Int. J. Cancer: 124, 2658–2670 (2009) ' 2008 Wiley-Liss, Inc.

Birth weight and childhood leukemia: A meta-analysis and review of the current evidence Robert W. Caughey1 and Karin B. Michels1,2* 1 Department of Epidemiology, Harvard School of Public Health, Boston, MA 2 Obstetrics and Gynecology Epidemiology Center, Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA A growing body of evidence suggests that childhood leukemia may be initiated in utero when lymphoid and myeloid cells are not fully differentiated and are particularly susceptible to malignant transformation. A fixed effects meta-analysis examining the association between birth weight and childhood leukemia was conducted including 32 studies and 16,501 cases of all types of leukemia (OL), 10,974 cases of acute lymphoblastic leukemia (ALL), and 1,832 cases of acute myeloid leukemia (AML). The odd ratios (OR) for the association of high birth weight with OL, ALL and AML were 1.35 (95% CI: 1.24, 1.48), 1.23 (95% CI: 1.15, 1.32), and 1.40 (95% CI: 1.11, 1.76), respectively, compared with normal birth weight. Low birth weight was not associated with overall and ALL leukemia, but with AML (OR 5 1.50; 95% CI: 1.05, 2.13). Per 1000 g increase in birth weight, the OR for OL was 1.18 (95% CI: 1.13, 1.23) and ALL 1.18 (95% CI: 1.12, 1.23). The combined available evidence from observational studies suggests that high birth weight is associated with an increased risk of overall leukemia and ALL. For AML the risk may be elevated at both high and low extremes of birth weight, suggesting a U-shaped association. ' 2008 Wiley-Liss, Inc. Key words: birth weight; early life; epidemiology; leukemia

Leukemia is the most common malignancy affecting children and accounts for 26% of all childhood cancers in the United States.1,2 There is a growing body of evidence indicating that childhood leukemia is initiated in utero. Acute lymphoblastic leukemia (ALL) may acquire the first of 2 key mutations in utero due to the particular susceptibility of lymphoid cells in the liver and bone marrow that results from their predifferentiated state.3,4 As the fetus grows, B-cell precursors rapidly proliferate and are exposed to high levels of circulating growth factors during embryogenesis. Simultaneously, the lymphocytes are maturing and are capable of responding to a broad range of antigens, which may permanently alter a cell to become more susceptible to malignant transformation.3,4 Likewise, stem cells that give rise to the myeloid cell line may also be susceptible to circulating growth factors and hormones.5 Growth factors and hormones act to increase stem cell pool size, which increases the total number of replicating cells at risk for conversion into tumor cells. This may increase the risk of leukemia. One factor related to stem cell pool size is birth weight, which has been postulated as a risk factor for childhood leukemia.6 A meta-analysis conducted in 2002 by Hjalgrim et al. including 18 studies suggested an increased risk of overall leukemia and 1 leukemia subtype, ALL, for children with birth weight