A nationwide study on reproductive function, ovarian reserve, and risk of premature menopause in female survivors of childhood cancer: design and methodological challenges.
BACKGROUND
Advances in childhood cancer treatment over the past decades have significantly improved survival, resulting in a rapidly growing group of survivors. However, both chemo- and radiotherapy may adversely affect reproductive function. This paper describes the design and encountered methodological challenges of a nationwide study in the Netherlands investigating the effects of treatment on reproductive function, ovarian reserve, premature menopause and pregnancy outcomes in female childhood cancer survivors (CCS), the DCOG LATER-VEVO study.


METHODS
The study is a retrospective cohort study consisting of two parts: a questionnaire assessing medical, menstrual, and obstetric history, and a clinical assessment evaluating ovarian and uterine function by hormonal analyses and transvaginal ultrasound measurements. The eligible study population consists of adult female 5-year survivors of childhood cancer treated in the Netherlands, whereas the control group consists of age-matched sisters of the participating CCS. To date, study invitations have been sent to 1611 CCS and 429 sister controls, of which 1215 (75%) and 333 (78%) have responded so far. Of these responders, the majority consented to participate in both parts of the study (53% vs. 65% for CCS and sister controls respectively). Several challenges were encountered involving the study population: dealing with bias due to the differences in characteristics of several types of (non-) participants and finding an adequately sized and well-matched control group. Moreover, the challenges related to the data collection process included: differences in response rates between web-based and paper-based questionnaires, validity of self-reported outcomes, interpretation of clinical measurements of women using hormonal contraceptives, and inter- and intra-observer variation of the ultrasound measurements.


CONCLUSIONS
The DCOG LATER-VEVO study will provide valuable information about the reproductive potential of paediatric cancer patients as well as long-term survivors of childhood cancer. Other investigators planning to conduct large cohort studies on late effects may encounter similar challenges as those encountered during this study. The solutions to these challenges described in this paper may be useful to these investigators.


BACKGROUND
NTR2922; http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2922
Department of Paediatrics, Division of Paediatric Oncology/Haematology, VU University Medical Center, PO Box 7057, Amsterdam, 1007MB, The Netherlands.
Annelies
A
Overbeek
Marleen H
MH
van den Berg
Leontien C M
LC
Kremer
Marry M
MM
van den Heuvel-Eibrink
Wim J E
WJ
Tissing
Jacqueline J
JJ
Loonen
Birgitta
B
Versluys
Dorine
D
Bresters
Gertjan J L
GJ
Kaspers
Cornelis B
CB
Lambalk
Flora E
FE
van Leeuwen
Eline
E
van Dulmen-den Broeder
D000328:Adult; D000970:Antineoplastic Agents / Q000009:adverse effects; D002648:Child; D015331:Cohort Studies; D005260:Female; D006801:Humans; D008594:Menopause, Premature / Q000187:drug effects / Q000528:radiation effects; D009369:Neoplasms / Q000628:therapy*; D009426:Netherlands; D010053:Ovary / Q000473:pathology*; D011878:Radiotherapy / Q000009:adverse effects; D060728:Reproductive Health / Q000706:statistics & numerical data*; D012107:Research Design; D012189:Retrospective Studies; D017741:Survivors / Q000706:statistics & numerical data*
D000970:Antineoplastic Agents