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Subject:Board Correspondence - FW: An Inconvenient Study
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Subject: An Inconvenient Study
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diana dreiss
Impact of Childhood Vaccination on Short and Long-Term Chronic Health Outcomes in Children:
A Birth Cohort Study
Lois Lamerato, PhD1, Abigail Chatfield, MS1, Amy Tang, PhD1, Marcus Zervos, MD2,3
Henry Ford Health System, Detroit MI
Department of Public Health Sciences1
Division of Infectious Diseases2
Wayne State University School of Medicine, Detroit MI3
Running head: Association of childhood vaccination on chronic health in children
Word Count: 292 (Abstract), 4143 (Body)
Corresponding Author:
Lois Lamerato, PhD
Senior Scientist
Public Health Sciences
Henry Ford Health System
1 Ford Place – 5C
Detroit, MI 48202
Phone: 313-874-6367
llamera1@hfhs.org
Financial Disclosure: This study had no external funding.
2
Abstract
Objective: To compare the short and long-term health outcomes, within a captured payer environment, of
children exposed to one or more vaccines to those unexposed.
Design: Birth cohort study
Setting: Integrated healthcare system in Michigan.
Participants: 18,468 children born between 2000 and 2016 enrolled in the health system insurance plan.
Main Outcome Measures: Development of a chronic health condition over time.
Results: A total of 18,468 consecutive subjects met eligibility criteria for the study, of which 1,957 had no
exposure to vaccination and 16,511 had received at least one vaccine during their enrollment in the plan
with various levels of exposure. After multivariate adjustment, Cox proportional hazards modeling
demonstrated that exposure to vaccination was independently associated with an increased risk of
developing a chronic health condition (HR 2.53, CI 2.16-2.96). Of the chronic health conditions, exposure
to vaccination was independently associated with an increased risk of asthma (HR 4.25, CI 3.23-5.59),
autoimmune disease (HR 4.79, CI 1.36-16.94), atopic disease (HR 3.03, CI 2.01-4.57), eczema (HR 1.31,
CI 1.13-1.52), and neurodevelopmental disorder (HR 5.53, CI 2.91-10.51). There were no chronic health
conditions associated with an increased risk in the unexposed group. The overall probability of being free
of a chronic health condition at 10-years of follow up was 43% in the group exposed to vaccination and
83% in the unexposed group.
Conclusion: This study found that exposure to vaccination was independently associated with an overall
2.5-fold increase in the likelihood of developing a chronic health condition, when compared to children
unexposed to vaccination. This association was primarily driven by asthma, atopic disease, eczema,
autoimmune disease and neurodevelopmental disorders. This suggests that in certain children, exposure
to vaccination may increase the likelihood of developing a chronic health condition, particularly for one of
these conditions.
3
Introduction
Over the past 30 years, the prevalence of chronic health conditions in children has increased.1
According to a 2011 study, approximately 43% of children in the United States (32 million) have at least 1
of the 20 chronic health conditions assessed in the study.2 Despite this, there is a paucity of published data
to determine contributing factors.
Vaccination has reduced the incidence of certain targeted childhood infections and their associated
morbidity and mortality.3 Nonetheless, vaccine hesitancy remains a significant barrier to maintaining and
increasing vaccine uptake and the number of parents foregoing all vaccinations has been increasing.4 5
Common parental concerns relate to the growth of the vaccine schedule, administering multiple vaccines
contemporaneously, and the potential for long-term adverse health outcomes from vaccination.6-9
Research addressing these vaccine safety concerns can assist clinicians in discussions with their patients
and serve to reassure parents of the overall safety of vaccination.10
The safety review period in pre-licensure clinical trials is typically of insufficient duration (<30 days)
to assess a vaccine’s impact on long-term health outcomes.11 However, a number of post-licensure
observational studies have, with mixed results, examined whether certain vaccines are associated with
developing certain health conditions.12-16 An important limitation to these studies, as highlighted by the
Institute of Medicine (IOM) report, The Childhood Immunization Schedule and Safety,10 is that “most
vaccine-related research focuses on the outcomes of single immunizations or combinations of vaccines
administered at a single visit,” instead of comparing completely unvaccinated populations with those
receiving one or more vaccines. This led the IOM to recommend retrospective studies evaluating the health
outcomes of vaccinated versus unvaccinated populations.
Hence, this study compared the short and long-term health outcomes, within a captured payer
environment, of children unexposed to vaccines with those exposed to one or more vaccines. Addressing
this significant data gap could allay parental concerns and bolster vaccine confidence.
Methods
Study Setting
4
Henry Ford Health System (HFHS) is a large, vertically integrated healthcare system, offering
primary, pediatric, acute, and specialty services in Metropolitan Detroit, with 4.2 million ambulatory care
visits annually. The Health Alliance Plan (HAP), a non-profit health maintenance organization (HMO) and
subsidiary of HFHS, has approximately 570,000 enrolled members, approximately one-third of whom
receive care within HFHS. HFHS’s diverse patient population, clinical resources and information
technology systems, make it uniquely suited for this study.
Study Design
This retrospective study evaluated health outcomes of a consecutive cohort of children born
between 2000 and 2016 and enrolled in HAP. This cohort was identified using the HAP and HFHS
administrative database. Subjects were observed from birth until the earlier of disenrollment in the plan or
December 31, 2017. Data sources for this study included medical, clinical and payer records from HFHS
and HAP, supplemented with data from the State of Michigan immunization registry. Data tables included
encounters (outpatient and emergency), hospitalizations, diagnoses, procedures and billing data on all
services. Vaccinations evaluated included all vaccines on the Centers for Disease Control & Prevention
(CDC) Recommended Child and Adolescent Immunization Schedule (Vaccine Schedule). Death data was
obtained from HFHS electronic medical records and the State of Michigan’s Vital Records System and
manual chart review was conducted to ascertain cause of death for subjects who died during plan
enrollment. All HFHS patients receive a lifetime medical record number that links across data-tables.
The study was reviewed and approved by HFHS’s Institutional Review Board and conducted in
accordance with the International Society for Pharmacoepidemiology’s Guidelines for Good
Pharmacoepidemiology Practices (https://www.pharmacoepi.org/resources/guidelines_08027.cfm).
Study Population
Inclusion criteria: born and enrolled in HAP for > 60 days between January 1, 2000 and December
31, 2016 with HFHS designated as their primary care system.
Exclusion criteria: chromosomal abnormalities, cerebral palsy, cystic fibrosis, spina bifida,
congenital heart disease, or brain, neurological, or other congenital conditions present or discovered after
5
birth. These exclusions correspond with the objective of evaluating long-term health outcomes in a
generally healthy birth cohort.
Definitions and Outcomes Assessment
The primary outcome of this study was a chronic health composite outcome which included
conditions identified by the Child and Adolescent Health Measurement Initiative,2 and augmented with
conditions considered to be of public concern or public health significance in the CDC’s White Paper on
Studying the Safety of the Childhood Immunization Schedule.17 The composite includes: diabetes, asthma,
food allergy, cancer, brain dysfunction, atopic and autoimmune disease, and neurological,
neurodevelopmental, seizure and mental health disorder. A subject with one or more of these was
classified as having a chronic health condition. Other health conditions evaluated, but not part of the
composite, include asthma attack or bronchospasm, anaphylaxis, eczema (acute and chronic), ear
infection (acute and chronic) and peanut allergy.
We identified the relevant International Classification of Diseases, Ninth and Tenth Revision (ICD-
9-CM and ICD-10-CM) diagnoses from healthcare encounters during enrollment in the plan for the
conditions of interest. Subjects were classified by exposure to immunizations prior to onset of each
condition (exposed versus unexposed) and then compared based on exposure status.
Brain dysfunction was defined as encephalopathy or encephalitis. Neurodevelopmental disorders
were defined as autism, tics, ADD/ADHD, developmental delay, speech disorder, and learning, motor,
intellectual, behavioral, and other psychological disability. Mental health disorder was defined as anxiety,
depression, bipolar, phobia, emotional disturbance, psychosis, somatoform, and eating, manic, mental,
mood, obsessive compulsive, personality, and stress/adjustment disorder. Only children 2 years and older
were evaluated for neurodevelopmental and mental health disorders. Chronic eczema was defined as at
least 1 reoccurrence 60 days or more after first episode. Chronic ear infection was defined as at least 2
reoccurrences within a year after first episode.
Statistical Analysis
Descriptive characteristics are reported as percentages, mean values ± standard deviations, or
6
median values with interquartile ranges (IQRs). Chi-square tests were used to compare the difference in
baseline characteristics differences between vaccinated and unvaccinated children at birth. The number
of events for each outcome and incidence rate per 1,000,000 patient-years (pt-yrs) were calculated.
Incidence-rate-ratios, calculated by Poisson regression models, are presented with their associated 95%
confidence intervals. Univariate and multivariate Cox proportional-hazards models were used to evaluate
the association between health outcomes and vaccination status. The Kaplan–Meier method was used to
estimate the 10-year cumulative risk of developing a chronic health condition from birth to the first episode
of the condition and classified by prior exposure to immunization (exposed versus unexposed). The groups
were compared with the use of a log-rank test. A P-value <0.05 was considered statistically significant.
Since enrollment time was shorter overall in the unexposed group, sensitivity analyses were conducted by
repeating the above analyses for subjects enrolled for at least 1-year, 3-years and 5-years. Additionally, to
overcome potential ascertainment bias in subjects with lower levels of health care utilization, we conducted
a sensitivity analysis by repeating the above analyses in only those subjects with at least one encounter
at HFHS during plan enrollment.
Results
Study Population
A total of 18,468 consecutive subjects met eligibility criteria, of which 1,957 were unexposed and
16,511 were exposed to at least one vaccine, see Table 1. In exposed subjects, the median number of
vaccinations was 18 (IQR 2-28). Characteristics more common in the exposed group were female sex,
African American race, low-birthweight, prematurity, respiratory distress and trauma at birth. The median
follow-up time was 904 (IQR 392-1,954) days for all subjects, 970 (IQR 430-2,093) days for exposed
subjects, and 461 (IQR 196-1,081) days for unexposed subjects (with enrollment up to 6,575 days in the
exposed group and 6,386 days in the unexposed group).
Clinical Outcomes
Incidence rates and incidence rate ratios (IRR), based on exposure status prior to developing the
condition, were calculated, see Table 2. Overall, the development of a chronic health condition occurred
7
more often in the group exposed versus unexposed to vaccination (277 vs. 112 per million pt-yrs,
(p<0.0001) and was more common in those exposed to vaccination (IRR 2.48, CI 2.12-2.91).
A statistically significant association was found between vaccination and the incidence of asthma,
atopic and autoimmune disease, and mental health and neurodevelopmental disorders including
developmental delay and speech disorder. A statistically significant association was not found between
vaccine exposure and the incidence of cancer, food allergy, autism, motor disability, or neurological or
seizure disorder.
Other conditions occurring more frequently in exposed subjects included ear infection (IRR 6.63,
CI 5.73-7.66), chronic ear infection (IRR 5.67, CI 4.37-7.37), anaphylaxis (IRR 8.88, CI 1.24-63.47), and
asthma attack or bronchospasm (IRR 6.30, CI 3.85-10.31). Vaccine exposure was not associated with
increased incidence of eczema (IRR 1.06, CI 0.91-1.23), chronic eczema (IRR 0.94, CI 0.74-1.20) or
peanut allergy (IRR 6.80, CI 0.95-48.69).
After multivariate adjustment, Cox proportional hazards modeling demonstrated that exposure to
vaccination was independently associated with an increased risk of developing a chronic health condition
(HR 2.54, CI 2.16-2.97), see Table 3. Vaccine exposure was independently associated with an increased
risk of asthma, eczema, atopic and autoimmune disease, and neurodevelopmental disorders including
developmental delay and speech disorder. Other variables in the model independently associated with
increased risk of developing a chronic health disorder were male gender (HR 1.33, CI 1.26-1.41), African-
American race (HR 1.11, CI 1.04-1.18), low-birth-weight (HR 1.20, CI 1.01-1.42), very-low-birth-weight (HR
1.48, CI 1.14-1.91) and prematurity (HR 1.24, CI 1.09-1.41). Vaccine exposure was not significantly
associated with higher risk for cancer, food allergy, autism, motor disability, or neurological, seizure or
mental health disorder. Incident rate ratios and hazard ratios could not be calculated for brain dysfunction,
diabetes, ADHD, tics, or behavioral, learning, intellectual, or other psychological disability since all cases
occurred in the group exposed to vaccination and no cases occurred in the unexposed group.
Vaccine exposure was also independently associated with increased risk for developing other
conditions, including ear infection (HR 7.00, CI 6.05-8.10), chronic ear infection (HR 7.89, CI 6.08-10.24),
anaphylaxis (HR 5.64, CI 1.11-28.74), asthma attack or bronchospasm (HR 5.82, CI 3.58-9.47) and
8
eczema (HR 1.31, CI 1.13-1.52). Vaccine exposure was not associated with chronic eczema (HR 1.26, CI
0.98-1.60) or peanut allergy (HR 6.31, CI 0.88-45.37).
Time to event analysis demonstrated that the overall probability of being free of a chronic health condition
at 10-years of follow up was 43% in the group exposed to vaccination and 83% in the unexposed group
(log-rank test, p<0.0001), see Figure 1.
There were six deaths in the cohort during enrollment. After manual review of medical records,
including death certificate where available, cause of death was determined to be due to a complicated
clinical course from birth (2 exposed, 1 unexposed), brain injury (1 exposed), and unknown cause (2
exposed).
Sensitivity Analyses
Since median enrollment time was shorter in the unexposed group, a sensitivity analysis for
developing a chronic health condition was conducted for subjects enrolled in the health plan for at least 1-
year, 3-years and 5-years which demonstrated consistent results. Vaccine exposure was associated with
higher incidence of a chronic health condition for subjects enrolled at least 1-year (IRR 2.75, CI 2.31-3.28),
3-years (IRR 3.38, CI 2.67-4.30), and 5-years (IRR 4.09, CI 2.84-5.90), as well as a higher risk for
developing a chronic health condition for subjects enrolled at least 1-year (HR 2.84, CI 2.38-3.38), 3-years
(HR 3.48, CI 2.74-4.42), and 5-years (HR 4.05, CI 2.82-5.83). To address the potential for ascertainment
bias in subjects with lower levels of health care utilization, we conducted a sensitivity analysis by repeating
the above analyses using only subjects with at least one encounter during enrollment. Vaccine exposure
was associated with higher incidence of a chronic health condition for subjects with at least one healthcare
encounter (IRR 1.83, CI 1.56-2.14) as well as a higher risk for developing a chronic health condition (HR
1.87, CI 1.60-2.19).
Discussion
Main Findings
9
This study is a comprehensive analysis to determine if exposure to vaccination is associated with
the development of any long-term chronic health condition in children, or if outcomes are similar, or
superior, to those unexposed. We did not find any statistical association between vaccine exposure and
cancer, food allergy, autism, seizure disorder and certain other conditions. Statistical comparisons could
not be conducted for certain conditions, such as diabetes and ADHD, because there were no cases in the
unexposed group. Despite this and in contrast to our expectations, we found that exposure to vaccination
was independently associated with an overall 2.5-fold increase in the likelihood of developing a chronic
health condition, when compared to children unexposed to vaccination. This association was primarily
driven by increased risk for asthma, atopy, eczema, autoimmune disease and neurodevelopmental
disorders. Overall, our findings suggest that in certain children exposure to vaccination may increase the
likelihood of developing a chronic health condition, particularly for one of these disorders.
Interpretation and comparison with previous studies
Vaccines have contributed to reducing many targeted infections and their related morbidity and
mortality, and are regarded as an important public health achievement of the last century.18 The CDC’s
Vaccine Schedule has evolved from five vaccines in 1994 to 15 in 2020. Despite these advancements,
there is a paucity of data evaluating the impact of vaccination on long-term health outcomes, whether
beneficial or detrimental, particularly for immune-related conditions.
Limited by ethical guidelines, pre-and-post-licensure clinical trials for vaccines rarely include a
comparator arm unexposed to vaccination. These trials also generally have a shorter safety review period
(<30 days) which limits their ability to assess long-term outcomes. Observational studies can address
these data gaps but, to date, have produced conflicting results. Some studies have found an association
between vaccination and an increased risk of asthma, atopy, eczema, autoimmune disease and
neurodevelopmental disorders, as found in this study.13 14 19-28 Other studies have found no association.12
15 29-38 A common and important limitation in this body of work is that almost all studies lack a truly
unexposed comparator group, such as the one in this study, and hence typically evaluate receiving
10
(vaccinated) versus not receiving one vaccine (unvaccinated) in a cohort that receives most other
vaccinations (vaccinated).
For example, one study designed to evaluate the relationship between vaccination status (one or
more versus none) and long-term health outcomes in children was a population-based parental survey
conducted in Germany.31 Although limited by selection bias and parental recall, it found no statistical
association of vaccination with atopy, eczema, or asthma.31 However, the measure of vaccination was
limited to certain vaccines, and the very small unexposed group may have been exposed to other
vaccinations such as varicella, rotavirus, pneumococcal, meningococcal, influenza and/or others.
According to the IOM (2013), few studies have evaluated the Vaccine Schedule, or variations thereof, and
its association with health outcomes and none have compared differences between entirely unvaccinated
populations and those fully or partially vaccinated.10 Our study, to our knowledge, is the first to compare
multiple clinical outcomes over time between vaccinated (any vaccine) and completely unexposed children
in a captured payer environment relying on diagnoses and vaccine status from medical records.
Biologic mechanisms elucidating how vaccine exposure in certain individuals might increase a
health risk are unclear and beyond the scope of this study, but likely differ by condition, vaccine and
recipient characteristics. A common theme in the literature is that vaccination may trigger a genetic and/or
immunologic susceptibility.39 40 Vaccines aim to stimulate an antigen-specific immune response, however
there are significant gaps in understanding the complex immunological mechanisms involved, and concern
has been raised about potential untoward or off-target immunological effects in susceptible recipients.41 42
According to an IOM report, epidemiologic and mechanistic research suggest that most individuals who
experience an adverse response to a vaccine have a preexisting susceptibility due to genetic variants (in
human or microbiome DNA), environmental exposures, behaviors, intervening illness, developmental
stage or others.43 Viewed as an environmental exposure, in addition to antigens, vaccines also contain
small amounts of preservatives, adjuvants, additives and residual substances from the manufacturing
process.44 While this study cannot delineate the impact of epigenetics or a particular vaccine component,
the unexposed group was not exposed to vaccine components, and the exposed group to one or more.
11
Epigenetics is an emerging field of study which explores how the environment can influence how
genes are expressed without involving alterations in the DNA gene sequence. Research has shown that
epigenetics may play a role in the pathogenesis of many diseases, including asthma, atopy, eczema,
autoimmune disease and neurodevelopmental disorders, though precise etiologies vary and remain largely
unknown.45-50 Genetically-mediated individual variations in the immunogenicity and reactivity of vaccines
has been demonstrated.51 52 The field of vaccine ‘adversomics’, though in its infancy, seeks to bring a
precision medicine approach into vaccine practice by utilizing advanced genomic, epigenetic and
biostatistical approaches to better identify individuals susceptible to an adverse vaccine outcome to
prevent or minimize adverse consequences.52 53 This is important because, as the CDC emphasizes,
vaccines are generally given to healthy persons preventatively, and because of their widespread use, any
safety issue, even if rare, can impact large numbers of people.54 The results of this study, while preliminary,
suggest that we currently underestimate the group susceptible to an adverse vaccine effect.
We found a 6-fold increased risk of autoimmune disease in the group exposed to vaccine(s).
Certain vaccines, or adjuvants, have been implicated in autoimmune conditions such as thrombocytopenic
purpura, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis and Guillain-Barré
syndrome.10 23 24 55 The spectrum of autoimmunity encompasses around 80 disorders, most considered
rare, but combined have an estimated population prevalence of 4.5% to 9.4%.56 57 While pathogenic
mechanisms of autoimmune disease are not well understood overall, and even less so with autoimmune
sequelae following vaccination, contemporary thinking favors environmental factors triggering
autoimmunity in genetically-susceptible individuals, involving epigenetic regulation.45 Proposed
mechanisms by which vaccines may contribute to autoimmune reactions are molecular mimicry (structural
similarity between a vaccine component and self-antigen) and bystander activation (microbial agents
activate pre-primed autoreactive immune cells).40
Some studies have found that vaccination and atopic disorders, such as asthma, eczema and other
allergies, are associated, while others have not.12 13 20 22 28 Childhood infections appear to provide significant
protection from atopy and it has been suggested that vaccination can contribute to atopy by inducing an
imbalance between the two classes of T helper cells (Th1 and Th2) in genetically-susceptible individuals.58
12
59 We found an over 4-fold increased risk of asthma and over 6-fold risk of asthma attack in those exposed
to vaccination. This finding is consistent with Odent et. al. which found receiving DTP vaccine, versus no
receipt, was associated with increased risk of asthma (RR=5.43; CI=1.93-15.30).20 In that study, over half
of the group not receiving DTP were exposed to other vaccines and the group with the lowest prevalence
of asthma were not exposed to any vaccine (10.7% for DTP group versus 1.1% in group receiving no
vaccines), though the latter’s small number limited statistical comparisons.
Most studies of vaccination and developmental outcomes evaluated MMR35 36 or thimerosol26 37 60
exposure and autism.61 These studies typically found no association, which is consistent with the results
of this study, though the number of autism cases in this study was small. The few studies that evaluate
potential associations between vaccination and neurodevelopmental disorders beyond autism have
typically used a small dataset of neuropsychiatric evaluations at 7-10 years from the 1990s in which all
participants received all first-year vaccines.38 62 Studies using this dataset have produced conflicting
results.38 62 A recent pilot study using claims data found a temporal relationship between vaccination and
onset of certain neuropsychiatric disorders.27
While contributors to the rise of developmental disability in children from 9.5% in 2009 to 16.9%63
has been grossly understudied, current thinking favors multiple contributors, including the immune system
which is essential to normal brain development and is implicated in the pathogenesis of several
neurodevelopmental disorders.64-66 Epigenetic research is exploring the complex relationship between
developmentally-regulated genetic expression and interplay of prenatal and childhood environmental risk
factors and exposures,47 in addition to factors such as socioeconomic status, preterm-birth, and birth-
weight.67 A study by Iqbal et al. did not find an association between the number of vaccine antigens and
neuropsychological outcomes.68 However, a recent study examined the feasibility of examining non-
antigen vaccine ingredients and found that out of 34 ingredients, only aluminum exposure could be
consistently quantified, but did not subsequently evaluate aluminum’s impact on clinically meaningful
outcomes.69 We found a strong association between vaccine exposure (versus no exposure) and
development of a neurodevelopmental disorder (HR 5.84, CI 3.02-11.27) even after controlling for gender,
race, birth-weight prematurity, and other factors. This increased risk was primarily driven by speech
13
disorders, developmental delays, tics, ADHD, and behavioral and motor disabilities. The etiology of this
association is unclear, but it suggests that vaccination may serve as an environmental influence in
susceptible children.
Strengths of this Study
Major strengths of this study are that it evaluated a captured population, enrolled a consecutive
birth cohort, evaluated subjects only while enrolled, only relied upon medical records to determine
diagnoses, encounters and vaccines administered (unlike prior works which often relied upon parental
recall and survey data), had a completely unexposed cohort, and utilized groupings of health conditions,
which can reveal relationships that are not apparent when evaluating specific disorders individually
(particularly if they are rare).
Though some results were unexpected, others are consistent with conclusions from prior
systematic reviews, including by the IOM, such as the accepted causal relationship between vaccination
and anaphylaxis, which we observed, or the rejection of a causal relationship between vaccination and
cancer or MMR vaccine and autism.43 70 This contributes to the internal validity of this study’s findings.
This study also minimized the risk of misclassifying vaccine exposure. First, studies have shown
good agreement between electronic vaccination and health records and both parental recall and manual
medical record review, particularly for those unexposed to vaccines.71 72 Second, each subject’s EHR
contained vaccine administration data from HFHS and the state immunization registry, ensuring full capture
of vaccinations. In Michigan, all providers are required to report vaccinations to the state registry within 72
hours of administration. This study, to our knowledge, includes the largest cohort of children completely
unexposed to vaccination with observation in some subjects up to 18 years.
Limitations of this Study
This study has limitations. As it is retrospective, we cannot exclude the possibility of unidentified
confounders. However, this concern is tempered by the finding of significant associations between
vaccination and particular outcomes, with some hazard ratios in the 2.5-6 times risk. We lacked information
14
on socioeconomic status, or potentially relevant post birth factors, such as diet or lifestyle, but did adjust
for several important baseline confounders such as gender, ethnicity, gestational age and birthweight. To
detect the potential for uncontrolled confounding, the literature suggests evaluating disorders with no
expected causal association with vaccination, a control outcome, such as injuries or cancer.17 Importantly
in this regard we found no association between vaccine exposure and cancer. Additionally, we relied on
diagnosis codes in administrative data, which is commonly used in epidemiologic research but has some
inherent limitations.
Unvaccinated children have less healthcare utilization overall.73 Well visits coincide with the
vaccination schedule and provide more opportunities for assessment and diagnosis in those receiving
vaccines, compared to unvaccinated children, which could introduce an ascertainment bias. In this study,
exposed children had an average of 7 annual encounters, irrespective of having a chronic health condition.
Unexposed children had an average of 2 annual encounters but an average of almost 5 annual encounters
if diagnosed with a chronic health condition. This likely demonstrates that when a child had a medical
condition, parents sought healthcare. In fact, many conditions evaluated in this study are serious and
cannot be self-treated, such as asthma, diabetes, anaphylaxis or asthma attack, warranting urgent medical
attention. We nonetheless conducted several sensitivity analyses to explore the influence of healthcare
utilization in order to improve the internal validity of this study and minimize potential ascertainment bias.
To ensure the unexposed group’s shorter follow-up duration did not influence the results, we repeated the
Cox proportional hazards analysis for the chronic health composite outcome for those in the plan for one,
three and five years and for those who had at least one healthcare encounter, which demonstrated results
consistent with the overall findings. The association between vaccination and developing a chronic health
condition was independent of these factors. Therefore, our findings do not appear to be due to differential
use of health resources.
Our study solely evaluated whether or not vaccination was associated with clinically relevant
outcomes, conditions that currently contribute to the rising chronic health disease burden in children. We
did not evaluate the influence of temporal relationships, individual vaccines, or the number of vaccines,
which limits this investigation but also minimizes the potential for reverse causality.
15
Conclusion
In this study, we found vaccine exposure in children was associated with an increased risk of developing
a chronic health disorder. This association was primarily driven by increased risk for asthma, atopy,
eczema, autoimmune disease and neurodevelopmental disorders. This suggests that in certain
susceptible children, exposure to vaccination may increase the likelihood of developing a chronic health
condition, particularly for one of these conditions. Our preliminary findings cannot prove causality and
warrant further investigation.
16
FIGURES AND TABLES
Table 1. Birth Characteristics and Demographics Stratified by Vaccine Exposure Status
Demographics
Study Population
(n=18,468)
No Vaccine
(n=1,957)
Any Vaccine
(n=16,511)
P-value
Male 9,395 (51%) 1,077 (55%) 8,318 (50%) <0.001
Race <0.001
White 6,858 (37%) 900 (46%) 5,958 (36%)
African American 6,625 (36%) 453 (23%) 6,172 (37%)
Asian 1,131 (6%) 87 (4%) 1,044 (6%)
Hispanic 503 (3%) 31 (2%) 472 (3%)
Other 3,351 (18%) 486 (25%) 2,865 (17%)
Birth weight <0.001
Normal 17,701 (96%) 1,907 (97%) 15,794 (96%)
Low 539 (3%) 21 (1%) 518 (3%)
Very low 228 (1%) 29 (2%) 199 (1.2%)
Prematurity 1,063 (6%) 34 (2%) 1,029 (6%) <0.001
Respiratory Distress at
Birth
685 (4%) 26 (1%) 659 (4%) <0.001
Birth Trauma 200 (1%) 4 (0%) 196 (1%) <0.001
Vaccine Injections
0
1-10
11-20
21-30
>30
1,958 (10.6%)
3,330 (18.0%)
7,476 (40.5%)
4,981 (27.0%)
724 (3.9%)
Definitions: Birth weight (Normal > 2,500g; low birth weight = less than 2,500g; very low birth weight =
less than 1,500g)
Vaccine exposure for the purpose of comparison of baseline characteristics was receipt of any vaccine
during enrollment in the plan.
17
Table 2. Incidence of Chronic Health Conditions Stratified by Vaccine Exposure Status*
Outcome
Any Vaccine
Exposure
N (Incidence per
1,000,000 pt-yrs)
No Vaccine
Exposure
N (Incidence per
1,000,000 pt-yrs) IRR (95% CI) P
Chronic Health Condition 4,732 (277.3) 160 (111.7) 2.48 (2.12-2.91) <0.0001
Asthma 2,867 (145.6) 52 (35.6) 4.09 (3.11-5.38) <0.0001
Atopic Disease 946 (41.2) 23 (15.6) 2.64 (1.74-3.99) <0.0001
Autoimmune Disease 201 (8.4) 2 (1.4) 6.16 (1.53-24.79) 0.01
Brain Dysfunction 8 (0.3) 0 (0.0)
Cancer 169 (7.0) 13 (8.8) 0.79 (0.45-1.39) 0.42
Diabetes 42 (1.7) 0 (0.0)
Food Allergy 577 (24.3) 30 (20.5) 1.19 (0.82-1.71) 0.36
Mental Health Disorder 341 (15.9) 5 (4.5) 3.50 (1.45-8.46) <0.01
Neurodevelopmental Disorder 1,029 (50.2) 9 (8.2) 6.15 (3.19-11.86) <0.0001
ADHD 262 (12.1) 0 (0.0)
Autism 23 (1.1) 1 (0.9) 1.16 (0.16-8.62) 0.88
Behavioral Disability 165 (7.6) 0 (0.0)
Developmental Delay 219 (10.1) 3 (2.7) 3.74 (1.20-11.68) 0.02
Learning Disability 65 (3.0) 0 (0.0)
Intellectual Disability 5 (0.2) 0 (0.0)
Speech Disorder 463 (21.8) 6 (5.4) 4.02 (1.80-9.00) <0.001
Motor Disability 150 (6.9) 2 (1.8) 3.83 (0.95-15.47) 0.06
Tics 46 (2.1) 0 (0.0)
Other Psychological Disability 9 (0.4) 0 (0.0)
Neurological Disorder 127 (5.2) 12 (8.1) 0.64 (0.35-1.16) 0.14
Seizure Disorder 319 (13.3) 12 (8.2) 1.63 (0.92-2.91) 0.09
* Incident rate ratios could not be calculated for brain dysfunction, diabetes, ADHD, tics, or behavioral,
learning, intellectual, or other psychological disability since all cases occurred in the group exposed to
vaccination and no cases occurred in the unexposed group.
18
Table 3. Cox Proportional Hazards Regression Analysis for Vaccine Exposure and Development
of a Chronic Health Condition*
Outcome
Unadjusted HR
(95% CI) P Adjusted HR (95% CI) P
Chronic Health Condition 2.59 (2.21-3.03) <0.0001 2.54 (2.16-2.97) <0.0001
Asthma 4.50 (3.42-5.93) <0.0001 4.29 (3.26-5.65) <0.0001
Atopic Disease 3.11 (2.06-4.71) <0.0001 3.03 (2.01-4.57) <0.0001
Autoimmune Disease 6.12 (1.52-24.67) 0.01 5.96 (1.48-24.11) 0.02
Brain Dysfunction
Cancer 0.86 (0.49-1.52) 0.61 0.90 (0.51-1.59) 0.72
Diabetes
Food Allergy 1.38 (0.96-2.00) 0.08 1.40 (0.97-2.02) 0.07
Mental Health Disorder 1.69 (0.70-4.09) 0.25 1.63 (0.69-3.82) 0.26
Neurodevelopmental Disorder 5.61 (2.91-10.82) <0.0001 5.53 (2.91-10.51) <0.0001
ADHD
Autism 1.01 (0.13-7.55) 0.99 0.62 (0.10-3.69) 0.60
Behavioral Disability
Developmental Delay 3.87 (1.24-12.10) 0.02 3.28 (1.13-9.55) 0.03
Intellectual Disability
Learning Disability
Motor Disability 3.33 (0.82-13.48) 0.09 2.92 (0.82-10.40) 0.10
Speech Disorder 4.84 (2.16-10.84) 0.0001 4.47 (2.05-9.74) <0.001
Tics
Other Psychological Disability
Neurological Disorder 0.75 (0.41-1.36) 0.34 0.83 (0.46-1.51) 0.55
Seizure Disorder 2.01 (1.13-3.59) 0.02 1.66 (0.94-2.94) 0.08
HR adjusted for gender, race, birth weight, respiratory distress at birth, birth trauma and prematurity.
* Hazard ratios could not be calculated for brain dysfunction, diabetes, ADHD, tics, or behavioral,
learning, intellectual, or other psychological disability since all cases occurred in the group exposed to
vaccination and no cases occurred in the unexposed group.
19
Figure 1. Kaplan Meier Curve: 10-year Chronic Disease-Free Survival by Vaccine Exposure
20
21
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