a Joint Departments of Epidemiology and Biostatistics, and Occupational Health, Faculty of Medicine, McGill University, Montréal, Québec, Canada.
b Department of Pediatrics, Université de Montréal, Montréal, Québec, Canada, H3T 1C5.
c Research Centre, Hôpital Sainte-Justine, Montréal, Québec, Canada,H3T 1C5.
Correspondence: Claire Infante-Rivard, Joint Departments of Epidemiology and Biostatistics, and Occupational Health, McGill University, 1130 Pine Avenue West, Montréal, Québec, Canada H3A 1A3. E-mail: cirivard{at}epid.lan.mcgill.ca
Abstract
Background With the exception of Down syndrome the association between congenital anomalies and acute lymphoblastic leukaemia (ALL) is presently unclear. We investigated this association in a population-based case-control study carried out in the province of Québec, Canada.
Methods A total of 491 incident cases diagnosed between 1980 and 1993 and aged 09 years were included in the study. Healthy controls (n = 491) matched on age, sex, and region of residence at the time of diagnosis were selected from government family allowance files. Using a structured questionnaire and the International Classification of Diseases (Ninth Revision) list of congenital anomalies, presence of an anomaly was determined by interviewing the parents of the study subjects; mothers gave information on anomalies in the study subject, their siblings and her family, whereas fathers provided information on anomalies in their family.
Results The adjusted risk for ALL was not increased in children who had any anomaly (odds ratio [OR] = 1.07 [95% CI : 0.701.65]) whereas compared to control siblings, case siblings had a higher risk of anomalies (OR = 1.54, 95% CI : 0.99 2.42). This increase was likely due to excesses in anomalies of the heart (OR = 2.49, 95% CI : 1.235.04). Risk for ALL was elevated in children with a history of a congenital anomaly in their mother (OR = 1.61, 95% CI : 0.803.22) or her family (OR = 1.45, 95% CI : 0.942.25).
Conclusions Although based on small numbers for specific anomalies, these findings suggest that congenital anomalies are more prevalent in siblings and maternal family of ALL cases than in controls.
Keywords Leukaemia, congenital abnormalities, risk factors
Accepted 26 July 2000
The aetiology of childhood leukaemia is complex and many factors, genetic and environmental, are postulated to play a role. While an overall excess of malignancies among children with congenital anomalies has been reported,1 evidence for the association between congenital anomalies and acute lymphoblastic leukaemia (ALL) in particular is still unclear except for Down syndrome.2 A population-based case-control study of ALL was carried out in the province of Québec (Canada).3 We report here on the association between congenital anomalies in study subjects and in their family and the risk of ALL.
Methods
Details on the selection of cases and controls have been provided elsewhere.3 Briefly, cases of ALL diagnosed between 1980 and 1993 in the province of Québec aged 09 years were recruited from the tertiary care centres. A case was determined to have ALL (International Classification of Diseases, Ninth Revision [ICD-9] coding 204.0) on the basis of a clinical diagnosis by an oncologist or a haematologist at the centre.
Population-based controls matched to the case for age (within 3 months for most pairs), sex, and region of residence at the calendar time of diagnosis were randomly chosen from family allowance files. The family allowance is a government stipend awarded to all families with children living legally in Canada. A total of 510 cases were identified and interviews obtained from 491 parents (96.3%); 588 controls were recruited to obtain interviews from 493 (83.3%) parents. In the end, 491 cases and 491 controls were used in the analyses.
Data collection
Information on major congenital anomalies and potential confounding variables was collected using a structured telephone interview with the parents conducted by trained interviewers. Mothers were asked if the child (study subject and each sibling) had major anomalies (yes/no) according to a list of anomalies from ICD-9, codes 741754. For each major category, questions were asked about the presence of a congenital anomaly belonging to that category. For ascertaining the presence of an anomaly in the family, fathers and mothers were interviewed separately. An anomaly was said to be present in the family if it was reported in the study subject's siblings, parents, grandparents, uncles or aunts.
Analysis
Conditional logistic regression analysis was used to analyse the data. Maternal education and maternal and paternal age at birth of the index child were treated as confounding variables. In addition, when examining the prevalence of anomalies in the siblings of the cases and controls, we adjusted for the number of siblings. Odds ratios (OR) and their 95% CI were estimated.
Results
Congenital anomalies in the ALL cases and controls
Among cases, 37% (181/491) were first-born, 34% (169/491) were second-born and 29% (141/491) were of higher birth order. The comparative numbers for the controls were 55% (250/491), 28% (139/491) and 23% (102/491), respectively. Congenital anomalies were reported for 9.9% (49/491) of the cases and 9.4% (46/491) of the controls (Table 1). After controlling for potential confounders, the OR for leukaemia was 1.07 (95% CI : 0.701.65). The prevalence of anomalies was not different among the comparison groups for most specific anomalies (data not shown) although there were some suggestions of elevated risks for anomalies affecting the musculo-skeletal system (OR = 2.55, 95% CI : 0.6110.10) and the pancreas-digestive tract (OR = 2.60, 95% CI : 0.2725.48).
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Congenital anomalies in the families of ALL cases and controls
The presence of any congenital anomaly in the maternal or paternal family of the case was associated with a moderately increased risk for leukaemia (OR = 1.57, 95% CI : 1.152.13) (Table 1). This increase seemed related to maternal inheritance as prevalence of congenital anomaly was higher in case mothers and their family and not in those in the case fathers and their family.
Discussion
Overall, leukaemic children did not have an excess of major congenital anomalies. No significant excesses were observed for most specific anomalies. However, siblings of leukaemia cases had a higher prevalence of congenital anomalies as compared to control siblings, most of which was due to anomalies of the heart. The risk for ALL was also increased with anomalies reported either in the mother or in her family.
Information on the possible association between congenital anomalies other than Down syndrome and ALL is presently limited and controversial. Whereas some authors have reported an excess of major congenital anomalies (all types),4 oral clefts,5 renal abnormalities,6 multiple birthmarks, congenital heart defects and pancreas-digestive tract,7 neurofibromatosis,8 Fanconi's anaemia,9 and ataxia telangiectasia10 others have not.1113 Similarly the association between a family history of congenital anomalies and the risk for leukaemia is also limited and unclear. Some authors have reported overall excesses in either siblings or the extended family of any congenital anomaly,14,15 Down syndrome,4 and congenital heart and lung disease.16 Others studies have, however, not reproduced these findings.7,17
Our findings are consistent with the reported absence of an excess for any anomaly in the leukaemic child. Although rare, the increased prevalence of some anomalies such as those affecting the musculo-skeletal system and the pancreas-digestive tract in both the cases and their siblings may suggest the involvement of genes belonging to the homeobox family or signal transduction genes such as the RET protooncogene.18,19 The finding of an increase in risk for ALL associated with the presence of anomalies only in the mother and her family is particularly interesting and suggests a role for complex genetic factors. Presently one can only speculate on the underlying biological mechanisms. Defective developmental genes inherited from the mother (and her family) seem to be differentially expressed. This differential expression could be the result of environmental exposures occurring during the in utero development of the fetus. Smoking during pregnancy and/or exposure to teratogenic agents such as pesticides or radiation through occupational or other circumstances could interact with genetic factors and increase the risk for ALL in the child.
Although, possible limitations of the study (underreporting and misclassification of anomalies, limited study power) preclude the reaching of definite conclusions, this study does provide some evidence of a higher prevalence of congenital anomalies in the families of ALL cases. Larger studies with details on specific anomalies within families of the ALL subjects suitably supplemented with genetic information would be necessary to confirm these findings.
Acknowledgments
This project was supported by a grant from the National Health and Welfare Research and Development Program Grant #6605330958.
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