The time interval between the ovulation triggering and oocyte retrieval is considered an important factor that contributes to the procedure success; it is crucial to perform the follicular puncture after LH surge has occurred in order to successfully collect the detached oocyte from the follicular fluid [23], and in order to allow the oocyte to accomplish its maturation [23]. It is clearly essential to perform adapt a time schedule that enables the oocyte retrieval surge previous to follicular rupture.

At the very beginning of IVF, in a report from 1982, hCG was given 36–38 h before performing laparoscopic oocyte retrieval [24]. However, according to other reports, the common practice was to administer hCG 32–36 h before oocyte retrieval in order to avoid cycle cancellation due to a spontaneous LH surge [14, 20]. Since then, and specifically after the incorporation of GnRHa which inhibits the spontaneous LH surge, several studies have investigated the optimal lag time between hCG administration and oocytes retrieval in GnRHa protocol, with inconsistent results. In a prospective study from 1994, Mansour et al. compared 3 interval groups: 35, 36 and 37 h. They found similar number of oocytes retrieved between all groups, but maturation rate was higher in the 36- and 37-hours groups compared to the 35 h (77.4%, 79.47% and 49.6%, respectively, P < 0.001) [20]. Later, in a prospective study by Bjercke et al., there was no significant difference between a 34 to a 38 h interval in terms of oocyte yield, number of embryos, embryo scores, implantation rate and pregnancy rate [23]. One year later, a larger study of 533 patients who were randomly allocated times for oocyte retrieval, with an interval range of 33–41 h, found no difference in the IVF outcomes- oocyte recovery rates, fertilization rates and pregnancy rates- between different interval groups (33 to < 36, 36 to < 38, 38 to < 41 h) [14]. Maturation rate was not evaluated [14]. A different point of view was that of Raziel and his colleagues, who have investigated the effect of prolonging the interval from 35.3 ± 0.7 h to 38.6 ± 1.2 h in patients with ≥ 47% immature oocytes in their previous cycle. They found a significant increase in maturation rate in the prolonged interval [25]. To summarize all those conflicting results, a meta-analysis was conducted in 2011, showing that in the longer time interval (> 36 h), oocyte maturation rate was higher (RR, 0.67; 95% CI, 0.62–0.73) than in the shorter interval (< 36 h) [21].

The treatment protocol, which was utilized in all aforementioned studies, as already specified, was long GnRH agonist with hCG for trigger. The GnRH antagonist protocol, using either an hCG trigger or a GnRHa trigger for final oocyte maturation was studied to much lesser extent, usually without distinguishing between the trigger types. Trigger-to-retrieval interval for antagonist cycles was adopted from former agonist cycles. In a retrospective study of 511 IVF/ICSI cycle, three different protocols were included (short agonist, long agonist and antagonist) with either hCG or GnRHa for ovulation triggering. The percentage of mature oocytes was significantly lower in the interval of 33.45–34.45 h and was stable between 35 and 38 h. Pregnancy rates were similar between interval groups. The study conclusion was that oocyte retrieval should be scheduled at least 35 h after triggering [16]. More recent study compared the trigger-to-retrieval interval in 4 different ovarian stimulation protocols. Again, different trigger types were included. According to this study, in order to retrieve more than 60% oocytes and more than 80% mature oocytes, trigger-to-retrieval interval should be delayed according to the stimulation type: mild stimulation protocol < GnRH antagonist protocol < short agonist protocol < long agonist protocol [17]. To the vet of our knowledge, the only study that explored the interval related solely to the GnRHa trigger was published by Hershkop et al. in 2021. In their study, 220 patients who underwent ICSI were divided unequally to four interval groups: 34.00-34.99, 35.00-35.99, 36.00-36.99 and from 37.00 and longer hours. The proportion of mature oocytes was similar between the groups [19].

In our study, we focused on antagonist protocol cycles which were exclusively triggered by GnRH agonist. As first described by Lanzone et al. in 1989 [26], and later was re-evaluated by Segal and Casper [27], GnRH agonist triggering results in an increase in serum LH and FSH, leading to final oocyte maturation. Therefore, GnRH agonist was found to be an effective alternative to hCG for ovulation triggering, while reducing the risk of OHSS [10]. Therefore, GnRH agonist triggering gained popularity and became the treatment of choice for ovulation triggering in fertility preservation cycles.

Our study population was unique – patients who elect to undergo planned fertility preservation, without any known infertility. This enabled us to lessen a possible influence of selection bias on the outcomes. We report no correlation between the interval and the outcome measures including number of oocytes retrieved, mature oocytes and maturation rate. Our results correspond with the only previous study in which ovulation was triggered solely by GnRHa, which found that the proportion of mature oocytes was similar between different interval groups [19].

As for the other variables that were investigated, we found that age was negatively associated with oocyte yield. Advanced age, especially above 37 years old, is a well-established contributing factor to a decline in the number of oocyte collected, and affects fertility treatment success rates including live birth rates [28,29,30]. This points again the significance of bringing forward the age in which elective fertility preservation is being performed, as already demonstrated by Cobo and her colleagues [31]. Contrary to age, AMH level was positively correlated with the number of retrieved oocytes. AMH, as an ovarian reserve marker, is well accepted predictor for number of oocytes retrieved and cycle cancellation [32]. In our study we also noticed an unexpected correlation between increased FSH dose and decreased number of oocytes collected. This could be attributed to the high dose that is given beforehand in patients expected to have poor response, according to their baseline AMH or AFC level. This association is reported in a regression model correcting for measurable confounders. Nonetheless, there are possibly unmeasurable confounders contributing to this finding. Such unmeasurable confounders can be the subject for future research. Interestingly, a recent study by Orvieto et al. they have investigated the effect of increasing gonadotropins dose in a patients` second cycle of elective/planned oocyte cryopreservation. They found that despite increased dose, 55.2% of patients will have less oocyte retrieved [33].

Our study has several limitations. First, its retrospective nature, which may explain lacking information regarding AMH levels for some of the patients. Second, some patients were contributing more than one cycle. Although this should not necessarily affect interval analysis, we performed a sub analysis for first cycle only demonstrating a lack of effect. Our study novelty arises from investigating a question that was rarely addressed before. Thanks to a computerized database, we were able to extract an exact time documentation for our analysis. The gathered population from two IVF clinics` has provided a sufficient sample size and homogenous as possible - these two centers are geographically close, with similar patients’ characteristics.

To summarize, in the new and growing era of planned fertility preservation, we were first, to the best of our knowledge, to investigate the role of a GnRHa trigger-to-retrieval interval on treatment outcomes. Lack of association may provide some reassurance for patients and the healthcare providers and allow more flexibility in scheduling operation time. Larger, randomized controlled studies are needed in order to further support our results.