Catharyn Stern

A randomized, double-blind, placebo-controlled trial of heparin and aspirin for women with in vitro fertilization implantation failure and antiphospholipid or antinuclear antibodies.

OBJECTIVE To investigate whether heparin and low-dose aspirin increase the pregnancy rate in antiphospholipid antibody or antinuclear antibody-seropositive women with IVF implantation failure. DESIGN A double-blind, randomized, transfer-by-transfer of fresh or cryopreserved embryos, crossover trial.A hospital infertility clinic and associated IVF service. PATIENT(S) Women seropositive for at least one antiphospholipid (APA), antinuclear (ANA), or beta(2) glycoprotein I autoantibody and >or=10 embryos transferred without achieving pregnancy (n = 143). INTERVENTION(S) Subcutaneous unfractionated heparin (5000 IU b.i.d.) and aspirin (100 mg daily) (158 transfers of 296 embryos) or placebo (142 transfers of 259 embryos) from the day of embryo transfer. MAIN OUTCOME MEASURE(S) Fetal heart per embryo transferred (implantation rate). RESULT(S) There was no significant difference in pregnancy rates or implantation rates between treated and placebo cycles; for example, fetal hearts per embryo transferred implantation rates were 6.8% (20/296) and 8.5% (22/259), respectively, and the generalized estimating equation covariate adjusted relative pregnancy rate was 0.65 (95% confidence interval, 0.33-1.28). The implantation rate for seropositive trial participants (42/555, 7.6%) compared favorably with that for IVF implantation-failure patients continuing treatment outside the trial (147/3237, 4.5%). CONCLUSION(S) Heparin and aspirin did not improve pregnancy or implantation rates for APA-positive or ANA-positive patients with IVF implantation failure.

First reported clinical pregnancy following heterotopic grafting of cryopreserved ovarian tissue in a woman after a bilateral oophorectomy.

Ovarian tissue cryopreservation and transplantation is a form of fertility preservation offered to young women at high risk of losing ovarian function after cancer treatment. While there have been successful births resulting from orthotopic site grafts, we report the first case of an ongoing pregnancy from a heterotopic graft in a patient who had previously undergone bilateral oopherectomy for a granulosa cell tumour. Frozen-thawed ovarian tissue was transplanted to the anterior abdominal wall. Subsequent ovarian stimulation and transabdominal ultrasound-guided oocyte retrieval from the grafts resulted in two oocytes. These were fertilized with ICSI and two embryos were transferred. Serial ultrasounds have confirmed an ongoing 26-week intrauterine twin pregnancy. Thus, this first demonstration of a pregnancy from a heterotopic graft site provides unequivocal evidence that cryopreservation preserves complete follicle development and that normal ovarian function can occur at a non-ovarian site. This provides optimism for further efforts to assist women who have had oophorectomy and pelvic surgery or radiotherapy, without an appropriate orthotopic site for grafting.

Lack of evidence of disease contamination in ovarian tissue harvested for cryopreservation from patients with Hodgkin lymphoma and analysis of factors predictive of oocyte yield.

Ovarian cryopreservation is a promising technique to preserve fertility in women with Hodgkin lymphoma (HL) treated with chemotherapy. Thus, the aim of this study was to examine harvested ovarian tissue for subclinical involvement by HL by morphology/immunohistochemistry, and to define patient and treatment factors predictive of oocyte yield. This was a retrospective analysis of 26 ovarian tissue samples harvested for cryopreservation from women with HL. Histology, immunohistochemistry and follicle density (number mm−3) was examined. Disease status and preharvest chemotherapy details were obtained on 24 patients. The median age was 22 years (range 13–29). Seven of 24 patients had infradiaphragmatic disease at time of harvest. Nine of 20 patients had received chemotherapy preharvest (ABVD (Adriamycin®, Bleomycin, Vinblastine and Dacarbazine)=7, other regimens=2). The seven receiving ABVD showed no difference in follicle density compared to patients not receiving treatment (n=14); (median=1555 vs 1620 mm3 P=0.97). Follicle density measurement showed no correlation with patient age (R2=0.0001, P=0.99). There was no evidence of HL involvement in the 26 samples examined (95% CI=0–11%). In conclusion, subclinical involvement of HL has not been identified in ovarian tissue, even when patients have infradiaphragmatic disease. Furthermore, the quality of tissue harvested does not appear to be adversely affected by patients age or prior ABVD chemotherapy.

The effects of cryopreservation regimens on the morphology of human ovarian tissue.

Human ovarian tissue consisting of stroma, pre-granulosa cells and oocytes, has been frozen using a variety of cooling rates and dehydration regimens. The differential survival of the various cell types under these conditions highlights the difficulty in defining optimum protocols for the cryopreservation of multicellular tissue.

Detection of Hodgkin lymphoma within ovarian tissue

OBJECTIVE To describe the detection of Hodgkin lymphoma within ovarian tissue taken at the time of harvest for cryopreservation. DESIGN Case report. SETTING University-affiliated womens hospital. PATIENT(S) A 19-year-old woman diagnosed with Hodgkin lymphoma. INTERVENTION(S) Laparoscopic removal of ovarian tissue for cryopreservation. MAIN OUTCOME MEASURE(S) Histologic and immunohistochemical evaluation of ovarian tissue harvested for fertility preservation. RESULT(S) Histologic and immunohistochemical identification of Hodgkin lymphoma within ovarian tissue harvested for cryopreservation. CONCLUSION(S) Ovarian cryopreservation and subsequent autografting is a procedure still in an experimental phase that has yielded promising findings. This option is frequently offered to young women with neoplasms such as Hodgkin lymphoma. Although the risk of Hodgkin lymphoma infiltration into the ovary may be low, the identification of lymphoma in this case emphasizes the importance of histologic examination of ovarian tissue before freezing and indicates that there is a possibility of reintroducing tumor.

Antiphospholipid antibodies and coagulation defects in women with implantation failure after IVF and recurrent miscarriage

Evaluation of patients with IVF implantation failure or recurrent miscarriage often frustratingly fails to elicit any particular cause for their problem. Testing for antiphospholipid antibodies or thrombophilia is commonly carried out, and interpretation of results in the light of the current evidence is extremely difficult. This paper reviews the purported pathogenetic mechanisms and clinical associations between both antiphospholipid antibodies and inherited thrombophilias, and reproductive failure. The current management strategies are also critically evaluated and recommendations are made for optimal, evidence-based clinical practice.

Delivery of twins following heterotopic grafting of frozen-thawed ovarian tissue

Sir, We have recently published a case report in your journal (Stern et al., 2013) describing the first reported clinical pregnancy following heterotopic grafting of cryopreserved ovarian tissue in a woman after a bilateral oophorectomy. At the time of writing the article the patient had a 26-week intrauterine twin pregnancy and we would like to provide an update on the outcome of this pregnancy. As described, the patient had undergone oophorectomy for a granulosa cell tumour 9 years previously followed by prophylactic removal of the remaining ovary and subsequent ovarian tissue cryopreservation. After repeated assessments revealed no tumour recurrence, and no evidence of tumour in the stored tissue, she had frozen-thawed ovarian tissue grafted to the anterior abdominal wall on two occasions. There was no evidence of tumour seen at either laparoscopy. The patient underwent low-dose stimulation and in vitro fertilization resulting in two embryos which were transferred. Her pregnancy proceeded uneventfully apart from a brief admission at 26 weeks for threatened preterm labour and a shortened cervix, which remained stable. The patient subsequently had an elective lower segment Caesarean section at 37 weeks and delivered two healthy girls weighing 3320 and 3262 g. At operation there was macroscopic evidence of tumour involving the diaphragm and a peritoneal deposit at the left pelvic brim. There was no evidence of tumour in the graft sites. All macroscopic tumour was resected and histology confirmed granulosa cell tumour. Recurrent tumour development could be directly related to grafting of ovarian tissue. It could also be due to a recurrence of peritoneal deposits precipitated by the hormonal environment provided by a pregnancy, in a tumour known to be sensitive to hormonal stimulation. Whilst the absence of tumour extraperitoneally at or near the graft sites might support hormonal reactivation, we cannot exclude the possibility that tumour recurrence resulted from the grafted tissue. The patient will commence hormonal suppression with an aromatase inhibitor once breastfeeding is discontinued and a further laparoscopy is planned. While the prognosis for this patient remains excellent, this unfortunate outcome serves to remind us of the possibility of tumour cell transmission with grafting despite comprehensive prior histological and biochemical assessment.

The first Australian experience of heterotopic grafting of cryopreserved ovarian tissue: evidence of establishment of normal ovarian function.

Cryostorage of reproductive potential, in the form of ovarian cortex, for young women about to undergo cytotoxic therapies has been offered clinically for some time. However, the prospects of re‐establishing reproductive function using this tissue remain unclear. We now report reproducible follicular development, oocyte retrieval and embryo development following heterotopic grafting of cryopreserved ovarian cortex which had been stored for over 10 years.

Fertility preservation in female oncology patients

Survival rates for patients treated for the majority of childhood and young adult cancers have improved dramatically in recent years. 1 Despite the high probability of survival, and often good quality of life in female survivors, until recently the concept of fertility preservation has not been seen to be an important component of the overall management of these patients. Over the last few years, various protection and preservation strategies have been developed, which may address potential reproductive concerns. Gametes or embryos may be frozen prior to potentially gonadotoxic cancer therapy, and ovarian tissue may be frozen and stored, with several pregnancies described after subsequent grafting. 2,3 There is also increasing interest in the possibility of ovarian protection using gonadotrophin‐releasing hormone analogues during chemotherapy, despite the lack of randomised controlled trials. 4 Additionally, there are reports of novel protective strategies, including therapeutic alteration or manipulation of the sphingomyelin pathways. 5 This review summarises methods of fertility protection and preservation currently available, as well as the emergence of promising new strategies.

Creating a Global Community of Practice for Oncofertility

Fertility preservation in the cancer setting, known as oncofertility, is a field that requires cross-disciplinary interaction between physicians, basic scientists, clinical researchers, ethicists, lawyers, educators, and religious leaders. Funded by the National Institutes of Health, the Oncofertility Consortium (OC) was formed to be a scientifically grounded, transparent, and altruistic resource, both intellectual and monetary, for building this new field of practice capable of addressing the unique needs of young patients with cancer. The OC has expanded its attention to include other nonmalignant conditions that can threaten fertility, and the work of the OC now extends around the globe, involving partners who together have created a community of shared effort, resources, and practices. The OC creates materials that are translated, disseminated, and amended by all participants in the field, and local programs of excellence have developed worldwide to accelerate the pace and improve the quality of oncofertility research and practice. Here we review the global oncofertility programs and the capacity building activities that strengthen these research and clinical programs, ultimately improving patient care.