QS ENDO Pilot - A Study by the Stiftung Endometrioseforschung (SEF) on the Quality of Care Provided to Patients with Endometriosis in Certified Endometriosis Centers in the DACH Region.

Introduction Endometriosis significantly reduces patients' quality of life and is additionally a burden on healthcare and social security systems. There are currently no quality indicators for the treatment of endometriosis. The care of patients with endometriosis must be considered inadequate. QS ENDO aims to record the quality of care available in the DACH region and to introduce quality indicators for the diagnosis and treatment of endometriosis as part of providing quality assurance in endometriosis care. The first phase, QS ENDO Real, recorded the reality of current care using a questionnaire. The second phase, QS ENDO Pilot, investigated the treatment of 435 patients who underwent surgical treatment within a defined one month period in certified endometriosis centers. Material and Methods An online tool was used to gather information about 9 points which covered both prior patient history and the process of clinical diagnosis. Surgery reports were reviewed to obtain information about the surgical approach, the investigated sites, findings of any histological examinations, the use of classification systems, and information about resection status. Results 85.3% of patients were asked all 4 questions about their prior medical history. All 5 diagnostic steps were carried out in 34.5% of patients. The 3 areas needed to describe potential sites of disease were recorded in 67.1% of patients. Samples for histological examination were taken in 84.1% of patients. The endometriosis stage was classified in 94.7% of surgeries. A combination of the rASRM and the ENZIAN classifications, which is needed for complex cases, was used in 46.1% of patients. Complete resection was achieved in 81.6% of surgical procedures. Conclusion For the first time, the quality of care in certified endometriosis centers has been recorded using QS ENDO Pilot. Despite the high certification standards, a substantial number of required indicators were omitted.

Dosing Characteristics of Recombinant Human Luteinizing Hormone or Human Menopausal Gonadotrophin-Derived LH Activity in Patients Undergoing Ovarian Stimulation: A German Fertility Database Study.

OBJECTIVES: The aim of the study was to evaluate dosing of recombinant human luteinizing hormone (r-hLH) or human menopausal gonadotrophin (hMG)-derived medications with LH activity in ovarian stimulation (OS) cycles for in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI). DESIGN: A non-interventional study was performed to analyse data from the German RecDate database (January 2007-December 2011). PARTICIPANTS/MATERIALS, SETTING, METHODS: Starting/total r-hLH/hMG dose, OS duration/cycle number, r-hLH/hMG initiation day (first day of administration), and population/cycle characteristics were assessed in women (≥18 years) undergoing OS for IVF/ICSI using r-hLH or hMG-derived medications (excluding corifollitropin alfa, clomiphene citrate, letrozole, mini/micro-dose human chorionic gonadotrophin, and urofollitropin alone). Data were summarized descriptively. RESULTS: 67,858 identified cycles utilized medications containing r-hLH (10,749), hMG (56,432), or both (677). Mean (standard deviation) OS duration with r-hLH and hMG was 10.1 (4.43) and 9.8 (6.16) days, respectively. Median (25th-75th percentile) r-hLH starting dose (75.0 [75.0-150.0] IU) was consistent across patients regardless of age, infertility diagnosis, or gonadotrophin-releasing hormone (GnRH) protocol. Median (25th-75th percentile) hMG-derived LH activity starting dose was 225.0 (150.0-300.0) IU, regardless of GnRH protocol, but was lower in women aged <35 years and those with ovulation disorders/polycystic ovary syndrome. Median (25th-75th percentile) total dose for r-hLH (750.0 [337.5-1,125.0] IU) and hMG-derived LH activity (1,575.0 [750.0-2,625.0] IU) varied according to patients' age, infertility diagnosis, cycle number, and r-hLH/hMG initiation day. GnRH antagonist use resulted in a numerically higher median total hMG-derived LH activity dose than GnRH agonist use. LIMITATIONS: The data used in this study were taken from electronic medical records relating to a specific timeframe (2007-2011) and therefore may not accurately reflect current clinical practice; however, it is likely that the differences between the two compounds would be maintained. Additionally, secondary data sources may suffer from uniformity and quality issues. CONCLUSIONS: The standard of care for OS cycles is described with respect to IVF/ICSI treatment including an LH component in Germany during the specified timeframe.

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.

Comparative effectiveness of recombinant human follicle-stimulating hormone alfa (r-hFSH-alfa) versus highly purified urinary human menopausal gonadotropin (hMG HP) in assisted reproductive technology (ART) treatments: a non-interventional study in Germany.

BACKGROUND: This study compared the effectiveness of recombinant human follicle-stimulating hormone alfa (r-hFSH-alfa; GONAL-f®) with urinary highly purified human menopausal gonadotropin (hMG HP; Menogon HP®), during assisted reproductive technology (ART) treatments in Germany. METHODS: Data were collected from 71 German fertility centres between 01 January 2007 and 31 December 2012, for women undergoing a first stimulation cycle of ART treatment with r-hFSH-alfa or hMG HP. Primary outcomes were live birth, ongoing pregnancy and clinical pregnancy, based on cumulative data (fresh and frozen-thawed embryo transfers), analysed per patient (pP), per complete cycle (pCC) and per first complete cycle (pFC). Secondary outcomes were pregnancy loss (analysed per clinical pregnancy), cancelled cycles (analysed pCC), total drug usage per oocyte retrieved and time-to-live birth (TTLB; per calendar week and per cycle). RESULTS: Twenty-eight thousand six hundred forty-one women initiated a first treatment cycle (r-hFSH-alfa: 17,725 [61.9%]; hMG HP: 10,916 [38.1%]). After adjustment for confounding variables, treatment with r-hFSH-alfa versus hMG HP was associated with a significantly higher probability of live birth (hazard ratio [HR]-pP [95% confidence interval (CI)]: 1.10 [1.04, 1.16]; HR-pCC [95% CI]: 1.13 [1.08, 1.19]; relative risk [RR]-pFC [95% CI]: 1.09 [1.05, 1.15], ongoing pregnancy (HR-pP [95% CI]: 1.10 [1.04, 1.16]; HR-pCC [95% CI]: 1.13 [1.08, 1.19]; RR-pFC [95% CI]: 1.10 [1.05, 1.15]) and clinical pregnancy (HR-pP [95% CI]: 1.10 [1.05, 1.14]; HR-pCC [95% CI]: 1.14 [1.10, 1.19]; RR-pFC [95% CI]: 1.10 [1.06, 1.14]). Women treated with r-hFSH-alfa versus hMG HP had no statistically significant difference in pregnancy loss (HR [95% CI]: 1.07 [0.98, 1.17], were less likely to have a cycle cancellation (HR [95% CI]: 0.91 [0.84, 0.99]) and had no statistically significant difference in TTLB when measured in weeks (HR [95% CI]: 1.02 [0.97, 1.07]; p = 0.548); however, r-hFSH-alfa was associated with a significantly shorter TTLB when measured in cycles versus hMG HP (HR [95% CI]: 1.07 [1.02, 1.13]; p = 0.003). There was an average of 47% less drug used per oocyte retrieved with r-hFSH-alfa versus hMG HP. CONCLUSIONS: This large (> 28,000 women), real-world study demonstrated significantly higher rates of cumulative live birth, cumulative ongoing pregnancy and cumulative clinical pregnancy with r-hFSH-alfa versus hMG HP.

COVID-19 and assisted reproductive technology services: repercussions for patients and proposal for individualized clinical management.

The prolonged lockdown of health services providing high-complexity fertility treatments -as currently recommended by many reproductive medicine entities- is detrimental for society as a whole, and infertility patients in particular. Globally, approximately 0.3% of all infants born every year are conceived using assisted reproductive technology (ART) treatments. By contrast, the total number of COVID-19 deaths reported so far represents approximately 1.0% of the total deaths expected to occur worldwide over the first three months of the current year. It seems, therefore, that the number of infants expected to be conceived and born -but who will not be so due to the lockdown of infertility services- might be as significant as the total number of deaths attributed to the COVID-19 pandemic. We herein propose remedies that include a prognostic-stratification of more vulnerable infertility cases in order to plan a progressive restart of worldwide fertility treatments. At a time when preventing complications and limiting burdens for national health systems represent relevant issues, our viewpoint might help competent authorities and health care providers to identify patients who should be prioritized for the continuation of fertility care in a safe environment.

A two-third majority of infertile women exhibit endometriosis in pre-ART diagnostic hysteroscopy and laparoscopic chromopertubation: only one-third have a tubal obstruction.

PURPOSE: This study was undertaken to evaluate the prevalence of endometriosis in infertile women of couples with non-male factor infertility. METHODS: A retrospective validation analysis was carried out of consecutive women of infertile couples with non-male factor infertility who received combined diagnostic hysteroscopy and laparoscopy, in the period from January 2017 to August 2019 in the Department for Gynecology and Reproductive Medicine (n = 300). Type, stage and site of endometriosis were assessed and matched with the occurrence of tubal stenosis. Binary regression analysis was used to estimate the prevalence of endometriosis. RESULTS: Endometriosis was diagnosed in 67% (n = 201). Primary infertility (OR 1.76; p = 0.036), dysmenorrhea (OR 2.47; p = 0.002), and a shorter cycle length (OR 0.972; p = 0.036) were independent risk factors for detection of endometriosis in diagnostic hystero-laparoscopy. The most frequent endometriosis sites were pelvic side wall (53.2%) and uterosacral ligaments (41.8%). Patients with endometriosis showed less often a tubal occlusion (34.32% vs. 41.4%; p = 0.205) and presented a lower rate of bilateral obstruction (9.5% vs. 18.8.%, p = 0.024). Women with endometriosis of a Fallopian tube showed a higher rate of tubal occlusion on the same side (right side p = 0.002; left side p = 0.001). Patients with rASRM score III showed the highest rate of tubal obstruction. CONCLUSIONS: The prevalence of endometriosis in infertile women was higher than expected. The indication for operative infertility diagnostics by minimal invasive techniques should be made much more generous as well as the complete clarification of the causes of female infertility.

QS ENDO Real - A Study by the German Endometriosis Research Foundation (SEF) on the Reality of Care for Patients with Endometriosis in Germany, Austria and Switzerland.

Endometriosis affects a significant number of young premenopausal women. Quite apart from the medical challenges, endometriosis is a relevant burden for healthcare and social security systems. Standardized quality indicators for the treatment of endometriosis have not previously been systematically verified. The three-stage study QS ENDO was initiated to record and improve the reality and quality of care. One of its aims is to create quality indicators for the diagnosis and treatment of endometriosis. For the first stage of QS ENDO Real, letters were sent to all 1014 gynecological departments in the German-speaking area of Europe (the DACH region) which included a questionnaire as a means of surveying the current state of care. A total of 296 (29.2%) of the centers which received the questionnaire participated in the survey. The subsequent evaluation of the completed questionnaires showed that the majority of patients with endometriosis (around 60%, based on estimates from the data) are not treated in hospitals which have been certified by the SEF. The guidelines recommend the use of specific classification systems (rASRM, ENZIAN) but, depending on the level of care offered by the hospital, only around 44.4 to 66.4% of departments used the rASRM score and only 27% of hospitals used the ENZIAN classification system to describe deep-infiltrating endometriosis. When taking patients' medical history, some centers (6.6 - 17.9%) considered questions about leading symptoms such as dyschezia, dysuria and dyspareunia to be unimportant. QS ENDO Real has made it possible, for the first time, to get an overview of the reality of care provided to patients with endometriosis in the German-speaking areas of Europe. The findings indicate that several of the measures recommended in international guidelines as the gold standard of care are only used to treat some of the patients. In this respect, more efforts will be needed to provide more advanced training. The approach used for treatment must be guideline-based, also in not-certified centers, to improve the quality of care in the treatment of patients with endometriosis.

The POSEIDON Criteria and Its Measure of Success Through the Eyes of Clinicians and Embryologists.

This article represents a viewpoint on the POSEIDON criteria by a group of clinicians and embryologists. Its primary objective is to contextualize the Poseidon criteria and their metric of success for the relevant Frontiers Research Topic "POSEIDON's Stratification of Low Prognosis Patients in ART: The WHY, the WHAT, and the HOW". "Low prognosis" relates with reduced oocyte number, which can be associated with low or sometimes a normal ovarian reserve and is aggravated by advanced female age. These aspects will ultimately affect the number of embryos generated and consequently, the cumulative live birth rate. The novel system relies on female age, ovarian reserve markers, ovarian sensitivity to exogenous gonadotropin, and the number of oocytes retrieved, which will both identify the patients with low prognosis and stratify such patients into one of four groups of women with "expected" or "unexpected" impaired ovarian response to exogenous gonadotropin stimulation. Furthermore, the POSEIDON group introduced a new measure of clinical success in ART, namely, the ability to retrieve the number of oocytes needed to obtain at least one euploid blastocyst for transfer in each patient. Using the POSEIDON criteria, the clinician can firstly identify and classify patients who have low prognosis in ART, and secondly, aim at designing an individualized treatment plan to maximize the chances of achieving the POSEIDON measure of success in each of the four low prognosis groups. The novel POSEIDON classification system is anticipated to improve counseling and management of low prognosis patients undergoing ART, with an expected positive effect on reproductive success and a reduction in the time to live birth.

Endometriosis reduces ovarian response in controlled ovarian hyperstimulation independent of AMH, AFC, and women's age measured by follicular output rate (FORT) and number of oocytes retrieved.

PURPOSE: To determine the influence of endometriosis on the ovarian response during controlled ovarian hyperstimulation measured by number of oocytes retrieved and the follicular output rate (FORT). METHODS: A retrospective, single center study included 96 women, who underwent ICSI treatments for male factor infertility according to World Health Organisation between 2016 until 2018. A total of 96 patients were included in the study with 205 fresh ICSI cycles. The study group included 26 patients with endometriosis after surgical and medical treatment; the control group included 70 patients without endometriosis. The women with endometriosis underwent 47 and the control group 158 ICSI cycles. Women underwent fresh intracytoplasmatic sperm injection cycles after controlled ovarian hyperstimulation following a GnRH-antagonist protocol. The FORT was calculated as the ratio of pre-ovulatory follicle count × 100/small antral follicle count at baseline. RESULTS: A lower number of retrieved oocytes (5.89 vs. 7.25, p = 0.045), lower FORT (75.67 vs. 94.63, p = 0.046), lower number of metaphase II oocytes (4.87 vs. 6.04, p = 0.046), and lower fertilization rate after intracytoplasmatic sperm injection (40.61 vs. 57.76, p = 0.003) were found in women with endometriosis compared to women without endometriosis. The number of oocyctes retrieved was 0.71 lower in the group with endometriosis than in the group without (p = 0.026). The FORT was 24.55% lower in the group with endometriosis (p = 0.025). CONCLUSIONS: Endometriosis reduces the FORT and the number of metaphase-II oocytes after controlled ovarian hyperstimulation independly of women's age, antral follicle count and anti-Müllerian hormone.

A cost-effectiveness evaluation of the originator follitropin alpha compared to the biosimilars for assisted reproduction in Germany.

Background and objectives: Demand for assisted reproduction technology (ART) in Germany is high, with 100,844 treatment cycles during 2016. Many ART procedures involve ovarian stimulation with follicle stimulating hormone (FSH). Recently, biosimilar FSH products have become available. The objective of this study was to evaluate the cost-effectiveness of the recombinant FSH Gonal-f® (Originator) in comparison to biosimilar follitropin alfa, Bemfola® (Biosimilar 1) and Ovaleap® (Biosimilar 2), from a German payer perspective in terms of cost per live birth. Methods: A decision tree model was developed, based on one cycle of assisted reproduction, to compare the original product to biosimilars. Clinical inputs, including live birth rates and adverse event rates were obtained from published randomized trials. Cost inputs were obtained from publicly available German sources. Clinical inputs, model structure and methodology were based on previous publications and validated by a clinical expert. Results: Results indicated that the live birth rate is higher for the Originator compared to Biosimilar 1 (40.7% vs 32.1% respectively), and Biosimilar 2 (32.2% vs 26.8%). The average cost per live birth for women treated with the Originator was estimated to be lower than those who were treated with biosimilars: Originator vs Biosimilar 1 (€10,510 vs €12,192), Originator vs Biosimilar 2 (€12,590 vs €13,606). The analysis also found that the Originator is associated with an incremental cost-effectiveness of €4,168 and €7,540 per additional live birth versus Biosimilar 1 and Biosimilar 2 respectively. Sensitivity analysis indicated probabilities of pregnancy, embryo transfer and live birth, were key drivers of model costs. Scenario analysis confirmed the robustness of the model outcomes. Conclusion: This study suggests that treatment with the Originator could result in a lower cost per live birth in comparison to biosimilars. Further analysis using real-world data, when available, is recommended to validate the results of the present study.

A cost-effectiveness modeling evaluation comparing a biosimilar follitropin alfa preparation with its reference product for live birth outcome in Germany, Italy and Spain.

BACKGROUND/OBJECTIVE: Although biosimilar drugs may be cheaper to purchase than reference biological products, they may not be the most cost-effective treatment to achieve a desired outcome. The analysis reported here compared the overall costs to achieve live birth using the reference follitropin alfa (GONAL-f) or a biosimilar (Ovaleap) in Spain, Italy and Germany. METHODS: Patient and treatment data was obtained from published sources; assisted-reproductive technology, gonadotropin, follow-up and adverse-event-related costs were calculated from tariffs and reimbursement frameworks for each country. Incremental cost-effectiveness ratios (ICERs) were calculated from the difference in costs between reference and biosimilar in each country, divided by the difference in live-birth rates. Mean cost per live birth was calculated as total costs divided by the live-birth rate. RESULTS: The published live birth rates were 32.2% (reference) and 26.8% (biosimilar). Drug costs per patient were higher for the reference recombinant human follicle-stimulating hormone in all three countries, with larger cost differences in Germany (€157.38) and Italy (€141.50) than in Spain (€22.41). The ICER for the reference product compared with the biosimilar was €2917.47 in Germany, €415.43 in Spain and €2623.09 in Italy. However, the overall cost per live birth was higher for the biosimilar in all three countries (Germany €8135.04 vs. €9185.34; Italy €8545.22 vs. €9733.37; Spain €14,859.53 vs. €17,767.19). Uncertainty in efficacy, mean gonadotropin dose and costs did not have a strong effect on the ICERs. CONCLUSIONS: When considering live birth outcomes, treatment with the reference follitropin alfa was more cost effective than treatment with the biosimilar follitropin alfa.

Recombinant luteinizing hormone supplementation in assisted reproductive technology: a systematic review.

OBJECTIVE: To assess the role of recombinant human LH (r-hLH) supplementation in ovarian stimulation for ART in specific subgroups of patients. DESIGN: Systematic review. SETTING: Centers for reproductive care. PATIENT(S): Six populations were investigated: 1) women with a hyporesponse to recombinant human FSH (r-hFSH) monotherapy; 2) women at an advanced reproductive age; 3) women cotreated with the use of a GnRH antagonist; 4) women with profoundly suppressed LH levels after the administration of GnRH agonists; 5) normoresponder women to prevent ovarian hyperstimulation syndrome; and 6) women with a "poor response" to ovarian stimulation, including those who met the European Society for Human Reproduction and Embryology Bologna criteria. INTERVENTION(S): Systematic review. MAIN OUTCOME MEASURE(S): Implantation rate, number of oocytes retrieved, live birth rate, ongoing pregnancy rate, fertilization rate, and number of metaphase II oocytes. RESULT(S): Recombinant hLH supplementation appears to be beneficial in two subgroups of patients: 1) women with adequate prestimulation ovarian reserve parameters and an unexpected hyporesponse to r-hFSH monotherapy; and 2) women 36-39 years of age. Indeed, there is no evidence that r-hLH is beneficial in young (<35 y) normoresponders cotreated with the use of a GnRH antagonist. The use of r-hLH supplementation in women with suppressed endogenous LH levels caused by GnRH analogues and in poor responders remains controversial, whereas the use of r-hLH supplementation to prevent the development of ovarian hyperstimulation syndrome warrants further investigation. CONCLUSION(S): Recombinant hLH can be proposed for hyporesponders and women 36-39 years of age.

The neuro control of the ovarain cycle - a hypothesis.

Since more than 100 years, it is known that pituitary function depends upon the function of higher centers in the brain. It was already assumed at this time that pituitary extracts could influence the gonads and postulated that their use could have practical applications. In 1926, the 'gonadal principle' was discovered revealing the regulation of ovarian function by the pituitary. The two pituitary hormones were called 'Prolan A' and 'Prolan B' which are responsible for ovarian function especially secretion of the hormones: 'lutein' and 'foliculin'. If the names of Prolan A and B are changed to follicle-stimulating hormone (FSH) and luteinizing hormone (LH), and the names of foliculin and lutein to estrogen and progesterone, it becomes obvious that the pituitary-gonadal relationship, as we know it today, was first described in 1930. Then, the next step was the isolation, sequence and synthesis of gonadotropin releasing hormone (GnRH) responsible for the secretion of gonadotropins (Gn). It could be shown that GnRH pulse frequency has differential effects on Gn secretion: low-frequency pulses of GnRH stimulate preferentially FSH and high frequency LH secretion. The pulse frequency control depends from a subpopulation of kisspeptin neurons within the infundibular region of the hypothalamus with coexpression of neurokinin B and dynorphin A - KNDy neurons showing a negative feedback to estrogen. A second group of kisspeptide neurons in the rostral periventricular area of the third ventricle is devoid of neurokinin-B and dynorphin, mediates positive feedback from estrogen and so induces the midcycle LH-surge. Therefore, the variability in the frequency and amplitude of GnRH pulsatility is central to the differential regulation of LH and FSH and thus ovarian follicle development, the correct selection of a single dominant follicle for ovulation, the LH surge and the luteal phase.

A cost-effectiveness evaluation comparing originator follitropin alfa to the biosimilar for the treatment of infertility.

OBJECTIVES: To perform a cost-effectiveness evaluation comparing the originator follitropin alfa (Gonal-f®) to the biosimilar (Bemfola®) in the Italian and Spanish contexts, with an assessment of the German and UK backgrounds. METHODS: Starting from the study by Rettenbacher et al, a cost-effectiveness model was developed in the Italian and Spanish contexts. Clinical data on subjects, doses of gonadotropin, pregnancies, live-born children, and ovarian hyperstimulation syndrome were used to feed the model. Costs related to drugs, hospitalizations, specialist visits, and examinations were retrieved from Italian and Spanish tariffs. Gonadotropin acquisition costs for Germany and the UK were also taken into account to expand the economical assessment to the other countries. The evaluation was done based on the National Health Service perspective. Sensitivity analyses, both univariate and probabilistic, as long as scenario analyses, tested the robustness of the model. RESULTS: Originator follicle-stimulating hormone (FSH) costs were €3,663 and €6,387 in Italy and Spain, respectively, whereas biosimilar FSH costs were €3,483 and €6,342. The efficacy was found to be 0.52 for the originator and 0.47 for the biosimilar. The average cost per live birth was estimated to be €7,044 and €12,283 for the originator FSH and €7,411 and €13,494 for the biosimilar for Italy and Spain, respectively. Furthermore, the originator FSH generated an incremental cost-effectiveness ratio of €3,600 for Italy and €900 for Spain compared to the biosimilar. Sensitivity analyses confirmed the results of the base case model. CONCLUSION: This analysis indicated that the originator FSH is a cost-efficient treatment strategy for Italian and Spanish health services compared to the biosimilar and it would be worthwhile extending this evaluation to other countries.

Managing infertility with the follitropin alfa prefilled pen injector - patient considerations.

Gonadotropin treatment has been used in fertility treatment since the 1930s. First, preparations coming from animals were injected, then, gonadotropins prepared from the pituitary glands of human cadavers. A great step was achieved with the introduction of human menopausal gonadotropin extracted from the urine of postmenopausal women. When cases of Creutzfeld-Jacob disease were recognized after the use of human pituitary-derived hormone injections, urinary gonadotropins were increasingly purified and then produced by the use of recombinant DNA technology. Recombinant gonadotropins were characterized by the extreme high specificity and the nearly 100% purity. This allows for follitropin alfa, the first recombinant-human follicle stimulating hormone (r-hFSH) approved, to be quantified and filled by mass, with a small variance of only ±2% and no more with a bioassay with a variance of 45%. With recombinant preparations, it is also possible to cover the tremendous growing demand for gonadotropins. Ovarian stimulation has become a self-injecting procedure for the patients. Accurate and easy-to-use injection devices which minimize pain, difficulty, and stress are essential for patient compliance. So, two pen injectors adapted from the well-known insulin pen were introduced in fertility treatment, one as a multiple-use device rechargeable with premixed, prefilled cartridges with r-hFSH (follitropin ß) and the other a disposable, prefilled drug delivery system with a liquid formulation of follitropin alfa filled by mass. The efficacy in comparison to the quite more cumbersome handling with ampoules and syringes has been proven very quickly. In several studies, it has been shown that patients had a preference to the prefilled follitropin alfa pen due to the faster preparation and were more confident of accurate dosing. The follitropin alfa (filled by mass [FbM]) prefilled pen is a move toward better quality of treatment and also better quality of life for the women within the stressful period of fertility treatment.

A large, multicentre, observational, post-marketing surveillance study of the 2:1 formulation of follitropin alfa and lutropin alfa in routine clinical practice for assisted reproductive technology.

BACKGROUND: Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) both have a role to play in follicular development during the natural menstrual cycle. LH supplementation during controlled ovarian stimulation (COS) for assisted reproductive technology (ART) is used for patients with hypogonadotropic hypogonadism. However, the use of exogenous LH in COS in normogonadotropic women undergoing ART is the subject of debate. The aim of this study was to investigate characteristics of infertile women who received the 2:1 formulation of follitropin alfa and lutropin alfa (indicated for stimulation of follicular development in women with severe LH and FSH deficiency) in German clinical practice. METHODS: A 3-year, multicentre, open-label, observational/non-interventional, post-marketing surveillance study of women (21-45 years) undergoing ART. Primary endpoint: reason for prescribing the 2:1 formulation of follitropin alfa and lutropin alfa. Secondary variables included: COS duration/dose; oocytes retrieved; fertilization; clinical pregnancy; ovarian hyperstimulation syndrome (OHSS). RESULTS: In total, 2220 cycles were assessed; at least one reason for prescribing the 2:1 formulation was given in 1834/2220 (82.6%) cycles. Most common reasons were: poor ovarian response (POR) (39.4%), low baseline LH (17.8%), and age (13.8%). COS: mean dose of the 2:1 formulation on first day, 183.1/91.5 IU; mean duration, 10.8 days. In 2173/2220 (97.9%) cycles, human chorionic gonadotrophin was administered. Oocyte pick-up (OPU) was attempted in 2108/2220 (95.0%) cycles; mean (standard deviation) 8.0 (5.4) oocytes retrieved/OPU cycle. Fertilization (≥1 oocyte fertilized) rates: in vitro fertilization (IVF), 391/439 (89.1%) cycles; intracytoplasmic sperm injection (ICSI)/IVF + ICSI, 1524/1613 (94.5%) cycles. Clinical pregnancy rate: all cycles, 25.9%; embryo transfer cycles, 31.3%. OHSS: hospitalization for OHSS, 8 (0.36%) cycles, Grade 2, 60 (2.7%), and Grade 3, 1 (0.05%). CONCLUSIONS: In German routine clinical practice, the most common reasons for using the 2:1 formulation of follitropin alfa and lutropin alfa for women undergoing ART were POR, low baseline LH, and age. Severe OHSS incidence was low and similar to that reported previously.