Childhood Acute Lymphoblastic Leukemia and Indicators of Early Immune Stimulation: A Childhood Leukemia International Consortium Study

Abstract

The associations between childhood acute lymphoblastic leukemia (ALL) and several proxies of early stimulation of the immune system, that is, day-care center attendance, birth order, maternally reported common infections in infancy, and breastfeeding, were investigated by using data from 11 case-control studies participating in the Childhood Leukemia International Consortium (enrollment period: 1980-2010). The sample included 7,399 ALL cases and 11,181 controls aged 2-14 years. The data were collected by questionnaires administered to the parents. Pooled odds ratios and 95% confidence intervals were estimated by unconditional logistic regression adjusted for age, sex, study, maternal education, and maternal age. Day-care center attendance in the first year of life was associated with a reduced risk of ALL (odds ratio = 0.77, 95% confidence interval: 0.71, 0.84), with a marked inverse trend with earlier age at start (P < 0.0001). An inverse association was also observed with breastfeeding duration of 6 months or more (odds ratio = 0.86, 95% confidence interval: 0.79, 0.94). No significant relationship with a history of common infections in infancy was observed even though the odds ratio was less than 1 for more than 3 infections. The findings of this large pooled analysis reinforce the hypothesis that day-care center attendance in infancy and prolonged breastfeeding are associated with a decreased risk of ALL.

Birth order and risk of childhood cancer in the Danish birth cohort of 1973–2010

“…Similarly, a Californian record-based case-control study with 3,402 ALL cases aged 0-5 years from 1988 to 2007 (overlapping with [4,6]) showed nonsignificant odds ratios of 1.00, 0.95, and 0.91 for birth orders second, third, and fourth or higher, respectively, compared with firstborn children, but indicated some stronger decrease in non-Hispanic Whites compared with Hispanic Whites [7]. A pooled analysis from the Childhood Leukemia International Consortium (CLIC), using data from 11 questionnaire-based case-control studies from eight countries with a total of 7,399 ALL cases diagnosed between 1979 and 2001, showed a pooled odds ratio of 0.94 (CI 0.88-1.00) for later-born versus firstborn with no monotonic trend of decrease with increasing birth order, but with substantial heterogeneity across studies (I 2 of 71 %) [8]. Individual study odds ratios ranged from 0.69 (CI 0.55-0.86; France) to 1.44 (CI 1.15-1.79; Quebec, Canada).…”

“…In Denmark, social contacts through day care are very common, and the proportion of 0-to 6-year-old children attending day care increased from just over 40 % in 1980 to 75 % in 1999 [40]; this is higher than in many other countries, and hence, in Denmark birth order may be a less predictive proxy of social contacts than elsewhere [8].…”

“…Many studies have investigated the possible association between birth order and risk of childhood cancer, although the evidence to date has been inconsistent [1,[4][5][6][7][8][9][10][11][12]. As birth order is relatively straightforward to record, either through routine data sources such as birth registries or through questionnaire-based studies, where it is generally acknowledged to be well reported [13], it has often been used as a surrogate marker for in utero and/or childhood exposures.…”

Childhood Leukemia and Primary Prevention

“…Epidemiological studies have, however, demonstrated clear effects of immune factors on leukemogenesis, most overtly in the form of a consistently-observed reduced risk of childhood ALL associated with more childhood contacts in daycare (odds ratio, OR=0.77, 95% Confidence Interval, 95% CI: 0.71–0.84; N =7399 cases) and other markers of early exposure to immune stimulus such as breastfeeding for at least six months (OR=0.86, 95% CI: 0.79–0.94), having an older sibling (OR=0.94, 95% CI: 0.88–1.00), or a history of four or more common infections in the first year of life (OR=0.88, 95% CI: 0.79–0.98). 33 Just as regular immune stimulation appears to reduce risk for allergies and asthma, the same immune exercise can reduce the risk of leukemia. In the absence of these priming exposures, children may respond too strongly to the myriad of infections subsequently encountered in school, resulting in a cytokine “storm” and excess cell stimulation, secondary mutations, and, in some cases, leukemia.…”

Childhood Leukemia: A Preventable Disease

“…69,71 It is well-documented that breastfeeding reduces the risk of childhood leukemia by ∼10% overall and by 20% for women breastfeeding 6 months and longer. 72,73 Promoting breastfeeding during prenatal and postnatal visits is practical and cost-efficient. However, there was a suggestion that maternal smoking during breastfeeding was associated with a higher risk of leukemia.…”