Childhood Leukemia

Leukemia is the most common cancer among children up to age fifteen. There are two main subtypes that affect this age group: acute lymphoblastic leukemia (ALL), the most common subtype, and acute myeloid leukemia (AML), a rather rare subtype. There are multiple phenotypes that are precursors to a child being diagnosed with ALL. B-cell precursor ALL is the predominant phenotype occurring mostly in children ages two to five, and the less common precursor is T-cell phenotype. There are different cytogenetic subtypes that fall under B-cell precursor ALL that include both numerical and structural chromosomal abnormalities.

In high-hyperdiploid ALL, there are 51-68 chromosomes as opposed to the normal 46 in a healthy human cell. This clone of chromosomes is nonrandom in nature in that it affects the same chromosome pairs in each case. Basically, there is a subset of chromosomes in a normal human cell that are duplicated in B-cell precursor ALL, which distinguishes this type from others. Another common chromosomal abnormality seen in B-cell precursor ALL is the reciprocal translocation of chromosomal pairs 12 and 21, referred to as translocation t (12;21). AML occurs in all ages, but in children it is characterized by recurrent chromosomal abnormalities, most commonly myeloid/lymphoid leukemia (MLL) fusions on chromosome 11. Genetic mutations can occur prior to conception, during fetal development, and after birth, and can have a wide variety of etiologies (Metayer, 2013).

This review will focus mainly on how both maternal and paternal smoking affects the incidence rates of childhood leukemia. While there are many other factors associated with the development of childhood leukemia such as certain environmental factors, parental smoking is one factor that can be eliminated by raising awareness to those wanting to start a family. This topic and its findings are important to understand, and that increasing awareness may result in a reduced incidence of childhood leukemia. While the reasons for the various genetic mutations are unknown, there is research suggesting that the chemicals found in tobacco smoke greatly affect the chromosomal formation throughout various times of a child’s development. Not only does maternal smoking affect the fetus, but paternal smoking also has a major impact on the risk of childhood leukemia (Liu, 2011). Evidence has been found to support the hypothesis of parental smoking being a causative agent of childhood leukemia, both ALL and AML subtypes. Numerous articles have been published demonstrating this association and they will be further discussed in this review.

In conducting the search for this topic, multiple databases were searched including PubMed, Medline, and Cochrane Library using the terms “childhood leukemia” and “parental smoking.” These searches resulted in an exhaustive list of findings including case-control studies, population-based studies, systematic reviews, and meta-analyses (see Appendix A, table 1). Studies that were done prior to 2010, focused on other risk factors of childhood leukemia such as radiation exposure or maternal alcohol or caffeine consumption, or that studied other types of childhood cancers were all excluded from the list of studies to be used (see Appendix A, table 2). Many of the articles were case control studies in which parental tobacco smoking was self-reported. Due to the limited willingness of mothers to disclose smoking habits during pregnancy, recall biases, and selective participation, case-control studies in which the data is self-reported is a weak method for statistical analysis (Heck, 2016). Due to the negative remarks made by society toward mothers who smoke while pregnant, mothers are less likely to report to doctors or interviewers the status of their smoking during pregnancy. These case-control studies resulted in a number of studies reporting no association between maternal smoking and the risk of childhood leukemia. Most of the articles that were found focused specifically on the effects of paternal smoking and the incidence of childhood leukemia. This is likely due to the reasons discussed previously regarding limited willingness to participate by women as well as the ignorance of fathers to realize the potential risk that smoking as a father can also lead to the development of various types of genetic mutations for their child.

Tobacco smoke is known to contain a mixture of at least 250 toxic or carcinogenic chemicals including benzene, formaldehyde, lead, arsenic, carbon monoxide and many others which cause damage to both somatic cells and germ cells during critical points of a developing fetus (Liu, 2011). Specifically, benzene has been shown to alter the blood-forming cells that occur in leukemia. According to an article by Matt and others (2011) that studied tobacco smoke, particles in tobacco smoke produce free radical species that permanently damage the cells causing a variety of issues including inhibiting apoptosis of the cancer cells and therefore increasing the risk of developing cancer. Additionally, smoking has been found to cause defects in sperm motility, morphology, and concentration which may account for the research that shows paternal smoking is associated with childhood leukemia (Matt, 2011).

In the research done by de Smith and others, they discussed how early exposure to tobacco smoke related to the frequently found gene mutations associated with childhood acute lymphoblastic leukemia (ALL). They found that childhood leukemia was directly associated with children exposed to parents that smoked cigarettes from the time prior to conception until after the child is born. This study represented a small sample size so the data they collected was not as significant as other studies that have been found. This study did find an association with the number of deletions and age at diagnosis. They confirmed that increased smoke exposure during child development increases the risk of childhood leukemia (de Smith, 2017). A study done by Metayer and others published in 2016 based their data off of 12 case-control studies. From those 12 studies, they found a correlation between paternal smoking, specifically, and childhood leukemia. As with all studies observed, they found that the risk between maternal smoking and childhood leukemia was mostly null. This is likely due to mothers not wanting to admit that they have smoked during pregnancy. Future research could involve studies that include only mothers that have been involved in a program that requires her to receive nicotine testing during each prenatal visit.

From the studies found throughout the search of parental smoking and incidence rates of childhood leukemia, it was concluded that smoking among parents does cause an increased risk of childhood leukemia. There are many case control studies that have shown a correlation between the incidence rates of childhood leukemia and whether either parent smoked during the first trimester as it is the most critical point in the pregnancy. A case control study collected data that suggested there is an increased risk of childhood ALL and AML if the fetus is exposed to tobacco smoke before and/or after birth. They also collected data reporting the incidence rates of the different subtypes of leukemia, including B-cell precursor ALL with either high hyperdiploidy or the translocation t (12;21). Metayer et al. (2013) concluded that combined exposure to tobacco smoking during pregnancy, including preconception and after birth, are associated with an increased risk of a child being diagnosed with ALL. They also found that these associations differed between subtypes of B-cell ALL. A table in this study showed consistency with the fact that ALL is more common than AML (figure 1). It also includes the child’s age at diagnosis, sex, and race, as well as the annual household income of the family, mother’s highest level of education, and father’s highest level of education (Metayer, 2013). While it is important to know the child’s age, sex, and race for genetic reasons, the other factors about the parents’ income and education were unnecessary to the question at hand.

In the study performed by de Smith and others published in 2017, they used bar graphs to compare the frequency of different subtypes of childhood ALL and how many deletions occurred. They also included data regarding the parents’ highest level of education and annual household income. This study included a table of the association between tobacco smoke exposure and the number of deletions in the child’s leukemia (figure 2). In this table, they included not only whether the parents smoked prior to conception, during the pregnancy, or after birth, but they also included whether the parent had ever smoked. This table was an important factor to include because while a person may have quit smoking years prior to conceiving, the damage to genes may have been done already. The human body is a remarkable being in that it can self-heal and regenerate certain cells, however, there are times in which the damage is too extensive, and the body is unable to reverse it. According to the p-values in this study, they found a correlation between tobacco smoke exposure and diagnosis in the following categories: maternal ever smoked, paternal and maternal smoking prior to conception, maternal smoking during pregnancy, child tobacco smoke exposure after birth, and maternal smoking while breastfeeding (de Smith, 2017).

According to Heck et al. (2017), the state of California began reporting maternal smoking information on the child’s birth certificate in 2007. In this population-based study, they collected this information and compared it to the association of maternal smoking during pregnancy and the incidence rate of childhood cancers. They point out that chemicals in tobacco readily cross the placenta and have been found in umbilical cord blood and fetal tissues. This is likely why a large portion of children who develop AML or ALL have parents that have smoked. They found a positive correlation for gliomas and retinoblastoma with maternal smoking during pregnancy, however, they were unable to determine a positive correlation with the diagnosis of childhood leukemia. They state that this may be due to the inconsistent reporting of maternal smoking on the birth certificates or to the complex pattern of smoking exhibited by women during pregnancy. Many women attempt to cut down or quit smoking while pregnant, but many times they relapse which likely caused a misrepresentation in the data. The lack of evidence may also be associated with competing risks such as miscarriage or the development of fatal birth defects. The authors of this study noted that with case-control studies that collect data via parental interview there is room for selective participation, recall biases, and a limited willingness to disclose smoking status (Heck, 2017).

A meta-analysis performed in Australia by Milne and others (2011), found that both the timing and dose of paternal smoking in particular are important in influencing risk of developing childhood ALL. They determined that the DNA in sperm can be damaged and permanently altered due to cigarette smoking, causing an increased risk of childhood leukemia. Although the sperm is altered, it is still able to function and reach the ovum to fertilize the egg leading to pathology of the offspring. A study found that sperm of smokers had higher levels of a dangerous chemical that is classified as a group I carcinogen and found in cigarette smoke (Milne, 2011). This study declared that there was no conflict of interest in performing the study, however they focused mainly on how paternal smoking plays a role in the development of childhood leukemia. The main author of this study was a woman; this can lead readers into believing that she wanted to focus on how men affect the risk of children developing childhood leukemia rather than women’s role in the problem.

After thoroughly reviewing the studies that were found, it was concluded that many studies are not reliable in that they do not represent the true number of parents who smoked during those three critical points of a child’s development: prior to conception, during pregnancy, and after birth (Metayer, 2013). This data is difficult to obtain however, due to the limited willingness of parents to participate in these types of studies. In order to obtain more accurate data, future studies could obtain results from routine salivary nicotine testing of the mothers whose child was diagnosed with leukemia. Although this testing would likely be cost inefficient, it may be possible if at each prenatal appointment, insurances required mothers, and possibly fathers, to have nicotine testing done throughout the span of the pregnancy. Insurances should take this risk to decrease incidence of childhood leukemia therefore reducing cost in the future. While doing this testing will not completely diminish childhood leukemia due to the many other etiologies of childhood leukemia, it is likely to significantly reduce the incidence rates. In the long-term, it will also prove to be less costly both for the insurance agencies as well as families affected by childhood leukemia because it will diminish the need for chemotherapy and other treatments for the cancer. This study performed by Metayer and others in 2013 had a rather large sample size of 767 cases of childhood ALL. With this large sample size, they likely collected relevant and true data that can be an important tool in the future of research on this topic. This same group of researchers continued with their findings in 2016 but focused more on how parental smoking correlates to the risk of developing AML.

A study by Liu et al. (2011), suggested that with a more defined time window in which smoking affects DNA alterations, fathers can be motivated to quit smoking, at least during that period alone. Providers could suggest ways to quit smoking and warn fathers about the likely dangers that smoking not only during the pregnancy, but when trying to start a family, will lead to for his unborn child. This would potentially reduce the incidence of childhood leukemia (Liu, 2011). With more studies like this producing similar results, these efforts can be effective in both mothers and fathers. Another meta-analysis by Milne et al. (2011), indicated that both the period during the pregnancy and how much the parent is smoking are important to the incidence of childhood leukemia, specifically ALL (Milne, 2011). Not a lot of the studies found in this research investigated the amount the parent or parents were smoking, which should be an important factor to investigate when analyzing the incidence rates of childhood leukemia in association with parental smoking habits. The final meta-analysis found concluded that paternal smoking increases the risk of childhood AML (Metayer, 2016). This is the only study in this research that found an association with smoking and this specific subtype of childhood leukemia. Cancer treatments are expensive and can last for years for each child who is diagnosed. By reducing the number of cases each year, it will eventually reduce the cost spent on treatments for childhood leukemia. Raising awareness of this topic is something that should be undertaken, as childhood leukemia is the number one diagnosed cancer in children under the age of fifteen. As a population, anything to reduce the incidence of childhood leukemia should be done so as to preserve the future of our population and avoid unnecessary suffering and ultimately deaths of children so innocent.

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