assessment of WTP for ART.

Comparative Assessment of the Structural Features of Originator Recombinant Human Follitropin Alfa Versus Recombinant Human Follitropin Alfa Biosimilar Preparations Approved in Non-European Regions.

Although the full primary structures of the alfa and beta subunits of reference r-hFSH-alfa and its biosimilars are identical, cell context-dependent differences in the expressing cell lines and manufacturing process can lead to variations in glycosylation profiles. In the present study, we compared the structural features of reference r-hFSH-alfa with those of five biosimilar preparations approved in different global regions outside Europe (Primapur®, Jin Sai Heng®, Follitrope®, Folisurge®, and Corneumon®) with respect to glycosylation, macro- and microheterogeneity, and other post-translational modifications and higher order structure. The mean proportion of N-glycosylation-site occupancy was highest in reference r-hFSH-alfa, decreasing sequentially in Primapur, Jin Sai Heng, Corneumon, Follisurge and Follitrope, respectively. The level of antennarity showed slightly higher complexity in Corneumon, Primapur and Follitrope versus reference r-hFSH-alfa, whereas Jin Sai Heng and Folisurge were aligned with reference r-hFSH-alfa across all N-glycosylation sites. Sialylation level was higher in Corneumon and Follitrope, but small differences were detected in other biosimilar preparations compared with reference r-hFSH-alfa. Jin Sai Heng showed higher levels of N-glyconeuramic acid than the other preparations. Minor differences in oxidation levels were seen among the different products. Therefore, in summary, we identified var ious differences in N-glycosylation occupancy, antennarity, sialylation and oxidation between reference r-hFSH-alfa and the biosimilar preparations analyzed.

Originator recombinant human follitropin alfa versus recombinant human follitropin alfa biosimilars in Spain: A cost-effectiveness analysis of assisted reproductive technology related to fresh embryo transfers.

This study compared the cost per live birth and cost-effectiveness of the originator recombinant human follicle-stimulating hormone follitropin alfa (r-hFSH-alfa) and r-hFSH-alfa biosimilars for ovarian stimulation prior to assisted reproductive technology treatment in Spain. A decision tree model was developed, comprising pregnancy and live birth for one treatment cycle with fresh embryo transfer. Clinical inputs were based on a recent meta-analysis by Chua et al. [4]. Cost inputs were extracted from publicly available Spanish sources. The costs per live birth were lower with originator r-hFSH-alfa (€18,138) versus r-hFSH-alfa biosimilars (€20,377). The incremental cost-effectiveness ratio was €7208 for originator r-hFSH-alfa versus biosimilars. Drug acquisition costs for originator r-hFSH-alfa represented 10.5% of total costs in the base case analysis, and 6.2% in a treatment cycle resulting in live birth with one fresh embryo transfer. Results from the sensitivity analyses confirmed the robustness of the findings.

Cost-effectiveness analysis of recombinant human follicle-stimulating hormone alfa(r-hFSH) and urinary highly purified menopausal gonadotropin (hMG) based on data from a large German registry.

This was a retrospective real-world evidence analysis of the costs per live birth for reference recombinant human follicle-stimulating hormone alfa (r-hFSH-alfa) versus highly purified urinary human menopausal gonadotropin (hMG-HP), based on data from a German in vitro fertilization registry (RecDate). Pregnancy and live birth rates from the RecDate real-world evidence study over three complete assisted reproductive technology (ART) cycles using the same gonadotropin drug were used as clinical inputs. Costs related to ART treatment and to drugs were obtained from public sources. Treatment with r-hFSH-alfa resulted in higher adjusted cumulative live birth rates versus hMG-HP after one (25.3% vs. 22.3%), two (30.9% vs. 27.5%), and three (31.9% vs. 28.6%) ART cycles. Costs per live birth were lower with r-hFSH-alfa versus hMG-HP after one (€17,938 vs. €20,054), two (€18,251 vs. €20,437), and three (€18,473 vs. €20,680) ART cycles. r-hFSH-alfa was found to be a cost-effective strategy compared with hMG-HP over three cycles.

Economic evaluation of Medically Assisted Reproduction: An educational overview of methods and applications for healthcare professionals.

Economic evaluations of the value-for-money of Medically Assisted Reproduction (MAR) interventions are increasingly important due to growing pressure on healthcare budgets. Although such evaluations are commonplace in the published literature, the number/methodological complexity of different evaluations available, and the challenges specific to MAR interventions, can complicate the interpretation of such analyses for fertility treatments. This article aims to serve as an educational resource and provide context on the design/interpretation of economic analyses for MAR interventions. Several areas are relevant for first-line providers and decision makers: scope of analysis, comparator used, perspective/time horizon considered, outcomes used to measure success, and how results from cost-effectiveness studies can be summarised and used in clinical practice. We aim to help clinicians better understand the strengths/weaknesses of economic analyses, to enable the best use of the evidence in practice, so resources available for MAR interventions can provide maximum value to patients and society.

Technical Verification and Assessment of Independent Validation of Biomarker Models for Endometriosis.

There is a great need for a noninvasive diagnosis for endometriosis. Several biomarkers and biomarker panels have been proposed. Biomarker models consisting of CA-125, VEGF, Annexin V, and glycodelin/sICAM-1 were previously developed by our group. The objective of our current study was to assess the impact of technical and biological variability on the performance of those previously developed prediction models in a technical verification and a validation setting. The technical verification cohort consisted of peripheral blood plasma samples from a subset of the patients included in the original study of Vodolazkaia et al. (99 women with and 37 women without endometriosis). The validation study was done in plasma samples of an independent patient cohort (170 women with and 86 women without endometriosis). Single immunoassays were used for CA-125, VEGF-A, sICAM-1, Annexin V, and glycodelin. Statistical analyses were done using univariate and multivariate (logistic regression) approaches. The previously reported prediction models for endometriosis had a low performance in both the technical verification and validation setting. New prediction models were developed, which included CA-125, Annexin V, and sICAM-1, but CA-125 was the only marker that was retained in the models across the technical verification and validation study. Overall, successful validation of a biomarker model depends on several factors such as patient selection, collection methods, assay selection/handling, stability of the marker, and statistical analysis and interpretation. There is a need for standardized studies in large, well-defined patient cohorts with robust assay methodologies.

Cost-effectiveness of ovarian stimulation with gonadotrophin and clomiphene citrate in an intrauterine insemination programme for subfertile couples.

Ovarian stimulation with low-dose human menopausal gonadotrophin (HMG) is superior to clomiphene citrate in intrauterine insemination (IUI) cycles with respect to clinical pregnancy rate, but it is unclear whether HMG is also the more cost-effective option. The aim of this study was to compare the cost-effectiveness of ovarian stimulation with low-dose subcutaneously administred HMG (37.5-75 IU per day) to orally administred clomiphene citrate (50 mg/day from day 3-7) in an IUI programme for subfertile couples. A cost-effectiveness analysis was conducted using the results of a randomized trial, including 620 IUI cycles. The primary outcome was the incremental cost-effectiveness ratio (ICER) of using HMG versus clomiphene citrate. Results are presented from the healthcare payer perspective. The total cost per patient associated with one IUI treatment with HMG is €764, whereas it is €558 if clomiphene citrate is used, resulting in an incremental cost of €206 for HMG per treatment. The incremental clinical pregnancy rate of using HMG instead of clomiphene citrate, however, is also 5.7 percentage points higher, resulting in an ICER of HMG versus clomiphene citrate of €3615 per additional clinical pregnancy achieved. On average, HMG was found to be more cost-effective than clomiphene citrate.

Transparent collaboration between industry and academia can serve unmet patient need and contribute to reproductive public health.

The pharmaceutical and device industry has greatly contributed to diagnostic and therapeutic approaches in reproductive medicine in a very highly regulated environment, ensuring that development and manufacturing follow the highest standards. In spite of these achievements, collaboration between industry and physicians/academia is often presented in a negative context. However, today more than ever, partnership between industry and academia is needed to shorten the timeline between innovation and application, and to achieve faster access to better diagnostics, drugs and devices for the benefit of patients and society, based on complementary knowledge, skills and expertise. Such partnerships can include joined preclinical/clinical and post-marketing research and development, joint intellectual property, and joint revenue. In Europe, the transparency of this collaboration between pharmaceutical industry and medical doctors has been made possible by the Compliance and Disclosure Policy published by the European Federation of Pharmaceutical Industries and Associations (EFPIA), which represents the major pharmaceutical companies operating in Europe, and includes as members some but not all companies active in infertility and women's health. Under the EFPIA Disclosure Code of conduct, companies need to disclose transfers of value including amounts, activity type and the names of the recipient Health Care Professionals and Organizations. EFPIA member companies have also implemented very strict internal quality control processes and procedures in the design, statistical analysis, reporting, publication and communication of clinical research, according to Good Clinical Practice and other regulations, and are regularly inspected by competent authorities such as the US Food and Drug Administration (FDA) or European Medicines Agency (EMA) for all trials used in marketing authorization applications. The risk of scientific bias exists not only in the pharmaceutical industry but also in the academic world. When academics believe in a hypothesis, they may build their case by emphasizing the arguments supporting their case, and either refute, refuse, oppose or ignore arguments that challenge their assumptions. A possible solution to reduce this bias is international consensus on study design, data collection, statistical analysis and reporting of outcomes, especially in the area of personalized reproductive medicine, e.g. to demonstrate superiority or non-inferiority of personalized ovarian stimulation using biomarkers. Equally important is that declarations of interest are reported transparently and completely in scientific abstracts and publications, and that ghost authorship is replaced by proactive and clear co-authorship for experts from industry where such co-authorship is required based on the prevailing ICMJE criteria. In that context, however, reviewers should stop believing that publications by industry authors only, or by mixed groups of co-authors from industry and academia, are more prone to bias than papers from academic groups only. Instead, the scientific quality of the work should be the only relevant criterion for acceptance of papers or abstracts, regardless of the environment where the work was done. In the end, neutrality does not exist and different beliefs and biases exist within and between healthcare professionals and organizations and pharmaceutical industries. The challenge is to be transparent about this reality at all times, and to behave in an informed, balanced and ethical way as medical and scientific experts, taking into account compliance and legal regulations of both industry and academic employers, in the best interest of patients and society.

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 the societal burden of endometriosis-associated symptoms? a prospective Belgian study.

Endometriosis is a complex disease that affects a large number of women of reproductive age and imposes a significant burden on patients and society. The aim of this study was to evaluate diagnosis, comorbidities, healthcare resource use, treatment patterns, costs and quality of life of women with endometriosis seen in a Belgian tertiary care centre. A total of 134 patients were included in a prospective questionnaire-based cost-of-illness study. Patients were diagnosed after a median delay of 2 years after onset of symptoms. Almost all patients reported having at least one comorbidity. Total annual costs per patient were €9872 (95% confidence interval €7930­11,870), with costs of productivity loss representing 75% of total costs. Hospitalizations, surgeries, infertility treatments, pain and anxiety increased total costs significantly (P 0.001). Patients generated an average of 0.82 QaLY over a 1-year time horizon. This study showed that direct and indirect costs attributable to endometriosis-associated symptoms are substantial. Earlier diagnosis and cost-effective treatment of endometriosis may decrease productivity loss, quality of life impairment and healthcare consumption and consequently reduce total costs to patients and society.

Baboon spermatology: basic assessment and reproducibility in olive baboons (Papio anubis).

BACKGROUND: Development of a reproducible baboon in vitro fertilization (IVF) system require optimized and reproducible sperm parameters. The objective of this study was to document basic spermatology values and investigate the reproducibility of these variables in the same baboons 1 or 3 months later in a larger number of baboons. METHODS: In this prospective study, sperm quality (semen volume, pH, concentration, motility, morphology and size) was evaluated in 27 sperm samples obtained from 9 baboons electroejaculated three times with a time interval of 1 month (between first and second sample collection) and 3 months (between second and third round sample collection). RESULTS: Baseline sperm values for semen volume (0.5 ± 0.3 ml), pH (7.5 ± 0.3), concentration (54.2 ± 19.3 million/ml), motility (67.3 ± 18.5%) and morphology (89.2 ± 4.8%) were similar to sperm samples obtained after 1 or 3 months (P > 0.05). Head, midpiece and tail abnormalities were rarely observed (0-9%). Sperm dimensions were characterized by a tail length of 69.6 ± 13.9 µm, a head width of 2.41 ± 0.43 µm and a head length of 3.49 ± 0.6 µm. CONCLUSION: Sperm quality was not affected by repeated electroejaculation with time intervals of 1 or 3 months, suggesting that the same baboon can participate multiple times in reproductive research.

Does the European Union Tissues and Cells Directive improve quality in the in vitro fertilization laboratory? A case study in a tertiary referral center.

Since 2004, assisted conception is encompassed by the European Directive on the Quality and Safety of Tissues and Cells (2004/23/EC). The aim of a standard for quality and safety is to minimize risks of errors, contamination, and accidents and to maximize efficiency of use. This article presents a case study of the implementation of the Tissues and Cells Directive in the Leuven University Fertility Center (LUFC) with a focus on the assisted reproductive technologies laboratory with respect to laboratory facilities, quality management system, traceability, storage conditions as well as serological screening. Although the current European Union (EU) Directive can be considered a step in the right direction to improve patient safety, questions remain as to whether the implementation of this EU Directive, requiring extra time and money, has resulted in higher quality with respect to the quality dimensions of effectiveness, efficiency, timeliness, equity, and patient centeredness.

The burden of endometriosis: costs and quality of life of women with endometriosis and treated in referral centres.

BACKGROUND: This study aimed to calculate costs and health-related quality of life of women with endometriosis-associated symptoms treated in referral centres. METHODS: A prospective, multi-centre, questionnaire-based survey measured costs and quality of life in ambulatory care and in 12 tertiary care centres in 10 countries. The study enrolled women with a diagnosis of endometriosis and with at least one centre-specific contact related to endometriosis-associated symptoms in 2008. The main outcome measures were health care costs, costs of productivity loss, total costs and quality-adjusted life years. Predictors of costs were identified using regression analysis. RESULTS: Data analysis of 909 women demonstrated that the average annual total cost per woman was €9579 (95% confidence interval €8559-€10 599). Costs of productivity loss of €6298 per woman were double the health care costs of €3113 per woman. Health care costs were mainly due to surgery (29%), monitoring tests (19%) and hospitalization (18%) and physician visits (16%). Endometriosis-associated symptoms generated 0.809 quality-adjusted life years per woman. Decreased quality of life was the most important predictor of direct health care and total costs. Costs were greater with increasing severity of endometriosis, presence of pelvic pain, presence of infertility and a higher number of years since diagnosis. CONCLUSIONS: Our study invited women to report resource use based on endometriosis-associated symptoms only, rather than drawing on a control population of women without endometriosis. Our study showed that the economic burden associated with endometriosis treated in referral centres is high and is similar to other chronic diseases (diabetes, Crohn's disease, rheumatoid arthritis). It arises predominantly from productivity loss, and is predicted by decreased quality of life.

Intra- and interobserver analysis in the morphological assessment of early stage embryos during an IVF procedure: a multicentre study.

BACKGROUND: Quality control programs are necessary to maintain good clinical practice. Embryo grading has been described as one of the external quality assurance schemes. Although the evaluation of embryos is based on the assessment of morphological characteristics, considerable intra- and inter-observer variability has been described. In this multicentre study, the variability in the embryo evaluation has been evaluated using morphological characteristics on day 1, day 2 and day 3 of embryo development. METHODS: Five embryologists of four different IVF centers participated in this study. Multilevel images of embryos were presented on a website at different time points to evaluate intra-and inter-observer agreement in the assessment of embryo morphology. The embryos were evaluated on day 1, day 2 and day 3 of their development and each embryologist had to decide if the embryo had to be transferred, cryopreserved or discarded. RESULTS: Both intra-observer agreement and inter-observer agreement were good to excellent for the position of the pronuclei on day 1, the number of blastomeres on day 2 and day 3 and the clinical decision (transfer, cryopreservation, discard). For all other characteristics (size of pronuclei, presence of cytoplasomic halo, degree of fragmentation and size of blastomeres) the intra- and inter-observer agreement was moderate to very poor. CONCLUSIONS: Mono- or multicentre quality control on embryo scoring by morphological assessment can easily be performed through the design of a simple website. In the future the website design can be adapted to generate statistical feedback upon scoring and can even include a training module.

Impact of endometriosis on quality of life and work productivity: a multicenter study across ten countries.

OBJECTIVE: To assess the impact of endometriosis on health-related quality of life (HRQoL) and work productivity. DESIGN: Multicenter cross-sectional study with prospective recruitment. SETTING: Sixteen clinical centers in ten countries. PATIENT(S): A total of 1,418 premenopausal women, aged 18-45 years, without a previous surgical diagnosis of endometriosis, having laparoscopy to investigate symptoms or to be sterilized. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Diagnostic delay, HRQoL, and work productivity. RESULT(S): There was a delay of 6.7 years, principally in primary care, between onset of symptoms and a surgical diagnosis of endometriosis, which was longer in centers where women received predominantly state-funded health care (8.3 vs. 5.5 years). Delay was positively associated with the number of pelvic symptoms (chronic pelvic pain, dysmenorrhoea, dyspareunia, and heavy periods) and a higher body mass index. Physical HRQoL was significantly reduced in affected women compared with those with similar symptoms and no endometriosis. Each affected woman lost on average 10.8 hours (SD 12.2) of work weekly, mainly owing to reduced effectiveness while working. Loss of work productivity translated into significant costs per woman/week, from US$4 in Nigeria to US$456 in Italy. CONCLUSION(S): Endometriosis impairs HRQoL and work productivity across countries and ethnicities, yet women continue to experience diagnostic delays in primary care. A higher index of suspicion is needed to expedite specialist assessment of symptomatic women. Future research should seek to clarify pain mechanisms in relation to endometriosis severity.

Non-health-care costs associated with endometriosis.

BACKGROUND: This study aims to quantify the non-health-care costs of endometriosis in a sample of Belgian patients over a 30-month period. METHODS: A longitudinal study enrolled patients who underwent surgical treatment for endometriosis in University Hospitals Leuven. Self-reported patient questionnaires measured costs at 1 month prior to surgical treatment and at 6, 12, 18 and 24 months following treatment. The number of days of work absence was valued using gross monthly income to estimate costs of productivity loss. Analysis included patient expenditure on support with household activities. The costs per patient over 6 months were obtained by linear extrapolation. RESULTS: Of 394 eligible patients, 180 participated in the study (response rate of 46%). The highest productivity loss was incurred during the 6 months preceding surgical treatment (€1514 ± 2576) and the 6 months following treatment (€2496 ± 4144). Mean costs dropped to €115-€225 during the following 6-month periods. Similarly, costs of support with household activities peaked during the 6 months preceding surgical treatment (€982 ± 908) and during the subsequent 6 months (€981 ± 1085), after which they dropped to €500-€675 during the following 6-month periods. Patients with severe endometriosis (Stage IV) (€4943) had higher total non-health-care costs over the 30-month period than patients with minimal-to-moderate endometriosis (Stages I-III) (€4510) (P = 0.048). CONCLUSIONS: As our study did not include a control population of women without endometriosis, patients were asked to report non-health-care costs associated with endometriosis only. Results show that the highest non-health-care costs associated with endometriosis are incurred during the 6 months prior to and following surgical treatment.