Fertility status among long-term childhood acute lymphoblastic leukaemia survivors enrolled between 1971 and 1998 in EORTC CLG studies: results of the 58 Late Adverse Effects study
Authors: Rossi Giovanna , Kicinski Michal , Suciu Stefan , Vandecruys Els , Plat Geneviève , Uyttebroeck Anne , Paillard Catherine , Barbati Mélissa , Dresse Marie-Françoise , Simon Pauline , Minckes Odile , Pluchart Claire , Ferster Alina , Freycon Claire , Millot Frederic , van der Werff ten Bosch Jutte , Chantrain Christophe , Paulus Robert , de Rojas Teresa , de Schaetzen Gaetan , Rohrlich Pierre , Benoit Yves , Piette Caroline 
Published: October 2021

Abstract

STUDY QUESTION
What are the fertility outcomes of male and female childhood acute lymphoblastic leukaemia (ALL) long-term survivors?

SUMMARY ANSWER
We observed similar fertility outcomes in both male and female childhood ALL survivors compared with the general population, with the exception of a higher proportion of miscarriages among partners of male survivors.

WHAT IS KNOWN ALREADY
Survival after childhood ALL is currently &gt;90% and fertility impairments are among the main concerns of the long-term survivors. Few studies have focused on the fertility issues within this selected population and the existing data are difficult to interpret due to the different treatment regimens received by the patients, the small sample sizes and the unavailability of control data in many studies.

STUDY DESIGN, SIZE, DURATION
Childhood ALL patients enrolled in European Organisation for Research and Treatment of Cancer (EORTC) studies between 1971 and 1998 in France and Belgium, &lt;18 years old at diagnosis and alive and ≥18 years at follow-up were eligible. Among 1418 eligible survivors, 507 (35.8%) participated (277 females, 230 males). Controls from the general population matched one to one by age, province, level of urbanization and sex could be identified for 503 survivors.

PARTICIPANTS/MATERIALS, SETTING, METHODS
Survivors and controls were invited to fill out a questionnaire including information about their menstrual cycles (for females), intention to have children, having children, use of medical help to become pregnant and occurrence of negative pregnancy outcomes (birth defect, miscarriage, medical abortion or stillbirth). The results were analysed separately for females and males. The association between age at diagnosis and fertility outcomes, adjusted by age at follow-up, study and country were investigated using logistic regression.

MAIN RESULTS AND THE ROLE OF CHANCE
The median time since diagnosis was 20.1 years and the median age at follow-up was 25 years. There were 144 survivors (97 females, 47 males) who wanted to have children. Among these, craniospinal radiotheraphy (CRT) and haematopoietic stem cell transplantation (HSCT) were administered to 18% and 4%, respectively. Of these who tried to have children, 75% of females and 69% of males succeeded, compared with 72% and 61% of the controls, respectively. These differences were not statistically significant (P = 0.73 for females and P = 0.50 for males). Overall, fertility outcomes were comparable between survivors and controls, except that a higher proportion of miscarriages occurred in partners of male survivors (28.1% versus 5.9%, P = 0.021). Among female survivors, an older age at diagnosis (10–17 years) was associated with a greater risk of pregnancy problems (adjusted OR 5.61, P = 0.046).

LIMITATIONS, REASONS FOR CAUTION
The interpretation of the incidence of miscarriage among the partners of male survivors is limited by the lack of data regarding the males’ partners and by a possibly higher tendency to recall and disclose fertility issues among male survivors compared with male controls.

WIDER IMPLICATIONS OF THE FINDINGS
Fertility outcomes were similar in childhood ALL survivors and controls, and the low proportion of patients treated with CRT or HSCT might explain this. Further studies should confirm the higher proportion of miscarriages in partners of male survivors.

STUDY FUNDING/COMPETING INTEREST(S)
This publication was supported by donations from the Fonds Cancer (FOCA) from Belgium and the KU Leuven from Belgium. G.R. has been awarded a fellowship by the EORTC Cancer Research Fund (ECRF). C.P. has been awarded a fellowship by Fonds Cancer (FOCA) from Belgium and the Kinderkankerfonds from Belgium (a non-profit childhood cancer foundation under Belgian law). No competing interests were declared.

TRIAL REGISTRATION NUMBER
NCT01298388 (clinicaltrials.gov).