1 Department of Social and Preventive Medicine, University at Buffalo, State of New York, Buffalo, NY.
2 Department of Pediatrics, Roswell Park Cancer Institute, Buffalo, NY.
3 Present address: Department of Physical Medicine and Rehabilitation, State University of New York Upstate Medical University, Syracuse, NY.
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ABSTRACT |
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case-control studies; child day care centers; infection; leukemia, lymphocytic, acute; schools, nursery
Abbreviations: ALL, acute lymphoblastic leukemia; SD, standard deviation
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INTRODUCTION |
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Kinlen postulated that mixing of immunologically isolated populations with newcomers has resulted in increases in ALL due to changes in the population dynamics of infectious diseases (38). Leukemia may be a rare response to a common infection (38
48
).
Another theory regarding the role of infectious agents in childhood ALL was developed by Greaves (4951
), who postulated that two separate genetic events may be responsible for the development of early B-lineage-derived ALLs. The first event occurs spontaneously in utero during the expansion of B-cell precursors. The second occurs in the same mutated clone following antigenic challenge in the first few years of life. Greaves theorized that children who have an abnormal pattern of common infectious disease acquisition, particularly delays in early exposure, may experience greater cell proliferation following infection, leading to an increased probability of a second mutation and childhood ALL (50
, 52
). This theory also is compatible with the view that leukemia may be a rare response to common infection(s) (53
, 54
).
The timing of infectious diseases in early childhood is influenced by several factors, including child-care practices, breastfeeding, birth order, maternal age, education, and other socioeconomic factors (49, 50
, 53
, 54
). We attempted to test Greaves' hypothesis concerning delays in the timing of infectious diseases in the first few years of life by examining several prenatal and early childhood factors in the development of ALL. Results from the analyses of day-care and preschool attendance prior to kindergarten or first grade are the focus of this report; attendance at programs outside the home was used as a measure of exposure to infectious agents, since infections have been shown to occur with greater frequency among children in day care (55
57
).
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MATERIALS AND METHODS |
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Potential cases included 400 children less than 15 years of age diagnosed with histologically confirmed ALL between January 1980 and December 1991. Cases were diagnosed at Children's Hospital of Buffalo, Roswell Park Cancer Institute (Buffalo), Strong Memorial Hospital (Rochester), and the State University of New York Upstate Medical University (Syracuse). Potential cases were identified by using the institutional tumor registries and department or section of pediatric hematology-oncology records. Eighty-eight percent of the cases of childhood ALL from the 31-county region reported to the New York State Cancer Registry between 1980 and 1987 were diagnosed at one of these four institutions (Martin Mahoney, New York State Department of Health, personal communication, 1991).
Potential controls included 1,563 randomly selected livebirths from the 31 counties served by the four cancer referral centers. Controls were frequency matched to cases at a 4:1 ratio on sex, race, and birth year, and they were identified through the Live Birth Certificate Registry maintained by the New York State Department of Health. Human subjects approval was granted by the University at Buffalo, the New York State Department of Health, and each of the four medical centers providing cases.
Data collection
Data were collected by using an eight-page, self-administered questionnaire that was mailed to the parents of cases and controls. Topics covered in the 32 multipart questions included demographic and socioeconomic indicators, birth characteristics, maternal pregnancy exposures, early childhood exposures, maternal reproductive history, and family history. A pretest of the instrument found a mean completion time of 28.5 (standard deviation (SD)), 14.8) minutes.
The mailing strategy followed a modified version of the Total Design Method (59), with four mailings from mid-November 1995 to early January 1996. Addresses were verified before the questionnaire was distributed by checking the most recent medical record listing (cases only), birth certificate listing (controls only), telephone and city directories, and motor vehicle records and by using licensed software to search the credit bureau.
Ninety percent (359/400) of cases and 88 percent (1,371/1,563) of potential controls were found to be eligible and to have valid addresses (i.e., questionnaires not returned by the post office). Reasons for case ineligibility included physician refusal (n = 4) and adoption (n = 6). Adopted children were excluded since data on prenatal exposures, maternal reproductive history, and family history were unavailable for these children. Eight percent (n = 31) of potential cases could not be located. Four controls were found to be ineligible: one was a case, the second was a sibling of a case, the third was a child of a case, and the fourth had acute myelogenous leukemia. Twelve percent (n = 188) of potential controls also could not be located despite the multifaceted tracing strategy used. Parents of 71 percent (255/359) of cases and 55 percent (760/1,371) of controls responded to the series of four mailings.
Operational definitions
Study participants were from several racial groups and were defined as Whites and non-Whites (i.e., African Americans, Asians, and American Indians) in the analyses. Socioeconomic status indicators included family income, maternal education, and maternal employment during the index pregnancy. Income and education data were collected from 1994, rather than at the time of the index child's birth, since the range of birth years extended from 1966 to 1990; income data from the earlier years of the study would not have been comparable to data from the latter study period. Maternal education was defined as the highest number of years of completed schooling. Maternal employment (yes/no) included both full- and part-time work at any time during the index pregnancy.
Maternal age (in years) at the birth of the index child was calculated from the mother's reported date of birth and the date of birth of the index child. The birth order of the index child was determined from the dates of birth of the index child and all siblings born to the same mother. Three percent of the index families (28/1,015) reported adopted siblings or stepsiblings, who were not included in the birth order tabulation since data concerning the timing of adoptions, divorces, and second marriages were not collected.
Infant feeding at birth was categorized as exclusively bottle (formula or cow's milk), exclusively breast, or a combination of breast milk and bottle. Duration of breastfeeding was collected in weeks or months (conversion to weeks was calculated as four times the number of months, plus one for each 3-month period). The total duration of breastfeeding (in weeks) was used as a covariate in these analyses.
Data were collected on day-care and nursery-school experiences before kindergarten or first grade. The types of care or programs included were attendance at a day-care center; day care in someone's home (called family-run day care); nursery school; or staying at home with a parent, grandparent, or baby-sitter. The number of hours of attendance per week, the number of children in the class, and the duration of attendance (in months) were collected for up to six care experiences per child. Separate care experiences included a change of room within one facility (e.g., moving from the infant room to the toddler room), a change from one type of program to another (e.g., attending a day-care center and then attending nursery school only), or a change from one day-care program to another (e.g., attending three different family-run day-care homes before age 6 years). Attendance at "a mix of facilities" included sequential care in different types of programs and concurrent attendance at more than one program. Duration of care for children attending concurrent programs was counted once.
Early childhood day-care and preschool experiences for both cases and controls were censored at the age at diagnosis, since child-care practice prior to the onset of leukemia was the exposure of interest. The age at diagnosis among cases was defined as the age at which the first bone marrow biopsy occurred. Controls (n = 1,563) were assigned an age at diagnosis based on the frequency distribution of the age at diagnosis and the birth years of the 400 cases. A reference date at diagnosis also was tabulated for controls from the assigned age at diagnosis (60). The mean age at diagnosis among the cases was 5.6 (SD, 3.6) years compared with 5.8 (SD, 3.7) years among the controls (p = 0.20).
Infectious disease history prior to age 2 years was collected for colds, otitis media, pneumonia, influenza, croup, bronchiolitis, vomiting, and diarrhea. Data concerning the occurrence of chickenpox, measles, mumps, rubella, or fifth disease before kindergarten or first grade also were collected.
Immunophenotype data were collected from the pathology and/or Pediatric Oncology Group reports in the charts of the 400 cases. Since the technique of immunophenotyping was evolving over the period when cases were diagnosed, some variability was noted both within and among institutions in the reporting of immunophenotype; more detailed reports were observed during the latter part of the study period than in the earlier years. Consequently, these data were categorized as B-lineage-derived ALLs (including early pre-B, pre-B, precursor B, not otherwise specified, or B-cell ALL) and T-cell ALL.
Statistical analyses
Statistical analyses were performed by using SPSS PC+ software (61). Descriptive comparisons included two-sided Student's t test for continuous variables and Pearson's chi-square test for categorical variables. In these comparisons, a p value of
0.05 was considered statistically significant.
Unconditional logistic regression modeling was used to calculate unadjusted and adjusted odds ratios and 95 percent confidence intervals. Tests for linear trend in the duration of care were performed by using the continuous version of the variable (in months). Analyses were conducted for the entire sample and after exclusion of the 35 cases with T-cell ALL, since the delayed-infection hypothesis is specific to B-lineage-derived ALL (49, 50
, 54
).
In the logistic regression models, duration of outside care (in months) was divided into four categories: children who stayed at home, 1 week to 18 months of outside care, 1936 months of care, and >36 months of care. The referent category was attendance at an outside program for >36 months. Covariates included in the adjusted models were maternal age at birth of the index child (years), maternal education in 1994 (years), maternal employment during the index pregnancy (yes/no), total duration of breastfeeding (weeks), birth order of the index child (19
), and birth year. Maternal education rather than income was used as a measure of socioeconomic status since education varies less over one's lifetime than do other socioeconomic status indicators (62
). In addition, income data were missing for approximately 10 percent of cases and controls.
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RESULTS |
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Cases and controls differed little with respect to number of hours per week in attendance or number of children in a class for a specific type of program (censored data shown in table 3). In addition, no differences were noted for these two measures of child care following exclusion of the 35 cases with T-cell ALL (data not shown). The mean duration of care (in months) was similar for cases and controls attending either nursery school only, a day-care center, or a family-run day-care home (table 3). Among children attending a mix of programs, duration of attendance was shorter for cases than for controls: 21.6 (SD, 7.9) months versus 32.4 (SD, 15.0) months, respectively. Nonetheless, the total duration of attendance at any outside program did not differ between cases and controls; the mean duration among cases was 20.1 (SD, 15.0) months compared with 22.4 (SD, 15.4) months among controls (p = 0.18).
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In the logistic regression models examining duration of outside care (table 5), increased odds ratios were observed for decreased duration; however, the confidence intervals included 1. Exclusion of the 35 cases with T-cell ALL resulted in a similar pattern of risk but an increase in the observed point estimates. The highest risk estimates observed were for children with 1 week to 18 months of care rather than for those who stayed home.
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DISCUSSION |
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In the censored analyses in which duration of care was assessed, we found that approximately 60 percent of participants were in the stay-at-home category, 20 percent were in the 118-month category, 13 percent were in the 1939-month category, and 7 percent were in the referent category>36 months of care. The small sample sizes in the categories of longer duration of care resulted in unstable risk estimates and wide confidence intervals in these models and may account, in part, for the weak pattern of risk found.
Day-care and nursery-school attendance were used as a measure of exposure potential to infectious agents. Common childhood infections were reported less frequently in both cases and controls who stayed home before age 2 years than in children attending an outside program. Staying at home, however, is not synonymous with isolation from infectious agents; neighbors, friends, and family members could serve as sources of exposure to bacterial and viral illnesses. The weak risk for those who stayed at home may reflect the approximate nature of day-care and preschool attendance as a measure of exposure to infectious diseases.
Data were not collected concerning the reasons for choosing to send a child to an outside program or to keep the child at home. The finding that children who stayed home had fewer episodes of common illnesses argues against illness as the reason for keeping the child at home.
Although categorized as a single entity, the stay-at-home group probably represented a mix of socioeconomic levels and at-home child-care strategies (e.g., two working parents who take turns caring for children, two working parents with a baby-sitter or relative who cares for children, families in which one parent is employed and one stays home). While socioeconomic variables (maternal education and employment) and potential confounders (maternal age, birth order, breastfeeding, and birth year) were included in the duration of care models, residual confounding may still have been present. The other categories of duration of care also might have consisted of a heterogeneous mix of socioeconomic levels; however, these categories included fewer participants represented by a single adjusted odds ratio.
Children with an ALL-related infection or symptom of ill health prior to diagnosis may have missed day care or preschool for several days, which may or may not have necessitated a change in child-care arrangements before diagnosis (e.g., child withdrawn from program). Nonetheless, child-care histories were censored at the age at which the first bone marrow biopsy occurred for cases and an equivalent age for controls; the mean duration of symptoms prior to the diagnostic bone marrow was brief, 20.5 (SD, 16.6) days. While use of an earlier event for censoring would take into account at least part of the latency period for ALL, selection of a suitable censoring event is not straightforward. Subtracting a set number of months from the date of diagnosis would result in disproportionately shorter exposure periods for children diagnosed at younger ages and may not be an appropriate method. In addition, the length of the latency period is unknown.
Use of the age at which symptoms appear as the censoring event would take into account part of the latency period; however, the symptoms of ALL are nonspecific and mimic a variety of nonmalignant conditions such as aplastic anemia and juvenile rheumatoid arthritis (6464). This age also is subject to parental recall, parental perception of a symptom, and the importance of the symptom to the child's health. Analyses conducted by using age at symptoms as the censoring event revealed a pattern of risk similar to that seen when age at diagnosis was used as the censoring event (data not shown). The strength of the odds ratios was similar as well (data not shown). As with age at diagnosis, controls were assigned an age at symptoms on the basis of the distribution of the age at symptoms among cases.
Another potential limitation of this study is misclassification of the exposure measures. Duration of care may have been misclassified since the details of child-care arrangements many years earlier would be difficult to recall, especially if there were several children in the family. Families of cases and controls would be subject to the same lengthy period of recall. Observed differences between types of programs with regard to the hours per week in attendance, the number of children in a class, and the duration of overall attendance are consistent with descriptions of nursery school and day care in the United States for comparable time periods (57, 65
). These similarities lend credibility to the measures of day care and preschool used in this study. It is unlikely that parents of cases and controls would differentially recall the duration of out-of-home care but not the number of children or the hours per week in attendance. In addition, published reports concerning the role of child-care practices in childhood ALL are limited; consequently, parents of cases would be less likely than parents of controls to associate day care with the development of leukemia and to recall these experiences differently.
Response bias is another potential limitation of this study. White parents were twice as likely as non-White parents to respond, and non-Whites were three to four times more likely to be among those who could not be located (p < 0.001 for the families of both cases and controls). Parents of older index children were more difficult to locate, particularly among controls (p < 0.001). Nevertheless, non-White and White mothers who responded had similar mean educational levels in this study. In a recent Children's Cancer Group leukemia study, responding parents of cases also were significantly more likely to be White and married; parents of controls were more likely to be White and to have a higher educational level and more children aged less than 10 years (6666).
Response bias could have influenced day-care results if nonrespondents differentially used early childhood programs in comparison to respondents. In our study, women with a high school education or less were more likely than more-educated mothers to stay home with their children. The same pattern was observed for White and non-White respondents and for cases and controls. As income increased, mothers also were less likely to stay home or use a part-time nursery school program and were more likely to use some form of day care. Again, these patterns were similar for cases and controls and for Whites and non-Whites. Response bias may have reduced the heterogeneity of the sample but appears to have done so in a similar manner for cases and controls and for Whites and non-Whites.
In summary, our results do not support the hypothesis that delays in the acquisition of childhood infectious diseases associated with infrequent peer contact may be associated with childhood ALL (4951
, 53
, 54
). Additional work by other investigators would be helpful in clarifying the role of early out-of-home care and infectious disease exposure in childhood ALL.
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ACKNOWLEDGMENTS |
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The authors thank Drs. Barbara Asselin (Strong Memorial Hospital) and Ronald Dubowy (Upstate Medical University) for providing access to their acute lymphoblastic leukemia patients. Dr. Philip C. Nasca provided helpful advice with regard to study design and facilitated implementation. In addition, many thanks to Dr. Mark S. Baptiste and the staff of the New York State Cancer Registry for tracing study participants.
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NOTES |
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REFERENCES |
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