Romain Imbert

Safety and usefulness of cryopreservation of ovarian tissue to preserve fertility: a 12-year retrospective analysis

STUDY QUESTION Do the benefits of ovarian tissue cryopreservation outweigh the risks for patients seeking to preserve fertility before gonadotoxic treatment in various indications? SUMMARY ANSWER In >90% of the patients undergoing cryopreservation of ovarian tissue, oncological treatment was associated with a reduced ovarian reserve and in 30% of patients, premature ovarian failure (POF) occurred within 5 years. WHAT IS KNOWN ALREADY Ovarian tissue cryopreservation is an effective fertility preservation option, especially for pre-pubertal patients and patients who have a short time between diagnosis of a disease and gonadotoxic treatment. STUDY DESIGN, SETTING, DURATION This study retrospectively analysed ovarian function and fertility recovery rates, as well as ovarian tissue characteristics, of patients who underwent ovarian tissue cryopreservation at Erasme Hospital between 1999 and 2011. PARTICIPANTS/MATERIALS, SETTINGS, METHODS A total of 225 patients referred from 15 Belgian oncological units underwent cryopreservation of ovarian tissue before gonadotoxic therapy for malignant or benign diseases. There were 28 patients (12.4%) who died during follow-up due to recurrence of disease. One severe adverse event occurred during anaesthesia for ovarian tissue collection, leading to the death of the patient. Ovarian function and fertility outcomes were available for 114 patients including 13 girls who were pre-pubertal at the time of the procedure. Eight patients had undergone ovarian tissue transplantation in order to restore their fertility after remission of the disease. MAIN RESULTS AND THE ROLE OF CHANCE Breast cancer and haematological disease were the most frequent indications for ovarian tissue cryopreservation. Overall, 90% of post-pubertal patients were diagnosed with poor ovarian reserve (AMH < 0.5 ng/ml) after a mean of 50 months of follow-up (11-125 months), including 30% with POF (FSH > 40 IU/ml). Breast cancer patients had a lower rate of POF than did post-pubertal patients with haematological diseases (11 versus 34.5%, respectively), despite the older age (mean 31 versus 23.5 years old, respectively) of the breast cancer patients. Ovarian function returned in 71 post-pubertal patients without the need for grafts of cryopreserved tissue. Spontaneous pregnancies were reported for 33 of them, leading to 34 live births. Among the 13 pre-pubertal patients who reached pubertal age during the follow-up, 10 had POF. Eight patients received cryopreserved ovarian grafts to reverse POF and three of them have already become pregnant. LIMITATIONS, REASONS FOR CAUTION This study is a retrospective analysis. The cohort was not compared with a control group of patients who did not undergo the procedure. WIDER IMPLICATIONS OF THE FINDINGS After careful evaluation of the surgical risks, ovarian tissue cryopreservation can be proposed as an efficient option to preserve the fertility of children and young adults facing gonadotoxic therapies. However, alternative procedures such as oocyte or embryo cryopreservation should be considered as first options especially for older patients or if there is high risk of neoplastic cells within the ovaries. STUDY FUNDING/COMPETING INTEREST This study was supported by the Télévie, FNRS-FRSM and Fondation Belge contre le cancer. There are no competing interests to report.

Variants of the BMP15 gene in a cohort of patients with premature ovarian failure.

BACKGROUND Bone morphogenetic protein 15 (BMP15) is an oocyte-derived growth factor acting as a major player in follicle differentiation in mammals. Mutations in the BMP15 gene, some of which lead to defective secretion of bioactive dimers, have been associated with premature ovarian failure (POF) in humans. METHODS Fifty patients diagnosed with POF with a normal karyotype were included in the study. After DNA extraction and amplification by PCR, the entire coding sequence and intron-exon junctions of BMP15 gene were analysed in the cohort of POF patients and in a control group of 214 patients. RESULTS Nine variants of the BMP15 gene including six missense substitutions and one insertion of three nucleotides were identified in the POF group. Three of them were previously described as single nucleotide polymorphisms and were also found in the control group. Two variants (H81R and G199R) have not been previously described and were not identified among controls but were not predicted to be deleterious. One variant (A180T) was identified among two POF cases, and also in two controls. One variant (F194S), predicted as potentially deleterious, was identified for the first time in a POF patient but also identified in one control. One variant (L148P), potentially deleterious, previously reported in POF patients, was identified for the first time among controls. The variant 788insTCT, previously identified among POF patients, probably has a low biological impact as it was also found in control patients and is a common polymorphism in sub-Saharan African populations. CONCLUSIONS Various missense variants of the BMP15 gene were identified among patients with POF. For most variants, the impact of the amino-acid substitution on the protein structure and function was predicted to be low. The two variants predicted as potentially deleterious were also identified among controls and could be considered as rare polymorphisms. Although some of these variants could contribute to the development of POF in a complex manner, the demonstration of their role in the pathogenesis of POF requires additional functional studies.

Pregnancy outcome after oocyte donation in patients with Turner's syndrome and partial X monosomy

BACKGROUND Fertility expectations for patients with Turners syndrome (TS) have clearly changed in the last three decades. However, medical risks during pregnancy are supposed to be highly increased. The aim of the study was to assess clinical outcome and obstetrical complications in a series of patients with TS in an oocyte donor programme. METHODS A retrospective study was carried out on 24 women with TS seeking a pregnancy in the Fertility Clinic of the Erasme Hospital from 1992 up until March 2011. RESULTS Twenty-three patients with TS were included in an oocyte donation cycle. Forty-nine oocyte donation cycles were performed, which led to 45 fresh and 10 frozen-thawed embryo transfers. Altogether, 18 pregnancies were obtained, 10 deliveries (9 singletons and 1 pair of twins), 3 miscarriages and 5 biochemical pregnancies. The clinical pregnancy rate per transfer was 24.4% in fresh cycles and 20% in frozen replacement cycles. Complications of pregnancy occurred in 5 of 10 pregnancies (50%), which led to three premature deliveries because of pregnancy-induced hypertensive disorders. The mean birthweight (g) (±SD) for singletons and twins was 2728 ± 577 and 2335 ± 318, respectively. Four babies were below the 10th percentile. No cardiac complications were observed in any of the pregnant women. CONCLUSIONS Pregnancy rates after oocyte donation in patients with TS are comparable with those previously published but a high risk of pregnancy hypertensive disorders and a high risk of low birthweight can be highlighted from our study. Strict inclusion criteria and single embryo transfer are necessary to minimize complications during pregnancy in this high-risk group.

Does oocyte donation compared with autologous oocyte IVF pregnancies have a higher risk of preeclampsia

The aim of this study was to evaluate whether pregnancies resulting from oocyte donation have a higher risk of preeclampsia compared with pregnancies after IVF using autologous oocytes. Propensity score matching on maternal age and parity was carried out on a one to one basis, and a total of 144 singleton pregnancies resulting in delivery beyond 22 gestational weeks, achieved by oocyte donation, were compared with 144 pregnancies achieved through IVF and intracytoplasmic sperm injection with the use of autologous oocytes. All pregnancies were achieved after fresh embryo transfer. Obstetric and neonatal outcomes were compared for each pregnancy. Singleton pregnancies after oocyte donation were associated with a significantly higher risk for preeclampsia (OR 2.4, CI 1.02 to 5.8; P = 0.046), as well as for pregnancy-induced hypertension (OR 5.3, CI 1.1 to 25.2; P = 0.036), and caesarean delivery (OR 2.3, CI 1.4 to 3.7; P = 0.001) compared with pregnancies using autologous oocytes.