Cancer in reproductive-aged women is a serious health concern, with approximately 80,550 women diagnosed before age 45 years annually.1 Medical advances have improved cancer survival,2 increasing focus on quality-of-life issues after cure,3 including motherhood.4 Data suggest posttreatment pregnancy does not heighten risk of cancer progression or adverse obstetric or neonatal outcomes for most tumors.5 Thus, pretreatment fertility counseling and preservation are now often considered.
Previously, cancer survivors with ovarian insufficiency could only achieve parenthood through donor gametes or adoption. However, recent innovations now allow use of autologous gametes through pretreatment oocyte, embryo, or ovarian tissue cryopreservation. Oocyte cryopreservation offers advantages over embryo cryopreservation, including enhanced reproductive autonomy and decreased ethical, personal, and religious dilemmas.
Oocytes have been successfully cryopreserved using slow cooling, which decreases temperature at a controlled rate, and vitrification, which involves rapid cooling. Some studies suggest vitrification results in improved survival and development compared with slow cooling6; however, prospective randomized controlled trials are lacking, and our center has not observed decreased survival or development with slow cooling.7
Importantly, oocyte cryopreservation is no longer considered experimental, and reported live birth outcomes are now comparable with those of fresh in vitro fertilization at some centers.8,9 Furthermore, more than 3,000 live births from oocyte cryopreservation have been reported, with no increase in birth anomalies.9–11 However, few live births from oocyte cryopreservation have been described in cancer survivors.12–14
We performed this study to demonstrate that oocyte cryopreservation is a feasible reproductive option for women of childbearing age who require gonadotoxic therapies.
MATERIALS AND METHODS
This study is a retrospective review of all patients with cancer who presented to the New York University Fertility Center for oocyte cryopreservation treatment between January 2005 and September 2014 (n=176). Fertility preservation counseling compliant with current American Society for Reproductive Medicine guidelines was provided to all patients,15 and those who elected to proceed were consented for treatment. Institutional review board approval (#S13-00389) was obtained to report outcomes. Because the focus of this report is oocyte cryopreservation, outcomes are reported for women who elected oocyte cryopreservation (n=176) but not for those who elected a combination of oocyte and embryo cryopreservation (n=44) or embryo cryopreservation alone (n=30).
Ovarian stimulation was achieved with the following protocols: injectable gonadotropins (follitropin β, menotropins) with luteinizing hormone suppression accomplished using gonadotropin-releasing hormone (GnRH) agonist (leuprolide acetate) or antagonist (cetrorelix acetate). Ovulation was triggered with chorionic gonadotropin (n=142; human chorionic gonadotropin [hCG]; 10,000 units or choriogonadotropin α, 500 micrograms), GnRH agonist (n=79; leuprolide acetate, 0.4 cc=2 mg), or a combination of the two drugs (n=10; 1,000 units hCG or approximately 60 micrograms [one fourth of a premixed syringe] of choriogonadotropin α+2 mg GnRH agonist). GnRH agonist alone was chosen as the trigger when peak serum estradiol level exceeded 2,500 pg/mL or if the patient was scheduled to undergo surgery or chemotherapy within 2 weeks of oocyte retrieval. If a patient had any of the following (n=61): her fertility preservation treatment was emergent, her menstrual cycle was other than early follicular or its phase was unclear, or she had no uterus, a GnRH antagonist±oral contraceptive pills or a GnRH agonist was administered to allow for timely ovarian stimulation per our previously published “quick-start” protocols.16 Because it became standard of care over the study period, women with estrogen-sensitive tumors (specifically, breast cancer) were administered aromatase inhibitor cotreatment to mitigate serum estradiol rise. Specifically, these patients were given 5 mg daily from the first day of gonadotropin stimulation until the day of ovulation trigger.
From January 2005 to September 2011, both slow-cooling and vitrification techniques were used for oocyte cryopreservation, as was routine in our laboratory. After September 2011, we only used vitrification. Our cryopreservation protocols have been previously reported.17
For oocyte thaw cycles, all surviving metaphase II oocytes were fertilized through intracytoplasmic sperm injection with resultant embryos cultured 3 (n=4) or 5 (n=7) days before transfer. Embryos were placed in the uterus under abdominal ultrasound guidance using a Wallace transfer catheter.
Because of its influence on reproduction, relationship status was determined for patients at the time of consult. Single was defined as being in no relationship or in a relationship for less than 1 year, whereas partnered was defined as being in a committed relationship for more than 1 year. In addition to reporting the number of retrieved oocytes, we also determined the number of oocytes that reached metaphase II, the maturation stage at which the oocyte is capable of being fertilized by sperm. Thaw data analyzed included oocyte survival, fertilization, embryo transfer, implantation, and pregnancy outcomes.
Data are presented as medians with interquartile ranges. Ninety-five percent confidence intervals (CIs) are provided for all percentages. Multiple logistic regression was used to detect the association among age, cancer diagnosis, and number of oocytes retrieved.
The data set included cycle outcomes of 176 patients with a median age of 31 years (interquartile range 24–36). Six patients underwent two cycles of ovarian stimulation and oocyte retrieval, resulting in a total of 182 oocyte cryopreservation treatment cycles. Table 1 shows patient demographics by cancer type. Malignant diagnoses included 75 breast, 51 gynecologic, 32 hematologic, and 18 other cancers. In 131 patients, it was timely to assess baseline serum hormone levels; the median follicle-stimulating hormone level was 5.4 international units/L (interquartile range 3.0–7.0) and the median estradiol level was 46 pg/mL (interquartile range 33–63). Baseline serum follicle-stimulating hormone was less than 12.5 international units/L in all but four patients with the highest out-of-range value being 13.5 international units/L. Median time from consult request to initiation of ovarian stimulation was 1 day (interquartile range 0–4), median length of ovarian stimulation was 10 days (interquartile range 9–12), and median time between consult request and oocyte retrieval was 12 days (interquartile range 10–14). As expected, median age was highest for patients with breast malignancies (36 years, interquartile range 32–39) and lowest for those with hematologic malignancies (23 years, interquartile range 19–26). Median age for patients with gynecologic cancers was intermediate (28 years, interquartile range 23–33) because this heterogeneous group is composed of relatively older women with invasive ovarian and uterine cancers as well as younger women with cervical and borderline ovarian tumors. At the initial consult, 74% (n=130) of patients were single and 26% (n=46) were partnered.
Ovarian stimulation results and oocyte yield at retrieval, classified by cancer diagnoses, are shown in Table 2. Outcomes were adequate irrespective of malignancy type. Median peak stimulation estradiol for the entire group was 1,446 pg/mL (interquartile range 730–2,687). Patients with breast cancer had the lowest median peak serum estradiol (856 pg/mL, interquartile range 472–1,546), likely because they are the oldest and had aromatase inhibitor cotreatment. Despite having full tumor loads, hematologic patients had the highest median peak estradiol (2,379 pg/mL, interquartile range 1,623–3,084), likely because they are the youngest patient population.
For the entire study cohort, a median of 15 (interquartile range 9–23) oocytes were retrieved and 15 (interquartile range 9–23) cryopreserved; a median of 10 (interquartile range 5–18) metaphase II oocytes were cryopreserved. Regardless of preretrieval ovulation trigger (hCG compared with GnRH agonist compared with hCG+GnRH agonist), two thirds or more of the oocytes retrieved were metaphase II. Commensurate with their higher estradiol response, those with hematologic malignancies had more oocytes retrieved (22, interquartile range 13–30), oocytes cryopreserved (19, interquartile range 10–30), and metaphase II oocytes cryopreserved (18, interquartile range 8–23) compared with those in the breast, gynecologic, and other malignancy groups. On the other hand, patients with breast malignancies had the fewest oocytes retrieved (14, interquartile range 9–20) and cryopreserved (12, interquartile range 7–17). When controlled for age, those with hematologic malignancies had a median of +1 (interquartile range −8 to 7) oocytes retrieved compared with the expected value for age. On the other hand, patients with all other diagnoses had fewer oocytes retrieved than expected for age. Compared with the expected value for age, patients with breast, gynecologic, and other malignancies had a median of −2 (interquartile range −6 to 4), −5 (interquartile range −12 to 6), and −1 (interquartile range −8 to 9) oocytes retrieved, respectively.
Because the gynecologic cancer group represented a heterogeneous blend of patients, and because this group is the oncologic patient population for which gynecologists provide care, we subdivided the oocyte yield outcomes of these patients to assess differences. These data are also shown in Table 2. Patients with ovarian cancer (median age 24 years, interquartile range 22–31) tended to have less oocytes retrieved (10, interquartile range 6–20), oocytes cryopreserved (9, interquartile range 5–19), and metaphase II oocytes cryopreserved (7, interquartile range 5–15), whereas patients with uterine cancer (median age 33 years, interquartile range 31–33) had a higher oocyte yield (oocytes retrieved 28, interquartile range 19–29; oocytes cryopreserved 20, interquartile range 17–22; metaphase II oocytes cryopreserved 15, interquartile range 14–19). Patients with cervical cancer (median age 30 years, interquartile range 26–36) had an intermediate oocyte yield (oocytes retrieved 21, interquartile range 10–27; oocytes cryopreserved 14, interquartile range 8–25; metaphase II oocytes cryopreserved 14, interquartile range 8–20). Compared with the expected value for age, patients with ovarian, uterine, and cervical malignancies had a median of −7 (interquartile range −14 to 1), +12 (interquartile range −3 to 13), and +4 (interquartile range −8 to 8) oocytes retrieved, respectively.
Thaw data are shown in Table 3. Six percent of the patients with cancer in our study have returned to thaw their oocytes. A total of 11 thaw procedures have been completed in 10 cancer survivors (median age at time of freeze 32 years, interquartile range 30–38). Two thaw procedures did not result in embryo transfer as a result of poor embryo development. Of note, 60% of returning patients were partnered at the time of cryopreservation. Median time from cryopreservation until first thaw was 2.3 years (interquartile range 1.9–3.5). Median number of oocytes cryopreserved was eight (interquartile range 6–13). We thawed a median of seven (interquartile range 6–11) oocytes. We chose to thaw such a large number because oocytes require fertilization before embryo culture and, as shown in our previous report, cryopreserved oocytes that have been thawed can have impaired blastocyst formation rates.18 Among thawed oocytes, the survival rate was 86% (CI 78%–94%) and, among surviving oocytes, the fertilization rate was 72% (CI 61%–83%). A median of two (range 1–4) embryos were transferred per pregnancy attempt. The embryo implantation rate was 27% (CI 8–46%), and the live birth rate was 44% (CI 12–77%).
Table 4 shows the live birth data from the oocyte thaw cycles. Four patients have delivered five neonates. Three of these neonates were the result of oocyte cryopreservation with slow freezing and two were from vitrification. The pregnancies included three singleton and one twin gestation (neonates 1 and 2 in Table 4). Median birth weight was 2,858 g (interquartile range 2,087–3,311), and median delivery gestational age was 38.6 weeks (interquartile range 33.0–39.0). Notably, three patients (two with gynecologic malignancies, one with breast malignancy) who underwent thaw cycles required a gestational carrier because they underwent hysterectomy as part of their cancer cure or had a breast malignancy for which avoidance of posttreatment pregnancy was recommended; one of these attempts resulted in a live birth (neonate 5).
Our study demonstrates that oocyte cryopreservation is a feasible reproductive option for patients with cancer who require gonadotoxic therapies regardless of malignancy type. Adequate ovarian stimulation and oocyte yield can be achieved promptly. More importantly, thawed oocytes had high survival and fertilization rates, and resultant embryos had reasonable implantation and live birth outcomes.
Per the American Society of Clinical Oncology, it is now standard of care to offer reproductive-aged patients with cancer a fertility preservation consult before administering gonadotoxic therapies.19 This discussion is crucial because fertility preservation can be accomplished with minimal to no delay in cancer treatment17,20 and many cancer treatments decrease fertility.21 Interestingly, nearly half of surveyed oncologists would accept 1–5% decreased survival in exchange for increased fertility. Furthermore, 42% believe their patients would accept the same decrease, and 35% felt they would sacrifice more,22 yet most patients with cancer are not offered fertility preservation.23 Thus, increased information dissemination and crossdisciplinary communication are necessary to ensure all reproductive-aged patients with cancer are offered the opportunity for parenthood after cure.
Cryopreserving oocytes instead of embryos enhances reproductive autonomy regardless of relationship status. Oocytes allow independence if relationship status changes after cancer treatment. This flexibility is important given the increased divorce and separation rates among cancer survivors.24 Moreover, cryopreserving oocytes for patients with uncertain prognoses mitigates potential ethical dilemmas. At our center, oocyte disposition is agreed on before fertility treatment. Unfortunately, three of our patients had fatal malignancies; in all cases, oocytes were donated to research.
Regardless of malignancy diagnosis, ovarian stimulation and oocyte yield were adequate. Patients with hematologic malignancies had the most oocytes cryopreserved, whereas patients with breast malignancies had the least. Among gynecologic patients, those with ovarian cancer had the least oocytes cryopreserved, likely secondary to recent ovarian surgical insult or removal of ovarian parenchyma. Patients with uterine cancer obtained more oocytes, likely as a result of polycystic ovarian syndrome endocrine abnormalities that increase responsiveness to gonadotropin stimulation.25
We did not routinely thaw patients' entire oocyte cohorts simultaneously; rather, we thawed the number we believed would result in a reasonable chance of a live birth with one embryo transfer. We believe thawing all oocytes together may lower subsequent pregnancy chance because, in our experience, not many resulting blastocysts meet criteria for refreeze. Furthermore, partnership at initial thaw does not guarantee lifetime partnership to the same person; therefore, residual unfertilized oocytes afford greater reproductive autonomy.
Most embryos transfers were performed 5 days after initial culture; however, some were performed after 3 days. The latter occurred when: 1) embryo development from cryopreserved oocytes was not well established at program onset; or 2) only the number of embryos desired for transfer was available on day 3.
A study of embryos in noncancer patients at our center demonstrated equivalent euploidy, implantation, and live birth rates between embryos derived from fresh and cryopreserved oocytes.26 More importantly, live births from oocyte cryopreservation are well documented in the literature.9–11 These studies support the safety and efficacy of oocyte cryopreservation, and the American Society for Reproductive Medicine and the American College of Obstetricians and Gynecologists now agree it is no longer experimental.27 Recent case reports have also demonstrated positive outcomes in patients with cancer who cryopreserved oocytes before treatment.12–14 Our thaw data lend further support to this conclusion.
Remarkably, patients in this study and noncancer patients undergoing the same oocyte cryopreservation treatment at our center before age 43 years had similar live birth rates (44% [CI 12–77%] in cancer compared with 33% [CI 22–44%] in noncancer patients). Our small sample precludes detection of statistical differences; thus, larger studies are necessary to determine whether this difference is meaningful. Nonetheless, our data suggest that cancer's systemic effects do not decrease oocyte quality or fertility preservation efficacy.
Although our sample is small, we did not observe any maternal or neonatal complications. Notably, requirement for a gestational carrier did not impede use of cryopreserved oocytes. Therefore, women who require hysterectomies during cancer treatment should still be offered fertility preservation.
Our study is limited because it is retrospective and only represents one fertility preservation program's data. Nonetheless, it is a comprehensive study of patients with cancer undergoing oocyte cryopreservation. Our data demonstrate the feasibility of this invaluable service, which not only provides patients with cancer with reproductive autonomy, but also mitigates ethical challenges by avoiding embryo creation for patients with uncertain prognoses. We think it is reasonable to offer fertility preservation to patients with cancer before age 43 based on our center's preliminary data, which demonstrates that 36% (CI 8–64%) of noncancer patients who cryopreserved oocytes at age 41–42 achieved live births (n=4 live births per 11 transfers).
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