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A nationwide study on reproductive function, ovarian reserve, and risk of premature menopause in female survivors of childhood cancer: design and methodological challenges

Annelies Overbeek12, Marleen H van den Berg1*, Leontien CM Kremer3, Marry M van den Heuvel-Eibrink4, Wim JE Tissing5, Jacqueline J Loonen6, Birgitta Versluys7, Dorine Bresters8, Gertjan JL Kaspers1, Cornelis B Lambalk2, Flora E van Leeuwen9, Eline van Dulmen-den Broeder1 and on behalf of the DCOG LATER-VEVO study group

Author affiliations

1 Department of Paediatrics, Division of Paediatric Oncology/Haematology, VU University Medical Center, PO Box 7057, Amsterdam, 1007MB, The Netherlands

2 Department of Obstetrics and Gynaecology, VU University Medical Center, Amsterdam, The Netherlands

3 Department of Paediatric Oncology, Emma Children’s Hospital/Academic Medical Center, Amsterdam, The Netherlands

4 Department of Pediatric Oncology, Sophia Children’s Hospital/Erasmus MC University Medical Center, Rotterdam, The Netherlands

5 Department of Pediatric Oncology, Beatrix Children’s Hospital/University Medical Center Groningen, Groningen, The Netherlands

6 Department of Pediatric Oncology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands

7 Department of Pediatric Oncology, Wilhelmina’s Children’s Hospital, University Medical Center Utrecht, Utrecht, The Netherlands

8 Department of Pediatric Stem Cell Transplantation, Willem-Alexander Children’s Hospital, Leiden University Medical Center, Leiden, The Netherlands

9 Department of Epidemiology, Netherlands Cancer Institute, Amsterdam, The Netherlands

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Citation and License

BMC Cancer 2012, 12:363  doi:10.1186/1471-2407-12-363

Published: 23 August 2012



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.


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.


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.

Trial registration

NTR2922; webcite

Childhood cancer survivors; Adverse effects; Female fertility; Study design; Methodological challenges