Study of Vaccinated Vs Unvaccinated Children Reveals Developmental delays, asthma, ear infections, gastrointestinal, and other disorders

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Introduction

Vaccination is considered to be one of the most important advances in modern public health.¹ Currently, children between birth and 6 years 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 2 years, 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 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.

Figure 1.

Creation of study cohorts for each 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 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.

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.

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 1 year of age (21 vaccine doses from birth to 1 year of age versus 33 vaccine doses from 1 to 18 years 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.

Results

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 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

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 thimerosal-containing 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 6 weeks of any dose among the recipients of RotaTeq as compared with the recipients of placebo.²⁶

Within the quartile analysis (Table 7), asthma was non-significant 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 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 6 months, only vaccine doses between birth and 6 months were counted and diagnoses were considered only after 6 months of age. The earlier cut-off of 6 months 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 24 months, 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 healthcare-seeking 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 ​and8).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 ⩾ 5 years 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 non-infective 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

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 cut-off in the temporal analysis, and when time permitted for a diagnosis was extended from children ⩾ 3 years of age to children ⩾ 5 years 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.

Acknowledgments

Footnotes

References