Cumulative delivery rate per aspiration IVF/ICSI cycle in POSEIDON patients: a real-world evidence study of 9073 patients.

STUDY QUESTION: What is the cumulative delivery rate (CDR) per aspiration IVF/ICSI cycle in low-prognosis patients as defined by the Patient-Oriented Strategies Encompassing IndividualizeD Oocyte Number (POSEIDON) criteria? SUMMARY ANSWER: The CDR of POSEIDON patients was on average ∼50% lower than in normal responders and varied across POSEIDON groups; differences were primarily determined by female age, number of embryos obtained, number of embryo transfer (ET) cycles per patient, number of oocytes retrieved, duration of infertility, and BMI. WHAT IS KNOWN ALREADY: The POSEIDON criteria aim to underline differences related to a poor or suboptimal treatment outcome in terms of oocyte quality and quantity among patients undergoing IVF/ICSI, and thus, create more homogenous groups for the clinical management of infertility and research. POSEIDON patients are presumed to be at a higher risk of failing to achieve a live birth after IVF/ICSI treatment than normal responders with an adequate ovarian reserve. The CDR per initiated/aspiration cycle after the transfer of all fresh and frozen-thawed/warmed embryos has been suggested to be the critical endpoint that sets these groups apart. However, no multicenter study has yet substantiated the validity of the POSEIDON classification in identifying relevant subpopulations of patients with low-prognosis in IVF/ICSI treatment using real-world data. STUDY DESIGN, SIZE, DURATION: Multicenter population-based retrospective cohort study involving 9073 patients treated in three fertility clinics in Brazil, Turkey and Vietnam between 2015 and 2017. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants were women with infertility between 22 and 42 years old in their first IVF/ICSI cycle of standard ovarian stimulation whose fresh and/or frozen embryos were transferred until delivery of a live born or until all embryos were used. Patients were retrospectively classified according to the POSEIDON criteria into four groups based on female age, antral follicle count (AFC), and the number of oocytes retrieved or into a control group of normal responders (non-POSEIDON). POSEIDON patients encompassed younger (<35 years) and older (35 years or above) women with an AFC ≥5 and an unexpected poor (<4 retrieved oocytes) or suboptimal (4-9 retrieved oocytes) response to stimulation, and respective younger and older counterparts with an impaired ovarian reserve (i.e. expected poor responders; AFC <5). Non-POSEIDON patients were those with AFC ≥5 and >9 oocytes retrieved. CDR was computed per one aspirated cycle. Logistic regression analysis was carried out to examine the association between patient classification and CDR. MAIN RESULTS AND ROLE OF CHANCE: The CDR was lower in the POSEIDON patients than in the non-POSEIDON patients (33.7% vs 50.6%; P < 0.001) and differed across POSEIDON groups (younger unexpected poor responder [Group 1a; n = 212]: 27.8%, younger unexpected suboptimal responder [Group 1b; n = 1785]: 47.8%, older unexpected poor responder [Group 2a; n = 293]: 14.0%, older unexpected suboptimal responder [Group 2b; n = 1275]: 30.5%, younger expected poor responder [Group 3; n = 245]: 29.4%, and older expected poor responder [Group 4; n = 623]: 12.5%. Among unexpected suboptimal/poor responders (POSEIDON Groups 1 and 2), the CDR was twice as high in suboptimal responders (4-9 oocytes retrieved) as in poor responders (<4 oocytes) (P = 0.0004). Logistic regression analysis revealed that the POSEIDON grouping, number of embryos obtained, number of ET cycles per patient, number of oocytes collected, female age, duration of infertility and BMI were relevant predictors for CDR (P < 0.001). LIMITATIONS, REASONS FOR CAUTION: Our study relied on the antral follicle count as the biomarker used for patient classification. Ovarian stimulation protocols varied across study centers, potentially affecting patient classification. WIDER IMPLICATIONS OF THE FINDINGS: POSEIDON patients exhibit lower CDR per aspirated IVF/ICSI cycle than normal responders; the differences are mainly determined by female age and number of oocytes retrieved, thereby reflecting the importance of oocyte quality and quantity. Our data substantiate the validity of the POSEIDON criteria in identifying relevant subpopulations of patients with low-prognosis in IVF/ICSI treatment. Efforts in terms of early diagnosis, prevention, and identification of specific interventions that might benefit POSEIDON patients are warranted. STUDY FUNDING/COMPETING INTEREST(S): Unrestricted investigator-sponsored study grant (MS200059_0013) from Merck KGaA, Darmstadt, Germany. The funder had no role in study design, data collection, analysis, decision to publish or manuscript preparation. S.C.E. declares receipt of unrestricted research grants from Merck and lecture fees from Merck and Med.E.A. H.Y. declares receipt of payment for lectures from Merck and Ferring. L.N.V. receives speaker fees and conferences from Merck, Merck Sharp and Dohme (MSD) and Ferring and research grants from MSD and Ferring. J.F.C. declares receipt of statistical services fees from ANDROFERT Clinic. T.M.H. received speaker fees and conferences from Merck, MSD and Ferring. P.H. declares receipt of unrestricted research grants from Merck, Ferring, Gedeon Richter and IBSA and lecture fees from Merck, Gedeon Richter and Med.E.A. C.A. declares receipt of unrestricted research grants from Merck and lecture fees from Merck. The remaining authors have no conflicts of interest to disclose. TRIAL REGISTRATION NUMBER: N/A.

Contribution of cryopreservation to the cumulative live birth rate: a large multicentric cycle-based data analysis from the Italian National Registry.

PURPOSE: To estimate the contribution of cryopreservation to the cumulative live birth rate (CLBR) after law modification in Italy in the era of vitrification and freeze-all. METHODS: The Italian National Registry performed a cycle-based data collection. Nine Italian IVF clinics were involved incorporating a total of 10,260 fresh cycles performed between January 2015 and April 2016 resulting in 9273 oocyte retrievals and 3266 subsequent warming cycles from the same oocyte retrievals performed up to December 2016. Mean female age was 37 ± 4.3 years. Primary outcome measure was CLBR per oocyte retrieval. Confounding factors were tested in multivariate regression analysis, and the relative impact of cryopreservation to the CLBR in different patient categories was calculated. RESULTS: CLBR per oocyte retrieval was 32.6%, 26.5%, 18.7%, 13.0%, and 5.5% for women younger than 36, aged 36-39, 40-41, and older than 41 years, respectively. The total relative contribution of oocyte/embryo cryopreservation was 40.6% (95% CI 38.41-42.75). An association between maternal age, number of oocytes retrieved, fertilization rate, cryopreservation, and cumulative live birth was shown. When adjusted for confounders, a 2.3-fold increase was observed in the chance of live birth when cryopreservation was performed (OR 2.3; 95% CI 1.99-2.56). In high responder patients (> 15 oocytes retrieved) where freeze-all was applied in 67.6% of cycles to avoid the risk of hyper stimulation syndrome, the relative contribution of vitrification to the CLBR was 80.6%. CONCLUSIONS: Cryopreservation is essential in IVF and should always be available to patients to optimize success rates. Multicentric, cycle-based data analyses are crucial to provide infertile couples, clinicians, and regulatory bodies with accurate information on IVF effectiveness including fresh and cryopreserved cycles.

The number of oocytes retrieved during IVF: a balance between efficacy and safety.

STUDY QUESTION: What is the relationship between the number of oocytes collected in fresh IVF treatments and the likelihood of cumulative delivery rate (fresh and frozen) per oocyte aspiration, severe ovarian hyperstimulation syndrome (OHSS) and thromboembolic events? SUMMARY ANSWER: Cumulative delivery rate per aspiration increases up to 20 oocytes retrieved and then evens out while the incidence of severe OHSS increases more rapidly from around 18 oocytes and thromboembolic events, although rare, occurs in particular if 15 or more oocytes are retrieved. WHAT IS KNOWN ALREADY?: Previous studies have shown that the number of oocytes retrieved for IVF is a positive predictor of live birth in fresh cycles. Few studies have investigated cumulative live birth rates and OHSS in relation to the number of aspirated oocytes. STUDY DESIGN, SIZE, DURATION: Retrospective population-based registry study including 39 387 women undergoing 77 956 fresh IVF cycles in the period 2007-2013 and 36 270 consecutive transfers of frozen/thawed embryos in the period 2007-2014. PARTICIPANTS/MATERIALS, SETTING, METHODS: Data from The Swedish National Quality Registry of Assisted Reproduction (Q-IVF) including all IVF cycles with oocyte retrieval performed in public or private infertility clinics during the study period, was cross-linked to the National Patient Register regarding diagnostic codes (ICD 10) for severe (OHSS) and thromboembolic events. Oocyte donation cycles were excluded. MAIN RESULTS AND THE ROLE OF CHANCE: Live birth delivery rate in fresh cycles increased up to 11 oocytes retrieved and then evened out, where the live birth rate was 30.3% for a 34-year-old woman. The cumulative delivery rate per aspiration, including fresh transfer and all subsequent transfers of frozen-thawed embryos (FET cycles) per oocyte retrieval, increased up to approximately 20 oocytes where it reached 45.8%. The adjusted odds ratio (AOR) for live birth by the number of oocytes was 1.064 (95% CI: 1.061; 1.067). The incidence of severe OHSS increased significantly by the number of oocytes, particularly if more than 18 oocytes were retrieved. The AOR for OHSS by the number of oocytes was 1.122 (95% CI: 1.08; 1.137). Thromboembolic events were rare, a total of 16 events in 14 patients were observed, and occurred in particular if 15 or more oocytes were retrieved. LIMITATIONS, REASONS FOR CAUTION: All FET cycles might not be included. Some embryos cryopreserved between 2010 and 2013 might still result in additional births until 2018. Furthermore the gonadotrophin dose was not included in the Q-IVF Registry in the study period, thus adjustment for dose was not possible. WIDER IMPLICATIONS OF THE FINDINGS: The results suggest a shift at approximately 18-20 oocytes where the cumulative delivery rate per aspiration levels off and, at the same time, the incidence of severe OHSS increases more rapidly. Thromboembolic events, although rare, should also be taken into consideration at stimulation regimes for IVF. Evaluating data taking both efficacy and the most serious safety aspects into account, is a new approach and of crucial importance both for patients undergoing IVF and their physicians. STUDY FUNDING/COMPETING INTEREST: Financial support was received through an agreement relating to research and the education of doctors (ALFGBG-70 940) and grant from the Hjalmar Svensson Research Foundation. None of the authors declares any conflict of interest.

How successful is TESE-ICSI in couples with non-obstructive azoospermia?

STUDY QUESTION: What are the chances of a couple with infertility due to non-obstructive azoospermia (NOA) having their genetically own child by testicular sperm extraction combined with ICSI (TESE-ICSI)? SUMMARY ANSWER: Candidate TESE-ICSI patients with NOA should be counselled that, when followed-up longitudinally, only a minority (13.4%) of men embarking for TESE eventually become a biological father. WHAT IS KNOWN ALREADY: Data available in the literature are only fragmentary because they report either on sperm retrieval rates after TESE or on the outcome of ICSI once testicular spermatozoa has been obtained, mostly in a selected subpopulation. Unfortunately, reliable data to counsel men with NOA on their chance to become a biological father are still lacking. STUDY DESIGN, SIZE, DURATION: This is a retrospective cohort study performed in the Centre for Reproductive Medicine, University Hospital of Brussel, approved by the institutional review board of the hospital. PARTICIPANTS/MATERIALS, SETTING AND METHODS: We identified all patients with NOA, based on histology, who had their first testicular biopsy between 1994 and 2009. Patients were followed longitudinally during consecutive ICSI cycles with testicular sperm. The primary outcome measure was live birth delivery. The cumulative live birth delivery rate was calculated, based only on ICSI cycles with testicular sperm (fresh and/or frozen) available for injection. When patients delivered after transfer of supernumerary frozen embryos, this delivery was tallied up to the (unsuccessful) original fresh ICSI cycle. The sperm retrieval rate and pregnancy rate were secondary outcome measures. MAIN RESULTS AND THE ROLE OF CHANCE: Among the 714 men with NOA, 40.5% had successful sperm retrieval at their first TESE. In total, 261 couples had 444 ICSI cycles and 48 frozen embryo transfer cycles, leading to 129 pregnancies and 96 live birth deliveries. Crude and expected cumulative delivery rates after six ICSI cycles were 37 and 78%. LIMITATIONS AND REASON FOR CAUTION: A retrospective cohort study design was the only way to study the cumulative delivery rate after TESE-ICSI in couples with NOA. Intrinsic limitations are related to the observational study design. WIDER IMPLICATION OF THE FINDING: TESE-ICSI is a breakthrough in the treatment of infertility due to NOA, with almost 4 out of 10 (37%) couples having ICSI obtaining a delivery. However, unselected candidate NOA patients should be counselled, before undergoing TESE, that only one out of seven men (13.4%) eventually father their genetically own child. STUDY FUNDING AND COMPETING INTERESTS: None declared.

Can repeated IVF-ICSI-cycles be avoided by using blastocysts developing from poor-quality cleavage stage embryos?

In many clinics, good-quality embryos are selected for embryo transfer and cryopreservation at the cleavage stage, and poor-quality embryos are discarded. The aim of this retrospective study was to examine how many repeated IVF cycles could be avoided by culturing the cleavage stage poor-quality embryos to blastocyst stage and transferring them after vitrification and warming (604 IVF and intracytoplasmic sperm injection [IVF-ICSI] cycles were included). Poor-quality cleavage stage embryos not eligible for transfer or cryopreservation were cultured until day 5 or 6, and those developing to the blastocyst stage were vitrified. The rate of vitrified blastocysts and clinical pregnancy and delivery rate of the warmed blastocysts was evaluated. The effect of the extended culture on the cumulative delivery rate, and the number of avoided new treatment cycles was calculated. The surplus blastocysts resulted in clinical pregnancy, spontaneous abortion and delivery rates of 24.6%, 27.3% and 17.2% respectively. The use of surplus blastocysts raised cumulative delivery rate from 43% to 47% and 53 repeated new cycles were avoided. This study shows that the cumulative delivery rate can be increased, and repeated IVF-ICSI treatments avoided by using blastocysts developing from poor-quality cleavage stage embryos, which otherwise would have been discarded.

The impact of legally restricted embryo transfer and reimbursement policy on cumulative delivery rate after treatment with assisted reproduction technology.

STUDY QUESTION: What is the impact of the Belgian legislation (1 July 2003), coupling reimbursement of six assisted reproduction technology (ART) cycles per patient to restricted embryo transfer policy, on cumulative delivery rate (CDR) per patient? SUMMARY ANSWER: The introduction of Belgian legislation in ART had no negative impact on the CDR per patient based on realistic estimates within six cycles or 36 months. WHAT IS KNOWN ALREADY: The introduction of Belgian legislation limiting the number of embryos for transfer resulted in a reduction of the multiple pregnancy rate (MPR) per cycle by 50%. STUDY DESIGN, SIZE, DURATION: A retrospective cohort study with a study group after implementation of the new ART legislation (July 2003 to June 2006) and the control group, before legislation (July 1999 to June 2002). PARTICIPANTS/MATERIALS, SETTING, METHODS: CDR was compared in an academic tertiary setting between a study group after legislation (n = 795 patients, 1927 fresh and 383 frozen-thawed embryo transfer (FET) cycles) and a control group before legislation (n = 463 patients, 876 fresh and 185 FET cycles) within six cycles or 36 months, delivery or discontinuation of treatment. The CDR was estimated using life table analysis considering pessimistic, optimistic and realistic scenarios and compared after adjustment for confounding variables. In the realistic scenario we included information on embryo quality to define the prognosis of each patient discontinuing treatment. MAIN RESULTS AND THE ROLE OF CHANCE: In the realistic scenario, CDR within 36 months was comparable (all ages, P = 0.221) in study group (60.8%) and control group (65.6%), as well as in different age groups (<36 years, P = 0.242; 36-39 years, P = 0.851; 40-42 years, P = 0.840). In the realistic scenario applied to six cycles, we found lower CDRs in the study group than in the control group within the two first cycles (all ages, P = 0.009; <36 years, P = 0.007) but no difference in CDRs between the two groups within the four subsequent cycles (all ages P = 0.232; <36 years, P = 0.198). The CDR within six cycles was 60 and 65.3% for study group and control group, respectively, for all ages, and 65.8 and 70.4%, respectively, in the subgroup younger than 36 years. In women ≥36 years, CDR within six cycles was comparable in both groups (36-39 years, 43% in study versus 44.4% in control group, P = 0.730; 40-42 years, 21% in study versus 23% in control group, P = 0.786). LIMITATIONS, REASONS FOR CAUTION: A retrospective cohort study design was the only way to study the impact of legislation on CDR. Owing to the retrospective nature of this analysis over a long period of time, our data are potentially influenced by improvements in techniques and therefore improved success rates in ART over time. WIDER IMPLICATIONS OF THE FINDINGS: This 'Belgian model' can now be considered for application worldwide in countries with the aim to reduce the main ART side effect (high MPR) and its associated costs without a negative effect on the main intended effect (high CDR). STUDY FUNDING/COMPETING INTEREST(S): The authors have no conflict of interest to declare. No funding was obtained for this study.

Number of oocytes and IVF outcomes: Real-world evidence.

Randomized controlled trials (RCTs) are gold standard to study the effect of an intervention and establish causation between the treatment and outcomes. However, RCTs have the disadvantage of being expensive, entailing high resource investments and involving only selected patient populations under experimental settings. Real-world evidence (RWE) from real-world data (RWD) involves a heterogenous patient population in real-world settings. RWE is less expensive and quicker than RCTs; it can provide complimentary evidence if methodological challenges, such as residual confounding and susceptibility to bias, are considered when interpreting the findings. This review examines RWE regarding the association between the number of oocytes following ovarian stimulation and IVF outcomes into shaping current IVF practices.

POSEIDON groups and their distinct reproductive outcomes: Effectiveness and cost-effectiveness insights from real-world data research.

The Patient-Oriented Strategies Encompassing IndividualizeDOocyte Number (POSEIDON) criteria identify and classify the so-called 'low-prognosis' patients undergoing assisted reproductive technology (ART). Recent large-scale studies using real-world data (RWD) have shown that patients classified under this system have distinct reproductive outcomes. Moreover, these studies also confirm that POSEIDON patients are commonly found in fertility centers. RWD has substantiated the validity of the POSEIDON biomarkers' thresholds (antral follicle count [AFC] and/or anti-Müllerian hormone [AMH]) for patient classification. Lastly, a predictive model has been developed and validated to estimate the POSEIDON metric of success (i.e., number of oocytes needed to achieve at least one euploid blastocyst). Although more evidence is needed in this area, current insights from RWD research indicate that infertility patients can be counseled and managed more effectively under the POSEIDON scope, with potential gains for all parties involved.

2017-2018 Assisted Reproduction Cost Analysis Performance Indexes: Lombardy County Case Study.

Objective: The aim of the present study was to analyze the IVF success rates and the economic cost per delivery in all the public funded IVF Units in Lombardy in the 2017-2018 period and to assess any significant difference in ART outcomes among the enrolled centers. Methods: Analysis of costs for the 2017 and 2018 fresh transfer delivery rate (DR) and Cumulative delivery rate (CDR) considering both fresh and frozen cycles were extracted from the ART Italian Registry on oocytes retrievals, fresh and frozen embryos and oocytes embryo transfer performed in 22 Lombardy IVF Units. Results: In 2017, 29,718 procedures were performed, resulting in 4,543 pregnancies and 3,253 deliveries. In 2018, there were 29,708 procedures, 4,665 pregnancies and 3,348 deliveries. Pregnancies lost to follow up were 5.0% with a (range of 0-67.68%) in 2017 and 3.4% (range of 0-45.1%) in 2018. The cost reimbursement for the cycles were €2,232 ($2,611) for oocyte retrieval and €2,194 ($2,567) for embryo transfer, excluding ovarian stimulation therapy and luteal phase support. 19.33 (5.80). The DR was 13.23 ± 5.69% (range 2.86-29.11%) in 2017 and 19.33 ± 5.80% in 2018 (range 11.82-34.98 %) and the CDR was 19.86 ± 9.38% (range 4.43-37.88%) in 2017 and 21.32 ± 8.84% (range 4.24-37.11%). The mean multiple pregnancy delivery rate (MDR) was 11.08 ± 5.55% (range 0.00-22.73%) in 2017 and 10.41 ± 4.99% (range 1.33-22.22%) in 2018. The mean CDR cost in euros was 26,227 ± 14,737 in 2017 and 25,018 ± 16,039 in 2018. The mean CDR cost among centers was 12,480 to 76,725 in 2017 and 12,973 to 86,203 in 2018. Conclusions: Our findings show impressive differences in the DR and CDR among centers and the importance of cryopreservation in patients' safety and economic cost reduction suggesting the formulation of specific KPI's (Key performance indexes) and minimal performance indexes (PI) as a basis for the allocation of public or insurance resources. In particular, the reduction of multiple pregnancy rates costs, may lead to a more widespread use of ART even in lower resources countries.