1 Centre for the Study of Mothers' and Children's Health, La Trobe University, 251 Faraday Street, Carlton, 3053, Victoria, 2 Australian Institute of Health and Welfare National Perinatal Statistics Unit, University of New South Wales, Sydney, 2031, NSW, 3 Reproductive Biology Unit, Royal Women's Hospital, Carlton, 3053, Victoria and 4 Monash IVF & Department of Obstetrics and Gynaecology, Monash University, Monash Medical Centre, Clayton, 3168, Victoria, Australia
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Abstract |
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Key words: cancer incidence/children/IVF/long-term follow-up
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Introduction |
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Case-control studies have reported a significantly increased risk of neuroblastoma with prenatal exposure to fertility drugs (Kramer et al., 1987; Michalek et al., 1996
). There have also been case series reports of embryonal tumours in children born to women who conceived as a result of fertility treatment (Melamed et al., 1982
; White et al., 1990
; Toren et al., 1995
). Neuroblastomas are tumours of the sympathetic nervous system that are derived from the embryonic neural crest. They are the most common type of cancer in children <1 year of age in Victoria, Australia (Giles et al., 1993
).
While case series reports are useful for suggesting possible adverse effects of treatment and generating hypotheses for further investigation, studies that measure associations between exposure and disease (such as case-control and cohort studies) are needed to substantiate the reports. Because case-control studies are often prone to recall bias, a well-designed cohort study is generally believed to provide a higher level of evidence of an association than that obtained from a case-control study (Greenhalgh, 1997).
Until very recently there were no population-based data on the incidence of cancer in children conceived as a result of in-vitro fertilization (IVF). The two published studies, conducted in the UK and Sweden, of children born after IVF did not find a significantly increased incidence of cancer (Doyle et al., 1998; Bergh et al., 1999
). The present study investigated the incidence of cancer in 5249 children born as a result of assisted reproductive technologies in Australia.
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Materials and methods |
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Data were collected from clinics and the National Perinatal Statistics Unit (NPSU), Australian Institute of Health and Welfare to ensure that we had the most complete coverage of births possible. Data collected from the clinics were obtained from computerized records (where available) or from medical records. The contribution of clinics to the register of births held by the NPSU is not mandatory; however, accreditation from the national accrediting body requires participation in the registry (Lancaster et al., 1995).
Data items collected on each birth included parents' names, mother's date of birth, address, baby's date of birth and sex, type of infertility, drugs used for ovarian stimulation in the conception cycle, drugs used in the luteal phase, obstetric complications and pregnancy outcome.
Ascertainment of cases of invasive cancer was by record-linkage with the population-based Victorian Cancer Registry (VCR). Cancer notification to the VCR became a statutory requirement of all hospitals and pathology laboratories in 1981. Ascertainment of childhood cancer cases diagnosed before this time is thought to be practically complete because the major treatment centre for the State had been part of a voluntary notification scheme since 1959. Data held by the cancer registry include full name, sex, date of birth, date of diagnosis, histological type of tumour, date of last known contact and vital status (Giles et al., 1993). Follow-up for each child was from the date of birth until (i) diagnosis of cancer, or (ii) the date of death, or (iii) the end of 1996 (if the child was <15 years old at that time) or, (iv) the date of the child's 15th birthday.
The expected number of cases was calculated by applying the Victorian age-specific population-based cancer incidence from the years 19821995 to the person-years follow-up in each age group of children. The standardized incidence ratio (SIR) was determined by calculating the ratio of the observed number of cancer cases to the expected number.
Prior to commencement of the study, calculations indicated that there was 80% power ( = 0.05) to detect a SIR of >6 for neuroblastoma and a SIR of 2.8 for all childhood cancers combined. The expected numbers of cancers were derived from the estimated age-specific person-years and age-specific population cancer rates.
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Results |
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Approximately 13% of singleton births and 60% of multiple births occurred prior to 37 weeks gestation. Only 15 deliveries occurred after 43 weeks. Overall, 10.4% of singleton births and 57.1% of multiple births were of low birthweight (<2500 g). A total of 12.9% of multiple births were very low birthweight (<1500 g) (Table III).
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Cancer cases
The expected number of cases of childhood cancer was calculated as 4.33, compared with an observed of six. This gave a SIR for all childhood cancers of 1.39 (95% CI 0.623.09). There were two cases of acute lymphoid leukaemia (ICD-9 = 204), one case of unspecified leukaemia (ICD-9 = 208), one malignant neoplasm of the brain (ICD-9 = 191), one malignant neoplasm of the soft tissue (ICD-9 = 171) and one malignant neoplasm of the salivary gland (ICD-9 = 142). When coded according to morphology, the soft tissue neoplasm was classified as a ganglioneuroblastoma (ICD-0 9490). Age at diagnosis ranged from 8 months to 6 years, 9 months (Table IV). One child died 13 months after diagnosis. The remaining five children were alive at the end of follow-up. The malignant neoplasm of the salivary gland was one of only two cases reported to the Victorian Cancer Registry between 1982 and 1995.
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Discussion |
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A limitation of our study was that the median length of follow-up was relatively short (3 years, 9 months). However, the study was initiated to address concerns about the incidence of neuroblastoma in children born after IVF. Neuroblastoma most commonly occurs in the first year of life. Secondly, the calculation of the expected number of cases is based on the number of person-years each child contributes and takes into account differential lengths of follow-up. Our population-based study contains the largest number of person-years follow-up to date and contributes to knowledge about the health of children born after IVF. Further large studies will be needed to detect a small increase in the overall incidence of cancer or an increase in the incidence of individual types of cancer with statistical significance.
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Acknowledgments |
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Notes |
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References |
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Buitendijk, S. (1999) Children after in vitro fertilisation. An overview of the literature. Int. J. Tech. Assist. Health Care, 15, 5265.
Doyle, P. (1999) The UK Human Fertilisation and Embryology Authority. How it has contributed to the evaluation of assisted reproduction technology. Int. J. Tech. Assist Health Care, 15, 310.
Doyle, P., Bunch, K., Beral, V. et al. (1998) Cancer incidence in children conceived with assisted reproduction technology. Lancet, 352, 452453.[ISI][Medline]
Giles, G., Farrugia, H., Thursfield, V. et al. (1993) Childhood cancer in Victoria, 1970 to 1989. Anti Cancer Council of Victoria, Melbourne.
Greenhalgh, T. (1997) How to read a paper. Getting your bearings (deciding what the paper is about). Br. Med. J., 315, 243246.
Hurst, T., Shafir, E. and Lancaster, P. (1997) Assisted Conception, Australian and New Zealand 1996. AIHW National Perinatal Statistics Unit, Sydney.
Kramer, S., Ward, E., Meadows, A. et al. (1987) Medical and drug risk factors associated with neuroblastoma: a case-control study. J. Natl Cancer Inst., 78, 797804.[ISI][Medline]
Lancaster, P., Shafir, E. and Huang, J. (1995) Assisted Conception, Australia and New Zealand, 1992 and 1993. AIHW National Perinatal Statistics Unit, Sydney.
Melamed, L., Bujanover, Y., Hammer, J. et al. (1982) Hepatoblastoma in an infant born to a mother after hormonal treatment for sterility. N. Engl. J. Med., 307, 820.[ISI][Medline]
Michalek, A., Buck, G., Nasca, P. et al. (1996) Gravid health status, medication use and risk of neuroblastoma. Am. J. Epidemiol., 143, 9961001.[Abstract]
Royal Commission on New Reproductive Technologies (1993) Proceed with care: Final report of the Royal Commission on New Reproductive Technologies. Minister of Government Services, Canada.
Toren, A., Sharon, N., Mandel, M. et al. (1995) Two embryonal cancers after in vitro fertilisation. Cancer, 76, 23722374.[ISI][Medline]
White, L., Giri, N., Vowels, M. et al. (1990) Neuroectodermal tumour in children born after assisted conception. Lancet, 336, 1577.[ISI][Medline]
Submitted on August 19, 1999; accepted on November 12, 1999.