Maternal cigarette, alcohol, and illicit drug use before and during pregnancy were evaluated as potential risk factors for infant leukemia. No statistically significant associations were observed for cigarette smoking and drug use. In contrast, alcohol use during pregnancy was inversely associated with infant leukemia overall and specifically among AML and MLL+ cases.
The absence of any association between maternal cigarette smoking and leukemia mirrors most previous findings, including those in infants.15
Only six of 25 recently-reviewed10
studies reported significant but inconsistent associations between maternal smoking and childhood leukemia. In light of this evidence, the International Agency for Research on Cancer recently concluded that maternal cigarette smoking is not causally related to childhood leukemia.22
For maternal alcohol use, a recent meta-analysis11
of 21 case-control studies reported a positive association with childhood AML [OR = 1.56; 95% CI = 1.13, 2.15] but not ALL [OR = 1.10; 95% CI = 0.93, 1.29] nor “grouped leukemias” [OR = 1.11; 95% CI = 0.88, 1.40]. The increased risk with AML was particularly strong for cases diagnosed at <5 years of age. Two studies observed inverse associations similar to ours, although children were 0–1423
years of age instead of exclusively infants. One of these studies speculated that chance likely played a role,23
while the other suggested two distinct potential biological mechanisms.24
First, alcohol may inhibit growth hormone/insulin-like growth factor (IGF-1), which could lead to lower birthweights and a reduced risk of childhood leukemia. Including birthweight in our models did not change effect estimates. A second plausible mechanism involves the cancer chemopreventive activity of flavonoids (i.e., antioxidants) contained in red wine and hopped beer.25–27
We performed a post-hoc analysis stratified by alcohol type (data not shown). Drinking two or more servings of beer and/or red wine per week during pregnancy was inversely associated with all of the leukemia strata, while liquor/spirits showed no associations. Thus, our overall results may lend some support to the proposed flavonoid hypothesis.
Few studies have explored maternal illicit drug use and childhood leukemia. Maternal use of marijuana prior to or during pregnancy was positively associated with childhood AML in one study12
and ALL in another.28
More recently, a study designed to specifically test the hypothesis that marijuana use was associated with an increased risk of AML actually observed an inverse association.13
While our study results did not reach statistical significance, there was a suggestion of an inverse association with any illicit drug use across most subtypes.
It is difficult to interpret our results in the context of other studies, especially in light of discrepant results. Notably, a case-control study of infant leukemia (< 18 months of age) conducted in the 1980s reported a positive
association with maternal alcohol consumption14
. In either study, misclassification of exposure could be an issue. Of note, misclassification of alcohol use was reported in 45% of pregnant women recalling first trimester use in their 7th
month of pregnancy and at delivery.29
This percentage could be even greater in our study population since the maternal interviews took place nearly three years on average after the index child’s birth. We attempted to reduce misclassification by focusing on the periods prior to and after knowledge of pregnancy, although results were similar. It may be fruitful for future case-control studies like ours to consider consistency in questionnaires (ideally they would be validated questionnaires) in order to more readily compare results across studies.
There is also concern regarding recall bias, especially with regard to exposures that may be perceived as harmful. In several states, alcohol and illicit drug use are subject to mandatory reporting by health professionals during pregnancy.30
Although our observational study was protected by a Certificate of Confidentiality from the federal government, mothers of infants with leukemia may have been reluctant to report certain exposures for fear of repercussions. In support of this contention, one study found that mothers of sick infants might be more apt to deny alcohol and cigarette use compared to mothers of healthy children.31
This differential misclassification could lead to odds ratios that are biased in unpredictable directions.32
Due to concerns regarding reporting of these types of exposure, it may be useful to validate certain exposures in future studies, at least in a subset of cases. For example, dried blood spots, collected shortly after birth to test for metabolic and other disorders,33
are kept in long-term storage by several health departments across the United States, potentially permitting their use in etiologic research.34
Several analytes, including cotinine in cigarette smoke35
have been measured in dried blood spots. Thus, with proper consideration of storage conditions, analyte half-life and stability, etc., newborn dried blood spots could potentially be used to provide an independent measure of certain exposures in case-control studies such as ours.37
Selection bias is another potential concern, however, the use of COG institutions for case ascertainment likely minimized selection bias among cases since these institutions treat nearly all leukemia patients diagnosed in the U.S. at <5 years.38
With a response rate of 64%, however, participating cases may be fundamentally different than cases who chose not to participate. The same concern exists among controls, who had a response rate of only 47%. Previously, both the RDD and birth certificate controls from our study were compared to U.S. National Center for Health Statistics data for all births in the year 2000.17
Compared to the U.S. population, control mothers were older, more often white, married, and had more years of education. Control children were more likely to be born at term and to weigh more at birth. Case and control mothers in our study were similar to each other on all measured demographic characteristics except race/ethnicity, as control mothers were more often white. This difference is of interest because, in general, white women consume alcohol more often than women of other racial/ethic groups. In the 2009 National Survey on Drug Use and Health,39
60% of white women reported drinking alcohol in the past month; only 45% of black and Hispanic women and 40% of Asian, American Indian, and Alaska Native women reported drinking. While we adjusted for race/ethnicity, residual confounding may remain.
In an ad hoc sensitivity analysis, we evaluated whether any differences occurred between the two study phases. Although the associations for alcohol use before pregnancy did not appear to change over time, the association between alcohol use during pregnancy and infant leukemia was attenuated in phase II. It is unclear whether this pattern is due to an actual trend, but data from the National Survey on Drug Use and Health (formerly called the National Household Survey on Drug Abuse)39
do not suggest any obvious trends in the prevalence of alcohol use during pregnancy over the past decade. These findings may instead be due to chance, especially given small cell counts. Nevertheless, our overall study results were driven primarily by the first phase of the study.
In conclusion, we found no evidence of an association with cigarette smoking and infant leukemia. In contrast to some previous reports, however, we found evidence of an inverse association between maternal alcohol use during pregnancy, and no evidence of an association with illicit drug use. Due to conflicting findings across the literature and the potential for recall bias, it is important for future studies to consider consistency in questionnaires (ideally validated), as well as an independent measure of exposure, such as prediagnostic biological samples when feasible.