STUDY QUESTION What is the number of oocytes where the maximum cumulative live birth rate per aspiration (CLBR) is observed during ART in women of different ages? SUMMARY ANSWER The maximum CLBR was observed when around 25 oocytes were retrieved in women between 18–35 years of age, around 9 oocytes in women more than 45 years of age and continued to increase beyond 30 oocytes in women between 36–44 years of age. WHAT IS KNOWN ALREADY The live birth rate per fresh or frozen/thaw embryo transfer (FET) procedure has traditionally been the main measure of ART success. However, with the introduction of highly efficient embryo cryopreservation methods, CLBR encompassing live delivery outcomes from the fresh and all subsequent FET following a single ovarian stimulation and oocyte collection is increasingly viewed as a more meaningful measure of treatment success. There is evidence suggesting that larger oocyte yields are associated with increased likelihood of cumulative live birth per aspiration. Whether this association is the same across female ages has not yet been properly investigated. STUDY DESIGN, SIZE, DURATION This is a large retrospective population-based cohort study using data from the Australian and New Zealand Assisted Reproduction Database (ANZARD). ANZARD contains information from all ART treatment cycles carried out in all fertility centres in Australia and New Zealand. Overall, 221 221 autologous oocyte aspiration cycles carried out between January 2009 to December 2015 were included in the analysis. PARTICIPANTS/MATERIALS, SETTING, METHODS Cumulative live birth per aspiration was defined as at least one liveborn baby at ≥20 weeks gestation resulting from an ART aspiration cycle, including all fresh and FET resulting from the associated ovarian stimulation, until one live birth occurred or all embryos were used. Cycles where no oocytes were retrieved were excluded from analysis as there is no possibility of live birth. Analyses of data were performed using generalized estimating equations to account for the clustered nature of data (multiple cycles undertaken by a woman). Univariate and multivariable regression analysis was performed to identify and adjust for factors known to independently affect cumulative live birth per aspiration. An interaction term between female age and the number of oocytes retrieved was included to assess whether the age of the women was associated with a different optimal number of oocytes to achieve at least one live birth from an aspiration cycle (i.e. the effect-modifying role of female age). The likelihood of cumulative live birth per aspiration was calculated as odds ratios (ORs) with 95% CI. MAIN RESULTS AND THE ROLE OF CHANCE The median number of oocytes retrieved was 7 (interquartile range, 4–12) and median age of patients was 36 (interquartile range, 33–40). The overall CLBR was 32.2%. The results from the multivariable regression analysis showed that the number of oocytes retrieved remained a significant predictor (P < 0.001) of cumulative live birth per aspiration after adjusting for female age, parity and cycle count. Compared to the reference group of 10–14 oocytes retrieved, the adjusted odds for cumulative live birth per aspiration increased with the number of oocytes retrieved: 1–3 oocytes, 0.21 (95% CI, 0.20–0.22); 4–9 oocytes, 0.56 (95% CI, 0.55–0.58); 15–19 oocytes, 1.38 (95% CI, 1.34–1.43); 20–24 oocytes, 1.75 (95% CI, 1.67–1.84); and 2.10 (95% CI, 1.96–2.25) with more than 25 oocytes. After stratifying by female age group, the rate of increase in CLBR per additional oocyte retrieved was lower in the older age groups, indicating that higher oocyte yields were more beneficial in younger women. CLBR of patients in the <30 years and 30–34 years age groups appeared to reach a plateau (with only minimal increase in CLBR per additional oocyte retrieved) after retrieval of 25 oocytes at 73% and 72%, respectively, while CLBR of patients in the 35–39 years and 40–44 years age groups continued to increase with higher oocyte yields, reaching 68% and 40%, respectively, when 30 or more oocytes were retrieved. CLBR of patients aged 45 years and above remained consistently below 5%. Findings suggest that the number of oocytes retrieved where CLBR appears to be maximized is around 25 in women between 18–35 years, more than 30 in women between 36–44 years and around 9 in women 45 years and older. However, results for women aged 45 years and older may not be as robust due to the relatively small sample size available in this age group. LIMITATIONS, REASONS FOR CAUTION As with all large retrospective database studies, there are potential confounders that cannot be accounted for. Despite the current study being based on complete ascertainment of ART cycles across two countries, ovarian stimulation protocols, oocyte quality parameters and a number of important patient characteristics are not collected by ANZARD. Additionally, a small number of cycles were available for women over 45 years yielding more than 15 oocytes, making these estimates unreliable. WIDER IMPLICATIONS OF THE FINDINGS The results from this study demonstrate that the number of oocytes retrieved where the maximum CLBR is observed during ART is dependent on female age. This provides information for clinicians and patients to understand the modifying effect of age on the number of oocytes retrieved and the likelihood of success with ART. STUDY FUNDING/COMPETING INTEREST(S) No external funding was used for this study. The Fertility Society of Australia funds the National Perinatal Epidemiology and Statistics Unit to manage ANZARD and conduct national reporting of ART in Australia and New Zealand. Associate Professor Georgina Chambers (G.C.) is employed by the University of New South Wales (UNSW) and is director of the National Perinatal Epidemiology and Statistics Unit at UNSW. G.C. was also a paid member of the Australian governments Medicare Benefits Scheme taskforce on assisted reproductive technologies in 2017.

Is there an optimal number of oocytes retrieved where live birth rates or cumulative live birth rates per aspiration are maximised after ART? A systematic review,

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Study question Is progesterone elevation (PE) in the presence of low number of follicles (unexpected PE) associated with oocyte or embryo quality? Summary answer PE on day of trigger in cycles with ≤4 follicles is associated with significantly reduced fertilisation rates and fewer top-quality blastocysts What is known already The negative effect of PE on pregnancy rates in fresh IVF cycles has been demonstrated by multiple studies and meta-analyses, and most studies support no negative effect on oocyte and embryo quality. However, as it is thought that PE is the product of cumulative secretion of low levels of progesterone from multiple developing follicles, PE in the presence of a low number of follicles (unexpected PE) is considered a different pathophysiological entity. It has been hypothesized, but never proven, that in these cases, PE is the result of follicular dysregulation and that it might indicate poorer follicular and oocyte health. Study design, size, duration This is a multi-centre retrospective analysis of a large cohort (n = 1,393) of IVF/ICSI cycles with a low response to ovarian stimulation (1-4 follicles ≥14mm) performed from January 2018 to April 2022. Only cycles of ovarian stimulation using gonadotrophins and GnRH analogues with a measurement of serum progesterone on the day of triggering final oocyte maturation were included. Natural cycles and cycles involving the administration of clomiphene were excluded. Participants/materials, setting, methods Unexpected PE was defined as serum progesterone levels greater than 4.77 nmol/L (1.5 ng/mL) on day of trigger. The primary outcome was the number of usable blastocysts. Secondary outcomes included the number of oocytes retrieved, two pronuclei (2PN) oocytes, number of top-quality embryos, fertilisation rate and blastocyst formation rate. Generalised estimating equations were used to account for the clustered nature of data. Multivariable regression analysis was performed to control for the effect of multiple confounders. Main results and the role of chance In the univariate regression analysis, the number of oocytes retrieved was not significantly different between cycles with and without PE (mean 2.3 vs. 2.1 respectively; p = 0.550). The number of 2PN oocytes was significantly (p = 0.021) lower in the PE group (mean 0.72, 95%CI 0.31-1.14) compared to the non-PE group (mean 1.21, 95%CI 1.12-1.31). The number of top-quality blastocysts was also significantly (p = 0.003) lower in the PE group (mean 0.03, 95%CI -0.03-0.10) compared to the non-PE group (mean 0.14, 95%CI 0.11-0.17). Fertilisation rates per oocyte retrieved, fertilisation rates per oocyte inseminated and the top-quality blastocyst rate per oocyte retrieved were consistently lower in the PE group at 33.3% (95% CI 19.0-47.6), 26.9% (95% CI 14.8-39.0) and 0.7% (95% CI -0.8-2.1) compared to 58.7% (95% CI 55.8-61.7), 52.3% (95% CI 49.3-55.2) and 5.5% (95% CI 4.3-6.8) in the non-PE group. The negative association of PE with the primary outcome measure of this study was confirmed in the multivariable regression analysis where the number of usable blastocysts was significantly lower in the PE group (adjusted mean 0.14, 95%CI 0.03-0.25) compared to the non-PE group (adjusted mean 0.27, 95%CI 0.23-0.31) after adjusting for confounders. Limitations, reasons for caution This is a retrospective observational study, thus not all confounders may be accounted for. Despite being one of the largest studies conducted in poor responders, the sample size of unexpected PE cycles is relatively small due to its rarity. Therefore, this study may be underpowered to detect smaller effect sizes. Wider implications of the findings This study demonstrates for the first time that unexpected PE on the day of trigger (i.e. in cycles with low ovarian response) is associated with poorer oocyte health as reflected in the reduced fertilisation rates and fewer blastocysts available for transfer. This information can aid in better understanding this phenomenon. Trial registration number Not applicable