Although smoking has historically been a predominantly male-related behavior until the beginning of the twentieth century (Einarson and Riordan, 2009
), women’s liberation movement during the 1960s and 1970s accelerated a lifestyle change, with smoking increase among women in industrialized countries. Hence, increasing rates of several smoking health related hazards among women started to be observed in Brazil and other countries (Lombardi et al., 2010
). Such epidemiological change has stimulated the organization of public policies toward smoking control programs addressed to prevent such addiction among women (Amos et al., 2012
Eleven cigarette compounds were detected as human carcinogens and others may be carcinogenic, but have not been yet fully evaluated (IARC, 2004
). Tobacco smoke also contains tumor promoters (phenolic substances), co-carcinogens (catechol and related compounds), toxic agents (acrolein and other aldehydes), and free radical species (nitric oxide and others; IARC, 2004
Even though, the role of parental prenatal smoking in childhood leukemia remains unknown. Nevertheless, such biological plausibility is supported by the presence of carcinogenic chemicals in tobacco smoke (IARC, 2004
; Thielen et al., 2008
), and their ability to cross the placenta (de la Chica et al., 2005
), to cause DNA damage (Potts et al., 1999
), oxidative damage (Fraga et al., 1996
), chromosomal abnormalities (Pluth et al., 2000
), and aneuploidy in human sperm (Shi et al., 2001
Maternal tobacco smoking during pregnancy was reported in this study by 17.5% of case mothers and 20.6% of controls’. Data from a population-based national survey carried out in 2008 indicated that smoking prevalence in women 15
year or older was 13.1% in Brazil (IBGE, 2008
). According to other national population-based survey with phone interviews, such figures are higher in the South and Southeast of Brazil, wherein they range around 22% among women, being lower in the Northeast, around 6% (Brazil, 2009).
The null association between maternal smoking and EAL risk regardless the period of exposure during pregnancy, as observed in this study, is consistent with the literature. The absence of an association between maternal smoking exposure and EAL according to the child age strata in this investigation, does not support an association between the occurrence of MLL gene rearrangements as a consequence of such exposure, considering the high prevalence of such rearrangements observed in infant leukemia (Marschalek, 2011
On the other hand, an association between maternal smoking during pregnancy and EAL cannot be completely ruled out, since a statistically significant association was observed for heavy smokers and ALL, adj. OR
5.28, 95% CI 1.40–19.95. Hence, this study results suggest that such association may occur, if the amount of tobacco daily exposure remains high during pregnancy or immediately later. Nevertheless, it is important to remark that these results were observed with few heavy smoker mothers (nine ALL and four control mothers). Additionally, the variable smoking consumption was highly correlated during the time windows of exposure (Pearson correlation coefficients ranging from r
0.66 between preconception and breastfeeding, and r
0.85 between the third trimester and breastfeeding). In regard to secondhand smoking during pregnancy, no association with EAL was observed.
A research published by IARC/WHO concluded that passive smoke is carcinogenic (IARC, 2004
), and smoke inhaled by passive smokers is responsible for tobacco-related diseases, especially lung cancer (Hackshaw et al., 1997
). Passive smoking may begin during the intrauterine life, due to pregnant smokers, workplaces and living with smokers, introducing toxic substances through the umbilical cord to the fetus. Besides differences according to carcinogenesis in early life, infants have distinct capacities from adults to metabolize and clear chemicals, which can result in larger or smaller internal doses of active agents, either increasing or decreasing risk (Ginsberg et al., 2002
A case-control study conducted in Australia (Milne et al., 2012
) examined the association between parental smoking and the risk of childhood ALL. Maternal smoking was not associated with risk of childhood ALL, but a performed meta-analyses suggested that heavier paternal smoking around the time of conception is a risk factor for childhood ALL (OR
1.44, 95% CI 1.24–1.68).
A Canadian study observed an association between AML and 10–19 cigarettes per day consumption during pregnancy, OR
3.89, 95% CI 1.31–11.58. The risk estimate for the same intake during the first trimester was OR
4.03, 95% CI 1.33–12.21 (MacArthur et al., 2008
). Conversely, two French studies did not find an association between maternal smoking and childhood leukemia. The first one did not either observed an association before, or during pregnancy, or during childhood (Menegaux et al., 2007
). The other study did not detect an association regardless the maternal period of smoking during pregnancy (Menegaux et al., 2005
). In a national registry-based case-control carried out in France (Rudant et al., 2008
), an association between maternal smoking and childhood leukemia was also not observed. In this sense, only few studies have found maternal smoking to be significantly associated with the risk of ALL (Sorahan et al., 2001
; MacArthur et al., 2008
The analyzed data in the current investigation were strictly dependent on a maternal report, which may have introduced incorrect exposure estimates, being over or underreported. Nevertheless, we believe that whether this lack of accuracy has occurred, it probably was non-differential, considering the use of a standardized questionnaire and interview procedures to get information from case and control mothers, which decreases the potential differential misclassification. Thus, we consider that the observed results are not likely to be explained by underreporting smoking controls, since the proportion of mothers who reported to have smoked during the study was higher than the average percentage of Brazilian population in 2003 (18.4%) and 2008 (13.1%; Wunsch Filho et al., 2010
). However, mothers of reported cases may have been not exposed to their own cigarettes, thus reducing the chance to produce an observable association. On the other hand, Menegaux et al. (2005
) suggested that the general feeling of guilty associated with smoking may be stronger in mothers of children with leukemia than among control’s, arising unequal accuracy of information provided by the former.
Most of the literature reveals a relationship between the risk of childhood leukemia and paternal smoke around the time of conception, probably due to its influence in spermatogenesis (Shu et al., 1996
; Pang et al., 2003
; Chang et al., 2006
; Rudant et al., 2008
; Lee et al., 2009
; Milne et al., 2012
). In this investigation, paternal smoking data was not obtained. Therefore, evaluation whether the offspring of heavy smoker mothers – showing higher EAL risk estimates – also had smoker fathers, was unfeasible to be accomplished.
Maternal smoking during pregnancy has been associated to several health hazards, including spontaneous abortion, infertility, and sudden infant death syndrome, among several others (Einarson and Riordan, 2009
). A higher incidence of spontaneous abortion among case mothers, comparatively to controls’, could yield to a null association between smoking and leukemia. If true, however, such fact would mainly target heavy smoker pregnants, and a null association would mainly occur in their offspring, which was not observed. Additionally, it is possible that heavy smoker mothers were less likely to be included in the current study as a consequence of the association between smoking with abortion and infertility.
In the current investigation, the choice of hospitalized controls with severe diseases may have probably mitigated the occurrence of such kind of bias. Controls were selected from the same regions wherein cases came from, as a procedure to assure that the study base principle could be accomplished, i.e., that all enrolled participants could share the background pattern of exposures, thus allowing to obtain unbiased risk estimates with the performed comparisons (Wacholder et al., 1992
). Finally, according to AML, the relatively small amount of enrolled cases in this study did not allow the ascertainment of some risk estimates.
This investigation presented some weaknesses. At first, sample size of AML cases limited data exploratory analysis. Secondly, considering the high correlation among the reported smoking prevalence in the different time windows of exposure, the obtained risk estimates in each of them are probably imprecise, and they need to be interpreted cautiously. Thirdly, data on paternal smoking before and during pregnancy was not collected during the interviews.
Nevertheless, the study presents some strengths. At first, it was feasible to collect maternal data exposure to smoking in a very rare cancer, such as leukemia in children under 2
year. At such age strata, with a short postnatal life span of exposures, the importance of in utero
environmental exposures is of paramount importance, and the investigation was able to either obtain a detailed report about timing and amount of tobacco (smoked cigarettes) exposure during pregnancy, or other important risk factors, such as birth weight and oral contraceptives use during the same period. Finally, to our knowledge, this is the first Latin American study exploring the association between maternal smoking during pregnancy and leukemia among children under 2
Consistent with most previous studies (Menegaux et al., 2005
), this study did not report an association between maternal smoking and EAL. This result is in agreement with a possible lower maternal contribution to the risk of embryonic genetic mutations, comparatively to paternal one. Such observation can result to the fact that the ova are formed and stored in the female embryo, being better protected against genotoxic stress, while the male germ cells, keeps the process continuously (Guerquin et al., 2009
). However, maternal daily consumption of 20 or more cigarettes during pregnancy showed a fivefold higher statistically significant association with the risk of ALL. Such risk estimates are indeed higher if considered such exposure during the second trimester of pregnancy, the third trimester, or breastfeeding.
To conclude, this investigation results observed the occurrence of an association between an intensive exposure to tobacco smoking during pregnancy and AAL, being higher if such exposure occurred after the first trimester of pregnancy, including breastfeeding.