Fetal Growth and Acute Childhood Leukemia: Looking Beyond Birth Weight

The authors examined the relation between birth weight, intrauterine growth, and risk of childhood leukemia using population-based linked health data from Western Australia. A cohort of 576,593 infants born in 1980–2004 were followed from birth to diagnosis of acute lymphoblastic leukemia (ALL) (n = 243) or acute myeloid leukemia (AML) (n = 36) before their 15th birthday, death, or the end of follow-up (December 31, 2005). Data were analyzed using Cox regression. Risk of ALL was positively associated with the proportion of optimal birth weight—a measure of the appropriateness of fetal growth—particularly among children younger than 5 years; the hazard ratio for a 1-standard-deviation increase in proportion of optimal birth weight was 1.25 (95% confidence interval: 1.07, 1.47). Among children younger than 5 years not classified as having high birth weight (defined as > 3,500 g, > 3,800 g, and > 4,000 g), a 1-unit increase in proportion of optimal birth weight was associated with an approximately 40% increase in ALL risk. This suggests that accelerated growth, rather than high birth weight per se, is involved in the etiology of ALL. These findings are consistent with a role for insulin-like growth factor I in the causal pathway. Findings for AML were inconclusive, probably because of small numbers.

Introduction

Leukemia is the most common childhood malignancy, accounting for 35 percent of childhood cancer cases diagnosed in Australia each year (Australian Institute of Health and Welfare, unpublished data). Despite extensive research, little is known about the etiology of childhood leukemia. Its early age of onset has focused attention on in-utero and perinatal factors. There is now growing evidence that some childhood leukemias, particularly those diagnosed after infancy, may be explained by a "two-hit model"^[1,2]—the first "hit" occurring in utero and often causing a chromosomal translocation and formation of a fusion gene. A number of studies have shown that specific translocations such as t(12;21) and t(8;21) are present at birth in children who later develop leukemia.^[3-5] Any subsequent necessary "hits" are thought to occur postnatally, causing proliferation of the leukemic clone. Putative etiologic factors include exposure to environmental toxins and infections and aberrant host responses to them.^[1]

Birth weight is one of the few perinatal factors reported to be related to risk of childhood leukemia. A 2003 meta-analysis by Hjalgrim et al.^[6] included 18 studies of this association; they reported a pooled odds ratio of 1.26 (95 percent confidence interval (CI): 1.17, 1.37) for birth weight over 4,000 g. Most of the studies published since^[7-13] have found a positive association. Some of the variation in reported findings may be due to differences in: 1) case definition (incident cases vs. deaths only); 2) type of leukemia examined (all leukemia vs. acute lymphoblastic leukemia (ALL) vs. acute myeloid leukemia (AML)); 3) categorization of birth weight (continuous variable vs. categorical variable); 4) definition of high birth weight (> 3,500 g, > 3,800 g, > 4,000 g, or > 4,500 g); 5) source of data on birth weight; 6) ages of the subjects at diagnosis; 7) nature of the comparison group used (e.g., population registers, hospital controls, random digit dialing); and 8) study design.

Despite such inconsistencies, most investigators have reported an increasing risk of ALL with increasing birth weight. However, few studies have taken account of gestational age in the analysis of birth weight. Since birth weight is a function of both intrauterine growth and length of gestation, it is not possible to differentiate between an association with high birth weight per se and an association with accelerated intrauterine growth, without accounting for gestational age. If there were an association with accelerated growth, the risk would extend to infants born at any gestation who had a higher-than-expected birth weight for their length of gestation, but who might not reach a particular definition of high birth weight. Such an association would suggest that factors such as exposure to high levels of growth hormone might be etiologically important. On the other hand, a different causal mechanism would be likely if the association were with high birth weight per se. For example, because birth weight is positively associated with bone marrow volume,^[14,15] heavier children may simply have more cells at risk of malignant transformation.^[16] Either of these proposed mechanisms—or a combination—could represent the first "hit" in the development of childhood ALL or could be involved in a subsequent "hit" by promoting proliferation of a leukemic clone. The relation between birth weight and AML has been even less well characterized. Clarifying the nature of these relations would assist in elucidating the causal pathways.

Our aims in this study were to use data from a population-based data linkage system to characterize the relations of birth weight and intrauterine growth with risk of childhood leukemia and to consider these findings in relation to possible causal pathways.