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As the number of infants born through in vitro fertilisation (IVF) grows, there is increased interest regarding the long term effects of IVF and other assisted reproduction techniques on such offspring. Recent reports have noted cancer in children born after IVF or fertility drug use (table 1).1
In 2001, retinoblastoma was reported to occur in a child born through IVF in Israel.2 Since then, an additional report documented four cases from the Netherlands.3 Here we add a sixth case and the first from the United States. Of these children four had unilateral retinoblastoma and two bilateral disease (table 2).
During 2002, a 16 month old child was referred to The New York Eye Cancer Center with no known family history of eye disease. She had a blind painful right eye with neovascular glaucoma. Intraocular pressures were 35 mm Hg in the right eye, and 14 in the left. Examination of the anterior chamber of the right eye revealed cells on the corneal endothelium and iris neovascularisation. While ophthalmoscopic examination of the right eye was not possible because of opaque media, ultrasonography revealed a densely calcified mass in the posterior pole (fig 1). Computed radiographic tomography demonstrated tumour calcification with no evidence of extrascleral or optic nerve extension.4 Post-enucleation histopathology confirmed the diagnosis of retinoblastoma.5 The parents did not approve genetic studies of the child.
Further history revealed that this child was born through IVF with a donor egg and the father’s sperm. In order to carry the child, the postmenopausal mother received oestrogen and progesterone before and during gestation.
Several theories of IVF related carcinogenesis exist. Prenatal exposure to fertility drugs may initiate cancer in the embryo or parental germ cells. However, an evidence based association between IVF treatments and cancer development (in the women taking the drugs) has not been established.6
Another possible mechanism has been associated with the culture medium used in the IVF test tube. Experiments on mice suggest that subtle changes in the ingredients of the culture media may alter the activity of imprinted genes.7 Like fertility drugs, it remains to be seen whether altered gene imprinting can lead to cancers such as retinoblastoma.
A third possible mechanism of carcinogenesis includes inheritance of genetic defects from gametes and embryo trauma performed during routine intracytoplasmic sperm injection (ICSI) type IVF.
The most likely explanation for an increased risk of secondary carcinogenesis is that the population of patients seeking IVF is dissimilar to the general population. Patients seeking IVF are older or have medical problems that interfere with fertility. This poses a problem with any study other than a randomised prospective trial that compares babies from untreated infertility patients who become pregnant versus babies from infertile patients who become pregnant using IVF. To date all studies published are observations of clusters of disease with the suggestion that there is a cause and effect relation.8
Retinoblastoma is the most common intraocular cancer of childhood and affects approximately 300 children each year in the United States. Retinoblastoma is a manifestation of a de novo deletion or mutation of the q14 band of chromosome 13, occurring as a “second hit” during embryogenesis or the result of two hit deletions in retinal cells. In that it could be the result of chromosomal breakage and deletions in IVF born children, surveillance of retinoblastoma incidence in children born through IVF is warranted.7–9
With the advent of assisted reproductive technology (ART) in 1977, American couples have increasingly turned to such treatments to overcome fertility problems. Nationwide, 99 629 procedures were performed in 2000 by ART. In that year, fertility treatments in which the egg and sperm are handled in the laboratory resulted in 25 228 live births and 35 025 infants. This report expands information on geography and determinants of both ART success and multiple birth risks (beyond that which appears in the 2000 Assisted Reproductive Technology Success Rates19). Therefore, it seems reasonable to maintain a registry of post-IVF children, to support large epidemiological studies with long term follow up, and prospective randomised studies of infertile couples in order to determine if there is a relation between IVF and cancers such as retinoblastoma.
Supported by The EyeCare Foundation, Inc and Research to Prevent Blindness, New York City, USA.
The authors have no proprietary interest in any material mentioned in this study.