Abstract

Background In 2002, a poster alerted the French health authorities to the possibility that the risk of childhood leukaemia might be increased by hepatitis B vaccination. Elucidating the role of vaccination in the aetiology of childhood acute leukaemia (AL) was therefore included in the objectives of an ongoing national study.

Methods The ESCALE study was a French national population-based case-control study conducted in France in 2003 and 2004 in order to investigate the role of infectious, environmental and genetic factors in four childhood neoplastic diseases (leukaemia, lymphoma, neuroblastoma and brain tumour). The controls were randomly selected from the French population and age and gender frequency matched with the cases. A total of 776 cases of AL (91% of the eligible cases) and 1681 controls (71% of the eligible controls) were included. In a specific standardized telephone interview, which was the same for both the cases and controls, each mother was asked to read out her child's complete vaccination record.

Results No association between vaccination and the risk of childhood AL: acute lymphoblastic leukaemia or acute myeloblastic leukaemia was observed. No relationship between the risk of leukaemia and the type of vaccine, number of doses of each vaccine, total number of injections, total number of vaccine doses or number of early vaccinations was evidenced. No confounding factor was observed.

Conclusion The study did not show any evidence of a role of vaccination in the aetiology of childhood leukaemia.

Introduction

In 2002, a poster alerted the French health authorities to the possibility that the risk of childhood leukaemia might be increased by hepatitis B vaccination (Ma X, Does M, Buffler PA, Wiencke JK. Hepatitis B vaccination and the risk of childhood leukaemia. Poster session abstract 3801, American Association for Cancer Research annual meeting, San Francisco, April, 2002). The potential public health implications of such an association provided the rationale for detailed investigation in the context of the ESCALE national population-based case-control study of the aetiology of childhood cancer. Childhood leukaemia is the most common childhood cancer worldwide. In France, the incidence is 43 cases per million people and per year, equivalent to about 470 new cases diagnosed each year.1 Very few risk factors, such as high dose ionizing radiation, some chemotherapeutic regimens and some genetic syndromes (Down syndrome, Fanconi syndrome), have been identified. Current research is focusing on infectious, environmental and genetic factors which may influence the risk of childhood leukaemia. Since leukaemia is a neoplastic disease of immune cells, a relationship between immune system events, such as infection, atopic disease or vaccination, and the risk of childhood leukaemia has been suggested. This article investigates the relationship between vaccination and the risk of the immunological sub-types of childhood acute leukaemia (AL): acute lymphoblastic leukaemia (ALL) and acute myeloblastic leukaemia (AML).

Methods

The ESCALE study, a national, comprehensive, case-control study conducted in 2003 and 2004, addressed four childhood neoplastic diseases (leukaemia, lymphoma, neuroblastoma and brain tumour) and infectious, environmental and genetic potential risk factors.

Study population

Each case of AL incident in 2003–04 in a child aged <15 years, residing in France at the time of diagnosis and with no previous history of malignancy, was eligible. All the childhood leukaemia cases were confirmed by bone marrow analysis. Children whose mother did not speak French or who had been adopted were not eligible. The cases’ mothers were interviewed at least 2 months after diagnosis, within 5 months on average. For ethical reasons, the mothers of children who died before the scheduled interview date were not interviewed. The leukaemia cases were recruited directly by investigators assigned to each French paediatric oncology hospital department, with the support of the French National Registry of Childhood Haematopoietic Malignancies. Out of the 948 cases of childhood AL diagnosed in France from January 1, 2003 to December 31, 2004, 860 cases were eligible. The reasons for exclusion consisted of: absence of a biological mother (10 cases); non-French-speaking mother (29 cases); serious psychological disorders (14 cases); physician's refusal (1 case); and death (34 cases). Finally, 776 (91%) case mothers have given their consent and been interviewed.

The controls were randomly selected from the French population using quotas, a priori determined to make the control group representative of all cancer cases in terms of age and gender. Additional quotas constrained the control group to have the same distribution as the national population in terms of number of children living in the household, conditionally to the age group. Random selection was based on a representative sample of 60 000 addresses from the French national telephone directory plus unlisted numbers, which have been randomly retrieved before dialling. Among the 50 217 phone numbers dialled, 27 633 belonged to a household and 8500 (30.8%) to a target household. Of them, 862 hanged up before eligibility could have been checked and 5277 suited to an already completed quota. Finally, among the 2361 eligible control mothers, 679 refused the interview and 1682 (71.2%) gave their consent and were interviewed. We then excluded one control that had a prior history of neuroblastoma, to end with a total number of 1681 controls.

Data collection

Each of the case and control biological mothers responded to a personal and standardized telephone interview lasting 40 min. The interview elicited data on demographic and socioeconomic characteristics, parental occupational history, childhood environment, familial and personal medical history, and history of the pregnancy.

In France, the vaccination section of a child's medical record contains a separate page for each vaccine. The healthcare professional reports the proprietary name of the vaccine and the date of vaccination on the appropriate page. For the study, each mother was asked to read out each page of the vaccination record, line by line. Each interviewer's computer screen displayed a vaccination record template and an exhaustive list, by record page, of the proprietary names of the vaccines available. Each vaccine administered and the vaccination dates were thus obtained. The mother's history of hepatitis B (disease and vaccination) was reported in the same way.

Since combined vaccines are frequently administered, four vaccination parameters were considered: vaccine type; the number of doses of each vaccine (vaccine doses); the total number of injections and the total number of vaccine doses received (all vaccines taken together). These variables were all treated as categorical variables. For example, two DTP (diphtheria + tetanus + poliomyelitis) vaccinations and one BCG vaccination are equivalent to four vaccines; two diphtheria vaccine doses + two polio vaccine doses + two tetanus vaccine doses + one BCG vaccine dose; three injections; and a total of seven vaccine doses. In France, during the first 6 months of life, children usually receive four vaccines: BCG, diphtheria, tetanus and poliomyelitis (DTP: usually in one injection). If parents wish, additional recommended vaccines such as Haemophilus influenzae B (HiB) and pertussis vaccines (both combined with the DTP injection) and Hepatitis B vaccine may also be administered. In some contexts, such as chronic disease, the child's physician may also recommend pneumococcal and meningococcal immunization. Pneumococcal immunization has recently been recommended for infants aged less than 2 years attending daycare. During the first 6 months of life, a child may thus receive up to 9 different vaccines, 12 injections and 24 vaccine doses (Figure 1). Vaccination is usually not scheduled for infants aged 6 months to 1 year. Even though the French immunization calendar recommends early vaccination, only four vaccines are mandatory (BCG, diphtheria, tetanus and poliomyelitis) and required for starting school at age 6 years.

Figure 1

French infantile vaccination calendar (1st year of life)

Figure 1

French infantile vaccination calendar (1st year of life)

Statistical analysis

The SAS® software package (version 8, Cary, NC, USA) was used for all the analyses. Non-conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI), with adjustment for age and gender. In order to compare the different types of leukaemia, analyses were carried out using polytomous logistic regression. Age adjustment for children aged less than 2 years was conducted at intervals of 3 months. For the other age groups, adjustment complied with the stratification categories.

When the exact day of injection was not reported, a default value of 15 was allocated. When the month was not reported, the date was considered missing. Only 25 case mothers (3.2%), consisted of 18 ALL (2.9%), 5 AML (5.5%) and 2 other types of AL, and 34 control mothers (2.1%) did not manage to have their child's immunization records for the interview.

Pre-diagnosis symptoms of childhood leukaemia such as fever, extreme fatigue or bone pain, develop at the latest, 2 or 3 months before diagnosis. As such symptoms may result in the child's physician postponing a scheduled vaccination, the vaccination data were censored at 6 months before the reference date for cases and controls. Similarly, surgery or disease related to a malformation (38 cases and 56 controls) or genetic abnormality (14 cases and 5 controls) may result in a scheduled vaccination date being modified. In consequence, those cases and controls were excluded from analysis. Thus, out of the 776 cases and 1681 controls who were eligible, 726 cases (three cases presented with both a malformation and a genetic abnormality) and 1620 controls were included in the analysis. When analyses concerned a given step of the vaccination calendar, only children having reached at least the corresponding age plus 6 months were included, so that both cases and controls could have completed this step. Therefore, analyses made for vaccinations before 6 months and 18 months were carried out among children at least 1 year and 2 years old, respectively.

Results

Among the 726 cases, 620 (85%) presented with ALL, 91 (13%) with AML, 11 (2%) with biphenotypic leukaemia and 4 with AL with no immunophenotyping at the date of interview.

The cases and controls did not differ with respect to gender or the number of children living in the household (Table 1). There was a small age discrepancy between the cases and controls, particularly for very young children, who were more strongly represented in the control group. The discrepancy simply reflects the fact that the cases were only a fraction of the total case population of the ESCALE study, since only the leukaemia cases are considered herein. There was at least one control for each case in each age group. Cases and controls were similar with respect to age (mean age 6.0 years for controls and 5.6 years for cases), maternal education or degree of urbanization. The paternal educational level was, however, higher for the controls.

Table 1

Characteristics of the cases and controls

 Cases (n = 726) Controls (n = 1620)   
 n n Control/Case ratio P 
Gender      NS 
    Male 395 54.4 892 55.1 2.3  
Age at the reference date (years) <0.01 
    <2 108 14.9 362 22.4 3.4  
    2 98 13.5 146 9.0 1.5  
    3–4 185 25.5 293 18.1 1.6  
    5–6 114 15.7 218 13.5 1.9  
    7–8 74 10.2 160 9.9 2.2  
    9–11 88 12.1 217 13.4 2.5  
    12–14 59 8.1 224 13.8 3.8  
Number of children (0–14 years) living in the household NS 
    1 226 31.1 528 32.6 2.3  
    2 321 44.2 688 42.5 2.1  
    ≥ 3 175 24.1 404 24.9 2.3  
    Missing data 0.6 0.0   
Birth order      <0.01 
    1 362 49.9 685 42.3 1.9  
    2 232 32.0 589 36.4 2.5  
    ≥ 3 132 18.2 346 21.4 2.6  
Day-care      NS 
    No 634 87.3 1418 87.5 2.2  
    Yes 92 12.7 202 12.5 2.2  
Maternal educational level NS 
    ≤High school 438 60.3 939 58.0 2.1  
    >High school 288 39.7 681 42.0 2.4  
Paternal educational level 0.02 
    ≤High school 497 68.5 1021 63.0 2.1  
    >High school 222 30.6 584 36.1 2.6  
    Missing data 1.0 15 0.9   
Degree of urbanization NS 
    Rural 226 31.1 569 35.1 2.5  
    Mixed 171 23.6 367 22.7 2.1  
    Urban 315 43.4 658 40.6 2.1  
    Missing data 14 1.9 26 1.6   
 Cases (n = 726) Controls (n = 1620)   
 n n Control/Case ratio P 
Gender      NS 
    Male 395 54.4 892 55.1 2.3  
Age at the reference date (years) <0.01 
    <2 108 14.9 362 22.4 3.4  
    2 98 13.5 146 9.0 1.5  
    3–4 185 25.5 293 18.1 1.6  
    5–6 114 15.7 218 13.5 1.9  
    7–8 74 10.2 160 9.9 2.2  
    9–11 88 12.1 217 13.4 2.5  
    12–14 59 8.1 224 13.8 3.8  
Number of children (0–14 years) living in the household NS 
    1 226 31.1 528 32.6 2.3  
    2 321 44.2 688 42.5 2.1  
    ≥ 3 175 24.1 404 24.9 2.3  
    Missing data 0.6 0.0   
Birth order      <0.01 
    1 362 49.9 685 42.3 1.9  
    2 232 32.0 589 36.4 2.5  
    ≥ 3 132 18.2 346 21.4 2.6  
Day-care      NS 
    No 634 87.3 1418 87.5 2.2  
    Yes 92 12.7 202 12.5 2.2  
Maternal educational level NS 
    ≤High school 438 60.3 939 58.0 2.1  
    >High school 288 39.7 681 42.0 2.4  
Paternal educational level 0.02 
    ≤High school 497 68.5 1021 63.0 2.1  
    >High school 222 30.6 584 36.1 2.6  
    Missing data 1.0 15 0.9   
Degree of urbanization NS 
    Rural 226 31.1 569 35.1 2.5  
    Mixed 171 23.6 367 22.7 2.1  
    Urban 315 43.4 658 40.6 2.1  
    Missing data 14 1.9 26 1.6   

About 40% of the mothers reported hepatitis B immunization before pregnancy (301 case and 719 control mothers, respectively) while only 25 mothers (6 case and 19 control mothers, respectively) reported having had hepatitis B.

At age 6 months, most of the children had been immunized against tuberculosis, diphtheria, tetanus, polio, pertussis and HiB (Table 2). About one-third of the children had been immunized against hepatitis B and less than 10% against Meningococcus or Pneumococcus. At age 18 months, most of the children had also been immunized against measles, mumps and rubella (Table 3).

Table 2

Vaccines usually administered before age 6 months (children's age >1 year)

 Controls (n = 1434) AL (n = 696) ALL (n = 606) AML (n = 76) 
 
 

 

 

 
 n (%) n (%) n (%) n (%) 
BCG     
    Yes 1309 (91.3) 624 (89.7) 548 (90.4) 63 (82.9) 
    No 94 (6.6) 48 (6.9) 39 (6.4) 8 (10.5) 
    Missing data 31 (2.2) 24 (3.5) 19 (3.1) 5 (6.6) 
Diphtheria     
    Yes 1365 (95.2) 663 (95.3) 578 (95.4) 71 (93.4) 
    No 38 (2.7) 9 (1.3) 9 (1.5) 0 (0.0) 
    Missing data 31 (2.2) 24 (3.5) 19 (3.1) 5 (6.6) 
Tetanus     
    Yes 1368 (95.4) 664 (95.4) 579 (95.5) 71 (93.4) 
    No 35 (2.4) 8 (1.2) 8 (1.3) 0 (0.0) 
    Missing data 31 (2.2) 24 (3.5) 19 (3.1) 5 (6.6) 
Poliomyelitis     
    Yes 1366 (95.3) 665 (95.6) 580 (95.7) 71 (93.4) 
    No 37 (2.6) 7 (1.0) 7 (1.2) 0 (0.0) 
    Missing data 31 (2.2) 24 (3.5) 19 (3.1) 5 (6.6) 
Pertussis     
    Yes 1325 (92.4) 646 (92.8) 565 (93.2) 67 (88.2) 
    No 78 (5.4) 26 (3.7) 22 (3.6) 4 (5.3) 
    Missing data 31 (2.2) 24 (3.5) 19 (3.1) 5 (6.6) 
Hepatitis B     
    Yes 510 (35.6) 250 (35.9) 211 (34.8) 31 (40.8) 
    No 893 (62.3) 422 (60.6) 376 (62.1) 40 (52.6) 
    Missing data 31 (2.2) 24 (3.5) 19 (3.1) 5 (6.6) 
HiB     
    Yes 1132 (78.9) 582 (83.6) 512 (84.5) 58 (76.3) 
    No 271 (18.9) 90 (12.9) 75 (12.4) 13 (17.1) 
    Unknown 31 (2.2) 24 (3.5) 19 (3.1) 5 (6.6) 
Pneumococcus     
    Yes 101 (7.0) 30 (4.3) 24 (4.0) 5 (6.6) 
    No 1302 (90.8) 642 (92.2) 563 (92.9) 66 (86.8) 
    Missing data 31 (2.2) 24 (3.5) 19 (3.1) 5 (6.6) 
Meningococcus     
    Yes 71 (5.0) 31 (4.5) 28 (4.6) 2 (2.6) 
    No 1332 (92.9) 641 (92.1) 559 (92.2) 69 (90.8) 
    Missing data 31 (2.2) 24 (3.5) 19 (3.1) 5 (6.6) 
 Controls (n = 1434) AL (n = 696) ALL (n = 606) AML (n = 76) 
 
 

 

 

 
 n (%) n (%) n (%) n (%) 
BCG     
    Yes 1309 (91.3) 624 (89.7) 548 (90.4) 63 (82.9) 
    No 94 (6.6) 48 (6.9) 39 (6.4) 8 (10.5) 
    Missing data 31 (2.2) 24 (3.5) 19 (3.1) 5 (6.6) 
Diphtheria     
    Yes 1365 (95.2) 663 (95.3) 578 (95.4) 71 (93.4) 
    No 38 (2.7) 9 (1.3) 9 (1.5) 0 (0.0) 
    Missing data 31 (2.2) 24 (3.5) 19 (3.1) 5 (6.6) 
Tetanus     
    Yes 1368 (95.4) 664 (95.4) 579 (95.5) 71 (93.4) 
    No 35 (2.4) 8 (1.2) 8 (1.3) 0 (0.0) 
    Missing data 31 (2.2) 24 (3.5) 19 (3.1) 5 (6.6) 
Poliomyelitis     
    Yes 1366 (95.3) 665 (95.6) 580 (95.7) 71 (93.4) 
    No 37 (2.6) 7 (1.0) 7 (1.2) 0 (0.0) 
    Missing data 31 (2.2) 24 (3.5) 19 (3.1) 5 (6.6) 
Pertussis     
    Yes 1325 (92.4) 646 (92.8) 565 (93.2) 67 (88.2) 
    No 78 (5.4) 26 (3.7) 22 (3.6) 4 (5.3) 
    Missing data 31 (2.2) 24 (3.5) 19 (3.1) 5 (6.6) 
Hepatitis B     
    Yes 510 (35.6) 250 (35.9) 211 (34.8) 31 (40.8) 
    No 893 (62.3) 422 (60.6) 376 (62.1) 40 (52.6) 
    Missing data 31 (2.2) 24 (3.5) 19 (3.1) 5 (6.6) 
HiB     
    Yes 1132 (78.9) 582 (83.6) 512 (84.5) 58 (76.3) 
    No 271 (18.9) 90 (12.9) 75 (12.4) 13 (17.1) 
    Unknown 31 (2.2) 24 (3.5) 19 (3.1) 5 (6.6) 
Pneumococcus     
    Yes 101 (7.0) 30 (4.3) 24 (4.0) 5 (6.6) 
    No 1302 (90.8) 642 (92.2) 563 (92.9) 66 (86.8) 
    Missing data 31 (2.2) 24 (3.5) 19 (3.1) 5 (6.6) 
Meningococcus     
    Yes 71 (5.0) 31 (4.5) 28 (4.6) 2 (2.6) 
    No 1332 (92.9) 641 (92.1) 559 (92.2) 69 (90.8) 
    Missing data 31 (2.2) 24 (3.5) 19 (3.1) 5 (6.6) 
Table 3

Vaccines usually administered before the age of 18 months (children's age >2 years)

 Controls (n = 1258) AL (n = 618) ALL (n = 544) AML (n = 62) 
 
 

 

 

 
 n (%) n (%) n (%) n (%) 
Measles     
    Yes 1110 (88.2) 541 (87.5) 480 (88.2) 50 (80.7) 
    No 119 (9.5) 55 (8.9) 46 (8.5) 8 (12.9) 
    Missing data 29 (2.3) 22 (3.6) 18 (3.3) 4 (6.5) 
Mumps     
    Yes 1103 (87.7) 539 (87.2) 478 (87.9) 50 (80.7) 
    No 126 (10.0) 57 (9.2) 48 (8.8) 8 (12.9) 
    Missing data 29 (2.3) 22 (3.6) 18 (3.3) 4 (6.5) 
Rubella     
    Yes 1104 (87.8) 540 (87.4) 479 (88.1) 50 (80.7) 
    No 125 (9.9) 56 (9.1) 47 (8.6) 8 (12.9) 
    Missing data 29 (2.3) 22 (3.6) 18 (3.3) 4 (6.5) 
 Controls (n = 1258) AL (n = 618) ALL (n = 544) AML (n = 62) 
 
 

 

 

 
 n (%) n (%) n (%) n (%) 
Measles     
    Yes 1110 (88.2) 541 (87.5) 480 (88.2) 50 (80.7) 
    No 119 (9.5) 55 (8.9) 46 (8.5) 8 (12.9) 
    Missing data 29 (2.3) 22 (3.6) 18 (3.3) 4 (6.5) 
Mumps     
    Yes 1103 (87.7) 539 (87.2) 478 (87.9) 50 (80.7) 
    No 126 (10.0) 57 (9.2) 48 (8.8) 8 (12.9) 
    Missing data 29 (2.3) 22 (3.6) 18 (3.3) 4 (6.5) 
Rubella     
    Yes 1104 (87.8) 540 (87.4) 479 (88.1) 50 (80.7) 
    No 125 (9.9) 56 (9.1) 47 (8.6) 8 (12.9) 
    Missing data 29 (2.3) 22 (3.6) 18 (3.3) 4 (6.5) 

The distribution of hepatitis B immunization was similar for the cases and controls [35.9 vs 35.6%: OR = 1.0 (0.8–1.3)], for ALL [34.8 vs 35.6%: OR = 1.0 (0.8–1.2)] and for AML [40.8 vs 35.6%: OR = 1.3 (0.8–2.1)]. The results were unchanged after adjustment for the mothers’ hepatitis B status (disease and immunization).

No association between the number of injections received and the risk of childhood leukaemia was observed (Table 4). The results were the same for ALL alone and for AML alone. There was no association between the total number of vaccine doses received and the risk of AL: ALL or AML.

Table 4

Total number of injections and vaccine doses (children's age >1 year)

 Controls (n = 1434) AL (n = 696)  ALL (n = 606)  AML (n = 76)  
 
 

 
 
 
 
 
 
 n (%) n (%) OR [95%CI]a n (%) OR [95%CI]a n (%) OR [95%CI]a 
Total number of injections 
    ≥10 446 (31.1) 176 (25.3) ref 148 (24.4) ref 21 (27.6) ref 
    9, 8 or 7 507 (35.4) 229 (32.9) 1.0 [0.8–1.3] 197 (32.5) 1.0 [0.7–1.3] 30 (39.5) 1.3 [0.7–2.3] 
    6, 5 or 4 380 (26.5) 246 (35.3) 1.3 [1.0–1.7] 223 (36.8) 1.4 [1.0–1.8] 18 (23.7) 0.9 [0.4–1.9] 
    3, 2 or 1 57 (4.0) 17 (2.4) 0.7 [0.4–1.3] 15 (2.5) 0.8 [0.4–1.5] 2 (2.6) 0.5 [0.1–2.5] 
    0 13 (0.9) 4 (0.6) 0.7 [0.2–2.2] 4 (0.7) 0.8 [0.3–2.7] 0 (0.0)  
    Missing data 31 (2.2) 24 (3.5)  19 (3.1)  5 (6.6)  
Total number of vaccine doses 
    ≥25 797 (55.6) 352 (50.6) ref 302 (49.8) ref 42 (55.3) ref 
    24–20 322 (22.5) 197 (28.3) 1.1 [0.9–1.5] 181 (29.9) 1.2 [0.9–1.5] 12 (15.8) 0.7 [0.4–1.5] 
    19–15 180 (12.6) 85 (12.2) 1.1 [0.8–1.6] 72 (11.9) 1.2 [0.8–1.7] 12 (15.8) 0.9 [0.3–2.2] 
    14–0 104 (7.3) 38 (5.5) 0.8 [0.5–1.2] 32 (5.3) 0.8 [0.5–1.2] 5 (6.6) 0.7 [0.3–2.1] 
    Missing data 31 (2.2) 24 (3.5)  19 (3.1)  5 (6.6)  
 Controls (n = 1434) AL (n = 696)  ALL (n = 606)  AML (n = 76)  
 
 

 
 
 
 
 
 
 n (%) n (%) OR [95%CI]a n (%) OR [95%CI]a n (%) OR [95%CI]a 
Total number of injections 
    ≥10 446 (31.1) 176 (25.3) ref 148 (24.4) ref 21 (27.6) ref 
    9, 8 or 7 507 (35.4) 229 (32.9) 1.0 [0.8–1.3] 197 (32.5) 1.0 [0.7–1.3] 30 (39.5) 1.3 [0.7–2.3] 
    6, 5 or 4 380 (26.5) 246 (35.3) 1.3 [1.0–1.7] 223 (36.8) 1.4 [1.0–1.8] 18 (23.7) 0.9 [0.4–1.9] 
    3, 2 or 1 57 (4.0) 17 (2.4) 0.7 [0.4–1.3] 15 (2.5) 0.8 [0.4–1.5] 2 (2.6) 0.5 [0.1–2.5] 
    0 13 (0.9) 4 (0.6) 0.7 [0.2–2.2] 4 (0.7) 0.8 [0.3–2.7] 0 (0.0)  
    Missing data 31 (2.2) 24 (3.5)  19 (3.1)  5 (6.6)  
Total number of vaccine doses 
    ≥25 797 (55.6) 352 (50.6) ref 302 (49.8) ref 42 (55.3) ref 
    24–20 322 (22.5) 197 (28.3) 1.1 [0.9–1.5] 181 (29.9) 1.2 [0.9–1.5] 12 (15.8) 0.7 [0.4–1.5] 
    19–15 180 (12.6) 85 (12.2) 1.1 [0.8–1.6] 72 (11.9) 1.2 [0.8–1.7] 12 (15.8) 0.9 [0.3–2.2] 
    14–0 104 (7.3) 38 (5.5) 0.8 [0.5–1.2] 32 (5.3) 0.8 [0.5–1.2] 5 (6.6) 0.7 [0.3–2.1] 
    Missing data 31 (2.2) 24 (3.5)  19 (3.1)  5 (6.6)  

aNon-conditional logistic regression adjusted on age and gender.

A child aged 6 months should have received at least four injections (one BCG and three DTP). An investigation to determine whether an unvaccinated or less-vaccinated status was associated with a risk of childhood leukaemia was therefore conducted. For all types of AL taken together, there was no association between the number of injections or doses received before age 6 months and the risk of childhood leukaemia (Table 5). The results were the same for ALL. An unvaccinated or less-vaccinated (one or two injections) status was positively associated with a risk of AML. Most of the less-vaccinated children (17/21) had not received BCG vaccine. However, this association observed with injections before 6 months was unstable for AML: the proportion of children with AML unvaccinated or less vaccinated no more differed to that of the controls when we set the threshold for early injections to four (31% of children with three or more injections in cases and 33% in controls before 4 months) or 8 months (82% of children with three or more injections in cases and 86% in controls before 8 months) instead of 6 months (58% of children with three or more injections in cases and 74% in controls before 6 months).

Table 5

Total number of injections and vaccine doses before the age of 6 months (children's age >1 year)

 Controls (n = 1434) AL (n = 696)  ALL (n = 606)  AML (n = 76)  
 
 

 
 
 
 
 
 
 n (%) n (%) OR [95%CI]a n (%) OR [95%CI]a n (%) OR [95%CI]a 
Total number of injections before age 6 months 
    ≥4b 684 (47.7) 310 (44.5) ref 278 (45.9) ref 26 (34.2) ref 
    3 380 (26.5) 207 (29.7) 1.2 [1.0–1.6] 185 (30.5) 1.2 [1.0–1.6] 18 (23.7) 1.3 [0.7–2.4] 
    2 or 1 266 (18.6) 121 (17.4) 1.1 [0.9–1.5] 97 (16.0) 1.0 [0.8–1.3] 21 (27.6) 2.3 [1.2–4.2] 
    0 73 (5.1) 34 (4.9) 1.1 [0.7–1.7] 27 (4.5) 1.0 [0.6–1.6] 6 (7.9) 2.2 [0.9–5.7] 
    Missing data 31 (2.2) 24 (3.5)  19 (3.1)  5 (6.6)  
Total number of vaccine doses before age 6 months 
    ≥10 1052 (73.4) 538 (77.3) ref 475 (78.4) ref 51 (67.1) ref 
    1–9 278 (19.4) 100 (14.4) 0.9 [0.7–1.1] 85 (14.0) 0.8 [0.6–1.1] 14 (18.4) 1.1 [0.6–2.1] 
    0 73 (5.1) 34 (4.9) 1.0 [0.6–1.5] 27 (4.5) 0.9 [0.6–1.4] 6 (7.9) 1.7 [0.7–4.2] 
    Missing data 31 (2.2) 24 (3.5)  19 (3.1)  5 (6.6)  
 Controls (n = 1434) AL (n = 696)  ALL (n = 606)  AML (n = 76)  
 
 

 
 
 
 
 
 
 n (%) n (%) OR [95%CI]a n (%) OR [95%CI]a n (%) OR [95%CI]a 
Total number of injections before age 6 months 
    ≥4b 684 (47.7) 310 (44.5) ref 278 (45.9) ref 26 (34.2) ref 
    3 380 (26.5) 207 (29.7) 1.2 [1.0–1.6] 185 (30.5) 1.2 [1.0–1.6] 18 (23.7) 1.3 [0.7–2.4] 
    2 or 1 266 (18.6) 121 (17.4) 1.1 [0.9–1.5] 97 (16.0) 1.0 [0.8–1.3] 21 (27.6) 2.3 [1.2–4.2] 
    0 73 (5.1) 34 (4.9) 1.1 [0.7–1.7] 27 (4.5) 1.0 [0.6–1.6] 6 (7.9) 2.2 [0.9–5.7] 
    Missing data 31 (2.2) 24 (3.5)  19 (3.1)  5 (6.6)  
Total number of vaccine doses before age 6 months 
    ≥10 1052 (73.4) 538 (77.3) ref 475 (78.4) ref 51 (67.1) ref 
    1–9 278 (19.4) 100 (14.4) 0.9 [0.7–1.1] 85 (14.0) 0.8 [0.6–1.1] 14 (18.4) 1.1 [0.6–2.1] 
    0 73 (5.1) 34 (4.9) 1.0 [0.6–1.5] 27 (4.5) 0.9 [0.6–1.4] 6 (7.9) 1.7 [0.7–4.2] 
    Missing data 31 (2.2) 24 (3.5)  19 (3.1)  5 (6.6)  

aNon-conditional logistic regression adjusted on age and gender.

Adjustment for birth order, maternal and paternal educational level and degree of urbanization, which were related to variables such as the number of injections received and age of vaccination, did not modify any of the results for AL, ALL or AML.

Discussion

ESCALE was the first national study to include all the cases of frequent childhood neoplastic diseases (leukaemia, lymphoma, neuroblastoma and brain tumour) diagnosed in France over a two-year period (2003–04). With a 5% α-error, the statistical power of the study was >80% for most results.

The study showed no evidence of a relationship between vaccination and the risk of childhood AL: ALL or AML, irrespective of the vaccine (including hepatitis B vaccine), total number of injections received or total number of vaccine doses received. There was no evidence for a relationship between unvaccinated or less-vaccinated status at age 6 months and the risk of AL or ALL.

The French National Registry of Childhood Haematopoietic Malignancies includes all the cases of childhood leukaemia diagnosed in the population of mainland France aged <15 years since January 1990. The exhaustiveness of the registry has been estimated to be 99.2% for leukaemia.1 It is, therefore, probable that almost all the cases diagnosed in 2003 and 2004 were registered. Since there is no evidence for a relationship between vaccination history and the prognosis of leukaemia, the exclusion of early deaths for ethical reasons is unlikely to have induced a selection bias.

The controls were randomly selected from the overall population. The national telephone directory was used as the basis for random selection, given that the sub-population of telephone owners is comparable to the overall population as regards most sociodemographic characteristics and lifestyle. Unlisted numbers were computer generated prior to the random selection in order to avoid selection bias. The cases and controls did not differ with respect to age (considering all types of cancer) or gender. There was no difference between the controls and overall population with regard to birth order,2–4 inicating that the quota recruitment process was successful. The controls were representative of the national population in terms of the number of children (0–14) living in the household, which was used as a proxy of birth order, in order to prevent selection bias. Birth order may be, indeed, highly sensitive to the sampling process and may also be related to a number of other variables such as early daycare, early common infections5 and compliance with the recommended vaccination program6. The control mothers’ educational level was very similar to that of the French population2–4 but the control fathers’ educational level was higher than that of the overall population. However, the results were unchanged after adjusting for those two variables. A report on childhood vaccinal coverage7 showed that, in France (1998), 97% of 2-year-old children had been immunized against diphtheria, poliomyelitis and tetanus, 81% against tuberculosis, 82% against measles and rubella, and 96% against mumps compared with 95, 90, 88 and 88%, respectively, in the 2-year-old controls in 2003 and 2004. The immunization status of the controls was thus very similar to that of the overall population.

The vaccination data were as objective as possible since each mother was asked to read out her child's vaccination records line by line. Moreover, in order to prevent recall bias, responses given by mothers unable to consult the vaccination records were considered missing data. Some vaccination records may have been incompletely filled out by the children's physicians. However, this should not have induced differential bias since record completion was independent of case/control status. A recent study has shown that children's personal health record is usually complete.8 It is, therefore, likely that vaccination records are also complete. It was difficult to exclude interviewer error in data recording. In order to minimize the risk of error, particularly that associated with the emotional stress of interviewing cases’ mothers, the same standardized questionnaire was used for both the cases and controls and each interviewer interviewed both case and control mothers.

The data on vaccinations 6 months prior to the reference date were censored. However, the results remained unchanged when none of those data were censored.

Most of the cases and controls had been immunized against tuberculosis, diphtheria, tetanus, poliomyelitis, pertussis and HiB at the reference date and very few children had never been vaccinated. There were no differences between the cases and controls. The results with regard to immunization prevalence rates and the lack of association with the risk of childhood leukaemia are consistent with those of most studies.9–13

An association between hepatitis B vaccination and the risk of childhood leukaemia has been suggested in a preliminary report from the Northern California Childhood Leukaemia Study.14 The present study provided no evidence of such an association irrespective of the type of AL, age or number of vaccine doses received. These results are consistent with the final results of the Northern California Childhood Leukaemia Study11 and with the two studies that have investigated hepatitis B vaccination and the risk of AL.9,11 This study is the first to include the mother's hepatitis B status in the analysis. Maternal hepatitis B status could not, therefore, have constituted a confounding factor.

Several studies have reported an increasing negative association between the number of vaccine or combined-vaccine injections received and the risk of childhood AL.9,11–13 Only one study of the relationship between the overall number of injections an the risk of ALL has been published.13 It showed the same increasing negative association. None of those studies addressed the relationship between the number of doses received and the risk of AL other than ALL. In this study, there was no obvious association between the number of injection received or the number of vaccine doses received and the risk of ALL or AML.

Given that a relationship between a low number of early common infections and the risk of AL has been suggested in several articles 5,15–19, it was considered pertinent to address the relationship between delayed early vaccinations and the risk of childhood leukaemia. No relationship between delayed early vaccinations and the risk of ALL was detected. An association was found for AML with fewer injections before the age of 6 months, but it appeared unstable and without any trend as regards the age of injections, suggesting that this association was most probably observed by chance.

Despite the statistical power of the study (80%), no evidence of a relationship between vaccination and the risk of ALL or AML was evidenced irrespective of the type of vaccine, number of doses or number of early vaccinations.

Acknowledgements

The authors are grateful to: Marie-Hélène Da Silva and Christophe Steffen (INSERM U754), who coordinated the recruitment of the cases; Aurélie Goubin and the staff of the French National Registry of Childhood Hematopoietic Malignancies, who contributed to case detection and verification; Sabine Mélèze and Marie-Anne Noel (Institut CSA), who coordinated the selection of the controls and the interviews; and Catherine Tricoche (Callson) and the team of interviewers, who interviewed the cases and the controls.

This work was supported by grants from INSERM, the Fondation de France, the Association pour la Recherche contre le Cancer, the Agence Française de Sécurité Sanitaire et des Produits de Santé (AFSSAPS), the Agence Française de Sécurité pour la Santé et l’Environnement et du travail (AFSSET) and the association, Cent pour Sang la Vie.

Conflict of interest: None declared.

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 SFCE: Société Française de lutte contre les Cancers de l’Enfant et de l’Adolescent (Appendix 1)

Appendix 1

(SFCE Investigators of the ESCALE study)

Principal Investigator Hospital City (France) 
André Baruchel Hôpital Saint-Louis Hôpital Robert Debré Paris 
Catherine Behar American Memorial Hospital Reims 
Claire Berger Centre Hospitalier Universitaire Saint-Etienne 
Christophe Bergeron Centre Léon Bérard Lyon 
Jean-Louis Bernard Hôpital La Timone Marseille 
Pierre Bordigoni Centre Hospitalier Universitaire Nancy 
Patrick Boutard Centre Hospitalier Régional Universitaire Caen 
Gérard Couillault Hôpital d’Enfants Dijon 
Lionel De Lumley Centre Hospitalier Régional Universitaire Limoges 
Anne-Sophie Defachelles Centre Oscar Lambrais Lille 
François Demeocq Hôpital Hôtel-Dieu Clermont-Ferrand 
Alain Fischer Hôpital des Enfants Malades Paris 
Virginie Gandemer Hôpital Sud Rennes 
Olivier Hartmann Institut Gustave Roussy Villejuif 
Jean-Pierre Lamagnere Centre Gatien de Clocheville Tours 
Françoise Lapierre Centre Hospitalier Universitaire Jean Bernard Poitiers 
Guy Leverger Hôpital Armand Trousseau Paris 
Patrick Lutz Hôpital de Hautepierre Strasbourg 
Geneviève Marguerite Arnaud de Villeneuve Montpellier 
Françoise Mechinaud Hôpital Mère et Enfants Nantes 
Gérard Michel Hôpital La Timone Marseille 
Jean Michon Institut Curie Paris 
Frédéric Millot Centre Hospitalier Universitaire Jean Bernard Poitiers 
Brigitte Nelken Hôpital Jeanne de Flandre Lille 
Brigitte Pautard Centre Hospitalier Universitaire Amiens 
Yves Perel Hôpital Pellegrin - le Tripode Bordeaux 
Yves Bertrand Hôpital Debrousse Lyon 
Alain Pierre-Kahn Hôpital des Enfants Malades Paris 
Emmanuel Plouvier Centre Hospitalier Régional Besançon 
Xavier Rialland Centre Hospitalier Universitaire Angers 
Alain Robert Hôpital des Enfants Toulouse 
Hervé Rubie Hôpital des Enfants Toulouse 
Nicolas Sirvent Hôpital L’Archet Nice 
Christine Soler Fondation Lenval Nice 
Danièle Sommelet Centre Hospitalier Universitaire Nancy 
Jean-Pierre Vannier Hôpital Charles Nicolle Rouen 
Principal Investigator Hospital City (France) 
André Baruchel Hôpital Saint-Louis Hôpital Robert Debré Paris 
Catherine Behar American Memorial Hospital Reims 
Claire Berger Centre Hospitalier Universitaire Saint-Etienne 
Christophe Bergeron Centre Léon Bérard Lyon 
Jean-Louis Bernard Hôpital La Timone Marseille 
Pierre Bordigoni Centre Hospitalier Universitaire Nancy 
Patrick Boutard Centre Hospitalier Régional Universitaire Caen 
Gérard Couillault Hôpital d’Enfants Dijon 
Lionel De Lumley Centre Hospitalier Régional Universitaire Limoges 
Anne-Sophie Defachelles Centre Oscar Lambrais Lille 
François Demeocq Hôpital Hôtel-Dieu Clermont-Ferrand 
Alain Fischer Hôpital des Enfants Malades Paris 
Virginie Gandemer Hôpital Sud Rennes 
Olivier Hartmann Institut Gustave Roussy Villejuif 
Jean-Pierre Lamagnere Centre Gatien de Clocheville Tours 
Françoise Lapierre Centre Hospitalier Universitaire Jean Bernard Poitiers 
Guy Leverger Hôpital Armand Trousseau Paris 
Patrick Lutz Hôpital de Hautepierre Strasbourg 
Geneviève Marguerite Arnaud de Villeneuve Montpellier 
Françoise Mechinaud Hôpital Mère et Enfants Nantes 
Gérard Michel Hôpital La Timone Marseille 
Jean Michon Institut Curie Paris 
Frédéric Millot Centre Hospitalier Universitaire Jean Bernard Poitiers 
Brigitte Nelken Hôpital Jeanne de Flandre Lille 
Brigitte Pautard Centre Hospitalier Universitaire Amiens 
Yves Perel Hôpital Pellegrin - le Tripode Bordeaux 
Yves Bertrand Hôpital Debrousse Lyon 
Alain Pierre-Kahn Hôpital des Enfants Malades Paris 
Emmanuel Plouvier Centre Hospitalier Régional Besançon 
Xavier Rialland Centre Hospitalier Universitaire Angers 
Alain Robert Hôpital des Enfants Toulouse 
Hervé Rubie Hôpital des Enfants Toulouse 
Nicolas Sirvent Hôpital L’Archet Nice 
Christine Soler Fondation Lenval Nice 
Danièle Sommelet Centre Hospitalier Universitaire Nancy 
Jean-Pierre Vannier Hôpital Charles Nicolle Rouen