Cumulative Live Birth Associated with Number of Oocytes in Ovarian Stimulation with Follitropin Delta: an Individual Patient Data Meta-Analysis

What is the optimum number of oocytes retrieved to maximise cumulative live birth rates in the fresh and subsequent frozen cycles following follitropin delta stimulation? The cumulative live birth rate increased steadily with number of oocytes retrieved up to a plateau starting at ∼21 oocytes retrieved. Live birth rate (LBR) per fresh ovarian stimulation cycle is the conventionally reported outcome of in vitro fertilisation (IVF). In recent years, there has been a marked increase in number and successful outcomes of cryopreserved cycles, suggesting that the cumulative live birth rate (CLBR) has emerged as a more clinically relevant outcome. In the fresh cycle, the number of oocytes retrieved is regarded as a prognostic factor for LBR. A similar association has been shown for CLBR implying that CLBR increases with the number of oocytes and continues to increase beyond the plateau observed for fresh cycle LBR. Individual patient data meta-analysis of 1746 patients from 4 randomised controlled trials using follitropin delta for ovarian stimulation. The analysis included patients with ≥1 oocyte retrieved following stimulation. The CLBR in the fresh and subsequent frozen cycles was evaluated. Predicted CLBR was obtained using a logistic regression analysis with fractional polynomials to assess the association between number of oocytes retrieved and CLBR. Subgroup analyses were performed based on age, AMH and number of oocytes retrieved. Participants were women, 18–42 years, undergoing their first or second in vitro fertilisation/intracytoplasmic sperm injection (IVF/ICSI) cycle in a GnRH antagonist/long agonist protocol with human chorionic gonadotrophin or GnRH agonist triggering and IVF/ICSI insemination. Single or double blastocyst transfer was performed on Day 5 and all viable surplus blastocysts were cryopreserved. All pregnancies from the fresh cycle and frozen cycles initiated within 1 year after start of stimulation were followed until birth. The study included 1746 patients who underwent a total of 2948 cycles; 1746 fresh and 1202 frozen. In total, 740 patients (42.4%) initiated frozen cycles (maximum of 6). The study population had a mean age of 33.8 years and a median AMH level of 17.0 pmol/l. The mean number of oocytes retrieved was 12.4, the fresh cycle LBR was 29.1% and the CLBR was 51.4%. The CLBR steadily increased with number of oocytes retrieved, reaching above 60% at > 15 oocytes and above 70% at > 20 oocytes. The CLBR started to plateau at ∼21 oocytes. Subgroup analyses by number of oocytes retrieved, age group or AMH group demonstrated that the CLBR decreased with increasing age (57.1%, 51.6% and 35.8% at < 35, 35-37 and ≥38 years). In comparison it was similar for AMH <15 and ≥15 pmol/l (52.0% and 50.9%, respectively). A continued increase in CLBR from 15 oocytes retrieved was observed in older patients (≥38 years); from 41.3% to 53.4% to 58.7% at 15-19, 20-24 and ≥25 oocytes. No equivalent benefit was observed in younger patients, where corresponding rates were 72.5%, 68.0% and 78.8% in patients <35 years, and 70.3%, 73.1% and 71.5% in patients 35-37 years. A limitation of this study is the small number of patients with >20 oocytes retrieved. The individual pooled studies were heterogenous regarding number of blastocysts transferred and hCG/agonist trigger. The current individual patient data meta-analysis suggests an increase in CLBR with number of oocytes retrieved up to a plateau starting at ∼21 oocytes following ovarian stimulation cycles with follitropin delta and subsequent frozen cycles. An increase in CLBR from 20 oocytes was evident in older but not younger patients. NCT01956110, NCT03564509, NCT03740737, NCT03738618