The increasing demand for donor oocytes by the widespread delay in childbearing in developed countries and new family structures[6], the difficulty for patients to access assisted reproduction treatments, a changing world with rising inflation and the difficulties of undersupply in some countries combined with problems of availability of some drugs make it essential to take an economic perspective. The aim is not just to find the cheapest treatment, it is to find the treatment that has the same outcomes at the lowest cost. There is a growing acceptance that health policy and planning should take economic considerations into account.
This study found that progesterone primed protocol is more cost-effective than antagonist protocol. The assumption of cost effectiveness of PPOS over conventional OS cycles is based on the lower cost of progestins when compared with GnRH analogues, especially GnRH antagonists[14]. PPOS was only more cost effective than the GnRH antagonist protocol in planned freeze all cycles and egg donation. The cost-effectiveness analyses assumed similar live birth rates with PPOS, the short GnRH agonist and GnRH antagonist protocols, similar gonadotrophin consumption with PPOS and GnRH antagonist protocol.[14]
To our knowledge, our study is the first to be performed among donors analyzing just cost-effectiveness between PPOS and antagonist protocol.
Reviewing published comparative studies between both protocols in oocyte donors we found several studies without differences in days of stimulation, doses of gonadotrophins used and mean number of mature retrieved oocytes (except Yildiz et al).
Begueria et al, performed a RCT. Treatment with medroxyprogesterone (MPA) (10 mg/day) was compared with the antagonist protocol (ganirelix, 0.25 mg/day, from Day 7 of stimulation) for OS in OD. In total, 216 were randomized and 173 reached oocyte retrieval. The required days of treatment and total dose of rFSH were the 11.20 days on average in both groups. Treatment with MPA was comparable to ganirelix in terms of number of metaphase II oocytes (MII) obtained [15.1 ± 8.3) with MPA versus [14.6 ± 7.0) with ganirelix[11].
Yildiz et al performed a retrospective study comparing the use of MPA administered in the form of the flexible antagonist protocol for the treatment of oocyte donors and the clinical outcomes in recipients of fresh oocytes (Yildiz et al., 2019). Each donor was stimulated with the flexible GnRH antagonist protocol in one cycle and with the new flexible-PPOS (fPPOS) protocol in the other, within a period of 6 months. They received FSH 225 IU from cycle Day 2–3, and 0.25 mg/day GnRH antagonist or 10 mg/day MPA was started on stimulation Day 7 or when the leading follicle reached 14 mm, whichever came first. There were no differences in the duration of stimulation and total gonadotrophin consumption, the PPOS was 2,475 UI (2,250–2,475) and the antagonist group 2,400 (2,250–2,475). The fPPOS yielded a significantly higher number of cumulus oocyte complexes than GnRH antagonist cycles (33 [range 21–39] vs 26 [18–36], respectively)[10].
More recently Giles et al perfomerd one RCT including 318 OD and compared MPA 10 mg/day with the use of a GnRH antagonist and found no significant differences in FSH dose (1964 UI ± 431 vs 1973 ± 392 respectively), neither in the days of stimulation (10.0 ± 1.5 vs 10.1 ± 1.3), nor number of oocytes retrieved (21.4 ± 11.7 vs 21.3 ± 9.3 respectively, P = 0.949)[12]
Finally, Castillo et al performed a retrospective analysis comparing the use of 200 mg oral micronized progesterone with cetrorelix in 1090 OD, and found no differences in the number of oocytes (15.8 ± 7.5 versus 15.2 ± 7.6, respectively, P= 0.7) (Castillo JC et al., 2020)
Meta-analysis of the previous studies comparing PPOS with GnRH antagonist protocols for the treatment of 2147 oocyte donors and 2260 recipients was performed and showed no differences in mean number of retrieved oocytes (MD 0.23, [95% CI 0.58, 1.05])(Martinez et al., 2021).
The results of the research are shown to be in line with those of the authors with the same donor population in days of stimulation 9.2 ± 2.4 vs 9.2 ± 2.6, and mean number of mature retrieved oocytes 13.2 ± 6.6 vs 14.8 ±7.8 corresponding antagonist group FSH vs Progesterone primed FSH, but less dose of gonadotrophins is used in antagonist group 1831 ± 663 vs 2005 ± 715, this might be explained by the fact that in some cases progesterone is started days before the start of ovarian stimulation and the ovaries may be slowed down.
According to the objective of this analysis, the economic assessment in the FSH antagonist group, the cost of gonadotrophins per mature oocyte retrieved was 49.27 € ± 17.94 and the cost of medication per mature oocyte retrieved was 59.26 € ± 28.01. In the FSH primed progesterone group the cost of gonadotrophins per mature oocyte retrieved was 44.67 € ± 16.65 and the cost of medication per mature oocyte retrieved was 44.91 ± 20.86.
If we perform an extrapolation exercise of the 80641 oocyte donation cycles performed in Europe in 2018[15], assuming that they were performed with antagonists and extrapolating our data with an average of 14 MII per cycle and a difference in cost per oocyte of 14.35 between the two protocols, we would be saving €16200776.9 annually without affecting the outcome.
Analyzing the subgroups, we observe that in group 1, the cost of gonadotrophins is the highest of all (694.62 € ± 24.93), this is related to the fact that 96 % of the cycles were stimulated with Puregon® which was the most expensive medication per IU. Group 2 was the lowest cost group (554.41 € ± 193.42), in this case Bemfola® was used in the largest proportion (98% of cases), it is hypothesized that the ease of injection of individual pens reduces medication losses, since if we compare with Ovaleap® and being the same biosimilar, more doses of gonadotrophins are required with the latter, both in group 2 (1840 IU ± 633 vs 2264 IU ± 786. 11) and in group 4 (1996 IU ± 869 vs 2177 IU ± 618), a prospective study should be considered for the future.
The cancelation rate in started cycle was 4,15% in Antagonist FSH group and 6,93% in the Progesterone primed FSH group. Giles et al reported 3,2% and 2,4% respectively[12]and Begueria et al[11] reported just 6,6% in antagonist group but n was low.
The cancellation of the cycle has a direct impact on the total cost of each group because an expense has been incurred without being able to assign oocytes. This expense is spread over the rest of the cycles in which oocytes are obtained. The average cost charged to the total cycle from suboptimal cycles with progesterone was 46.2 €, and in case of suboptimal cycles with antagonists it was 32.5 €.
It is important to note that the costs presented here are only a part of the total cost of the treatment, and other factors such as the cost of monitoring, anesthesia, and laboratory procedures also contribute to the overall cost. Plasma E2, LH or P4 data have not been included in the study because of missing data.
The cost of monitoring included the costs of nursing, infrastructure, patient care time and consumables were not taken into account in this study and were considered comparable between groups. Both groups needed the equivalent stimulation days. It should be taken into account that in our centre follicular monitoring starts on day 6 of stimulation for all groups, although this calendar at the beginning was determined by the fact that stimulation was performed with flexible antagonist introduction. Various published studies also support the flexible introduction of progesterone[10]. In our centre, progesterone is started at the time of the period or even 5 days earlier if the patient has been using hormonal contraception and has been switched to progesterone. This shows the flexibility in use.
Typically, a one-size-fits-all standardised approach is used to schedule multiple donor appointments during monitoring. Further studies are needed to optimise the number of monitoring controls to optimise the aggregate costs involved in the monitoring visit. Artificial Intelligence might offer the opportunity to influence workflow and scheduling during stimulation process with clinical data, across operational and clinical boundaries. Outcomes could be optimized, efficiencies improved, and costs reduced through more tailored and patient-specific scheduling[16].
On the other hand, attention has increasingly focused on improving the quality of care and the patient experience, in our case donors experience, including treatment.
Nowadays, the focus is on reducing injections, thus ovarian stimulation or the suppression of the LH peak, hence LH surge suppression with progesterone has been reported to increase the level of donor satisfaction because of their simplicity and oral administration instead of subcutaneous[17] Higher patient comfort and lower cost makes it attractive. Moreover, probably less need for monitoring visits during treatment and better adherence to it to obtain similar outcomes compared to antagonist protocols. Still evidence on safety is essential[8]
Strength and Limitations
We assessed the cost effectiveness of two different protocols, comparing PPOS and antagonist protocol and data on this topic is quite limited. However, our study has some limitations that are cause for caution. First, the retrospective nature of the design that can’t exclude a selection bias, second, data are observational, therefore, further studies would be needed to establish causality or to determine the optimal protocol for achieving the best outcomes and third only one medical center was involved, which may limit the possibility of generalizing our results. However, in our study progestins present an effective option for egg donation programs in terms of cost and the sample size is enough to validate our results.
Conclusion
The cost-effectiveness results presented in this paper illustrate one compelling reason for clinics to move to PPOS protocol. This option should be a good strategy in an egg donation program.