Fertility preservation in women with marrow failure syndromes prior to allogeneic stem cell transplantation
Authors: Alexander R. Mehm, David P. Steensma, Serene S. Srouji, Elizabeth S. Ginsburg, Paula C. Brady
Journal: American Journal of Hematology (2018)

To the Editor: Myelodysplastic syndromes (MDS) and aplastic anemia (AA) are bone marrow failure syndromes often treated with allogeneic hematopoietic stem-cell transplantation (HSCT), resulting in permanent ovarian failure in 80% of women.1 Cryopreservation of unfertilized oocytes and/or embryos are widely accepted fertility preservation methods, while ovarian tissue cryopreservation remains experimental and gonadotropin releasing hormone agonists (GnRHa) lack efficacy in the setting of sterilizing total body irradiation (TBI).2 Risks of fertility preservation procedures in these patients include hemorrhage due to thrombocytopenia and platelet functional defects, and infection due to neutropenia and granulocyte functional defects.3 Following oocyte retrieval, all patients have some intraabdominal bleeding from ovarian punctures, requiring adequate and functioning platelets and clotting factors for hemostasis, though transfusion is exceedingly rare. The objective of this study was to evaluate our protocol for oocyte retrieval in MDS/AA patients and describe procedural complications. This study was approved by the Partners Healthcare Institutional Review Board. Reproductive-age women with MDS or AA referred to Brigham Women's Hospital for fertility preservation from 2008 to 2016 were included. Severe neutropenia (<500/mm3) was a contraindication to fertility preservation; pre-procedural transfusions were administered for hemoglobin ≤8 g/dL and platelets ≤75 × 109 (conservative compared to other surgical guidelines in healthy patients, but reflecting the nature of oocyte retrieval).4 We identified a comparison group of women undergoing in vitro fertilization (IVF) for male factor infertility (presumably fertile themselves), matched by age (within two years), antral follicle count (AFC), body mass index (<18.5 kg/m2, 18.5–24.9 kg/m2, 25–29.9 kg/m2, ≥30 kg/m2), and treatment year. Stimulation protocols were selected based on age and ovarian reserve. Injections of human chorionic gonadotropin (hCG) or GnRHa with low-dose hCG were used for final oocyte maturation, self-administered 36 hours pre-retrieval. GnRHa for oocyte maturation has gained popularity over the past decade as it reduces the risk of ovarian hyperstimulation syndrome (OHSS, a syndrome of vascular permeability in <5% of IVF patients), but GnRHa triggers rely on luteinizing hormone, LH) release by the pituitary.5 Patients who recently utilized depot GnRHa or oral contraceptives (OCPs) for menstrual suppression may have no LH surge response due to pituitary suppression. For this reason, patients would ideally not receive GnRHa and OCPs for menstrual suppression prior to fertility preservation (as these may preclude GnRHa-only trigger), though prevention of menorrhagia takes precedence. Prior to all oocyte retrievals, an intravenous third-generation cephalosporin was administered. In MDS/AA patients, complete blood counts (CBC) were checked at oocyte retrieval. CBCs were obtained immediately postoperatively for clinical concern for acute bleeding; otherwise, postoperative CBCs were checked by patients' oncologists per their routines. Cryopreserved embryos were frozen at the pronuclear stage (2PN). Recorded complications included hemorrhage (≥500 mL and/or requiring transfusion), infection, OHSS, and HSCT delay incurred due to fertility preservation. Outcomes also included number of oocytes and mature oocytes retrieved and embryos cryopreserved. Univariate comparisons between cases and controls were performed using the Fisher's exact or Wilcoxon Rank Sum test as indicated. A P-value of ≤.05 was considered statistically significant. Analyses were performed using online calculators available at http://astatsa.com. Seven patients with bone marrow failure were included (4 MDS, 3 AA). Cases and controls were similar in age, BMI, reproductive history, and AFC (Table 1). Mean AMH among case patients (1.0 ng/mL, checked in five patients) was lower than in control patients (3.8 ng/mL, checked in 15 patients, reflecting adoption of AMH over the study period), but failed to reach statistical significance. Four case patients (57%) had low AFC (<10). Six case patients used hormonal medications prior to ovarian hyperstimulation and administered hCG for final oocyte maturation, while the remaining patient utilized GnRHa plus low-dose hCG. Cases and controls performed similarly in response to stimulation with similar numbers of oocytes retrieved, once the excessive response (91 eggs) of case patient 1 was removed from analysis (Table 1). CBC with differential was checked in all case patients within three hours before oocyte retrieval. Preoperative mean hemoglobin was 9.8 ± 1.8 g/dL (range 7.4–12.8), with mean platelets of 256 ± 349 × 109/L (median 118, range 67–1032). AA patients had significantly lower hemoglobin than MDS patients (8.2 vs. 11.0 g/dL, respectively, P = .047). All three AA patients required preoperative transfusions per protocol. Patient 2 received 2 units (u) of packed red cells (pRBC) for hemoglobin 7.4 g/dL, and 2u irradiated platelets for a count of 74 × 109/L. Patient 3 received 2u irradiated platelets for a count of 55 × 109/L (improved to 119), and patient 4 received 3u irradiated platelets for a count of 19 × 109/L (improved to 67 × 109/L after the second unit and not rechecked thereafter). Postoperative CBCs were drawn at various times after oocyte retrieval; there were no significant differences among postoperative CBCs in AA and MDS patients. Transfusions of irradiated pRBCs were required within 24 hours postoperatively in two AA patients. Patient 2 received 2u pRBC the next day, following routine monitoring by her oncologist (for hemoglobin 8.5 g/dL) without postoperative complications. Patient 4 developed hemorrhage after oocyte retrieval. She developed abdominal pain and distension in the recovery room; her hemoglobin fell from 8.4 to 6.1 g/dL, with platelets of 101 × 109/L. She was hospitalized overnight and received 2u pRBC, with appropriate response (to hemoglobin 10.1 g/dL); she required no further interventions. MDS patient 1 was hospitalized for severe OHSS. In 2008, at age 37 years, she had high AFC (20) and peak estradiol (8420 pg/mL); she received an hCG trigger with a 10-day course of a dopamine agonist (which reduces OHSS risk by antagonizing VEGF).5 In 2008, GnRHa triggers were not yet widely accepted. Following retrieval of 91 eggs, she was admitted for 4 days for serial paracentesis, without further complications. No transfusion reactions, infectious, or anesthetic complications occurred. Oncological treatment was purposefully postponed by referring oncologists in two cases to allow time for fertility preservation; no oncologic treatments were delayed due to postoperative complications. No comparison patients required transfusions or hospitalization. Regarding fertility outcomes, 2–10 years have elapsed since these procedures. Among case patients, only patient 1 returned for fertility treatment. After cyclophosphamide, TBI (14 Gray) and successful HSCT for MDS, she had permanent amenorrhea. Despite estradiol supplementation to promote endometrial proliferation for embryo transfer, her maximum endometrial thickness was 2.3 mm (goal ≥ 7 mm) presumably due to radiation-induced damage to uterine vasculature; she was counseled regarding gestational carrier and declined.6 Conversely, patient 3, following low-dose TBI, cyclophosphamide (100 mg/kg), and successful HSCT for AA at age 22 years, resumed menses 18 months later and conceived spontaneously within 6 months. She developed diet-controlled gestational diabetes and delivered a term healthy infant. In summary, case and control patients produced similar numbers of oocytes, suggesting that AA/MDS patients' responses to ovarian stimulation are not compromised by their underlying disease. Mean AMH among case patients was lower than in control patients (1.0 vs. 3.8 ng/mL); two young case patients (<30 years) had severe diminished ovarian reserve (AMH 0.2-0.3 ng/mL, AFC 3) despite no prior chemotherapy. While premature ovarian insufficiency is associated with Fanconi's anemia, it has not been described in other marrow failure syndromes and warrants further study.7 At the same time, contraception should be encouraged in patients with menstrual cycles post-HSCT who wish to avoid pregnancy. As few data are available regarding gamete utilization and pregnancy outcomes in this population, continued research is important. This series contributes to the limited body of literature regarding fertility preservation in this population. This series demonstrates the feasibility of fertility preservation in these patients before HSCT, when adhering to a protocol of preoperative assessment and transfusion as needed, which must be complemented by close immediate post-procedural monitoring. Despite this protocol, this remains a high-risk population (as one patient sustained significant hemorrhage), and these patients should be referred to a tertiary care center for fertility preservation. Nothing to report.