Objectives. To evaluate suggested associations between childhood vaccinations, particularly against hepatitis B and Haemophilus influenzae type b, and risk of developing type 1 diabetes; and to determine whether timing of vaccination influences risk.
Methods. We conducted a case-control study within 4 health maintenance organizations (HMOs) that participate in the Vaccine Safety Datalink project of the Centers for Disease Control and Prevention. Study eligibility was restricted to children who met the following criteria: 1) born during 1988 through 1997; 2) HMO member since birth; 3) continuously enrolled for first 6 months of life; and 4) at least 12 months of HMO membership before diabetes incidence date (or index date for controls) unless incidence date was before 12 months of age. All 4 HMOs maintain registries of their members who have diabetes, and we used the registries to identify potential cases of diabetes. We conducted chart reviews to verify that potential cases met the World Health Organization epidemiologic case definition for type 1 diabetes mellitus (ie, a physician’s diagnosis of diabetes plus treatment with daily insulin injections). We defined the incidence date of diabetes as the first date that the child received a diagnosis of diabetes. We attempted to match 3 controls to each case. Controls had the same eligibility criteria as cases and were matched to individual cases on HMO, sex, date of birth (within 7 days), and length of health plan enrollment (up to the incidence or index date). The index date for controls was defined as the incidence date of the case to which the control was matched. Chart abstraction was performed by trained chart abstractors using standardized forms. In addition to complete vaccination histories, the chart abstraction forms for both cases and controls included information on sociodemographic characteristics, selected medical conditions, history of breastfeeding, and family medical history. We used conditional logistic regression to estimate the odds ratio (OR) of diabetes associated with vaccination, with vaccine exposure defined as before the diabetes incidence date (or index date for controls).
Results. Two hundred fifty-two confirmed cases of diabetes and 768 matched controls met the study eligibility criteria. The OR (95% confidence interval) for the association with type 1 diabetes was 0.28 (0.07–1.06) for whole cell pertussis vaccine (predominantly in combination as diphtheria, tetanus toxoids and pertussis vaccine), 1.36 (0.70–2.63) for measles-mumps-rubella, 1.14 (0.51–2.57) for Haemophilus influenzae type b, 0.81 (0.52–1.27) for hepatitis B vaccine, 1.16 (0.72–1.89) for varicella vaccine, and 0.92 (0.53–1.57) for acellular pertussis-containing vaccines. Compared with children who had not received hepatitis B vaccine, the OR of diabetes was 0.51 (0.23–1.15) for children vaccinated at birth and 0.86 (0.54–1.35) for those first vaccinated against hepatitis B at 2 months of age or later. Race and ethnicity and family history of diabetes were independently associated with risk of type 1 diabetes, but adjustment for these factors did not materially alter the ORs for any of the vaccines.
Conclusions. In this large, population-based, case-control study, we did not find an increased risk of type 1 diabetes associated with any of the routinely recommended childhood vaccines. Our study adds to previous research by providing data on newer vaccines, including hepatitis B, acellular pertussis, and varicella vaccines. For the older vaccines, our results are generally in agreement with previous studies in not finding any increased risks. Ours is the first epidemiologic study to evaluate the possibility that timing of vaccination is related to risk of clinical diabetes in children. Our results on hepatitis B vaccine do not support the hypothesis; risk of type 1 diabetes was not different between infants vaccinated at birth and those who received their first vaccination later in life. The results of our study and the preponderance of epidemiologic evidence do not support an association between any of the recommended childhood vaccines and an increased risk of type 1 diabetes. Suggestions that diabetes risk in humans may be altered by changes in the timing of vaccinations also are unfounded.
Comments
Childhood vaccinations and type 1 diabetes
The reference Classen cites in support of his claim that Haemophilus influenzae type B (Hib) vaccine increases the risk of developing type 1 or insulin-dependent diabetes mellitus (IDDM) with a relative risk of 1.17 is actually a letter to the editor. We are not aware that his analysis has ever been published in a peer-reviewed publication. The data are from a follow-up study of a cohort of children who participated in a national Hib clinical trial in Finland. The definitive analysis of the follow-up study was published by Karvonen (1) and no statistically significant increased risk of type 1 diabetes was found to be associated with Hib vaccination or with age at vaccination. An editorial by Elliman (2) accompanying the Karvonen paper concluded that, "This was a well designed and very carefully conducted study whose metholology cannot be criticised, so we can be reassured about the validity of the findings." The contention that the relative risks of 1.14 (unadjusted) and 1.23 (adjusted) from our case-control study (3) are similar to the 1.17 relative risk noted by Classen, completely ignores the wide 95% confidence intervals that extend down to 0.5 on the lower end for both estimates. As we noted in our paper, the relative risk estimates from our study were too unstable for Hib vaccine and we feel Karvonen's study provides the most reliable data on this question. Since the publication or our study, we have become aware of another large multicenter European case-control study of vaccines and type 1 diabetes (4). The study included 900 cases of type 1 diabetes and 2302 controls. The relative risk for Haemophilus influenzae vaccine adjusted for potentially confounding risk factors was 0.75 (95% confidence interval, 0.30-1.92), providing additional evidence of a lack of an increased risk of type 1 diabetes associated with Hib vaccine.
Next, Classen claims that the incidence of IDDM in Finland increased by about 60% following the introduction of MMR vaccine in 1982 and Hib vaccine in 1986. He failed to mention, however, that the incidence of type 1 diabetes in Finland has been increasing virtually linearly since the 1960's (1). Classen goes on to speculate that the combined effects of Hib and MMR vaccine may increase the risk of diabetes by 60%. He arrived at this figure by multiplying the two non-statistically significant odds ratios from our study of 1.14 for Hib and 1.36 for MMR. There is no support for a possible increase in risk associated with either vaccine from any other study. The Karvonen study did not find an increase in risk associated with Hib vaccine and the only other study with data on MMR, a large case-control study from Sweden (5), found an odds ratio of 0.95 (95% confidence interval, 0.71-1.28). Thus, the weight of the epidemiological evidence is that neither MMR nor Hib increases the risk of type 1 diabetes and, without evidence to the contrary, there is no reason to expect that their combined effects would be any different. We were not able to study the simultaneous effects of the two vaccines in our study because too few children were not vaccinated with either vaccine.
There are no references to the claim that "... the increased risk of IDDM associated with most vaccines does not occur until three years after immunization." Classen further asserts that there may have not been sufficient time of follow-up in our study to see an increased risk of IDDM with certain vaccines. As noted in our manuscript, half of our cases and controls were followed up until at least age 4 years, with a maximum of 10 years. Thus, a large number of children in our study had more than 3 years of follow-up after vaccination with the common infant vaccines.
Next, Classen attempts to discount our study and other previous studies as "small case-control studies" in highly immunized populations. Certainly, that most children in our study had received MMR and Hib limited our ability to obtain precise relative risk estimates for these vaccines. However, there have been other large case-control studies of these vaccines that had large proportions of unvaccinated subjects and provide stable estimates of relative risk. The Swedish case-control study (5) which found an odds ratio of 0.95 (0.71-1.28) for MMR vaccine had 339 cases and 528 controls, with over 50% of both case and control children not having received MMR vaccine. The european multicenter study (4) that found no increased risk associated with Hib vaccine included 900 cases and over 2000 controls.
Finally, Classen states that our results for hepatitis B vaccine are consistent with his findings and support the need for additional research on possible decreased risk of type 1 diabetes associated with immunizing against hepatitis B at birth. Again, Classen is very selective in the result he chose to emphasize. Although we did find that the unadjusted odds ratio for hepatitis B vaccination at birth was 0.51 compared with unvaccinated children, the result was not statistically significant (95% confidence interval, 0.23-1.15). Moreover, the odds ratio was less than 1.0 for children vaccinated at later ages. In adjusted analyses, the odds ratio for children who were vaccinated against hepatitis B at birth, 0.66 (0.27- 1.59) was not greatly different than the odds ratio for children who were first vaccinated at 2 months of age or later, 0.74 (0.45-1.21). It may be worthwhile to continue to pursue research into possibly preventing diabetes through vaccinations at birth, but our results do not provide strong support for such research.
References
1. Karvonen M, Cepaitis Z, Tuomilehto J. Association between type 1 diabetes and Haemophilus influenzae type b vaccination: birth cohort study. BMJ 1999;318:1169-1172.
2. Elliman D. Vaccination and type 1 diabetes mellitus. BMJ 1999;318:1159-1160.
3. DeStefano F, Mullooly JP, Okoro CA, et al. Childhood vaccinations, vaccination timing, and risk of type 1 diabetes mellitus. Pediatrics 2001;108:e112.
4. The EURODIAB Substudy 2 Study Group. Infections and vaccinations as risk factors for childhood Type 1 (insulin-dependent) diabetes mellitus: a multicentre case-control investigation. Diabetologia 2000;43:47-53.
5. Blom L, Nystrom L, Dahlquist G. The Swedish childhood diabetes study: Vaccinations and infections as risk determinants for diabetes in childhood. Diabetologia 1991;34:176-181.
CDC data support association between vaccines and IDDM
DeStefano et al. (1) recently published a paper in which they reference our work. We estimated that the 4 doses of the hemophilus influenza B vaccine increased the risk of IDDM, relative risk 1.17, P<0.05, based on 10 years of follow up of a large clinical trial (2). Our data indicated the risk of vaccine induced IDDM exceeded the benefit by 3 to 1. DeStefano's data indicated an identical risk, odds ratio 1.14 or 1.23 depending on their regression analysis. We also found the incidence of IDDM rose in Finland about 60% percent following the introduction of the MMR vaccine in 1982 and the Hemophilus vaccine in 1986 (3). DeStefano's data on the combined odds ratio of the hemophilus vaccine and the MMR vaccine (1.14*1.36=1.55 OR) support our conclusion that vaccines can explain the 60% rise. DeStefano erroneous concludes his findings do not support our data and conclusions. Clearly it is not in the public interest to deny that vaccines can explain the rise in IDDM.
Case control studies like DeStefano's and others also do not adjust for the confounding effects of several different vaccines that can have opposing effects on the development of IDDM. For example patients born in 1994 may have received the hepatitis B vaccine at birth, which is associated with a decreased risk, but also have received a HiB vaccine which is associated with an increased risk. By contrast our studies have involved large cohorts which only differed by a single vaccine. We have also found that the increased risk of IDDM associated with most vaccines does not occur until three years after immunization. A finding supported by published literature There may not have been sufficient time of follow up for DeStefano to see an increased risk of IDDM with certain vaccines.
In conclusion the study by DeStefano and other studies he cites just prove that small case control studies in highly immunized populations will not lead to an statistical significant association even when clinically significant end points are reached. Large cohort studies on 100,000 patients or more are needed. The fact that DeStefano found the hemophilus and MMR vaccines associated with risks near identical to what we found in cohort studies is supportive of our conclusions. The finding that immunization with the Hepatitis B vaccine starting at birth is associated with an odds ratio well below 1 (0.51) is also consistent with our findings and needs to be studied further.
References:
1. DeStefano F, Mullooly JP, Okoro CA, et al. Childhood vaccinations, vaccination timing, and risk of type 1 diabetes mellitus. Pediatrics 2001;108:e112.
2. Classen JB, Classen DC. Association between type 1 diabetes and Hib vaccine, causal relation likely. BMJ 1999;319:1133.
3. Classen DC, Classen JB. The timing of pediatric immunization and the risk of insulin-dependent diabetes mellitus. Infectious Diseases in Clinical Practice 1997;6:449-54.
4. Sultz HA, Hart BA, Zielezny M, Schlesinger ER. Is the mumps virus an etiologic factor in juvenile diabetes mellitus. J. Pediatrics 1975, 86:654-656.
5. Hyoty H, Leinikki P, Reunanen A et al. Mumps infection in the etiology of type 1 diabetes. Diabetes Res 1988, 9:111-116.
Author: John Barthelow Classen M.D., M.B.A. President and Chief Executive Officer Classen Immunotherapies, Inc. 6517 Montrose Avenue Baltimore, MD 21212 U.S.A. E-mail: Classen@vaccines.net Tel: (410) 377-4549 Fax: (410) 377-8526 http://vaccines.net