IVF, Increased risk of Beckwith-Wiedemann Syndrome?

Recent data suggest that assisted reproductive technology (ART) might affect the epigenetics of early embryogenesis and cause birth defects - specifically Angelman syndrome [Cox GS, et al, 2000, Am J Hum Genet 71:162-164]. In animals, nuclear transfer (as in cloning) or even exposure to in vitro environments by tissue culture has been associated with the birth of unusually large offspring (referred to as "large offspring syndrome") [Young LE et al, Rev Reprod 3:155-163, 1998]. Direct evidence indicates that overgrowth in ART offspring of animals is linked to imprinting. Studies have shown that sheep affected with large offspring syndrome that are derived from cultured embryos undergo loss of imprinting at the insulin-like growth factor-2 (IGF2) receptor gene [Young LE et al, Nat Genet 27:153-154, 2001]. These data have been used as one of a number of reasons why reproductive cloning of human embryos would be difficult and unwise.  In a new human study [DeBaun M et al, Am. J Hum. Genet. 72:156-160, 2003], evidence is reported of an increased risk of the overgrowth syndrome, Beckwith-Wiedemann syndrome (BWS),  in subjects born via ART. In this study derived from a registry of BWS cases, the prevalence of ART was 4.6% (3 of 65) versus the background rate of 0.8% of births in the United States. In addition to this registry study, a total of seven children with BWS born after ART have been identified by these workers, five of whom were conceived after intracytoplasmic sperm injection.  Molecular testing of these children indicate that five of six studied have specific epigenetic alterations associated with BWS.  The authors interpret these data as indicating that ART is associated with human overgrowth similar to the large offspring syndrome reported in ruminants.

COMMENT: These data demonstrate the power of registries in identifying clinical, biological and etiological features of very rare diseases.  The number of BWS cases in this study is relatively modest, and the incidence of cancer in children with BWS who are less than 4 years of age is 0.02 per hundred patient years [DeBaun and Tucker, J Pediatr 132:398-400, 1998]. It is not possible from this study to identify a role of ART in the incidence of cancer.  However, the authors reasonably postulate that ART may be associated with increased frequencies of embryonal cancers of childhood in which methylation abnormalities of H19 have been described (Wilms' tumor, hepatoblastoma, and rhabdomysarcoma). Prospective analysis of large data sets may be necessary to address this question.  

ART and Retinoblastoma

In continuing the theme of associations between in vitro fertilization (IVF) and adverse affects on offspring, we describe a report by Moll A et al from the Netherlands that appeared recently in the Lancet [2003; 361:309-310]. During the period November 2000 through February 2002, the authors diagnosed retinoblastoma in five children (2 bilateral, 3 unilateral) who were born after IVF. They wished to determine whether this number of cases exceeded what would have been expected in the population. Using data from the Dutch retinoblastoma registry and the Netherlands cancer registry, they calculated observed-to-expected ratios. Based on incidence estimates of the number of cases expected (by age group) and the estimated 1-1.5% of children conceived by IVF in the Netherlands, they calculated that 0.69 cases of retinoblastoma would occur in IVF births during the period 1995 and 2001. Assuming that all five patients they saw at their clinic represented all IVF-associated cases during the same time period, they calculated a relative risk of 7.2 (95% CI=2.4-17.0). This estimate is likely conservative. For the 5 patients who were conceived through IVF, none had a family history of retinoblastoma. Interestingly, although IVF was performed during the period 1980-1995, no retinoblastoma cases were reported in  children born during this time. The authors question whether some change in the IVF procedure itself since 1995 may be etiologically relevant.

COMMENT: While some reports have suggested no link between ART and childhood cancer [Klip H, et al; Hum Reprod 2001; 16:2451-2458; Bruinsma F, et al; Hum Reprod 2000; 15:604-607],  Moll et al’s suggestion that this is a more recent phenomenon is of interest. We anxiously await further reports. The Children’s Oncology Group Epidemiology Committee will also be discussing some of these findings at the 2003 Spring meeting in Atlanta, and how they might be pursued in a rigorous investigation.  

Hepatocellular carcinoma: A stick in time may save lives

Beasley RP, et al’s report [Lancet 1981; 2:1129-1133] that hepatitis B surface antigen (HBsAg) positive men develop hepatocellular carcinoma (HC) at vastly higher rates than do HBsAg negative men was a classic read in epidemiologic literature. Dozens of studies and multiple lines of evidence have since confirmed that chronic carriage of hepatitis B virus causes HC. Thus, a worldwide hepatitis B vaccination effort was started that has had well-documented success in disrupting the chronic carrier state. Since the program began only twenty years ago, it was thought that decades would pass before an effect was seen on the incidence of HC, which is quite rare in children. However, a recent Taiwanese study has documented that the rate of HC among 0-14 year olds declined following the advent of mass newborn hepatitis B vaccination. Lee C-L, et al. [Cancer Epidemiol Biomark Prev 2003; 12: 57-59] used data from the Taiwan Mortality Registry and census data to calculate the mortality rate of liver cancer by sex and age (0-14 and 15-100 years) for seven time periods between 1974 and 1999. The researchers tested the periods 1974-1983 and 1984-1999 separately to see if there were significant trends in the mortality rate before and after the start of the hepatitis B vaccination campaign. The rate of death from liver cancer increased significantly (p < 0.05) among males of both age groups and nonsignificantly among females of both age groups in the earlier period. Thereafter the rate declined significantly among both sexes in the younger age group but continued to rise in the older age group, significantly among males but not females. Thus, during 1984-1999, the mortality rate from liver cancer decreased in both boys and girls compared to older males, and compared to boys and girls before the start of newborn hepatitis B vaccination (1974-1983). 

COMMENT: The use of mortality data, which may reflect survival of a disease more than incidence, and the inclusion of deaths from hepatoblastoma in the rate calculations give pause.  The authors, aware of these problems, reported that the rate of survival of HC was low and did not change over the study period.  Thus, the mortality rate in this case should have been a good reflection of the incidence rate.  Also, the authors cited evidence that hepatoblastoma incidence and survival were steady throughout the study period.  Therefore changes in the mortality rate of liver cancer should reflect changes for HC alone.  Despite these potential flaws of the study, the results are credible given the strong biological plausibility of prevention of HC through hepatitis B vaccination. 

Thyroid disease and childhood leukemia: A grave link?

Previous epidemiological studies of childhood leukemia have suggested potential associations with a family history of autoimmune diseases including multiple sclerosis, thyroid disease, or diabetes mellitus. If such associations exist, however, the biological mechanisms are unclear. In this case-control study in France, Perillat-Menegaux F, et al [Cancer Epidemiol Biom Prev 2003; 12:60-63] explored family history of autoimmune disease in first- and second degree relatives of 279 newly diagnosed children with leukemia (240 ALL, 39 AML) and 285 hospital-based controls. Diseases considered to be autoimmune included: Graves’ disease and/or hyperthyroidism; Hashimoto’s thyroiditis and/or hypothyroidism; diabetes mellitus; rheumatoid arthritis; ankylosing spondylitis; multiple sclerosis; systemic lupus erythematosus; Behcet’s syndrome; Crohn’s disease; celiac disease; Landry-Guillain-Barr? syndrome; and psoriasis. Overall, the authors found a positive relationship between a history of autoimmune disease in first- or second-degree relatives of children with ALL (OR=1.7; 95% CI=1.0-2.8) and AML (OR=2.2; 95% CI=0.9-5.5). When diagnoses-specific analyses were performed, it was apparent that autoimmune thyroid diseases (hyper- and/or hypothyroidism) were mainly responsible for these positive relationships (OR=3.5; 95% CI=1.1-10.7 and OR=5.6; 95%CI=1.1-31.1 for ALL and AML, respectively). No other statistically significant associations were demonstrated.  There also were no differences with respect to which side of the family (mother’s or father’s) the autoimmune disease resided, nor were there differences between first and second degree relatives, suggesting that disease-related medication use or a hormonal effect during pregnancy was not a factor.  

COMMENT: The results of this study are provocative, as it is unlikely that recall or self-report of thyroid disease would differ between cases and controls. It would be helpful, however, if there was some description of how thyroid disease (particularly in a second degree relative) would somehow be biologically linked with leukemia in children. 

Editors’ Note:

The Children’s Oncology Group Epidemiology Committee is hosting a special scientific symposium on March 27th (10am-noon) at the Spring meeting in Atlanta. The title of the symposium is: ‘Genetics of Childhood Cancer: Clinical, Biological, and Ethical Issues’. Speakers (and titles) include: Professor Jillian Birch from Royal Manchester Children’s Hospital (‘Familial cancer clusters, cancer syndromes and associated genetic defects’); Dr. Claire Infante-Rivard from McGill University (‘Including genetic polymorphisms in epidemiologic studies of childhood cancer:relevance and challenges’); and Dr. Rebecca Pentz from Emory University (‘Pre-emptive ethics: how researchers can address ethical concerns in genetic research’). All are welcome to attend.

C3 Quarterly Newsletter
Children's Cancer Research Fund
Epidemiology Research Unit
Division of Pediatric Epidemiology
Clinical Research
University of Minnesota
420 Delaware St. SE, Box 422
Minneapolis, MN 55455
pedsepi@umn.edu

Editors: 
Stella M. Davies, MD, PhD, and Julie A. Ross, PhD