Retinoblastoma in a child conceived by in vitro fertilisation
http://www.100md.com
《英国眼科学杂志》
1 The New York Eye Cancer Center, New York City, NY, USA
2 New York University School of Medicine, New York City, NY, USA
3 Albert Einstein College of Medicine, New York City, New York, USA
Keywords: in vitro fertilisation; intracytoplasmic sperm injection; retinoblastoma; genetics; fertilisation; cancer
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
Table 1 Anomalies and cancers reported in offspring of IVF
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).
Table 2 Retinoblastoma in children born through IVF
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.
Figure 1 B-scan ultrasonography. (A) A longitudinal view of the right eye demonstrates a tumour posterior to a closed funnel retinal detachment. (B) A transverse view of the eye demonstrates a rounded, densely calcified tumour. R, retina; S, shadow in orbit; C, calcification; T, tumour; ON, optic nerve.
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.
Comment
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.
References
Klip H , Burger CW, deKraker J, et al. Risk of cancer in the offspring of women who underwent ovarian stimulation for IVF. Hum Reprod 2001;16:2451–8.
Anteby I , Cohen E, Anteby E, et al. Ocular manifestations in children born after in vitro fertilization. Arch Ophthalmol 2001;119:1525–9.
Moll AC, Imhof SM, Cruysberg JR, et al. Incidence of retinoblastoma in children born after in-vitro fertilisation. Lancet 2003;361:309–10.
Finger PT, Harbour JW, Karcioglu Z. Risk factors for metastasis in retinoblastoma. Surv Ophthalmol 2002;47:1–16.
Moshfeghi DM, Moshfeghi AA, Finger PT. Enucleation. Surv Ophthalmol 2000;44:277–301.
Lerner-Geva L , Geva E, Lessing JB, et al. The possible association between in vitro fertilization treatments and cancer development. Int J Gynecol Cancer 2003;13:23–7.
Doherty AS, Mann MR, Tremblay KD, et al. Differential effects of culture on imprinted H19 expression in the preimplantation mouse embryo. Biol Reprod 2000;62:1526–35.
Bruinsma F , Venn A, Lancaster P, et al. Incidence of cancer in children born after in-vitro fertilization. Human Reprod 2000;15:604–7.
Lerner-Geva L , Toren A, Chetrit A, et al. The risk for cancer among children of women who underwent in vitro fertilization. Cancer 2000;88:2845–7.
White L , Giri N, Vowels MR, et al. Neuroectodermal tumours in children born after assisted conception. Lancet 1990;336:1577.
Kobayashi N , Matsui I, Tanimura M, et al. Childhood neuroectodermal tumours and malignant lymphoma after maternal ovulation induction. Lancet 1991;338:955.
Kramer S , Ward E, Meadows AT, et al. Medical and drug risk factors associated with neuroblastoma: a case-control study. J Natl Cancer Inst 1987;78:797–804.
Michalek AM, Buck GM, Nasca PC, et al. Gravid health status, medication use, and risk of neuroblastoma. Am J Epidemiol 1996;143:996–1001.
Cruysberg JR, Moll AC, Imhof SM. Bilateral sporadic retinoblastoma in a child born after in vitro fertilization. Arch Ophthalmol 2002;120:1773 author reply 1773–4.
Melamed O , Bujanover Y, Hammer J, et al. Hepatoblastoma in an infant born to a mother after hormonal treatment for sterility. N Engl J Med 1982;307:820.
Toren A , Sharon N, Mandel M, et al. Two embryonal cancers after in vitro fertil zation. Cancer 1995;76:2372–4.
Lancaster PA. Congenital malformations after in vitro fertilization. Lancet 1987;2:1392–3.
Berg T , Ericson A, Hillensjo T, et al. Deliveries and children born after in-vitro fertilization in Sweden 1982–95: a retrospective cohort study. Lancet 1999;354:1579–85.
National Summary and Fertility Clinic Report. Assisted reproductive technology success rates. MMWR 2000;52 No SS-9.(I Lee1,2, P T Finger1,2, )
2 New York University School of Medicine, New York City, NY, USA
3 Albert Einstein College of Medicine, New York City, New York, USA
Keywords: in vitro fertilisation; intracytoplasmic sperm injection; retinoblastoma; genetics; fertilisation; cancer
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
Table 1 Anomalies and cancers reported in offspring of IVF
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).
Table 2 Retinoblastoma in children born through IVF
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.
Figure 1 B-scan ultrasonography. (A) A longitudinal view of the right eye demonstrates a tumour posterior to a closed funnel retinal detachment. (B) A transverse view of the eye demonstrates a rounded, densely calcified tumour. R, retina; S, shadow in orbit; C, calcification; T, tumour; ON, optic nerve.
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.
Comment
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.
References
Klip H , Burger CW, deKraker J, et al. Risk of cancer in the offspring of women who underwent ovarian stimulation for IVF. Hum Reprod 2001;16:2451–8.
Anteby I , Cohen E, Anteby E, et al. Ocular manifestations in children born after in vitro fertilization. Arch Ophthalmol 2001;119:1525–9.
Moll AC, Imhof SM, Cruysberg JR, et al. Incidence of retinoblastoma in children born after in-vitro fertilisation. Lancet 2003;361:309–10.
Finger PT, Harbour JW, Karcioglu Z. Risk factors for metastasis in retinoblastoma. Surv Ophthalmol 2002;47:1–16.
Moshfeghi DM, Moshfeghi AA, Finger PT. Enucleation. Surv Ophthalmol 2000;44:277–301.
Lerner-Geva L , Geva E, Lessing JB, et al. The possible association between in vitro fertilization treatments and cancer development. Int J Gynecol Cancer 2003;13:23–7.
Doherty AS, Mann MR, Tremblay KD, et al. Differential effects of culture on imprinted H19 expression in the preimplantation mouse embryo. Biol Reprod 2000;62:1526–35.
Bruinsma F , Venn A, Lancaster P, et al. Incidence of cancer in children born after in-vitro fertilization. Human Reprod 2000;15:604–7.
Lerner-Geva L , Toren A, Chetrit A, et al. The risk for cancer among children of women who underwent in vitro fertilization. Cancer 2000;88:2845–7.
White L , Giri N, Vowels MR, et al. Neuroectodermal tumours in children born after assisted conception. Lancet 1990;336:1577.
Kobayashi N , Matsui I, Tanimura M, et al. Childhood neuroectodermal tumours and malignant lymphoma after maternal ovulation induction. Lancet 1991;338:955.
Kramer S , Ward E, Meadows AT, et al. Medical and drug risk factors associated with neuroblastoma: a case-control study. J Natl Cancer Inst 1987;78:797–804.
Michalek AM, Buck GM, Nasca PC, et al. Gravid health status, medication use, and risk of neuroblastoma. Am J Epidemiol 1996;143:996–1001.
Cruysberg JR, Moll AC, Imhof SM. Bilateral sporadic retinoblastoma in a child born after in vitro fertilization. Arch Ophthalmol 2002;120:1773 author reply 1773–4.
Melamed O , Bujanover Y, Hammer J, et al. Hepatoblastoma in an infant born to a mother after hormonal treatment for sterility. N Engl J Med 1982;307:820.
Toren A , Sharon N, Mandel M, et al. Two embryonal cancers after in vitro fertil zation. Cancer 1995;76:2372–4.
Lancaster PA. Congenital malformations after in vitro fertilization. Lancet 1987;2:1392–3.
Berg T , Ericson A, Hillensjo T, et al. Deliveries and children born after in-vitro fertilization in Sweden 1982–95: a retrospective cohort study. Lancet 1999;354:1579–85.
National Summary and Fertility Clinic Report. Assisted reproductive technology success rates. MMWR 2000;52 No SS-9.(I Lee1,2, P T Finger1,2, )