title: Fertility preservation for girls and young women with cancer: population-based validation of criteria for ovarian tissue cryopreservation.
abstract: BACKGROUND
  Ovarian tissue cryopreservation with later reimplantation has been shown to preserve fertility in adult women, but this approach remains unproven and experimental in children and adolescents. We aimed to assess the use of the Edinburgh selection criteria for ovarian tissue cryopreservation in girls and young women with cancer to determine whether we are offering this invasive procedure to the patients who are most at risk of premature ovarian insufficiency.
  
  
  METHODS
  Cryopreservation of ovarian tissue has been selectively offered to girls and young women with cancer who met the Edinburgh selection criteria since 1996. Between Jan 1, 1996, and June 30, 2012, 410 female patients younger than 18 years at diagnosis were treated for cancer (including leukaemia and brain tumours) at the Edinburgh Children's Cancer Centre, which serves the whole South East of Scotland region. We determined the ovarian status of these patients from review of clinical records and classified them as having premature ovarian insufficiency or not, or as unable to be determined. Patients younger than 12 years at time of data cutoff (Jan 31, 2013) were excluded from the analysis.
  
  
  RESULTS
  34 (8%) of the 410 patients met the Edinburgh selection criteria and were offered ovarian tissue cryopreservation before starting cancer treatment. 13 patients declined the procedure and 21 consented, and the procedure was completed successfully in 20 patients. Of the 20 patients who had ovarian tissue successfully cryopreserved, 14 were available for assessment of ovarian function. Of the 13 patients who had declined the procedure, six were available for assessment of ovarian function. Median age at the time of follow-up for the 20 assessable patients was 16·9 years (IQR 15·5-21·8). Of the 14 assessable patients who had successfully undergone ovarian cryopreservation, six had developed premature ovarian insufficiency at a median age of 13·4 years (IQR 12·5-14·6), one of whom also had a natural pregnancy. Of the six assessable patients who had declined the procedure, one had developed premature ovarian insufficiency. Assessment of ovarian function was possible for 141 of the 376 patients who were not offered cryopreservation; one of these patients had developed premature ovarian insufficiency. The cumulative probability of developing premature ovarian insufficiency after treatment was completed was significantly higher for patients who met the criteria for ovarian tissue cryopreservation than for those who did not (15-year probability 35% [95% CI 10-53] vs 1% [0-2]; p<0·0001; hazard ratio 56·8 [95% CI 6·2-521·6] at 10 years).
  
  
  CONCLUSIONS
  The results of this analysis show that the Edinburgh selection criteria accurately identify the few girls and young women who will develop premature ovarian insufficiency, and validate their use for selection of patients for ovarian tissue cryopreservation. Further follow-up of this cohort of patients is likely to allow refinement of the criteria for this experimental procedure in girls and young women with cancer.
  
  
  BACKGROUND
  UK Medical Research Council.
authors.affiliation: Department of Haematology/Oncology, Royal Hospital for Sick Children, Edinburgh, UK; Department of Child Life and Health, University of Edinburgh, Edinburgh, UK. Electronic address: hamish.wallace@nhs.net.
authors.forename: W Hamish B
authors.initials: WH
authors.lastname: Wallace
authors.affiliation: Department of Child Life and Health, University of Edinburgh, Edinburgh, UK.
authors.forename: Alice Grove
authors.initials: AG
authors.lastname: Smith
authors.affiliation: School of Computer Science, University of St Andrews, St Andrews, UK.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Kelsey
authors.affiliation: Department of Haematology/Oncology, Royal Hospital for Sick Children, Edinburgh, UK.
authors.forename: Angela E
authors.initials: AE
authors.lastname: Edgar
authors.affiliation: MRC Centre for Reproductive Health, University of Edinburgh, Edinburgh, UK.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Anderson
mesh_terms: D000293:Adolescent; D000367:Age Factors; D002648:Child; D015331:Cohort Studies; D015925:Cryopreservation / Q000379:methods*; D005260:Female; D059247:Fertility Preservation / Q000379:methods*; D005500:Follow-Up Studies; D006801:Humans; D009369:Neoplasms / Q000175:diagnosis / Q000628:therapy*; D006080:Ovarian Follicle; D010053:Ovary; D018579:Patient Selection; D011247:Pregnancy; D018873:Pregnancy Rate / Q000639:trends*; D016649:Primary Ovarian Insufficiency / Q000517:prevention & control; D012189:Retrospective Studies; D018570:Risk Assessment; D016896:Treatment Outcome; D055815:Young Adult