SAGE Open Medicine
Volume 8: 1–11
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DOI: 10.1177/2050312120925344

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https://doi.org/10.1177/2050312120925344
SAGE Open Medicine
Volume 8: 1–11
© The Author(s) 2020
Article reuse guidelines:
sagepub.com/journals-permissions
DOI: 10.1177/2050312120925344
journals.sagepub.com/home/smo
Introduction
Vaccination is considered to be one of the most important
advances in modern public health.1
Currently, children
between birth and 6years of age receive up to 36 vaccine
doses to protect against 14 different diseases, according to the
Centers for Disease Control and Prevention’s (CDC) recommended schedule.2
By ages 1 and 2years, the CDC recommends approximately 21 and 28 such vaccination doses,
respectively. The number of vaccine doses received by infants
and children has increased most notably since the early 1990s,
when the hepatitis B and Haemophilus influenzae type B
vaccines were introduced. Currently, children in the United
States are vaccinated for hepatitis A and B, Haemophilus
influenzae type B, diphtheria, pertussis, tetanus, polio,
measles, mumps, rubella, rotavirus, pneumococcal pneumonia, influenza and varicella.
Although short-term clinical testing is completed on
individual vaccines (with limited longer-term follow-up for
specific vaccine adverse events) prior to approval by the US
Food and Drug Administration (FDA), the health outcomes
related to these vaccines and the vaccination schedule as a
Analysis of health outcomes in vaccinated
and unvaccinated children: Developmental
delays, asthma, ear infections and
gastrointestinal disorders
Brian S Hooker1 and Neil Z Miller2
Abstract
Objective: The aim of this study was to compare the health of vaccinated versus unvaccinated pediatric populations.
Methods: Using data from three medical practices in the United States with children born between November 2005 and
June 2015, vaccinated children were compared to unvaccinated children during the first year of life for later incidence of
developmental delays, asthma, ear infections and gastrointestinal disorders. All diagnoses utilized International Classification
of Diseases–9 and International Classification of Diseases–10 codes through medical chart review. Subjects were a minimum
of 3years of age, stratified based on medical practice, year of birth and gender and compared using a logistic regression model.
Results: Vaccination before 1year of age was associated with increased odds of developmental delays (OR=2.18, 95% CI
1.47–3.24), asthma (OR=4.49, 95% CI 2.04–9.88) and ear infections (OR=2.13, 95% CI 1.63–2.78). In a quartile analysis,
subjects were grouped by number of vaccine doses received in the first year of life. Higher odds ratios were observed in
Quartiles 3 and 4 (where more vaccine doses were received) for all four health conditions considered, as compared to
Quartile 1. In a temporal analysis, developmental delays showed a linear increase as the age cut-offs increased from 6 to 12
to 18 to 24months of age (ORs=1.95, 2.18, 2.92 and 3.51, respectively). Slightly higher ORs were also observed for all four
health conditions when time permitted for a diagnosis was extended from⩾3years of age to⩾5 years of age.
Conclusion: In this study, which only allowed for the calculation of unadjusted observational associations, higher ORs were
observed within the vaccinated versus unvaccinated group for developmental delays, asthma and ear infections. Further
study is necessary to understand the full spectrum of health effects associated with childhood vaccination.
Keywords
Vaccination, developmental delays, asthma, ear infections, gastrointestinal disorders
Date received: 18 June 2019; accepted: 20 April 2020
1
Department of Sciences and Mathematics, Simpson University, Redding,
CA, USA
2
Institute of Medical and Scientific Inquiry, Santa Fe, NM, USA
Corresponding author:
Brian S Hooker, Department of Sciences and Mathematics, Simpson
University, 2211 College View Drive, Redding, CA 96003, USA.
Email: drbrianhooker@gmail.com
925344SMO0010.1177/2050312120925344SAGE Open MedicineHooker and Miller
research-article2020
Original Article
2 SAGE Open Medicine
whole are largely unknown.3
For instance, Kuter et al.4
detailed 23 different post-licensing trials conducted on the
measles, mumps and rubella (MMR)-II vaccine and in no
instance were the patients followed for more than 42 days
post-vaccination. In 2011, the Institute of Medicine (IOM)5
published the report “Adverse Effects of Vaccines: Evidence
and Causality” where the relationships between specific
vaccines and different adverse health effects were considered. Based on the current scientific literature, the IOM
committee found inadequate evidence to accept or reject a
causal relationship between 135 of 158 relationships
between vaccines and adverse events. Among the remaining
23 adverse events, 18 were found to be associated with vaccination and 5 were not.
The medical community does in general acknowledge
that vaccination is not without health risks, including death.6
However, it is widely purported that these side effects or
“adverse events” are extremely rare and justified compared
to the overall benefit of vaccination.7
There have been very
few studies reported where health effects of the US infant
and childhood vaccination schedule have been assessed.
This is in part based on ethical concerns of withholding vaccination from an unvaccinated control group within such a
study.8
Indeed, this precludes the use of double-blinded placebo studies on vaccine health effects, and even in clinical
trials an earlier version of the same vaccine is often used as
the placebo control for the newly tested vaccine.
One study, published by Mawson et al.,3
was based on a
convenience sample of homeschooled children where a significant portion of the sample (39%) was unvaccinated. In
this small sample, vaccinated children showed higher odds
of being diagnosed with pneumonia, otitis media, allergies
and neurodevelopmental disorders. In addition, preterm birth
coupled with vaccination significantly increased the odds of
a neurodevelopmental disorder diagnosis. This study was
unique in the inclusion of entirely unvaccinated populations
to provide a comparison to partially vaccinated and fully
vaccinated children. However, the risk of bias is high when
comparing vaccinated versus unvaccinated children. Also,
health outcomes were based on parental survey, not confirmed by medical chart review, and may be subject to recall
bias, and the small size of the sample (666 patients) made it
difficult to analyze for rare disorders.
Between 2001 and 2004, the IOM9
Immunization Safety
Review Committee rejected a relationship between multiple
vaccinations and sudden infant death syndrome (SIDS) but
could not rule out a relationship with other types of “sudden
unexpected infant death.” This included the neonatal hepatitis B vaccine as well as the diphtheria and tetanus toxoids
and whole-cell pertussis (DTwP) vaccine, which was
strongly associated with anaphylaxis but is no longer given
in the United States. A relationship between multiple vaccines and type 1 diabetes was ruled out, but evidence was
inadequate to accept or reject a relationship with asthma.10 In
addition, the committee rejected a relationship between
multiple vaccines and increased “heterologous” infections,
such as bacterial infections unrelated to vaccine-preventable
diseases, although recent studies have provided evidence of
both beneficial and detrimental non-specific effects associated with several vaccines.11–13 The remainder of the IOM
Immunization Safety Review Committee focused on single
types of vaccines and specific adverse events as recommended by the CDC who commissioned these studies.
In the study presented here, children from three different
pediatric medical practices in the United States were used as
a convenience sample for comparing patients vaccinated and
unvaccinated within the first year of life. Vaccination records
were based on data within each practice’s electronic medical
records (EMRs) system. Four different diagnoses were evaluated, along with one control diagnosis presumed not to correlate with vaccination status. To allow time for a diagnosis
to be made, children were a minimum of 3 years of age for
each analysis completed (except for Table 9, where the minimum age was extended).
Materials and methods
Source of data
Patient data were obtained from EMR systems from three
pediatric practices in the United States. All data used directly
for the study were first de-identified such that specific patient
identification could not be made from the source files used in
statistical programming. The Institutional Review Board at
Simpson University for research with human subjects
reviewed and authorized this analysis independent of the
researchers.
Patients in the study were a minimum of 3 years of age
and continuously enrolled in their medical practice from
birth to June 2018. All patients were born after November
2005. The process of cohort selection is shown in Figure 1.
Vaccination date, age at the time of vaccination and type
(when available) were obtained from practice EMRs and
tabulated in a separate, de-identified data file. All diagnoses
considered were based on appropriate International
Classification of Diseases (ICD)-9 and ICD-10 codes.
Diagnoses considered included developmental delays,
asthma, ear infections and gastrointestinal disorders. Head
injury was included as a negative control outcome, or control
diagnosis, presumed not to be associated with vaccination
status. Other diagnoses, including autism and ADD/ADHD,
were considered for assessment. However, insufficient numbers of cases existed among the practices to complete a rigorous statistical analysis.
Diagnosis codes (ICD-9 and ICD-10) used for each condition are shown in Table 1. Truncated codes, for example,
ICD-9 code 315 (specific delays in development) as a broad
category for developmental delays, include all codes under
that classification. An ICD-9 code of 315.9 (unspecified
delay in development) would, therefore, be counted as a case
Hooker and Miller 3
in the category “developmental delay.” Also, in some
instances, such as “gastrointestinal disorders,” a range of
ICD-9 and ICD-10 codes was used to determine cases.
Specifically for gastrointestinal disorders, only non-infective
enteritis and colitis were considered.
Since ear infections may occur more than once in the
same child, cases were identified as children who received
the diagnosis code in at least one medical provider visit.
Thus, for example, children who had one ear infection or
multiple ear infections were counted as cases and children
with no reported ear infections were counted as non-cases.
Patients in the “vaccinated” category received a minimum
of one vaccine dose prior to their first birthday plus 15 days
to capture 1-year vaccines as recommended in the CDC
schedule, whereas “unvaccinated” patients had no vaccine
doses on record prior to their first birthday plus 15 days.
Number of vaccine doses received prior to 1 year of age was
calculated as the number of times an ICD-9 or ICD-10 code
for vaccination was recorded in the patient’s EMR. This age
cut-off was used because the largest proportion of vaccines
given based on the US CDC infant and child vaccination
schedule is administered prior to 1year of age (21 vaccine
doses from birth to 1 year of age versus 33 vaccine doses
from 1 to 18years of age). This also accounted for multiple
vaccine doses given in a single visit to the medical provider.
(Tetanus–diphtheria–acellular pertussis (TdaP) and MMR,
among other combination vaccinations, were counted as one
vaccine, although they consist of three vaccines in a single
injection.) Due to differences in recording practices among
the participating pediatricians, no attempts were made in this
study to differentiate between the types of vaccines administered to these infants. In addition, due to unavailability of the
type of vaccine given in each visit in one of the medical practices, temporal relationships between specific vaccines and
diagnoses were not taken into account.
Analysis method
This study employed a cohort study design with strata for
medical practice, year of birth and gender. Cases were evaluated against non-cases for an association between vaccination status and the different health conditions considered
using a conditional logistic regression model. SAS®
University Edition was used for statistical analyses with relationships deemed significant at p<0.05 without correction
for the number of statistical tests performed. In general, with
a sample size of approximately 2000 subjects, the study was
designed to have a power of 80% to detect odds ratios of 1.8
(α=0.05 and a confidence level of 0.95), but because of
some more rare diagnoses, 80% power in select instances
was only sufficient to detect odds ratios of 2.4 and above. No
covariates were considered in this model due to the lack of
availability of relevant maternal and birth data.
In the primary analysis (Table 4), outcomes for “vaccinated children” were compared directly to those for “unvaccinated children.” Children who received no vaccines during
the first year of life (plus 15days) were considered as “unvacFigure 1. Creation of study cohorts for each analysis. cinated” regardless of vaccines that might have been received
Table 1. Diagnosis codes used.
Diagnosis ICD-9 code(s) ICD-10 code(s) Description
Developmental delay 315 F80–F82 Specific delays in development
Asthma 493 J45 Asthma, excludes wheezing, not otherwise specified
Ear infection 382 H66, H67 Suppurative and unspecified otitis media
Gastrointestinal disorder 555–558 K50–K52 Non-infective enteritis or colitis
Head injury 959.01 S00–S09 Head injury (non-specific)
ICD: International Classification of Diseases.
4 SAGE Open Medicine
after their first birthday. The unvaccinated group consisted of
83.7% children unvaccinated within their entire EMR and
16.3% children who received their first vaccine after 1 year
of age, based on the 3-year-old and above total cohort. This
analysis was completed on all children as well as males and
females separately (Tables 5 and 6). Diagnoses were considered for both vaccinated and unvaccinated subjects only
when they occurred after the first birthday (plus 15 days).
Children receiving diagnoses prior to their first birthday
(plus 15 days) were excluded from each specific analysis.
In the second analysis (Table 7), subjects were separated
into quartiles based on the number of vaccine doses received
within the first year of life (plus 15 days) calculated based on
the distribution among the sample with a median of nine vaccine doses. The first quartile included children who received
1–5 vaccine doses (n=353), the second included children
who received 6–10 vaccine doses (n=390), the third included
children who received 11–12 vaccine doses (n=417) and the
fourth included children who received 13–21 vaccine doses
(n=254). Diagnoses for conditions within this analysis were
considered only if they were made after each child’s first
birthday (plus 15 days). This analysis was limited to vaccine
doses received in the first year of life to capture a significant
portion of the diagnoses that may occur early in life, including ear infections and gastrointestinal disorders.
In the third analysis (Table 8), vaccination status was considered at separate age intervals from birth to 6months,
1year, 18months and 2years in four separate analyses.
Diagnoses were considered only after the age interval of
vaccination. A fourth analysis (Table 9) was also completed
which was identical to the first analysis (considering vaccination status up to the first birthday). However, the age cutoff for the cohort was 5 years and above, rather than 3years
and above, to give additional time for children to be diagnosed with the conditions considered.
Results
Demographic data
Demographic data for the study sample are shown in Table 2.
The overall sample size, including children under 3years of
age, is 4821, of which 44.5% were unvaccinated, while 55.5%
were vaccinated. Among the 3797 children over 1year of age,
37.6% were unvaccinated and 62.4% were vaccinated.
Considering children with continuous follow-up who were
over 3years of age reduced the sample to 2047 patients, with
52% males. Unvaccinated children by 1year of age comprised
30.9% of the sample as compared to vaccinated children
(69.1%). The most prevalent diagnosis was ear infection.
Additional demographic data in Table 3 include the number of vaccines administered prior to each child’s first birthday (range=1–21), the age of first vaccination in days
(mean=102, or 3.3months) and the age of the children at the
conclusion of the study period (mean=5.6years). Finally,
the ages of the first diagnosis for each of the conditions
considered in the analyses are included. While diagnoses,
such as developmental delays, asthma and head injury,
occurred generally after the 1-year cut-off age for the analyses, a significant number of ear infection (48.2%) and gastrointestinal disorder (38.7%) diagnoses were made prior to the
first birthday.
Statistical analysis
Table 4 shows results when cases were compared to noncases in vaccinated versus unvaccinated categories (3years
of age and above with diagnoses considered only after the
first birthday). Vaccination before 1 year of age was associated with increased odds of developmental delays (odds
ratio, OR=2.18, 95% CI 1.47–3.24), asthma (OR=4.49,
95% CI 2.04–9.88) and ear infections (OR=2.13, 95% CI
1.63–2.78). No relationship was observed for gastrointestinal disorders and head injuries (the control diagnosis).
Similar results were observed for males only (Table 5) with
a sharp increase in the OR for asthma (6.89, 95% CI 2.10–
22.6, p=0.0015). In females only (Table 6), an increase in
OR was observed for developmental delays (OR=3.10, 95%
CI 1.37–7.01, p=0.0068). Confidence intervals for this relationship are consistent with overall and “males only” results.
Also for females only, the result for asthma fell below the
level of significance (p=0.068). The remainder of the conditions studied showed responses consistent with previous
results for males and the entire sample.
Results from the quartile analysis, assessing number of
vaccine doses received over the first year of life compared to
unvaccinated children, are shown in Table 7. Higher ORs were
observed in Quartiles 3 and 4 (where more vaccine doses were
received) for all four health conditions considered, as compared to Quartile 1. A consistent linear increase in ORs with
increasing vaccine doses is observed for gastrointestinal disorders, although the relationship is only significant in the third
and fourth quartiles (OR=3.77, 95% CI 1.65–8.59 and
OR=4.03, 95% CI 1.57–10.3, respectively). Relationships for
asthma and developmental delay are non-significant for the
first quartile only but ORs peak within the second quartile for
Table 2. Demographic data.
Category Male Female Total
Total sample 2483 2338 4821
Over 3years of age 1063 984 2047
Unvaccinated by age 1year 345 288 633 (30.9%)
Vaccinated by age 1 year 718 696 1414 (69.1%)
First vaccine after age 1year 64 39 103 (16.3%)a
Developmental delay 140 57 197 (9.6%)
Asthma 48 32 80 (3.9%)
Ear infection 451 375 826 (40.4%)
Gastrointestinal disorder 64 55 119 (5.8%)
Head injury 83 63 146 (7.1%)
a
Percentage of unvaccinated sample by age 1year.
Hooker and Miller 5
asthma and within the third quartile for developmental delay,
followed by a decline—although still highly significant—
within subsequent quartiles. The control diagnosis does not
show a relationship in any of the quartiles.
Within the temporal analysis (results shown in Table 8),
vaccines were considered to the cut-off ages (6, 12, 18 and
24months) and diagnoses were included only after those cutoff ages. Thus, the 6-month cut-off would help to account for
early diagnoses, especially of ear infections and gastrointestinal disorders which were diagnosed often within the first year
of life. The unvaccinated group was comprised of children
receiving their first vaccines only after each age cut-off. A
consistent linear increase in ORs was observed for developmental delays as the age cut-offs increased from 6 to 12 to 18
to 24months of age (ORs=1.95, 2.18, 2.92 and 3.51, respectively). All results for developmental delays were statistically
significant as were all results for asthma and ear infections.
Asthma, which was associated with the highest mean age of
diagnosis of all conditions studied, showed the highest OR at
the 24-month cut-off (OR=5.99, 95% CI 2.15–16.7), similar
to the result for developmental delays. However, the increase
observed between the 6-month and 24-month cut-offs was
not consistent. The ORs for ear infections were nearly constant at all age cut-offs while the relationship for gastrointestinal disorders was highest and significant only at the 6-month
cut-off (OR=2.02, 95% CI 1.23–3.33). A single significant
relationship was seen for the head injury control diagnosis at
the 18-month vaccination cut-off.
A final analysis was completed similar to the analysis presented in Table 4 but with children in the sample who were
5years and above prior to the cut-off date of June 2018.
Results for this group (Table 9) are consistent with those
observed previously. When the time permitted for a diagnosis was extended from children⩾3years of age to children⩾5years of age, slightly higher ORs were detected for
all four health conditions: developmental delays (OR=2.36,
95% CI 1.29–4.31), asthma (OR=4.93, 95% CI 1.75–13.9),
ear infections (OR=2.49, 95% CI 1.65–3.76) and gastrointestinal disorders (OR=2.48, 95% CI 1.02–6.02).
Discussion
Within this study, the number of vaccines received and vaccination status early in life are related to different acute and
chronic conditions. The strongest relationships observed for
vaccination status were for asthma, developmental delays
and ear infections (Table 4). Although the association
between vaccinations and asthma in males was elevated
(Table 5), it should be noted that there were only three asthma
cases in the unvaccinated group. No association between
Table 4. Vaccinated versus unvaccinated (during the first year of life), stratified based on medical practice, gender and year of birth
(child⩾3years of age).
Diagnosis Vaccinated
Cases/total
Unvaccinated
Cases/total
Odds ratio
(95% CI)
p-value
Developmental delay 153/1407
(10.9%)
34/630
(5.4%)
2.18 (1.47–3.24) 0.0001
Asthma 67/1412
(4.7%)
7/629
(1.1%)
4.49 (2.04–9.88) 0.0002
Ear infection 324/1116
(29.0%)
104/533
(19.5%)
2.13 (1.63–2.78) <0.0001
Gastrointestinal disorder 55/1382
(4.0%)
18/619
(2.9%)
1.47 (0.84–2.57) 0.17
Head injury 93/1398
(6.7%)
31/627
(4.9%)
1.26 (0.82–1.94) 0.29
CI: confidence interval.
Table 3. Additional demographic data (children aged 3years and above).
Variable Mean Standard
deviation
Minimum Maximum
Number of vaccines (vaccinated by age 1 year) 8.9 4.1 1 21
Age of first vaccine (days, vaccinated by age 1year) 102 65 2 380
Age as of June 2018 (years) 5.6 2.2 3 12.8
Age of developmental delay diagnosis (days/years) 775/2.1 458/1.3 113/0.31 2284/6.3
Age of asthma diagnosis (days/years) 1156/3.2 608/1.7 274/0.75 2616/7.2
Age of ear infection diagnosis (days/years) 520/1.4 464/1.3 3/0.01 4393/12.0
Age of gastrointestinal disorder diagnosis (days/years) 647/1.8 556/1.5 27/0.07 4073/11.2
Age of head injury diagnosis (days/years) 1034/2.8 767/2.1 33/0.09 3714/10.2
6 SAGE Open Medicine
vaccinations and asthma in females was found (Table 6); this
may also be due to just four asthma cases in the unvaccinated
group. Although some studies were unable to find correlations between vaccines and asthma,14,15 a relationship
between vaccination and allergy/atopy incidence (including
asthma) has been reported.16–18 In a study involving Korean
children who were all vaccinated against hepatitis B, a significantly higher asthma incidence was seen among children
who had actually seroconverted to produce anti-HepB.16 In
addition, Hurwitz and Morgenstern17 reported an association
between diphtheria–tetanus–pertussis (DTP) and tetanus
toxoid vaccination and allergy symptoms and could not rule
out a relationship with asthma. In an animal study, mice vaccinated according to the Chinese infant vaccine schedule
showed airway hyperresponsiveness at a significantly higher
rate than unvaccinated mice.18
Table 7. Quartile analysis, vaccinated versus unvaccinated (during the first year of life), stratified based on medical practice, year of
birth and gender (child⩾3 years of age).
Diagnosis Quartile 1
1–5 vaccines
(95% CI)
Quartile 2
6–10 vaccines
(95% CI)
Quartile 3
11–12 vaccines
(95% CI)
Quartile 4
13–21 vaccines
(95% CI)
Developmental delay 1.36 (0.53–3.48) 2.54 (1.30–4.96) 3.22 (1.70–6.09) 2.42 (1.17–4.99)
Asthma 1.94 (0.59–6.40) 6.48 (2.64–15.9) 3.66 (1.42–9.46) 4.62 (1.68–12.7)
Ear infection 1.43 (0.98–2.07) 2.48 (1.72–3.60) 2.26 (1.53–3.33) 2.81 (1.80–4.40)
Gastrointestinal disorder 0.49 (0.19–1.31) 1.61 (0.68–3.84) 3.77 (1.65–8.59) 4.03 (1.57–10.3)
Head injury 0.68 (0.32–1.44) 1.56 (0.93–2.62) 1.12 (0.65–1.94) 1.37 (0.73–2.56)
CI: confidence interval.
Table 6. Females only, vaccinated versus unvaccinated (during the first year of life), stratified based on medical practice, gender and
year of birth (child⩾3 years of age).
Diagnosis Vaccinated
Cases/total
Unvaccinated
Cases/total
Odds ratio
(95% CI)
p-value
Developmental delay 46/693
(6.6%)
7/287
(2.4%)
3.10 (1.37–7.01) 0.0068
Asthma 27/696
(3.9%)
4/287
(1.4%)
2.70 (0.93–7.87) 0.068
Ear infection 154/562
(27.4%)
42/243
(17.3%)
2.20 (1.48–3.26) <0.0001
Gastrointestinal disorder 26/681
(3.8%)
8/282
(2.8%)
1.44 (0.64–3.25) 0.39
Head injury 42/688
(6.1%)
10/285
(3.5%)
1.69 (0.83–3.43) 0.15
CI: confidence interval.
Table 5. Males only, vaccinated versus unvaccinated (during the first year of life), stratified based on medical practice and year of birth
(child⩾3years of age).
Diagnosis Vaccinated
Cases/total
Unvaccinated
Cases/total
Odds ratio
(95% CI)
p-value
Developmental delay 107/714
(15.0%)
27/343
(7.9%)
1.92 (1.21–3.04) 0.0054
Asthma 40/716
(5.6%)
3/342
(0.9%)
6.89 (2.10–22.6) 0.0015
Ear infection 170/554
(30.7%)
62/290
(21.4%)
2.07 (1.45–2.57) <0.0001
Gastrointestinal disorder 29/701
(4.1%)
10/337
(3.0%)
1.51 (0.70–3.23) 0.29
Head injury 51/710
(7.2%)
21/342
(6.1%)
1.05 (0.61–1.80) 0.87
CI: confidence interval.
Hooker and Miller 7
The IOM19 Immunization Safety Review Committee
conducted an evaluation regarding thimerosal-containing
vaccines and concluded that “the hypothesis that exposure to
thimerosal-containing vaccines could be associated with
neurodevelopment disorders” was biologically plausible.
Mawson et al.3
found a relationship between vaccination status and learning disability and neurodevelopmental disorders.
Delong20 also reported a significant relationship to neurodevelopmental disorders (autism and speech and language
delay) when looking at the proportions of vaccine uptake in
US children. Other research, focused more on the uptake of
specific vaccines, has elucidated such relationships. Gallagher
and Goodman21 saw a greater number of boys receiving special education services if they had received the entire hepatitis
B vaccine series in infancy. Geier et al.22–24 also documented
a link between neurodevelopmental disorders and thimerosalcontaining vaccines. (Although thimerosal has been phased
out of most vaccines administered in the United States, it still
remains in some formulations of the influenza vaccine given
to pregnant women and infants.)
Mawson et al.3
reported a significant relationship between
vaccination status and ear infections. Wilson et al.25 found
that for both males and females, top reasons for emergency
room visits and/or hospital admissions after their 12-month
vaccinations included ear infections and non-infective gastroenteritis or colitis. Prior to the RotaTeq rotavirus vaccine
achieving FDA approval, 71,725 infants were evaluated in
three placebo-controlled clinical trials. Otitis media (middle
ear infection) occurred at a statistically higher incidence
(p<0.05) within 6weeks of any dose among the recipients
of RotaTeq as compared with the recipients of placebo.26
Within the quartile analysis (Table 7), asthma was nonsignificant in the first quartile, peaked in the second quartile
(OR=6.48, 95% CI 2.64–15.9), then decreased in the third
and fourth quartiles but maintained significance (OR=3.66,
95% CI 1.42–9.46 and OR=4.62, 95% CI 1.68–12.7, respectively). Developmental delays followed a similar pattern,
although the peak occurred in the third quartile. This may
indicate the presence of “healthy user bias” within the overall sample where healthy subjects continue to vaccinate but
subjects with health issues limit or curtail further vaccination, as defined previously by Fine and Chen.27 These authors
discussed the phenomenon where avoidance or delay of
vaccination is associated with an increased risk of vaccine
adverse events. In other words, healthier vaccinated children
are more likely to stay “up-to-date” with vaccinations,
whereas children showing health issues may opt for a delayed
schedule or to skip specific vaccines. In the context of their
article, Fine and Chen pointed out that this may confound
analyses of risks associated with vaccinated versus unvaccinated children leading to an under-ascertainment of risk.
However, in the analysis presented in this article, the number
Table 8. Temporal analysis, vaccinated versus unvaccinated (during 6, 12, 18 and 24months of life), stratified based on medical practice,
year of birth and gender (child⩾3years of age).
Diagnosis 6months
(95% CI)
12months
(95% CI)
18months
(95% CI)
24months
(95% CI)
Developmental delay 1.95 (1.35–2.84) 2.18 (1.47–3.24) 2.92 (1.81–4.72) 3.51 (1.94–6.35)
Asthma 3.10 (1.64–5.85) 4.49 (2.04–9.88) 3.74 (1.69–8.28) 5.99 (2.15–16.7)
Ear infection 1.97 (1.58–2.46) 2.13 (1.63–2.78) 2.22 (1.61–3.05) 2.08 (1.42–3.04)
Gastrointestinal disorder 2.02 (1.23–3.33) 1.48 (0.84–2.57) 1.45 (0.74–2.82) 1.25 (0.60–1.45)
Head injury 1.32 (0.88–1.99) 1.26 (0.82–1.94) 1.77 (1.04–3.01) 1.29 (0.73–2.29)
CI: confidence interval.
Table 9. Vaccinated versus unvaccinated (during the first year of life), stratified based on medical practice, gender and year of birth
(child⩾5years of age).
Diagnosis Vaccinated
Cases/total
Unvaccinated
Cases/total
Odds ratio
(95% CI)
p-value
Developmental delay 83/800
(10.4%)
14/272
(5.1%)
2.36 (1.29–4.31) 0.0051
Asthma 45/803
(5.6%)
4/273
(1.5%)
4.93 (1.75–13.9) 0.0026
Ear infection 168/648
(25.9%)
40/235
(17.0%)
2.49 (1.65–3.76) <0.0001
Gastrointestinal disorder 37/776
(6.5%)
6/268
(2.2%)
2.48 (1.02–6.02) 0.045
Head injury 63/797
(7.9%)
16/270
(5.9%)
1.58 (0.89–2.81) 0.12
CI: confidence interval.
8 SAGE Open Medicine
of vaccine doses was compared (through quartiles) directly
to fully unvaccinated children to minimize such bias. In contrast to asthma and developmental delays, higher ORs were
observed in Quartiles 3 and 4 for all four health conditions
considered, as compared to Quartile 1, which may indicate a
cumulative effect of vaccine doses.
The temporal analysis (Table 8) allowed different cut-off
ages of vaccination status and diagnosis. For example, at
6months, only vaccine doses between birth and 6months
were counted and diagnoses were considered only after
6months of age. The earlier cut-off of 6months allowed the
accounting of more diagnoses of ear infections and gastrointestinal disorders which possess an earlier mean diagnosis
age. However, this resulted in a trade-off whereby fewer vaccinated children were available to assess. Conversely, at
24months, a greater number of vaccinated children were
accounted for but at the expense of diagnoses prior to that age
cut-off. Interestingly, developmental delays, which possessed
a higher mean age of diagnosis showed a linear increase in
ORs with increasing cut-off age. Asthma, which possessed
the highest mean age of diagnosis of all conditions studied
also showed the highest OR at the 24-month cut-off. However,
the increase observed between the 6-month and 24-month
cut-offs was not consistent and may reflect the low number of
asthma cases in the overall sample. The OR for gastrointestinal disorders was highest and significant only at the 6-month
cut-off, which may suggest a connection with earlier vaccination in children. A single significant relationship was seen for
the head injury control diagnosis at the 18-month vaccination
cut-off, which may be indicative of differences in healthcareseeking behavior among families of vaccinated versus unvaccinated children. This might also be an artifact of the small
number of injuries overall in the analysis group which could
introduce granularity within analyses involving subgroups of
vaccinated subjects (Tables 7 and 8). This limits our ability to
see potential confounding and bias within this study.
In the final analysis (Table 9), higher ORs were detected
for all four health conditions when the time permitted for a
diagnosis was extended from children⩾3 years of age to
children⩾5years of age. This higher age requirement
allowed additional time for children to receive diagnoses,
which is important especially for developmental delays and
asthma which are diagnosed later within the sample (Table
3). However, this also resulted in fewer children overall,
including only four children with an asthma diagnosis in the
unvaccinated group.
Statistical significance was seen for gastrointestinal disorders when considering the third and fourth quartiles of
vaccine doses, at the 6-month cut-off age in the temporal
analysis, and when additional time was permitted for a diagnosis. The remaining analyses did not show a relationship.
Although Wilson et al.25 found an association between
12-month vaccinations and emergency room visits for noninfective gastroenteritis, there is a paucity of research elsewhere regarding gastroenteritis following vaccination, with
the majority focused on intussusception following the rotavirus vaccine.28–31 Other reports have attributed gastrointestinal disorders as adverse events following the oral polio
vaccine32 and the human papillomavirus vaccine.33
Study strengths
One of the main strengths of this study is that the data are
based directly on patient chart records and diagnosis codes.
Practitioners making these diagnoses were also directly
available for consultation on how specific diagnosis codes
were applied. In addition, vaccination records were based on
patient chart data, although coding practices for vaccination
varied among the three different pediatric practices. To
account for any differences in diagnosing among the three
different practices, cases and non-cases were stratified based
on medical practice. Thus, no “cross comparisons” were
made among two or more medical practices. To account for
differences in likelihood of particular diagnoses based on the
age and gender of the patient, cases and non-cases were stratified based on the year of birth and gender.
It is possible that diagnoses may have been missed or
information regarding vaccines administered could have been
incorrectly recorded leading to exposure misclassification,
which might explain the high rates of unvaccinated children
in the cohort. However, all children considered in the study
were enrolled in their medical practice from birth and followed up continuously to minimum age cut-offs of 3years
(Tables 4–8) and 5years (Table 9). This minimized the risk of
missing vaccination doses or diagnoses associated with tracking patients with multiple practitioners. This also eliminated
recall bias associated with studies focused on parental surveys. The high proportion of unvaccinated children is most
likely indicative of pediatric practices which accepted unvaccinated and partially vaccinated children into their case load.
Also, cut-off dates (e.g. 1year plus 15days) established
clear boundaries between the time when a child’s vaccination
status could be determined and when diagnoses would be considered. Any vaccines received by the child were tallied prior
to the cut-off and diagnoses were considered only after the
cut-off. Any child receiving a diagnosis prior to the age cut-off
was eliminated from that portion of the analysis. In this
respect, this study focuses more on vaccines received earlier in
life rather than those received after 1 and 2years of age. For
the 1-year and 2-year cut-offs, 83.7% and 91.1% of individuals were by definition “completely unvaccinated,” respectively (calculated based on the entire unvaccinated sample for
each cut-off), whereas the remainder received their first vaccines after the cut-off age. This would tend to exert bias toward
the null hypothesis as diagnoses in the “unvaccinated” group
could instead be those in the vaccinated group.
Finally, effect estimates in this article were generally
above 2.0. Thus, for some confounder to explain this association, it would need to be twice as frequent in vaccinated
children.34
Hooker and Miller 9
Potential limitations
The main weakness of this study is the use of a convenience
sample of three different pediatric practices. In addition, the
size of the sample, although sufficient for some diagnoses,
such as the five main conditions studied, was too small for
analysis of conditions with lower prevalence, such as autism.
Also, this sample may not accurately represent a crosssection of US children given the low incidence of autism
(0.5%) and ADD/ADHD (0.7%) compared to incidences
observed nationwide (at 1.7%35 and between 5% and 9%,36
respectively). In addition, vaccine uptake, which is approximately 95% nationwide, is rather low in these practices and
may reflect demographic differences between the study sample and the general population. Also, due to different coding
practices among the three caseloads studied, we were unable
to differentiate between the types of vaccinations given. This
limited the analysis to counting the number of vaccinations
received by 1 year of age.
The low level of vaccine uptake overall in these practices
(mean=8.9 vaccines by 1year of age) obviates our ability to
do a comparison between fully vaccinated and unvaccinated
children within this cohort. Also, the median age at first vaccine dose in the cohort was 81days (just under 3months) as
compared to the hepatitis B vaccine that is recommended
within 24h of birth. Medical chart records did not include specific demographic factors that may be associated with health
outcomes, including socioeconomic status, maternal education, gestational age at birth, Appearance, Pulse, Grimace,
Activity and Respiration (APGAR) score, type of birth and
duration of breastfeeding, among others. The “hygiene
hypothesis” has shown relationships between type of birth/
breastfeeding and allergies, asthma and eczema.37,38 There are
undoubtedly demographic differences within the two groups
studied (vaccinated versus unvaccinated), especially regarding socioeconomic status and maternal education. According
to Smith et al.,39 mothers in families where vaccines were
delayed and refused tended to have higher levels of college
education and families were more affluent. Although there are
no direct studies on gestational age at birth in vaccinating versus non-vaccinating families, Zerbo et al.40 indicated that children born to women receiving the influenza vaccine during
pregnancy had significantly higher gestational age. Dueker
et al.41 showed that each week of gestational age beyond 35–
41weeks significantly decreased developmental delays in
infants. In addition, children born prematurely (34–37weeks)
also showed a higher rate of hospitalizations for asthma.42
It was also difficult to discern healthcare-seeking behavior among families of vaccinated versus unvaccinated children outside of assessment of the control diagnosis, head
injury, which showed significance only within one group in
the temporal analysis. The three participating medical practices recommended that all children go to well-child visits
regardless of whether they were receiving vaccines.
However, none of the practices kept data on the frequency of
visits. If more vaccinated than unvaccinated children showed
up at these check-ups, this would be indicative of a difference in healthcare-seeking behavior and could lead to more
diagnoses in the group that was seen by the practitioner more
often. There was a higher proportion of unvaccinated children in the overall sample as compared to those who were
included in the main analysis, which could be indicative of
divergent healthcare-seeking behavior. However, the overall
sample included children who were excluded from the main
analysis because they were younger than the study permitted
(Figure 1). Many of these children were classified as unvaccinated prior to their exclusion although their true vaccination status was indeterminate as they had not yet achieved
1year (and 15 days) of age. This had the effect of artificially
inflating the proportion of unvaccinated children in the overall sample.
Glanz et al.43 reported that undervaccinated children
showed significantly lower rates of outpatient medical provider visits (incidence risk ratio=0.89, 95% CI 0.89–0.90)
within a large retrospectively matched cohort study involving
the CDC’s Vaccine Safety Datalink. However, in this study,
consistent relationships were observed within three of the
health conditions considered as compared to marginal significance seen for head injury in only one analysis involving a
subgroup of the cohort. Homeschooling families have been
shown to have lower vaccination rates44 which may also contribute to differences in healthcare-seeking behavior given
that homeschooled children could be underdiagnosed. This
type of demographic data was not available for the analysis.
Recent studies have shown that some vaccines have nonspecific effects that either increase or decrease susceptibility
to infectious diseases not targeted by the vaccine. The most
recent vaccine administered exerts the greatest effect. Live
vaccines, such as measles, MMR and Bacillus Calmette–
Guérin (BCG), tend to lower risk (providing a protective
influence), while non-live vaccines, such as hepatitis B,11 DTP
and inactivated polio (IPV), tend to increase risk. For example, Bardenheier et al.12 found a lower risk of non-targeted
infectious disease hospitalizations among children whose last
vaccine received was live compared with inactivated vaccine
(hazard ratio (HR)=0.50, 95% CI 0.43–0.57). In a recent
meta-analysis conducted by Aaby et al.,13 girls who received
an inactivated vaccine after receiving a measles vaccine were
significantly more likely to die from other causes compared
with girls who received an inactivated vaccine before receiving a measles vaccine (mortality rate ratio (MRR)=1.89, 95%
CI 1.27–2.80). Although this current study did not consider
non-specific effects (due to differences in how the three pediatricians recorded patient data), it is possible that the most
recent vaccine administered could have influenced the results.
No effort was made to assess children who may have lost
diagnoses for chronic disorders, such as developmental delay
and asthma. However, according to the CDC, developmental
disabilities “usually last throughout a person’s lifetime.”45
Asthma is normally a lifelong chronic condition as well.46
Since losing these diagnoses is rare, this is unlikely to have
affected the results.
10 SAGE Open Medicine
Conclusion
In this study, based on a convenience sample of children
born into one of three distinct pediatric medical practices,
higher ORs were observed within the vaccinated versus
unvaccinated group for developmental delays, asthma and
ear infections. No association was found for gastrointestinal
disorders in the primary analysis, but a significant relationship was detected in the third and fourth quartiles (where
more vaccine doses were administered), at the 6-month cutoff in the temporal analysis, and when time permitted for a
diagnosis was extended from children⩾3 years of age to
children⩾5years of age. Similar results have been observed
in earlier studies by Mawson et al.3
and Delong.20 The findings in this study must be weighed against the strengths and
limitations of the available data and study design, which
only allowed for the calculation of unadjusted observational
associations. Additional research utilizing a larger sample
from a variety of pediatric medical practices will yield
greater certainty in results and allow for the investigation of
health conditions with lower prevalence, such as autism. A
thorough evaluation of vaccinated versus unvaccinated populations is essential to understanding the full spectrum of
health effects associated with specific vaccines and the childhood vaccine schedule in totality.
Acknowledgements
The authors thank Dr David Rice III (Assistant Professor of
Biology, Simpson University) for his expert assistance in preliminary setup of the patient database. They also thank Dr Beatrice
Golomb (Professor of Medicine, University of California, San
Diego) for her critical review of the original study design.
Declaration of conflicting interests
The authors declared the following potential conflicts of interest
with respect to the research, authorship, and/or publication of this
article: Dr Hooker is a paid scientific advisor and serves on the
advisory board for Focus for Health (formerly Focus Autism). He
also serves on the Board of Trustees for Children’s Health Defense
(formerly World Mercury Project) and is a paid independent contractor of Children’s Health Defense as well. Dr Hooker is the
father of a 22-year old male who has been diagnosed with autism
and developmental delays. Mr Miller is the director of Thinktwice
Global Vaccine Institute and was a paid consultant to Physicians for
Informed Consent.
Ethical approval
Ethical approval for this study was waived by the Simpson
University Institutional Review Board because the above referenced research project meets the conditions for exemption under
45 CFR 46.101(b)(4). All of the data are in existence as of 1 June
2018 and the information will be recorded in such a manner that
subjects cannot be identified, directly or through identifiers linked
to the subjects. The authors have also confirmed that the results of
this study will not be submitted to the Food and Drug Administration
(FDA) for marketing approval.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.
Informed consent
Informed consent was not sought for this study because all of the
data are in existence as of 1 June 2018 and the information was
recorded in such a manner that subjects cannot be identified,
directly or through identifiers linked to the subjects.
ORCID iD
Brian S Hooker https://orcid.org/0000-0003-2010-1899
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