Oocyte cryopreservation versus ovarian tissue cryopreservation for adult female oncofertility patients: a cost-effectiveness study

Abstract

Purpose

In December 2019, the American Society for Reproductive Medicine designated ovarian tissue cryopreservation (OTC) as no longer experimental and an alternative to oocyte cryopreservation (OC) for women receiving gonadotoxic therapy. Anticipating increased use of OTC, we compare the cost-effectiveness of OC versus OTC for fertility preservation in oncofertility patients.

Methods

A cost-effectiveness model to compare OC versus OTC was built from a payer perspective. Costs and probabilities were derived from the literature. The primary outcome for effectiveness was the percentage of patients who achieved live birth. Strategies were compared using incremental cost-effectiveness ratios (ICER). All inputs were varied widely in sensitivity analyses.

Results

In the base case, the estimated cost for OC was $16,588 and for OTC $10,032, with 1.56% achieving live birth after OC, and 1.0% after OTC. OC was more costly but more effective than OTC, with an ICER of $1,163,954 per live birth. In sensitivity analyses, OC was less expensive than OTC if utilization was greater than 63%, cost of OC prior to chemotherapy was less than $8100, cost of laparoscopy was greater than $13,700, or standardized discounted costs were used.

Conclusions

With current published prices and utilization, OC is more costly but more effective than OTC. OC becomes cost-saving with increased utilization, when cost of OC prior to chemotherapy is markedly low, cost of laparoscopy is high, or standardized discounted oncofertility pricing is assumed. We identify the critical thresholds of OC and OTC that should be met to deliver more cost-effective care for oncofertility patients.

Introduction

Until recently, oocyte cryopreservation (OC) [1] was the only approved method of fertility preservation (FP) for women without partners, women who prefer to not use donor sperm, and women who choose to postpone the contribution of a male partner [2]. However, in 2019, the American Society for Reproductive Medicine designated ovarian tissue cryopreservation (OTC) as no longer experimental and an acceptable technique to be offered to patients seeking FP [2–4]. OTC involves the practice of obtaining ovarian cortical tissue for cryopreservation, to be stored until after the patient completes gonadotoxic therapy, and to be transplanted if she develops premature ovarian insufficiency (POI). POI is defined as the loss of ovarian function before age 40, associated with not only loss of fertility but also hypoestrogenism and its detrimental effects on the cardiovascular and skeletal systems [5]. Transplantation of cryopreserved ovarian tissue has the potential benefit of restoring ovarian function and premenopausal endocrine status. This allows the patient the chance to conceive spontaneously during the years the graft remains perfused and to potentially pursue in vitro fertilization (IVF) following chemotherapy. OTC is an option for women who cannot or do not want to delay cancer therapy, given that OC requires a longer duration of time (approximately 2–3 weeks) for ovarian stimulation and oocyte retrieval prior to starting chemotherapy.

As an example, a 30-year-old with high-grade breast cancer recommended to start neoadjuvant chemotherapy may struggle with the decision to delay chemotherapy for OC versus to proceed immediately with surgery for OTC [6]. This decision is multifactorial, including predicted risk of POI, perceived safety of the time required and hormonal milieu of ovarian stimulation for OC, and (importantly) the cost of each option. As the example highlights, post-pubertal pre-menopausal oncofertility patients undergoing high-risk chemotherapy will now have the fertility-preserving options of both OC and OTC. And in a time where OTC will be more utilized as a viable alternative to OC, it is imperative to discern the ranges of costs, efficacy, and other clinical utilities that will make one strategy dominate the other. This may guide the delivery of cost-effective care.

To date, there have been no studies to estimate the comparative cost-effectiveness of fertility-preserving strategies for women undergoing gonadotoxic therapy. There has only been one study comparing the cost-effectiveness of planned OC versus OTC for age-related fertility decline (planned OC) [7] and one other from Schumacher et al. (2017) that solely examined OC versus not undergoing OC as the only available strategy approved for FP at the time. In this study, we estimate the relative cost-effectiveness of OC versus OTC for fertility preservation in adult oncofertility patients with a focus on live birth. Additional outcomes and benefits of OTC, such as reversal of premature ovarian insufficiency, were deemed outside the scope of this study.

Materials and methods

Overall model

The target population for this model is adult women of reproductive age under the age of 40 with no male partner, no chosen donor sperm, and/or the desire to postpone the contribution of a male counterpart to preserve their reproductive autonomy, who have been recommended high-risk gonadotoxic therapy. The model functions under the assumption that patients who receive high-risk gonadotoxic therapy (high cyclophosphamide equivalent doses) will likely develop POI. This model compared two potential strategies appropriate for this population of interest: (1) OC and (2) OTC; it did not include embryo cryopreservation or expectant management (“watch and wait”) as alternative strategies. We used commercially available software (TreeAge Pro, Williamstown, MA, 2020) to build a decision analytic model (Fig. 1).

Fig. 1.

The decision tree

Ethical approval

This study was declared exempt by the Duke University Internal Review Board and met all relevant criteria of the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist [8].

Decision-analysis model

The decision tree is illustrated in Fig. 1. The model starts at the time at time of evaluation for FP, with a follow-up of 5 years [2]—the “time horizon.” In each arm, rates of live births and clinical pregnancies were estimated based on published literature of women of reproductive age requiring gonadotoxic therapy who desired FP. The model estimated the average cost of care for each strategy, calculated as the weighted average of cost for each intervention in each clinical pathway (defined by branches with specified probabilities along the decision tree), and the incidence of clinical pregnancy and live birth. We defined cost-effectiveness as cost per live birth, and the incremental cost-effectiveness ratio (ICER) as the difference in costs between strategies divided by the difference in the incidence of live births.

Clinical estimates and key assumptions

Clinical parameter estimates were obtained from previously published literature (Table 1). Based on a prospective cohort study of 1824 women undergoing gonadotoxic treatments, 4.8% of patients undergoing OC and 5.5% of patients undergoing OTC returned (after a median follow-up of 5 years) to utilize their respective method of FP to attempt to achieve pregnancy[2]. The OC utilization rate was similar to that of another study examining utilization of cryopreserved oocytes among cancer survivors in Milan, Italy, in which 4.5% returned to use their oocytes [9]. In the former study, patients who underwent OC and OTC and desired a pregnancy had a 40.8% and 27.3% probability of having a clinical pregnancy, respectively. Of those who achieved clinical pregnancies, 80% of patients who underwent OC and 67% of patients who underwent OTC achieved live births [2]. For patients who underwent OC, the average number of cycles per patient was 1.04, and approximately 35% of these patients required more than one frozen embryo transfer. For patients who underwent OTC, 2.3% had a repeat laparoscopy for re-transplantation of ovarian tissue, and 63.6% underwent IVF after tissue transplantation. Of those who underwent IVF, it was assumed that patients proceed with just one cycle based on a comprehensive review of IVF outcomes post-transplant. It is important to note that, in the OTC cohort, no pregnancies were achieved when the tissue was harvested over age 36 years.

Table 1.

Clinical estimates

Clinical parameter	Value	Range	Reference
Oocyte cryopreservation (OC)
Probability of clinical pregnancy	40.8%		Diaz-Garcia et al. (2018), Cobo et al. (2018), Specchia et al. (2019)
If clinical pregnancy, probability of live birth	79.9%		Diaz-Garcia et al. (2018), Cobo et al. (2018), Specchia et al. (2019)
Utilization rate of OC after chemo	4.8%	1–80%	Diaz-Garcia et al. (2018), Devine et al. (2015), Specchia et al. (2019), Hoekman et al. (2020)
Average # of cycles per patient	1.041	1.0–1.71	Diaz-Garcia et al. (2018), Simon et al. (2018), Cobo et al. (2018)
Probability of requiring add. FETs	34.7%	26.3–34.7%	Diaz-Garcia et al. (2018), Cobo et al. (2018), Specchia et al. (2019)
Ovarian tissue cryopreservation (OTC)
Probability of clinical pregnancy	27.3%	27.3–62.5%	Diaz-Garcia et al. (2018), Donnez et al. (2015), Van der Ven et al. (2016), Andersen et al. (2019)
If clinical pregnancy, probability of live birth	66.7%	66.7–79.3%	Diaz-Garcia et al. (2018), Donnez et al. (2015), Van der Ven et al. (2016), Andersen et al. (2019)
IVF after transplant	63.6%	0–100%	Diaz-Garcia et al. (2018), Andersen et al. (2019)
Utilization rate of OTC after chemo	5.5%	1–80%	Diaz-Garcia et al. (2018), Devine et al. (2015)
Probability of repeating laparoscopy	2.3%	0–10%	Diaz-Garcia et al. (2018), Expert review (2020)

Cost estimates

Identified from a payer perspective, cost estimates were derived in/inflated to 2019 United States dollars (USD) [10] (Table 2). The base case cost of treatment for OC included the average cost of the oocyte cryopreservation cycle, including medications, 5 years of storage, the thaw cycle with intracytoplasmic sperm injection (ICSI) and fresh transfer, and subsequent frozen embryo transfer if indicated. The base case cost of treatment for OTC included the average cost of laparoscopic oophorectomy, 5 years of storage, tissue processing costs, cost of robotic-assisted laparoscopic transplantation of ovarian tissue, repeat transplantation if indicated, and subsequent IVF cycle if indicated. The costs of laparoscopic oophorectomy and robotic-assisted laparoscopic gynecologic surgery were used as proxies for the costs of obtaining ovarian tissue and of transplantation [11, 12]. These costs for minimally invasive oophorectomy for OTC were found to be in line with the following quotes (including surgeon, hospital, and anesthesia fees) obtained via correspondence with several other academic institutions: $5700, $5500, $8000, $7500, $5000, $7000, $7840, $25000. The designated range of $4145 to $25,000 captured all of the quotes we were able to obtain.

Table 2.

Cost estimates

Item	Cost	Range	Reference
Oocyte cryopreservation (OC)
PrechemoOC (OC cycle with meds)	$14,621	$4992–18,327	Devine et al. (2015), Mesen et al. (2015), Weizman et al. (2020), Institutional pricing (2019–2020), Livestrong Fertile Hope pricing (2019–2020)
Cryopreservation storage cost for 5 yrs	$1618	$0–3238	Devine et al. (2015)
PostchemoThawcycle	$5498	$3699–13,891	Devine et al. (2015), Mesen et al. (2015)
Frozen embryo transfers (FET)	$4499	$3535–14,146	Mesen et al. (2015)
Ovarian tissue cryopreservation (OTC)
Tissue processing for cryopreservation	$3500	$2000–5000	Expert review, Hirshfeld-Cytron et al. (2012)
Tissue storage cost (5 years)	$1618	$0–3238	Devine et al. (2015)
Laparoscopic oophorectomy	$5478	$4145–25,000	Wright et al. (2014), Expert review, Quotes from 5+ academic institutions (2019–2020)
Laparoscopic re-implantation (robotic)	$8682	$4145–28,000	Wright et al. (2014), Khorgami et al. (2017), Expert review
IVF cycle post-transplantation	$16,175	$13,931–18,417	Devine 2015

The costs related to oocyte cryopreservation and IVF, including storage fees, thawing, fertilization, and fresh and frozen embryo transfers, were obtained from literature that obtained charges from 17 randomly selected regionally diverse clinics [13–15]. All charges were confirmed with other primary studies[16], and when available, with published cost ranges through the Oncofertility Consortium (oncofertility.msu.edu), Livestrong Foundation (livestrong.org), Attain Fertility (attainfertility.com), Cost Helper Health (health.costhelper.com), and Resolve (resolve.org). Charges were also compared to internal institutional pricing for patients with medically indicated reasons for FP. Because we used a payer perspective, indirect costs such as loss of productivity were not included in calculations. Because detailed data on timing of post-chemotherapy strategies were not available, we were unable to apply discounting for future costs incurred after the first year. In addition, the appropriate discount rate for the “value” of a future live birth in the setting of gonadotoxic chemotherapy has not previously been defined.

Sensitivity analyses

We performed multiple one-way sensitivity analyses on the following key clinical parameters to assess for variations in costs: probability of utilization, probability of repeat ovarian tissue re-implantation, average number of OC cycles, probability of requiring frozen embryo transfers (FETs), probability of requiring IVF post-transplant, probability of requiring repeat transplantation, probability of clinical pregnancy with OTC, and probability of live birth with OTC. These clinical probabilities and their respective ranges were derived from the literature and reviewed by expert opinion [2, 17, 18]. Given the notable consistency in the probabilities of clinical pregnancy and live birth after OC [2, 3, 19], we did not vary these in sensitivity analysis.

We additionally performed multiple one-way sensitivity analyses on the following costs, given considerable variation by institution and region: cost of oocyte cryopreservation prior to chemotherapy, cost of thaw cycles, cost of ovarian tissue processing for cryopreservation, cost of IVF after OTC, cost of laparoscopic oophorectomy, and cost of transplantation surgery.

Results

Baseline characteristics

A total of 1824 reproductive-aged women with cancer diagnoses were ultimately enrolled in the Diaz-Garcia et al. prospective observational cohort study and received the same FP counseling [2]. The average ages at retrieval for OC and OTC were 31.7 and 28.2 years, respectively; patients older than 40 years were not included in the study. The two cohorts had similar BMI, AMH, and parity. The most prevalent cancer types (breast cancer and lymphoma) were similarly represented in both groups. Student’s t or Mann-Whitney tests for continuous variables and c2 and Fischer’s tests for categorical variables with P<0.05 were considered statistically significant differences.

Base case analysis

The base case costs of each strategy given current costs and short-term utilization estimates were as follows: OTC $10,032 and OC $16,588, with 1% of patients undergoing OTC and 1.56% of patients undergoing OC achieving live birth. These estimates factor in the low utilization rates of 4.8–5.5% in current literature [2, 9, 13]. OC had an ICER of $1,163,954 per additional live birth when compared to OTC.

Sensitivity analyses

One-way sensitivity analyses were performed (Fig. 2). The following variables were assessed over the clinically reasonable ranges depicted in Table 3 and had minimal effect on the model: probability of repeat ovarian tissue transplantation, average number of OC cycles, probability of requiring frozen embryo transfers, and probability of pursuing IVF post-transplantation. The following costs were varied over the ranges depicted in Table 3 and also had minimal effect on the model: cost of thaw cycles, cost of tissue transplantation, cost of IVF post-transplantation.

Fig. 2.

One-way sensitivity analyses

Table 3.

Cost-effectiveness of OTC versus OC

Strategy	Cost ($)	Eff (LB)	Eff (CP)	C/E ($/LB)	C/E ($/CP)	ICER ($/LB)	ICER ($/CP)
Tissue cryopreservation	10,032	0.010015005	0.015015	1,001,726	668,151
Oocyte cryopreservation	16,588	0.015648	0.019584	1,060,123	847,038	1,163,954	1,434,909

Eff, effectiveness; C/E, cost-effectiveness ratio; ICER, incremental cost-effectiveness ratio; LB, live birth rate; CP, clinical pregnancy rate

In a one-way sensitivity analysis of probability of utilization (1–80%) increased utilization improved the efficiency of OC, with OC becoming cost-saving (more effective and less expensive) with a utilization rate of 63%. OC became more cost-effective with increased utilization; OTC is dominated when utilization is 63%, meaning OTC was less effective and more costly than OC.

In a one-way sensitivity analysis of probability of clinical pregnancy resulting from OTC (27–62.5%) [2, 4, 20, 21], OC had an ICER of $1,163,951 to $13,8548,941 per additional live birth compared to OTC. OC became both more expensive and less effective if OTC had a probability of clinical pregnancy greater than 42.5%. Similarly, in a one-way sensitivity analysis for probability of live birth (66.7–79.3%), OC had an ICER of $1,163,954 to $1,752,630 per additional live birth compared to OTC.

In a one-way sensitivity analysis of the cost of oocyte cryopreservation prior to treatment with chemotherapy ($4992–$18,327) [13, 14], OTC was dominated if the cost of oocyte cryopreservation prior to treatment with chemotherapy was less than $8100. OC became increasingly expensive with higher cost prior to treatment, with an ICER of $1,821,908 per additional live birth compared to OTC at the upper limit of this range.

In a one-way sensitivity analysis of the cost of ovarian tissue processing ($2000–$5000), OC had an ICER range of $1,430,261–$897,648 per additional live birth compared to OTC within this range. The ICER became lower as cost of ovarian tissue processing increased.

In a one-way sensitivity analysis of the cost of laparoscopic oophorectomy ($4145–$25,000), OC had an ICER up to $1,400,6111 per additional live birth at the lower end of the cost range. If the cost of laparoscopic oophorectomy was greater than $13,700, OTC became dominated, meaning OTC was more expensive and less effective.

Alternative scenario analysis

We modified the base case cost estimates to assume the application of standardized discounted oncofertility procedure and medication pricing for eligible cancer patients (e.g., through the LiveStrong Fertile Hope program) [22]. If this pricing is offered by almost all oncofertility centers, the average low out-of-pocket self-pay cost for an OC stimulation cycle with medications is $4992. Additionally, from cost quotes for laparoscopic oophorectomy for OTC obtained via correspondence with other oncofertility institutions, the median low out-of-pocket self-pay cost for this surgery, including hospital, surgery, and anesthesia fees, was $5700. In this alternative scenario, including the additional cost of tissue processing and oocyte or tissue storage, the cost for OTC was $10,254 and for OC was $6959. Therefore, OTC was absolutely dominated by OC, meaning OC was less expensive and more effective than OTC at this pricing.

Discussion

In this cost-effectiveness analysis of FP strategies for adult women undergoing gonadotoxic therapy, we found OC to be the more costly but more effective strategy in the base case analysis, owing to the greater upfront cost of OC. This is based on current pricing and utilization estimates, which are constantly evolving. If our example 30-year-old breast cancer patient chose to undergo fertility preservation with OC, her entry cost would be $16,588 as opposed to $10,032 with OTC. This, in combination with the low utilization rates of OC or OTC banked tissue [2], can explain why OC is currently not cost-effective compared to OTC. Given the existing high upfront financial costs of OC, despite its position as the FP method more likely to afford a chance of live birth after chemotherapy (32.6% versus 18.2% with OTC) [2], OC had an ICER of $1,163,954 per additional live birth compared to OTC, reflecting the impact of low utilization. There is no standard willingness-to-pay threshold for an additional live birth in the existing literature [7, 16]. However, seeing as entry costs for OC and OTC are generally less than $20,000 for a patient desiring FP, more than $1 million for one additional live birth is unlikely to be considered cost-effective. Importantly, in the alternative scenario using standardized discounted oncofertility self-pay pricing, OC was less expensive than OTC, making OC cost-saving compared to OTC. It is important to point out, however, that this discounted self-pay pricing does not necessarily reflect the true umbrella cost of the service of oocyte cryopreservation, which is closer to what is represented in the IVF cost literature. Additionally, the cost of OTC may be reduced in specific cases if the oophorectomy were scheduled concurrently with another scheduled surgery (e.g., mastectomy, colorectal surgery prior to adjuvant chemotherapy, or port placement).

We found that the two main factors driving the lack of cost-effectiveness of OC compared to OTC in the base case are the high entry cost of OC and the low utilization rate among this population. The current estimated entry cost of OC, specifically for ovarian stimulation and oocyte retrieval, is considerably more expensive than OTC, which primarily consists of the cost of a laparoscopic adnexal surgery, often coupled with another medically indicated surgery, to lower upfront overhead costs. In a sensitivity analysis of this entry cost[14], OC becomes more effective and less expensive than OTC when the entry cost of OC is less than $8100, which falls outside of a previously published cost range for OC from $10,896 to $18,327, when costs of medication, oocyte cryopreservation, and storage are included [13]. In other words, if the upfront costs for OC were less expensive, then OC would be the more cost-effective strategy compared to OTC. This high entry cost is also the primary reason that the utilization rate post-chemotherapy impacts cost of the strategies, with OC having a high upfront cost and both having a low utilization rate given current short-term data. This helps to explain the contrasting results of the alternative scenario using standardized discounted self-pay oncofertility pricing, where OC is cost saving. Similarly, although OC was not cost-effective using the 5% utilization rate seen with this prospective cohort [2], it becomes cost-saving at a utilization rate of 63%. If cumulative utilization rates increase with longer follow-up beyond the median duration of 5 years in the available literature [2, 4, 20, 23, 24] and the relative effectiveness [2, 3, 16, 17, 25] of the two strategies remain the same, then the results may change as well. As many women may delay their return to thaw their cryopreserved oocytes or ovarian tissue, utilization will likely increase over time [13]. Another potential barrier for return for utilization may stem from patient concerns about malignant cell contamination, especially with high-risk cancers such as leukemias [3]. As more studies demonstrate the reliability of histology/RT-PCR panels to screen and reduce reseeding risk, these legitimate concerns will be better addressed in the future and may result in increased utilization of cryopreserved tissue [2]. Most importantly, with ongoing research to establish prediction models to predict the risk of POI after gonadotoxic therapy [18, 26, 27], the ability to better counsel patients about their individualized risk with selection of high-risk patients for OTC will likely increase return utilization rates for tissue transplantation as well, thereby possibly improving effectiveness of OTC to that of OC.

To our knowledge, this model is the first to estimate the cost-effectiveness of two now non-experimental FP strategies for adult female oncofertility patients. This is a critical time in which the utilization of both methods is likely to increase, and the thresholds at which cost effectiveness is reached are currently unknown. This study uses wide-ranging sensitivity analyses to offer valuable information regarding specific costs, treatment outcomes, and utilization rates of each method, showing that at current estimates of higher cost and low utilization, OC is not cost-effective when compared to OTC. It also offers a more accurate, up-to-date view of the current landscape of costs and effectiveness of both strategies than has been previously published in different patient populations. A previous analysis examined the cost-effectiveness of these two strategies in women pursuing planned FP to prevent age-related infertility, in which the ICER for OC was $135,520 per live birth compared to OTC. At the time, OTC was still considered experimental; thus, costs for tissue processing were assumed to be $0 (no charge) [7]. For our model, we assumed that this would no longer be cost-free without the experimental label. The prior model also did not account for the use of robotic-assisted laparoscopy for tissue transplantation; we assumed the use of robotic-assisted laparoscopy due to recent studies demonstrating better tissue handling outcomes with regard to increased precision, more delicate graft handling, and reduced time from thaw-to-transplantation [28, 29]. Our model also took into account the strong differences in expert opinion regarding whether IVF should be attempted on transplanted thawed ovarian tissue by assigning a broad range of 0 to 100% for the probability of IVF post-transplantation [17].

This study has a number of limitations. First, financial charges for all oocyte cryopreservation and IVF-related procedures were used, which may overestimate the costs. Given that for many patients these services are not covered by insurance due to lack of a state mandate, charge data is frequently used in cost-effectiveness analyses within the reproductive endocrinology and infertility literature, which may contribute to an over-estimation of OC cost (mainly based on charge data) relative to the underestimation of OTC (cost data) [13, 14, 30]. Additionally, costs were estimated from published literature, which is fairly limited based on a recent review published in 2020 [15]. The institutions from which the pricing ranges were queried may also have had considerable variations. The costs were also based on US estimates and may not reflect costs in other parts of the world. To mitigate this, sensitivity analyses were done using wide ranges for costs to capture meaningful conclusions based on considerable variances in costs. Secondly, we did not account for patients who may spontaneously conceive prior to thawing their cryopreserved oocytes and ovarian cortical tissue. While this would impact the patients’ live birth rates, we assumed that the chance of spontaneous live birth (prior to embryo transfer or ovarian tissue transplantation) would be similar between patients who had chosen one method or the other. Ideally, cancer patients at high risk of POI would be offered fertility preservation (in this population of interest, OC versus OTC), and so a “no intervention” arm did not fall under the scope of this particular model. Third, this decision analysis was performed from a strictly payer perspective; patient and societal perspectives would have been an interesting complement. However, given the sizable variations in out-of-pocket cost of FP depending on eligibility for assistance programs, state-mandated coverage, or institution-specific philanthropic funding and overhead cost variation, determination of costs for such a model was not feasible at this time. Fourth, key clinical parameters were derived from primarily one study. We acknowledge the paucity of comparison data on outcomes between OC and OTC overall; however, this was the largest controlled prospective cohort study in current literature that compared OC and OTC effectiveness and was thought to accurately reflect the current state of FP in our desired study population. Based on this single study, we also did not account for the wide range in longevity of transplanted ovarian tissue, which may last up to 7–10 years [3, 17, 28], potentially changing the effectiveness of OTC, as multiple pregnancies may be achieved with one OTC. Although there exists a thorough systematic review on OTC outcomes, it focused solely on the use of assisted-reproductive technology (ART) after OTC, when in reality there is little uniformity regarding whether ART is recommended post-transplant [17]. However, we did include these outcomes in our sensitivity analysis. Additionally while our findings are not generalizable to women older than the age of 40, future studies are required to establish further granularity into the impact of age stratification on OC versus OTC outcomes. Given the finding of no clinical pregnancies with OTC when tissue was harvested over age 36, it stands to reason that at the upper end of the ages included, OTC would be significantly less effective than OC [2]. This idea is discussed in the systematic review of outcomes of IVF after OTC, as younger age (and presumably better oocyte quality) is thought to be necessary to overcome the detrimental effect of diminished ovarian reserve (and low AMH) present after OTC transplantation [17]. Finally, this model focused on live birth and did not capture patient preferences for other outcomes, including secondary outcomes for OTC such as return of premenopausal estrogen levels or desire for multiple live births. In contrast to OC, OTC offers the potential for spontaneous cycles and can reverse the onset and delay the downstream effects of POI. As more data accumulates over time for OTC, this would be important to address when considering longer-term effectiveness and quality-adjusted life years (QALY) in a future study.

The field of fertility preservation is rapidly progressing, and increased innovation of practice, utilization of services, and improved outcomes will continue to evolve the treatment landscape. Although many patients have only one option for FP method given time constraints prior to gonadotoxic therapy, pubertal status, need for a gestational carrier, or hormonal concerns, there is an increasing population of adult female premenopausal oncofertility patients facing highly gonadotoxic chemotherapy who are candidates for either OC or OTC (or both) for FP. These two methods vary widely in their availability, upfront and backend costs, and efficacy; importantly, no study to date had compared the cost-effectiveness of these two methods in the oncofertility population. We found that OC, while the more clinically effective for achieving live birth, is not cost-effective compared to OTC in this patient population given current pricing and utilization estimates. However, we found that an increase in utilization and a decrease in upfront cost for oocyte cryopreservation prior to chemotherapy have significant effects on the relative efficiency of the two strategies, as shown in our sensitivity analyses and alternative scenario (in which standardized discounted oncofertility pricing was assumed as the standard of care). Given the current climate in which the high upfront cost of OC predominates, OTC may be a reasonably cost-effective option for women seeking FP prior to receiving gonadotoxic chemotherapy.

Author contribution

EHC, SLL, EM HAM, and KSA contributed to the conception and design of the study. EHC and KSA reviewed the literature and collected the data needed for the analysis. EHC and SLL developed the model and performed the analysis, supervised by HAM, EM, and KSA. All authors participated in interpretation of the data analysis. EHC and SLL drafted the article. All authors edited the manuscript closely and approved the final submitted version as guarantors for the study.

Data availability

The data underlying this manuscript are available in the article.

Declarations

Conflict of interest

The authors declare no competing interests.

Ethics approval

The Duke Institutional Review Board approved this study for IRB exemption status.

Consent to participate

Not applicable

Consent for publication

Not applicable