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

Abstract

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.

Keywords: ART; POSEIDON criteria; cumulative delivery rate; embryo transfer; infertility; life table; live birth; real-world evidence.

Figure 1.

Flow diagram showing total patient breakdown. POSEIDON (Patient-Oriented Strategies Encompassing IndividualizeD Oocyte Number) Group 1: younger (<35 years) unexpected poor or suboptimal responders; Subgroup 1a (poor): <4 oocytes retrieved, Subgroup 1b (suboptimal): 4–9 oocytes. POSEIDON Group 2: older (≥35 years) unexpected poor or suboptimal older responders; Subgroup 2a (poor): <4 oocytes retrieved; Subgroup 2b (suboptimal): 4–9 oocytes. POSEIDON Group 3: younger (<35 years) expected poor responder. POSEIDON Group 4: older (≥35 years) expected poor responders. Non-POSEIDON (Group 5): normal responders (>9 oocytes retrieved) with an adequate AFC (≥5).

Figure 2.

Cumulative delivery plots and their correspondent tables. Patients were stratified according to the POSEIDON criteria, and the time-to-event plots were generated by (A) all POSEIDON patients—combined into a single group—and the control group of non-POSEIDON patients, (B) the four POSEIDON groups and the control group of non-POSEIDON patients, and (C) the four POSEIDON groups, in which Groups 1 and 2 were further stratified in Subgroups ‘a’ and ‘b’, and non-POSEIDON patients further stratified by age using the 35-year threshold. Cumulative delivery rate survival functions were calculated using the nonparametric Kaplan–Meier method and non-censored values. The ‘time’ response was the order of embryo transfers (ETs); the patient was the observational unit, and live birth delivery was the event. The survival tables detail the number of patients who failed to achieve a live birth delivery (number at risk). The tables are sectioned (columns) by each ET from one aspirated IVF/ICSI cycle (see ET order, 1, 2., 3… on the ‘x’ axis of correspondent survival plots), and each group occupies its own row in the tables. The start of the tables (left column) indicates the number of patients who commenced treatment and had an oocyte pick-up. The lines in each plot represent the cumulative proportion of patients achieving a live born from the start of treatment until the ‘time’ response.