Birth Characteristics and Leukemia in Young Children

Peggy Reynolds1, Julie Von Behren1 and Eric P. Elkin2

1 California Department of Health Services, Environmental Health Investigations Branch, Oakland, CA.
2 Lewin Group, San Francisco, CA.


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The relation between birth characteristics and leukemia in young children was investigated in a large population-based study in California. Cases were obtained from the statewide cancer registry for 1988–1997. During this time, 1,957 leukemia cases were diagnosed among children under age 5 years. Of these, 1,728 (88%) were matched to a California birth certificate. Two control birth certificates, matched on date of birth and sex, were randomly selected from the statewide birth registry for each case. Analyses were performed separately for acute lymphoid leukemia (ALL) and acute nonlymphoid leukemia (ANLL). Odds ratios and 95% confidence intervals were estimated from conditional logistic regression. The strongest finding was for greatly increased risk of both types of leukemia in children with Down's syndrome (22 cases and no controls). African-American children had strikingly decreased risk for ALL (odds ratio (OR) = 0.29, 95% confidence interval (CI): 0.20, 0.42), and Asian/Pacific Islanders had increased risk for ANLL (OR = 2.00, 95% CI: 1.19, 3.36). Older maternal age was associated with slightly increased risk for ALL (maternal age >=35 years, OR = 1.25, 95% CI: 1.04, 1.52), although this odds ratio was somewhat reduced when adjusted for other factors. No strong relations were observed for birth weight and ALL or ANLL.

leukemia; lymphocytic; acute; leukemia; myeloid; leukemia; nonlymphocytic; acute

Abbreviations: ALL, acute lymphoid leukemia;; AML, acute myeloid leukemia;; ANLL, acute nonlymphoid leukemia;; CI, confidence interval;; odds ratio.


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Leukemia is the most common type of cancer diagnosed in children under age 14 years, comprising roughly a third of pediatric malignancies (1Go). The causes of these malignancies are poorly understood. The only well-established risk factors for childhood leukemia are intrauterine exposure to ionizing radiation, Down's syndrome, and certain other inherited disorders (2Go).

The peak in childhood leukemia incidence occurs between ages 2 and 4 years, which has generated a number of provocative hypotheses about the potential influence of perinatal factors. In particular, high birth weight has been reported to be associated with this disease in many (3GoGoGoGoGoGoGoGoGo–12Go), although not all (13GoGoGoGo–17Go), previous studies. Several of these studies have reported that high birth weight is most strongly related to leukemia risk in children diagnosed in the first few years of life (Go, GoGoGo, 10Go). One interesting hypothesis offered to explain this finding is that high birth weight may be related to production of insulin-like growth factor in the infant, which may stimulate the growth of myeloid and lymphoid cells (18Go).

Parental age has not been found to be related to leukemia risk in most studies (2Go). Being the firstborn child was reported as a potential risk factor for leukemia in some early studies (17Go, 19Go), but most recent investigations have not confirmed this finding (2Go). Birth order and number of siblings may be proxy measures for exposure to infections in early childhood. An infectious etiology for childhood leukemia has been postulated by several authors (20GoGo–22Go). Kinlen (20Go) proposed that childhood leukemia is a rare manifestation of infection, which may be introduced to a previously isolated rural community by sudden in-migration. Another hypothesis is that exposure to infections in immunologically isolated children causes rapid proliferation of lymphoblastic progenitor cells, increasing the chance of a spontaneous mutation, which can lead to cancer (21Go).

Because of increasing interest in the role of perinatal factors in the etiology of early childhood leukemia, this study was undertaken to take advantage of information available from California's large and well-established population-based cancer registry along with details historically recorded on the California birth certificate. The examination of risk relations for these rare outcomes in such a large population provided opportunity for a more detailed examination of factors for the major leukemia subtypes as well as a greater opportunity to consider the pattern of risk in a more ethnically diverse population than has been reported in most studies.


    MATERIALS AND METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Selection of cases and controls
Information on childhood leukemia cases was obtained from the statewide, population-based cancer registry (the California Cancer Registry). A total of 1,957 leukemia cases were diagnosed in children under age 5 years between 1988 and 1997. Using probabilistic record linkage (23Go, 24Go), 1,728 (88 percent) of these cases were matched to a California birth certificate (birth years, 1983–1997). Two control birth certificates, matched on date of birth and sex, were randomly selected for each case. Control births were selected from mothers who were California residents at the time of the birth to be consistent with case selection criteria. The birth certificates of the controls were then matched to the California birth cohort files, which contain linked birth and death records for infants in the first year of life. Controls who died in infancy were replaced only if their death occurred at an age younger than the corresponding case's age at diagnosis. Twenty-two controls who died in the first year of life were excluded and replaced by the next eligible certificate of a livebirth in the file (again matched for birth date and gender). Two controls were later dropped because we determined that the maternal addresses were not California locations. Use of these files for this project was approved by the California Health and Human Services Agency Committee for the Protection of Human Subjects.

Birth certificate information
The birth certificates contained demographic information on the parents, including age, race, and Hispanic ethnicity. The educational level of each parent was added to the California birth certificate in 1989. For the birth years for which this information was available, a household education variable was constructed for this study based on the highest level of education of the mother or father. Maternal pregnancy history was also available, including the number of pregnancies, livebirths, pregnancy losses (spontaneous abortions and stillbirths), and time since last livebirth. Information was available about prenatal care and delivery method (vaginal or cesarean). Infant data included gender, date of birth, race/ethnicity, singleton or multiple birth, birth weight, and gestational age. The birth certificate also contained information about complications during pregnancy and delivery, as well as abnormal conditions present in the infant (such as Down's syndrome). The numbers of missing values are shown in tables for factors for which at least 1 percent of the cases or controls had missing information. The range of missing values was 0 percent for single/multiple birth to 8.9 percent for father's age.

Statistical analysis
To take into account the matched nature of the cases and controls, univariate odds ratios and 95 percent confidence intervals were calculated from conditional logistic regression models. Multivariate conditional logistic regression models included all variables with odds ratios for which the confidence intervals excluded one in the univariate analyses. The multivariate models were restricted to those case-control sets in which the case and at least one control were singletons without indication of Down's syndrome. Multiple births and Down's syndrome could influence birth weight and leukemia risk, yet they occurred too infrequently to provide stable estimates of risk in multivariate models. Subjects with missing values were excluded from the logistic regression models.

Analyses were performed separately for cases of acute lymphoid leukemia (ALL) and their controls, acute nonlymphoid leukemia (ANLL) and their controls, and acute myeloid leukemia (AML) and their controls. Because results were so similar for ANLL and AML (AML constituted 68 percent of ANLL cases in these children), results for ANLL are presented in tables, and key results for AML are summarized in the text. All analyses were performed in SAS, version 7.0 (25Go).


    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
ALL
There were 1,407 cases of ALL successfully matched to California birth certificates. In univariate analyses, there was a slight excess of ALL in children born to mothers aged 35 years or older (odds ratio (OR) = 1.25, 95 percent confidence interval (CI): 1.04, 1.52) (table 1). No differences between cases and controls were observed for high birth weight (>=4,000 vs. 2,500–3,999 g, OR = 1.09, 95 percent CI: 0.90, 1.31) or later gestational age (>=42 vs. 37–41 weeks, OR = 1.00, 95 percent CI: 0.80, 1.25). Putting terms for both gestational age and birth weight into the same model did not appreciably change these point estimates. Infants born more than 7 years after a previous birth had a somewhat increased risk of ALL (OR = 1.23, 95 percent CI: 0.97, 1.56). In an analysis of births after 1988, increased risk of ALL was observed for children born to more highly educated parents (OR = 1.34, 95 percent CI: 1.07, 1.68 for college graduates compared with those parents who did not graduate from high school).


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TABLE 1. Unadjusted analysis of birth certificate characteristics in relation to early childhood acute lymphoid leukemia cases and controls, California, 1987–1997

 
Some birth certificate characteristics appeared to be inversely associated with ALL, including non-Hispanic Black race/ethnicity (OR = 0.29, 95 percent CI: 0.20, 0.42 compared with non-Hispanic Whites) and late prenatal care (OR = 0.79, 95 percent CI: 0.68, 0.93).

There were nine ALL cases and no controls with an indication of Down's syndrome on the birth certificate. There was no evidence for multiple birth increasing the risk of ALL, nor were there any differences for maternal parity.

A multivariate conditional logistic regression model was run that included maternal age (>=35 vs. <35 years), infant race/ethnicity (categories collapsed as Black vs. not Black), and prenatal care (table 2). Point estimates were similar to those from univariate models. Black infants had a greatly decreased risk of ALL compared with other children (adjusted OR = 0.31, 95 percent CI: 0.22, 0.45). The OR for older maternal age was 1.19 (95 percent CI: 0.98, 1.45), and the OR for late prenatal care was 0.81 (95 percent CI: 0.69, 0.95). The same model was run for the 1989–1997 births only, with terms for parental education. The OR for college-educated parents was 1.24 (95 percent CI: 0.97, 1.59) compared with parents who did not graduate from high school. However, differences in the education effect were observed between males and females. When the model was stratified by gender, the OR for boys of college-educated parents was 0.91 (95 percent CI: 0.66, 1.25), whereas the OR for girls was 1.91 (95 percent CI: 1.29, 2.81). In the same stratified models, gender differences were also observed in the maternal age odds ratios. For boys, the adjusted OR for maternal age (>= 35 vs. <35 years) was 1.47 (95 percent CI: 1.08, 2.01), and the OR for girls was 0.93 (95 percent CI: 0.64, 1.35). No gender differences were observed for birth weight.


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TABLE 2. Adjusted analysis of selected birth certificate characteristics in relation to early childhood acute lymphoid leukemia, California, 1987–1997

 
We tested for interactions between race and the other birth characteristics. No statistically significant interactions were observed (data not shown). Because age at onset also serves as a marker for heterogeneity of disease within ALL, we also examined birth characteristics stratified by the case's age at diagnosis as less than 2 and 2–4 years (table 3). No increased risk for birth weight was observed for either age group. Young maternal age appeared to decrease risk for ALL in the youngest cases, while older maternal age was a risk factor in the age group 2–4 years. The increased risk observed for high level of parental education appeared to be present for the older cases only. Most other factors showed little difference between the two groups. Of the nine cases of Down's syndrome that occurred among ALL cases, one occurred among the cases diagnosed under age 2 years, and the remaining eight cases occurred among those aged 2–4 years.


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TABLE 3. Unadjusted analysis of birth certificate characteristics in relation to early childhood acute lymphoid leukemia cases and controls, stratified by age, California, 1987–1997

 
ANLL
A total of 240 cases of ANLL were included in the study. In the univariate analysis, Asian and Pacific Islander children were at an increased risk of developing ANLL (OR = 2.00, 95 percent CI: 1.19, 3.36 compared with non-Hispanic White infants) (table 4). In addition, children born to fathers aged 35 years or older appeared to be at increased risk of ANLL (OR = 1.57, 95 percent CI: 1.06, 2.33). Increased risk of ANLL was seen among mothers with more than two previous livebirths (OR = 1.59, 95 percent CI: 1.00, 2.53). Furthermore, those infants born more than 7 years after a previous livebirth were at increased risk (OR = 1.64, 95 percent CI: 0.91, 2.96). Postmature infants were at decreased risk, with an OR of 0.56 (95 percent CI: 0.31, 1.01). Putting terms for both gestational age and birth weight into the same model did not appreciably change this point estimate. Because of the much smaller number of ANLL than of ALL cases, we reduced the number of education categories from three to two. Among births that occurred after 1988, children in households with higher educational levels were at somewhat higher risk of ANLL (OR = 1.54, 95 percent CI: 0.98, 2.42 for high school graduates vs. less than high school).


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TABLE 4. Unadjusted analysis of birth certificate characteristics in relation to early childhood acute nonlymphoid leukemia cases and controls, California, 1987–1997

 
There were 13 cases of ANLL and no controls with an indication of Down's syndrome on the birth certificate. Only three cases of ANLL and eight controls were part of a multiple birth.

A multivariate conditional logistic regression model was fit that included father's age (>=35 vs. <35 years), child's race (Asian/Pacific Islander compared with all others), number of previous livebirths, and gestational age (table 5). Although the confidence interval included one, decreased risk of ANLL was suggested for late gestational age (adjusted OR = 0.54, 95 percent CI: 0.27, 1.08) and increased risk for Asian race/ethnicity (adjusted OR = 1.73, 95 percent CI: 0.99, 3.02). Adding birth weight to this model, a factor strongly related to gestational age, did not change these results.


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TABLE 5. Adjusted analysis of selected birth certificate characteristics in relation to early childhood acute nonlymphoid leukemia, California, 1987–1997

 
Another model was run for the 1989–1997 births only that included terms for parental education (as high school graduate vs. not a high school graduate) as well as father's age, child's race as Asian/Pacific Islander (compared with others), number of previous livebirths, and gestational age (as >=42 compared with others). The odds ratio for high school graduate parents was 1.45 (95 percent CI: 0.84, 2.50) compared with parents who did not graduate from high school. However, as with ALL, differences in the education effect were observed between males and females. When the model was stratified by gender, the OR for boys with high school graduate parents was 0.98 (95 percent CI: 0.44, 2.15) whereas the OR for girls was 2.03 (95 percent CI: 0.93, 4.45).

AML
AML is a subset of the ANLLs, comprising the majority of ANLL cases in children. When analysis was restricted to only those 164 children diagnosed with AML and their controls, the results were very similar to the analysis for all types of ANLL. In a univariate analysis, Asian and Pacific Islander children had an elevated risk for AML (OR = 1.89, 95 percent CI: 1.02, 3.47) compared with non-Hispanic White infants. In addition, the risk for older paternal age was still increased in the AML diagnostic group (age >=35 vs. 20–34 years, OR = 1.65, 95 percent CI: 0.99, 2.74). Higher parity and longer time since last livebirth also showed some elevated risk (OR = 1.85, 95 percent CI: 1.04, 3.31 for >=3 vs. 1–2 previous births and OR = 1.56, 95 percent CI: 0.77, 3.17 for >=7 vs. <7 years since last livebirth). As with ANLL, both low- and high-birth-weight infants had a decreased risk of developing AML when compared with infants who weighed 2,500–3,799 g (OR = 0.61 and 0.73, respectively). Odds ratios were also reduced for premature (OR = 0.84, 95 percent CI: 0.42, 1.69) and postmature (OR = 0.60, 95 percent CI: 0.29, 1.23) infants when they were compared with infants born between 37 and 41 weeks gestation. Firstborn children were at decreased risk (OR = 0.64, 95 percent CI: 0.42, 0.96). Risk was elevated for infants born to parents who graduated from high school compared with nongraduates (OR = 1.36, 95 percent CI: 0.80, 2.30). Eight AML cases had an indication of Down's syndrome on their birth certificate compared with none of their controls.


    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
This large, population-based study provided a rich opportunity to evaluate the mixed evidence from the literature on suggested risk relations between birth characteristics and childhood leukemia. In particular, the large sample size provided an opportunity to examine reasonably stable point estimates for risk factors that may be of great interest and have been inconsistently reported in the past. Additionally, these relations could be examined by leukemia subtype. The strongest risk relation observed in the study was for Down's syndrome, particularly for children with ANLL. This genetic condition, although rare, has been the most consistently reported risk factor for leukemia in the literature.

A notably null association was observed for high birth weight and early childhood leukemia. Many previous studies have reported high birth weight as a risk factor, especially in young children (3GoGoGoGoGoGoGoGoGo–12Go). Our study is not alone, however, in reporting the lack of an association with birth weight (14GoGoGo–17Go) and is consistent with generally null associations reported in two earlier California studies (13Go, 26Go). In the 1971 mortality study by Fasal et al. (26Go), higher birth weight appeared to be a risk factor only for a subgroup of female children of older mothers with a high socioeconomic status. We did not observe a difference in the birth weight effect for boys and girls, nor did we see an elevation in the same subgroup of girls. Among the positive birth weight studies, two include small overlapping case series from Minnesota hospitals (3Go, 5Go), but many represent large, population-based samples both from Europe (8Go, 12Go) and the United States (6Go). The Swedish studies conducted by Cnattingius et al. reported positive associations for ALL (12Go), but not for AML (16Go), and no association in an overlapping earlier subset of the cases in the paper by Zack et al. (14Go). Because Ross et al. (18Go) have reported that high birth weight is a risk factor for leukemia in infants, we also examined the risk for high birth weight (>=4,000 g) in the 139 leukemia cases in our data diagnosed before age 1 year. Based on this small subset of cases, the point estimate was close to one (OR = 0.84, 95 percent CI: 0.43, 1.64). We also saw no evidence of a risk association when we examined birth weight for broader subgroups of age.

Because previous studies of leukemia and birth weight have focused primarily on Caucasian children, the racial/ethnic diversity of the California population is of particular interest for this association. Differences in birth weight exist between ethnic groups in California, even after controlling for the many known risk factors for low and high birth weight (27Go). We examined the data for interaction effects between birth weight and race/ethnicity on our data but did not find any. There is no evidence from these analyses that the lack of a birth weight effect is explained by the different racial/ethnic mix of our study population. Infants with a late gestational age, independent of birth weight, were at decreased risk of ANLL compared with infants born at term, even when adjustment was made for race/ethnicity and paternal age. This finding is perplexing. It should be noted that only 17 cases were born at more than 41 weeks gestation so this observation is based on small numbers.

In our study, ALL risk was slightly elevated for the children born to mothers over age 35 years. The odds ratios for ANLL were also elevated for older maternal age. Older paternal age was also associated with increased risk for ANLL, although the confidence interval included one when adjusted for race and gestational age. Many of the earliest epidemiologic studies of childhood leukemia found increased risk with older maternal age (17Go, 26Go, 28Go). The maternal age effect has also been observed in a few of the more recent studies (3Go, 8Go, 29Go). However, several other studies have reported no significant differences in maternal ages between cases and controls (9Go, 10Go, 12Go, 14GoGo–16Go).

Just as maternal age was found to be associated with increased risk of leukemia in earlier studies but not in later ones, firstborn children were reported to be at increased risk in the earliest reports (17Go, 19Go, 30Go) but not in many subsequent studies (3Go, 9Go, 12Go, 13Go, 16Go). In our study, neither firstborn nor later born children were at increased risk for ALL. For ANLL, we observed increasing risk with increasing birth order, but these point estimates were based on small numbers of cases (n = 40). Similarly, Ross et al. (10Go) found that later-born children had increased risk for infant AML, but not for ALL.

California's ethnically diverse population provided a chance to examine the risk for leukemia by race and Hispanic ethnicity. For ALL, a large deficit of cases in Blacks was observed, consistent with national incidence data for childhood leukemia (1Go). This deficit in African Americans was not observed for ANLL. We did not see any difference in leukemia risk between non-Hispanic Whites and Hispanics. Incidence rates for childhood leukemia have been reported to be higher in California Hispanics, but the increase was noted only in children aged 5–14 years (31Go). Asian infants had a twofold increased risk for ANLL in our study. A report from Hawaii also noted higher incidence of childhood ANLL among some Asian and Pacific Islander groups compared with Whites (32Go). National incidence data are not readily available by detailed race/ethnicity for comparison.

The risk of leukemia appeared to be elevated in children born to parents with a higher level of education. However, for both ALL and ANLL, the point estimates for education were reduced when controlling for other factors such as race. Later initiation of prenatal care, which may be considered a proxy for lower socioeconomic status, was associated with decreased ALL risk. These factors provide some support for a weakly positive association between leukemia and high socioeconomic status, but also suggest that the relation may be complex.

This analysis was a records-based study with information restricted to that available from the birth certificates. While this represents an advantage because all eligible subjects could be included for study, it also presents a disadvantage because information was limited to that available from public records. Some potentially important risk factors, such as smoking, were not available on the California birth certificate. Furthermore, educational data were available only for more recent years.

The data on birth certificates may not always be accurate or may be nonrandomly missing. We examined the percent of missing data for each factor of interest during the study years and found a high level of completeness for most data elements. For example, maternal age was available for all subjects, and birth weight information was available for all but one child. Most missing data were on paternal factors. A total of 8.9 percent of the births were missing information on father's age. We also examined the percent of missing data for the factors of interest by race/ethnicity group. Most factors did not vary substantially by race/ethnicity, but the birth certificates for non-Hispanic White children had less missing data on father's age and education than the other race groups. Certain data elements such as complications during pregnancy and delivery and abnormal conditions present in the infant, including Down's syndrome, are most likely incompletely reported. On the other hand, the accuracy of birth certificate data may be quite high for some factors of interest, such as birth weight and race. Birth weight is measured and recorded at the time of the birth. A recent analysis of the validity of race and Hispanic ethnicity information on the California birth certificate found that the information is a valid measure for all groups except Native Americans (33Go). Data on other birth characteristics, such as gestational age (34Go) and birth defects (35Go), have not been reported to be as reliable.

One of the major advantages of this study was that the controls were randomly selected from state birth files rather than from recruited volunteers as in most case-control studies. In addition, the use of vital records eliminates the problem of recall bias because the data were not self-reported after a diagnosis of leukemia. The cases were drawn from the statewide population-based cancer registry that has an estimated 99 percent completeness of ascertainment (36Go). Although the cases were limited to children both diagnosed and born in California, which would exclude highly mobile subjects, it included a very high proportion (88 percent) of all cases occurring in this young segment of the population. The cases that were not matched to a California birth certificate were somewhat more likely to be Hispanic than were the matched cases (43 percent Hispanic among matched cases vs. 47 percent among the unmatched cases). The proportions of Blacks and Asians were very similar. An additional advantage of this study was the opportunity to examine risk relations by leukemia subgroup. The strikingly different risk associations for some factors are consistent with the notion of different etiologies for these diseases.

The literature to date contains conflicting findings on childhood leukemia and birth characteristics. These inconsistencies may be due to the varying sample sizes, racial/ethnic differences in study populations, methodological artifacts of case and control selection procedures, and the combining of the two major subtypes of leukemia. This study provided a large sample size with analysis by leukemia subtype, an ethnically diverse population, and equivalent data collection for both cases and controls.


    ACKNOWLEDGMENTS
 
Funded by grant R01 CA71745 from the National Cancer Institute.

The authors thank the staff of the California Cancer Registry and the staff of the Office of Vital Records. Ceciley Wilder and Theresa Saunders assisted with manuscript preparation.


    NOTES
 
Reprint requests to Dr. Peggy Reynolds, Environmental Health Investigations Branch,1515 Clay Street, 17th Floor, Oakland, CA 94612 (e-mail: preynold{at}dhs.ca.gov).


    REFERENCES
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 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
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Received for publication April 16, 2001. Accepted for publication October 2, 2001.