Planned Immediate Chemotherapy and Cryopreservation of Oocytes or Embryos for Fertility Preservation in Women with Malignancies

Abstract

Purpose:

Oocyte and embryo cryopreservation before gonadotoxic treatment are established methods to increase the likelihood of live births. Although several sociodemographic factors were found to be associated with undergoing fertility preservation (FP) treatment, clinical characteristics such as planned immediate chemotherapy were not fully investigated. We aimed to investigate whether the planned immediate chemotherapy is related to the decision to undergo oocyte/embryo cryopreservation for FP with adjustment for other clinical characteristics.

Methods:

This institutional cohort study included 491 premenopausal women aged 19 years or older who visited the FP clinic at a tertiary medical center between 2006 and 2019. The primary outcome was whether the participants underwent oocyte/embryo cryopreservation. We evaluated the odds ratios (ORs) and corresponding 95% confidence intervals (CIs) of undergoing oocyte/embryo cryopreservation according to whether immediate chemotherapy was planned using univariable and multivariable logistic regression.

Results:

Women scheduled for immediate chemotherapy were much less likely to undergo oocyte/embryo cryopreservation than women not scheduled for immediate chemotherapy (OR = 0.46, 95% CI 0.27–0.76) in univariable logistic regression analysis. After adjustment for covariates such as marital status, type of malignancies, and calendar year period, women scheduled for immediate chemotherapy were still less likely to undergo oocyte/embryo cryopreservation than women not scheduled for immediate chemotherapy (OR = 0.31, 95% CI: 0.17–0.56). The association was not different according to the type of malignancies (p for interaction = 0.13). Regarding breast cancer, the OR for undergoing oocyte/embryo cryopreservation in women scheduled for immediate chemotherapy was robust compared with those not planned for immediate chemotherapy (OR = 0.25, 95% CI: 0.12–0.53).

Conclusion:

The present study demonstrated that planned immediate chemotherapy was negatively associated with undergoing oocyte/embryo cryopreservation. This information can be helpful for FP counseling.

Introduction

Gonadotoxic therapy, such as chemotherapy and radiotherapy, is commonly used to treat malignant tumors. It can adversely affect the gonads and lead to infertility and premature ovarian insufficiency in women. Because childbearing and child-rearing are fundamental aspects of the quality of life, fertility preservation (FP) has become an important issue for reproductive-aged women with cancer, as highlighted in recent guidelines.^1–3 Furthermore, the increasing survival rates among cancer patients have heightened the significance of FP strategies in oncological care and reproductive medicine.⁴ Currently, several FP options are available, including oocyte/embryo cryopreservation, ovarian tissue cryopreservation, gonadotropin-releasing hormone agonist (GnRHa) treatment during chemotherapy, and ovarian transposition before pelvic radiotherapy.⁵ Ovarian tissue cryopreservation, another FP option, is still considered experimental in South Korea, although it is an acceptable fertility-preservation technique and is no longer considered experimental, according to the American Society for Reproductive Medicine (ASRM) Committee Opinion.⁶

Oocyte and embryo cryopreservation before gonadotoxic treatment are established methods to increase the likelihood of live births.^7–9 However, every woman does not want to undergo oocyte/embryo cryopreservation.^10–13 Although several sociodemographic factors are associated with undergoing FP treatment, clinical characteristics such as planned immediate chemotherapy, time from diagnosis of malignancies to consultation with a fertility specialist, and when the ASRM and American Society of Clinical Oncology (ASCO) revised guidelines^2,3 have not been fully investigated. Furthermore, previous studies are limited by small sample sizes, which may decrease the power of these studies and affect the margin of error.

In the present study, we aimed to investigate whether planned immediate chemotherapy is associated with the decision to undergo oocyte/embryo cryopreservation for FP with adjustment for other clinical characteristics.

Materials and Methods

Study population

This institutional cohort study included 615 premenopausal women who visited the FP clinic and for whom chemotherapy was planned at a tertiary medical center between 2006 and 2019. The following are criteria for the exclusion of the women: (1) women were younger than 19 years (n = 32); (2) women who had non-malignant diseases such as systemic lupus erythematosus and aggressive fibromatosis (n = 3); (3) women who started chemotherapy before their first visit (n = 15); (4) women who visited with recurrent cancer (n = 13); (5) women in whom chemotherapy was canceled after surgery (n = 17); (6) women who needed urgent chemotherapy or were not adequate for oocyte/embryo cryopreservation because they had acute leukemia, mediastinal lymphoma, and metastatic breast cancer (n = 44). Finally, 491 women were included in the present study, all of whom were diagnosed with malignant tumors and were naïve to chemotherapy (Fig. 1). All women received counseling from fertility specialists about FP options before chemotherapy, including oocyte/embryo cryopreservation, ovarian tissue cryopreservation, and GnRHa treatment.

FIG. 1.

Flowchart of the study population.

The estimated number of study participants was determined using G-power 3.1.¹⁴ We assumed an expected proportion of patients undergoing oocyte/embryo cryopreservation of 0.25 in women in whom immediate chemotherapy was planned and an odds ratio (OR) of 1.8 according to whether immediate chemotherapy was planned. An R-squared statistic of 0.20 was expected based on covariates other than planned immediate chemotherapy.

Data collection

Demographic and clinical characteristics were obtained from electronic medical records. Variables including age, body mass index (BMI), marital status, parity, level of anti-Mullerian hormone (AMH), cancer diagnosis, FP decision, and whether immediate chemotherapy were planned. Marital status was classified into five categories: virgin (women who had not experienced a sexual relationship), single (women who had previously experienced a sexual relationship but were not married), married with children (women who were married and had at least one child), married without children (women who were married but had no child), and divorced (women who were divorced). Cancer diagnoses were classified into four categories: breast cancer, other solid tumors, hematological malignancies, and gynecological malignancies. Other solid tumors included gastrointestinal cancer, brain tumor, head and neck cancer, lung cancer, thymoma, mesothelioma, and malignant melanoma. Hematological malignancies included lymphoma, myelodysplastic syndrome, pure red cell aplasia, and plasmacytoma. Gynecological malignancies were invasive cervical cancer, ovarian cancer, and endometrial cancer. Additionally, cancer diagnoses were divided into two categories, including breast cancer and non-breast cancer. The time to visit the FP clinic was calculated as the first date of visiting the FP clinic minus the date of cancer diagnosis. Planned immediate chemotherapy was defined as neoadjuvant chemotherapy scheduled before surgery for a solid tumor or immediate chemotherapy required at the request of oncologists for hematological malignancies. The ASRM and ASCO declared that oocyte cryopreservation was no longer an experimental option in 2013^2,3; therefore, the calendar year period was divided into 2006–2013 and 2014–2019.

Statistical analysis

Participant characteristics were summarized as the median and interquartile range for continuous variables and as the number of participants and proportion for categorical variables.

The primary outcome was whether the participants underwent oocyte/embryo cryopreservation. Using univariable logistic regression, we evaluated the ORs and corresponding 95% confidence intervals (CIs) of undergoing oocyte/embryo cryopreservation according to whether immediate chemotherapy was planned. Furthermore, adjustments for age, marital status, type of malignancies, and calendar year period were performed with multivariable logistic regression. In addition, the interaction between planned immediate chemotherapy and covariates on undergoing oocyte/embryo cryopreservation was investigated. Covariates for adjustment were chosen a priori because they were considered to be related to undergoing oocyte/embryo cryopreservation. They were first tested using univariable logistic regression. Then, any variable with a p < 0.1 was included in the adjusted model. If the p value calculated with the Wald chi-square test was <0.05, the variable was retained in the adjusted model except for age tertiles.

The analyses were conducted based on complete-case analyses, and missing data were not found except for the AMH level (n = 91). All statistical analyses were conducted using Stata 17 (StataCorp LLC, College Station, TX), and statistical significance was defined as p < 0.05. The plot illustrating the OR was generated using GraphPad Prism 10.2.3 (GraphPad Software, Boston, MA).

Institutional review board approval statement

This study was conducted after approval from the Institutional Review Board of Seoul National University Hospital (IRB No. 1905-004-1030), and informed consent was waived because of the retrospective study nature. All data were collected and analyzed according to the Declaration of Helsinki guidelines.

Results

Of 491 women included in the study, all underwent GnRHa treatment, and 92 women (17.8%) decided to undergo oocyte/embryo cryopreservation (Table 1). Immediate chemotherapy was planned in 185 women (37.7%). The median age of the study participants was 33 years, and their median BMI was 20.9 kg/m². Most women had not experienced pregnancy or delivery, and only one-quarter of participants (n = 128) reported at least one pregnancy. With respect to marital status, most women were single (49.3%) or virgins (18.9%). Seventy-one women (14.5%) were married and had at least one child, whereas 80 women (16.3%) were married but had no child. Only five women reported that they had been divorced. The most commonly diagnosed cancer was breast cancer (80.0%), and the second most common was other solid tumors (9.0%). Over half of the women (52.6%) visited our fertility clinic from 2014 to 2019.

Table 1.

Baseline Characteristics of the Study Participants

	Median (interquartile range) or n (%)
Planned immediate chemotherapy	185 (37.7%)
Age (years)	33 (29–37)
Tertiles of age (years)
Lowest	27 (25–29)
Middle	33 (31–34)
Highest	39 (37–41)
Body mass index (kg/m²)	20.9 (19.4–23.0)
Experience of pregnancy	128 (26.1%)
Number of previous pregnancies	0 (0–1)
Number of live births	0 (0–0)
Level of anti-Mullerian hormone (ng/mL)	3.9 (2.1–6.8)
Marital status
Virgin	93 (18.9%)
Single	242 (49.3%)
Married, multiparous	71 (14.5%)
Married, nulliparous	80 (16.3%)
Divorced	5 (1.0%)
Time to visit the fertility preservation clinic (days)	3 (1–6)
Time to visit the fertility preservation clinic <7 days	388 (79.0%)
Type of malignancies
Breast cancer	393 (80.0%)
Other solid tumors	44 (9.0%)
Hematological malignancies	42 (8.6%)
Gynecological malignancies	12 (2.4%)
Calendar year period
2006–2013	233 (47.4%)
2014–2019	258 (52.6%)
Modality of fertility preservation
GnRHa only or refused fertility preservation	399 (80.0%)
Oocyte/embryo cryopreservation ± GnRHa	92 (17.8%)

GnRHa, gonadotropin-releasing hormone agonist.

In univariable logistic regression analysis, women scheduled for immediate chemotherapy were much less likely to undergo oocyte/embryo cryopreservation than women not scheduled for immediate chemotherapy (OR = 0.46, 95% CI: 0.24–0.76) (Table 2). Single women and married nulliparous women were more likely to undergo oocyte/embryo cryopreservation than women who were virgins (OR = 2.24, 95% CI: 1.12–4.50; OR = 3.01, 95% CI: 1.36–6.65, respectively). As expected, married multiparous women were significantly less likely to undergo oocyte/embryo cryopreservation than women who were virgins (OR = 0.11, 95% CI: 0.01–0.85). Women with non-breast cancer were significantly more likely to undergo oocyte/embryo cryopreservation than women with breast cancer (OR = 2.69, 95% CI: 1.63–4.45). Regarding the calendar year, the odds of undergoing oocyte/embryo cryopreservation during 2014–2019 were 5.21 times higher than those during 2006–2013 (95% CI: 2.97–9.14). The odds of undergoing oocyte/embryo cryopreservation did not differ according to age, BMI, serum AMH concentration, or the time to visit the FP clinic.

Table 2.

Univariable Logistic Regression of Fertility Preservation Including Oocyte/Embryo Cryopreservation

	Odds ratio (95% confidence interval)
Planned immediate chemotherapy
No	Ref
Yes	0.46 (0.27–0.76)
Tertiles of age
Lowest	Ref
Middle	0.91 (0.53–1.57)
Highest	0.70 (0.40–1.24)
Body mass index (kg/m²)	1.02 (0.95–1.09)
Experience of pregnancy
No	Ref
Yes	0.41 (0.22–0.76)
Tertiles of anti-Mullerian hormone level
Lowest	Ref
Middle	1.30 (0.70–2.39)
Highest	1.47 (0.80–2.70)
Marital status
Virgin	Ref
Single	2.24 (1.12–4.50)
Married, multiparous	0.11 (0.01–0.85)
Married, nulliparous	3.01 (1.36–6.65)
Divorced	1.86 (0.19–18.22)
Time to visit the fertility preservation clinic
<7 days	Ref
≥7 days	0.80 (0.45–1.45)
Type of malignancies
Breast cancer	Ref
Other malignancies	2.69 (1.63–4.45)
Calendar year period
2006–2013	Ref
2014–2019	5.21 (2.97–9.14)

After adjustment for the aforementioned significant covariates including marital status, type of malignancies, and calendar year period, women scheduled for immediate chemotherapy were still less likely to undergo oocyte/embryo cryopreservation than women not scheduled for immediate chemotherapy (OR = 0.31, 95% CI: 0.17–0.56) (Table 3 and Fig. 2). In addition, interaction between planned immediate chemotherapy and covariates on undergoing oocyte/embryo cryopreservation was analyzed, but no variable had a significant interaction with planned immediate chemotherapy. The p value of the Hosmer–Lemeshow goodness-of-fit test was 0.76, meaning that the model fit our data.

FIG. 2.

Fertility preservation including oocyte/embryo cryopreservation by clinical characteristics.

Table 3.

Multivariable Logistic Regression of Fertility Preservation Including Oocyte/Embryo Cryopreservation

	Odds ratio (95% confidence interval)	p for interaction
Planned immediate chemotherapy
No	Ref
Yes	0.31 (0.17–0.56)
Tertiles of age		0.66
Lowest	Ref
Middle	1.06 (0.56–2.01)
Highest	0.89 (0.45–1.74)
Marital status		N/A
Virgin	Ref
Single	2.77 (1.28–5.96)
Married, multiparous	0.11 (0.01–0.90)
Married, nulliparous	3.65 (1.51–8.83)
Divorced	1.24 (0.10–14.89)
Type of malignancies		0.13
Breast cancer	Ref
Other malignancies	2.66 (1.46–4.87)
Calendar year period		0.82
2006–2013	Ref
2014–2019	5.95 (3.25–10.88)
p for goodness of fit test	0.76

We presented the results of the data of women with breast cancer and those with non-breast cancer separately (Tables 4 and 5). The OR for undergoing oocyte/embryo cryopreservation was significantly lower in women scheduled for immediate chemotherapy compared with those not planned for immediate chemotherapy in breast cancer (OR = 0.25, 95% CI: 0.12–0.53). Regarding non-breast cancer, women scheduled for immediate chemotherapy were less likely to undergo oocyte/embryo cryopreservation than women not planned for immediate chemotherapy (OR = 0.38, 95% CI: 0.11–1.27). The direction of the OR did not change according to the type of malignancies as expected from P for interaction (p = 0.13).

Table 4.

Multivariable Logistic Regression of Fertility Preservation Including Oocyte/Embryo Cryopreservation in Women with Breast Cancer

	Odds ratio (95% confidence interval)
Planned immediate chemotherapy
No	Ref
Yes	0.25 (0.12–0.53)
Tertiles of age
Lowest	Ref
Middle	1.01 (0.48–2.13)
Highest	0.64 (0.30–1.39)
Marital status
Virgin	Ref
Single	1.73 (0.72–4.13)
Married, multiparous	0.11 (0.01–0.89)
Married, nulliparous	2.37 (0.88–6.38)
Divorced	2.53 (0.19–33.18)
Calendar year period
2006–2013	Ref
2014–2019	4.95 (2.55–9.59)
p for goodness of fit test	0.42

Table 5.

Multivariable Logistic Regression of Fertility Preservation Including Oocyte/Embryo Cryopreservation in Women with Non-Breast Cancer

	Odds ratio (95% confidence interval)
Planned immediate chemotherapy
No	Ref
Yes	0.38 (0.11–1.27)
Tertiles of age
Lowest	Ref
Middle	1.33 (0.35–5.04)
Highest	3.49 (0.59–20.75)
Marital status
Virgin	Ref
Single	8.00 (1.55–41.42)
Married, multiparous	N/A
Married, nulliparous	8.97 (1.32–60.97)
Divorced	N/A
Calendar year period
2006–2013	Ref
2014–2019	13.10 (2.53–67.85)
p for goodness of fit test	0.76

Discussion

To our knowledge, this is the first study to evaluate the association of planned immediate chemotherapy with undergoing oocyte/embryo cryopreservation. In the present study, which included 491 women, we found that women scheduled for immediate chemotherapy were less likely to undergo oocyte/embryo cryopreservation than women not scheduled for immediate chemotherapy, even after adjustment for other characteristics.

Vitrified/warmed oocytes demonstrate similar fertilization and pregnancy rates as fresh oocytes upon in vitro fertilization/intracytoplasmic sperm injection; therefore, oocyte cryopreservation with vitrification is no longer considered experimental.¹⁵ With random-start ovarian stimulation,¹⁶ oocyte/embryo cryopreservation is now possible within about 2 weeks.¹⁷ However, time pressures may lead to FP not being pursued and greater decision regret after cancer treatment.¹⁸ As expected, in the present study, women scheduled for immediate chemotherapy were less likely to undergo oocyte/embryo cryopreservation, suggesting that their perception of pressure was significant. These results are consistent with a previous study reporting that women with breast cancer who receive neoadjuvant chemotherapy are more likely to decline referral to a fertility specialist.¹⁹ Contrary to our findings, Flink et al.¹¹ reported that a cancer treatment plan is not a significant variable in FP decision-making, but the cancer treatment plan variable in their study was not described in detail and is unlikely to be identical to the variable in our study. Furthermore, the number of participants was smaller in their study (n = 108) than in our study.

Although fertility is a priority for young women, half of women with a history of cancer reported that their concerns about fertility were not addressed adequately.²⁰ Furthermore, women with late referral to a fertility specialist demonstrated a higher decisional conflict scale.²¹ To decrease the pressure surrounding upcoming chemotherapy and to ensure women have less regret about their decision of whether to undergo oocyte/embryo cryopreservation, early pre-treatment counseling may have an important role in FP. Recently, Flink et al.¹¹ showed that the time to visit the FP clinic was a predictor of FP, and significantly differed between women who chose to undergo FP and those who did not (29.5 vs. 58.8 days). However, in our study, the odds of undergoing oocyte/embryo cryopreservation did not differ according to the time to visit the FP clinic. This discrepancy might be because the time to visit the FP clinic was short in our study (median: 2 days) compared with the study by Flink et al. (29.5 days).¹¹ Many oncofertility centers are committed to seeing oncology patients as quickly as possible,²² and our clinic is trying to get patients seen by a fertility specialist within 24 hours of referral request, excluding weekends. Furthermore, in a previous study, the time from cancer diagnosis to chemotherapy initiation did not differ according to FP, although women who underwent oocyte/embryo cryopreservation might have perceived a delay in cancer treatment.²³

To promote oocyte/embryo cryopreservation in women scheduled for immediate chemotherapy, the attitude of the oncologist is also critical. If the oncologist mentions immediate chemotherapy as more important than oocyte/embryo cryopreservation, the patients cannot easily undergo FP. Indeed, the study, which investigated the referral pattern of oncologists, reported that less than half of U.S. physicians routinely refer their patients with malignancies to a reproductive endocrinologist.²⁴ Furthermore, most health care professionals in the United Kingdom rated their knowledge of FP as “very poor” or “‘poor,” and they had not experienced training on FP.²⁵ Therefore, educating oncologists and creating materials for newly diagnosed patients to change negative attitudes toward FP may be imperative.

In the present study, women with breast cancer and non-breast cancer were analyzed separately because women with breast cancer accounted for a large proportion of our study (80.0%), and the median age at diagnosis (34 years) in women with breast cancer was significantly different from that in the other malignancies (31 years). In addition, breast cancer is a hormone-dependent tumor, and women with breast cancer might have been reluctant to oocyte/embryo cryopreservation, which can lead to an elevation of estrogen. However, in this study, the interaction between planned immediate chemotherapy and the type of malignancies on undergoing oocyte/embryo cryopreservation was not significant. Regarding non-breast cancer, planned immediate chemotherapy was not significantly associated with undergoing oocyte/embryo cryopreservation (OR = 0.38, 95% CI: 0.11–1.27), which might have resulted from the small study population (n = 88).

We also found that the likelihood of undergoing oocyte/embryo cryopreservation significantly differed according to the calendar year period. As mentioned earlier, the ASRM and ASCO revised guidelines address the fact that oocyte cryopreservation is considered standard practice.^2,3 After the publication of these guidelines, the practice pattern of fertility specialists or clinical oncologists might have changed to favor unfertilized oocyte cryopreservation. Our results are also in line with the findings of Schon et al.²⁶ who reported that publication of the ASRM revised guidelines increased the likelihood of undergoing oocyte cryopreservation. Considering that the awareness of patients of the gonadotoxic effect of chemotherapy is relatively poor,²⁷ the revised guidelines may have increased the awareness of FP among fertility specialists or clinical oncologists, not patients, although this has not been proven.

This study has several shortcomings. First, we did not include minors. Whether minor patients undergo oocyte cryopreservation depends on the attitude of their parents, not the patients. Therefore, previous studies that investigated the factors associated with FP did not include minors.^10–13 Second, information about economic status was unavailable in the present study. However, previous studies did not find any association between income and referral to FP.^28,29 In addition, over 99% of the Korean population is covered by the national health insurance program, and cancer patients pay only 5% of their total medical expenses for 5 years from the day of the diagnosis. Although the national health insurance program does not cover FP, the average cost of FP does not exceed about 3000 U.S. dollars in Korea. Given that the gross national income per capita in Korea was $35,490 in 2023,³⁰ oocyte/embryo cryopreservation-related medical expenses may be minimal, if any. Finally, in our study, psychological factors could not be investigated thoroughly compared with the previous studies. For example, Di Mattei et al. reported that individual desire for parenthood was the most important predictor of high motivation to undergo FP.¹⁰ Similarly, another study described that most women who underwent FP reported a strong desire for parenthood, whereas women who declined tended to have focused on surviving cancer.¹² However, they did not adjust other clinical variables such as marital status, type or malignancies, and planned immediate chemotherapy. The inclusion of marital status as a covariate in our study might be the proxy for individual desire for parenthood in the previous studies.

Despite the limitations, our study population included 491 women, while the sample sizes of previous studies are relatively small.^10–13 A large sample size does not guarantee generalizability to represent a population but can provide more reliable results with adjustments for covariates. Another strength is that various factors, including marital status and virginity, were investigated. In Korea, virginity is still valued, and the possibility of losing it during the oocyte retrieval procedure can be an important factor in the decision. The results showed that single women who had previously experienced sexual relationships were more likely to undergo oocyte cryopreservation than women who were virgins.

Conclusion

The decision to undergo oocyte/embryo cryopreservation should be individualized based on each patient’s unique medical history and treatment plan and should be made in consultation with a multidisciplinary team, including reproductive specialists, oncologists, and other health care providers, as needed. The present study demonstrated that planned immediate chemotherapy is negatively associated with undergoing oocyte/embryo cryopreservation. This information can be helpful for FP counseling.

Footnotes

Authors’ Contributions

J.Y.H.: Data curation, methodology, writing—original draft, and writing—reviewing and editing. H.K.: Conceptualization, data curation, formal analysis, funding acquisition, investigation, methodology, software, supervision, validation, writing—original draft, and writing—reviewing and editing. Y.S.H.: Data curation, formal analysis, investigation, methodology, validation, and writing—reviewing and editing. M.L.: Conceptualization and data curation. S.J.H.: Investigation and data curation. S.Y.K.: Resources and supervision.

Data Availability Statement

The data that support the findings of this study are available on request from the corresponding author, Hoon Kim. The data are not publicly available due to information that could compromise the privacy of research participants.

Author Disclosure Statement

J.Y.H. has received payment for lectures from Bayer, which are unrelated to this article. H.K. has received honoraria for participation on the advisory board of Bayer, consulting for Merck and LG Chemical, and lectures from Roche Diagnostics and Organon, which are unrelated to the subjects addressed in this article. Other authors report no financial or commercial conflicts of interest.

Funding Information

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (No. 2023R1A2C1005003).

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