Vaccinations have prevented millions of infectious illnesses, hospitalizations and deaths among U.S. children, yet the long-term health outcomes of the vaccination schedule remain uncertain. Studies have been recommended by the U.S. Institute of Medicine to address this question. This study aimed 1) to compare vaccinated and unvaccinated children on a broad range of health outcomes, and 2) to determine whether an association found between vaccination and neurodevelopmental disorders (NDD), if any, remained significant after adjustment for other measured factors. A cross-sectional study of mothers of children educated at home was carried out in collaboration with homeschool organizations in four U.S. states: Florida, Louisiana, Mississippi and Oregon. Mothers were asked to complete an anonymous online questionnaire on their 6- to 12-year-old biological children with respect to pregnancy-related factors, birth history, vaccinations, physician-diagnosed illnesses, medications used, and health services. NDD, a derived diagnostic measure, was defined as having one or more of the following three closely-related diagnoses: a learning disability, Attention Deficient Hyperactivity Disorder, and Autism Spectrum Disorder. A convenience sample of 666 children was obtained, of which 261 (39%) were unvaccinated. The vaccinated were less likely than the unvaccinated to have been diagnosed with chickenpox and pertussis, but more likely to have been diagnosed with pneumonia, otitis media, allergies and NDD. After adjustment, vaccination, male gender, and preterm birth remained significantly associated with NDD. However, in a final adjusted model with interaction, vaccination but not preterm birth remained associated with NDD, while the interaction of preterm birth and vaccination was associated with a 6.6-fold increased odds of NDD (95% CI: 2.8, 15.5). In conclusion, vaccinated homeschool children were found to have a higher rate of allergies and NDD than unvaccinated homeschool children. While vaccination remained significantly associated with NDD after controlling for other factors, preterm birth coupled with vaccination was associated with an apparent synergistic increase in the odds of NDD. Further research involving larger, independent samples and stronger research designs is needed to verify and understand these unexpected findings in order to optimize the impact of vaccines on children’s health.

acute diseases, chronic diseases, epidemiology, evaluation, health policy, immunization, neurodevelopmental disorders, vaccination

ADHD: Attention Deficit Hyperactivity Disorder; ASD: Autism Spectrum Disorder; AOM: Acute Otitis Media; CDC: Centers for Disease Control and Prevention; CI: Confidence Interval; NDD: Neurodevelopmental Disorders; NHERI: National Home Education Research Institute; OR: Odds Ratio; PCV-7: Pneumococcal Conjugate Vaccine-7; VAERS: Vaccine Adverse Events Reporting System.

Vaccines are among the greatest achievements of biomedical science and one of the most effective public health interventions of the 20th century [1]. Among U.S. children born between 1995 and 2013, vaccination is estimated to have prevented 322 million illnesses, 21 million hospitalizations and 732,000 premature deaths, with overall cost savings of $1.38 trillion [2]. About 95% of U.S. children of kindergarten age receive all of the recommended vaccines as a requirement for school and daycare attendance [3,4], aimed at preventing the occurrence and spread of targeted infectious diseases [5]. Advances in biotechnology are contributing to the development of new vaccines for widespread use [6].

Under the currently recommended pediatric vaccination schedule [7], U.S. children receive up to 48 doses of vaccines for 14 diseases from birth to age six years, a figure that has steadily increased since the 1950s, most notably since the Vaccines for Children program was created in 1994. The Vaccines for Children program began with vaccines targeting nine diseases: diphtheria, tetanus, pertussis, polio, Haemophilus influenzae type b disease, hepatitis B, measles, mumps, and rubella. Between 1995 and 2013, new vaccines against five other diseases were added for children age 6 and under: varicella, hepatitis A, pneumococcal disease, influenza, and rotavirus vaccine.

Although short-term immunologic and safety testing is performed on vaccines prior to their approval by the U.S. Food and Drug Administration, the long-term effects of individual vaccines and of the vaccination program itself remain unknown [8]. Vaccines are acknowledged to carry risks of severe acute and chronic adverse effects, such as neurological complications and even death [9], but such risks are considered so rare that the vaccination program is believed to be safe and effective for virtually all children [10].

There are very few randomized trials on any existing vaccine recommended for children in terms of morbidity and mortality, in part because of ethical concerns involving withholding vaccines from children assigned to a control group. One exception, the high-titer measles vaccine, was withdrawn after several randomized trials in west Africa showed that it interacted with the diphtheria-tetanus-pertussis vaccine, resulting in a significant 33% increase in child mortality [11]. Evidence of safety from observational studies includes a limited number of vaccines, e.g., the measles, mumps and rubella vaccine, and hepatitis B vaccine, but none on the childhood vaccination program itself. Knowledge is limited even for vaccines with a long record of safety and protection against contagious diseases [12]. The safe levels and long-term effects of vaccine ingredients such as adjuvants and preservatives are also unknown [13]. Other concerns include the safety and cost-effectiveness of newer vaccines against diseases that are potentially lethal for individuals but have a lesser impact on population health, such as the group B meningococcus vaccine [14].

Knowledge of adverse events following vaccinations is largely based on voluntary reports to the Vaccine Adverse Events Reporting System (VAERS) by physicians and parents. However, the rate of reporting of serious vaccine injuries is estimated to be <1% [15]. These considerations led the former Institute of Medicine (now the National Academy of Medicine) in 2005 to recommend the development of a five-year plan for vaccine safety research by the Centers for Disease Control and Prevention (CDC) [16,17]. In its 2011 and 2013 reviews of the adverse effects of vaccines, the Institute of Medicine concluded that few health problems are caused by or associated with vaccines, and found no evidence that the vaccination schedule was unsafe [18,19]. Another systematic review, commissioned by the US Agency for Healthcare Research and Quality to identify gaps in evidence on the safety of the childhood vaccination program, concluded that severe adverse events following vaccinations are extremely rare [20]. The Institute of Medicine, however, noted that studies were needed: to compare the health outcomes of vaccinated and unvaccinated children; to examine the long-term cumulative effects of vaccines; the timing of vaccination in relation to the age and condition of the child; the total load or number of vaccines given at one time; the effect of other vaccine ingredients in relation to health outcomes; and the mechanisms of vaccine-associated injury [19].

A complicating factor in evaluating the vaccination program is that vaccines against infectious diseases have complex nonspecific effects on morbidity and mortality that extend beyond prevention of the targeted disease. The existence of such effects poses a challenge to the assumption that individual vaccines affect the immune system independently of each other and have no physiological effect other than protection against the targeted pathogen [21]. The nonspecific effects of some vaccines appear to be beneficial, while in others they appear to increase morbidity and mortality [22,23]. For instance, both the measles and Bacillus Calmette–Guérin vaccine reportedly reduce overall morbidity and mortality [24], whereas the diphtheria-tetanus-pertussis [25] and hepatitis B vaccines [26] have the opposite effect. The mechanisms responsible for these nonspecific effects are unknown but may involve inter alia: interactions between vaccines and their ingredients, e.g., whether the vaccines are live or inactivated; the most recently administered vaccine; micronutrient supplements such as vitamin A; the sequence in which vaccines are given; and their possible combined and cumulative effects [21].

A major current controversy is the question of whether vaccination plays a role in neurodevelopmental disorders (NDDs), which broadly include learning disabilities, Attention Deficit Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD). The controversy has been fueled by the fact that the U.S. is experiencing what has been described as a “silent pandemic” of mostly subclinical developmental neurotoxicity, in which about 15% of children suffer from a learning disability, sensory deficits, and developmental delays [27,28]. In 1996 the estimated prevalence of ASD was 0.42%. By 2010 it had risen to 1.47% (1 in 68), with 1 in 42 boys and 1 in 189 girls affected [29]. More recently, based on a CDC survey of parents in 2011–2014, 2.24% of children (1 in 45) were estimated to have ASD. Rates of other developmental disabilities, however, such as intellectual disability, cerebral palsy, hearing loss, and vision impairments, have declined or remained unchanged [30]. Prevalence rates of Attention Deficit Hyperactivity Disorder (ADHD) have also risen markedly in recent decades [31]. Earlier increases in the prevalence of learning disability have been followed by declining rates in most states, possibly due to changes in diagnostic criteria [32].

It is believed that much of the increase in NDD diagnoses in recent decades has been due to growing awareness of autism and more sensitive screening tools, and hence to greater numbers of children with milder symptoms of autism. But these factors do not account for all of the increase [33]. The geographically widespread increase in ASD and ADHD suggests a role for an environmental factor to which virtually all children are exposed. Agricultural chemicals are a current focus of research [34-37].

A possible contributory role for vaccines in the rise in NDD diagnoses remains unknown because data on the health outcomes of vaccinated and unvaccinated children are lacking. The need for such studies is suggested by the fact that the Vaccine Injury Compensation Program has paid $3.2 billion in compensation for vaccine injury since its creation in 1986 [38]. A study of claims compensated by the Vaccine Injury Compensation Program for vaccine-induced encephalopathy and seizure disorder found 83 claims that were acknowledged as being due to brain damage. In all cases it was noted by the Court of Federal Claims, or indicated in settlement agreements, that the children had autism or ASD [39]. On the other hand, numerous epidemiological studies have found no association between receipt of selected vaccines (in particular the combined measles, mumps, and rubella vaccine) and autism [10,40-45], and there is no accepted mechanism by which vaccines could induce autism [46].

A major challenge in comparing vaccinated and unvaccinated children has been to identify an accessible pool of unvaccinated children, since the vast majority of children in the U.S. are vaccinated. Children educated at home (“homeschool children”) are suitable for such studies as a higher proportion are unvaccinated compared to public school children [47]. Homeschool families have an approximately equal median income to that of married-couple families nationwide, somewhat more years of formal education, and a higher average family size (just over three children) compared to the national average of just over two children [48-50]. Homeschooling families are slightly overrepresented in the south, about 23% are nonwhite, and the age distribution of homeschool children in grades K-12 is similar to that of children nationwide [51]. About 3% of the school-age population was homeschooled in the 2011-2012 school year [52].

 The aims of this study were 1) to compare vaccinated and unvaccinated children on a broad range of health outcomes, including acute and chronic conditions, medication and health service utilization, and 2) to determine whether an association found between vaccination and NDDs, if any, remained significant after adjustment for other measured factors.

To implement the study, a partnership was formed with the National Home Education Research Institute (NHERI), an organization that has been involved in educational research on homeschooling for many years and has strong and extensive contacts with the homeschool community throughout the country (www.nheri.org). The study protocol was approved by the Institutional Review Board of Jackson State University.

The study was designed as a cross-sectional survey of homeschooling mothers on their vaccinated and unvaccinated biological children ages 6 to 12. As contact information on homeschool families was unavailable, there was no defined population or sampling frame from which a randomized study could be carried out, and from which response rates could be determined. However, the object of our pilot study was not to obtain a representative sample of homeschool children but a convenience sample of unvaccinated children of sufficient size to test for significant differences in outcomes between the groups.

We proceeded by selecting 4 states (Florida, Louisiana, Mississippi, and Oregon) for the survey (Stage 1). NHERI compiled a list of statewide and local homeschool organizations, totaling 84 in Florida, 18 in Louisiana, 12 in Mississippi and 17 in Oregon. Initial contacts were made in June 2012. NHERI contacted the leaders of each statewide organization by email to request their support. A second email was then sent, explaining the study purpose and background, which the leaders were asked to forward to their members (Stage 2). A link was provided to an online questionnaire in which no personally identifying information was requested. With funding limited to 12 months, we sought to obtain as many responses as possible, contacting families only indirectly through homeschool organizations. Biological mothers of children ages 6-12 years were asked to serve as respondents in order to standardize data collection and to include data on pregnancy-related factors and birth history that might relate to the children’s current health. The age-range of 6 to 12 years was selected because most recommended vaccinations would have been received by then.

Homeschool leaders were asked to sign Memoranda of Agreement on behalf of their organizations and to provide the number of member families. Non-responders were sent a second notice but few provided the requested information. However, follow-up calls to the leaders suggested that all had contacted their members about the study. Both the letter to families and the survey questions were stated in a neutral way with respect to vaccines. Our letter to parents began:

Respondents were asked to indicate their consent to participate, to provide their home state and zip code of residence, and to confirm that they had biological children 6 to 12 years of age. The communications company Qualtrics (http://qualtrics.com) hosted the survey website. The questionnaire included only closed-ended questions requiring yes or no responses, with the aim of improving both response and completion rates.

A number of homeschool mothers volunteered to assist NHERI promote the study to their wide circles of homeschool contacts. A number of nationwide organizations also agreed to promote the study in the designated states. The online survey remained open for three months in the summer of 2012. Financial incentives to complete the survey were neither available nor offered.

Vaccination status was classified as unvaccinated (i.e., no previous vaccinations), partially vaccinated (received some but not all recommended vaccinations) and fully vaccinated (received all recommended age-appropriate vaccines), as reported by mothers. These categories were developed on the premise that any long-term effects of vaccines would be more evident in fully-vaccinated than in partially-vaccinated children, and rare or absent in the unvaccinated. Mothers were asked to use their child’s vaccination records to indicate the recommended vaccines and doses their child had received. Dates of vaccinations were not requested in order not to overburden respondents and to reduce the likelihood of inaccurate reporting; nor was information requested on adverse events related to vaccines, as this was not our purpose. We also did not ask about dates of diagnoses because chronic illnesses are often gradual in onset and made long after the appearance of symptoms. Since most vaccinations are given before age 6, vaccination would be expected to precede the recognition and diagnosis of most chronic conditions.

Mothers were asked to indicate on a list of more than 40 acute and chronic illnesses all those for which her child or children had received a diagnosis by a physician. Other questions included the use of health services and procedures, dental check-ups, “sick visits” to physicians, medications used, insertion of ventilation ear tubes, number of days in the hospital, the extent of physical activity (number of hours the child engaged in “vigorous” activities on a typical weekday), number of siblings, family structure (mother and father living in the home, divorced or separated), family income and/or highest level of education of mother or father, and social interaction with children outside the home (i.e., amount of time spent in play or other contact with children outside the household). Questions specifically for the mother included pregnancy-related conditions and birth history, use of medications during pregnancy, and exposure to an adverse environment (defined as living within 1-2 miles of a furniture manufacturing factory, hazardous waste site, or lumber processing factory). NDD, a derived diagnostic category, was defined as having one or more of the following three closely related and overlapping diagnoses: a learning disability, Attention Deficit Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD) [53].

Unadjusted bivariate analyses using chi-square tests were performed initially to test the null hypothesis of no association between vaccination status and health outcomes, i.e., physician-diagnosed acute and chronic illnesses, medications, and the use of health services. In most analyses, partially and fully vaccinated children were grouped together as the “vaccinated” group, with unvaccinated children as the control group. The second aim of the study was to determine whether any association found between vaccination and neurodevelopmental disorders remained significant after controlling for other measured factors. Descriptive statistics on all variables were computed to determine frequencies and percentages for categorical variables and means (± SD) for continuous variables. The strength of associations between vaccination status and health outcomes were tested using odds ratios (OR) and 95% Confidence Intervals (CI). Odds ratios describe the strength of the association between two categorical variables measured simultaneously and are appropriate measures of that relationship in a cross-sectional study [54]. Unadjusted and adjusted logistic regression analyses were carried out using SAS (Version 9.3) to determine the factors associated with NDDs.

The information contained in 415 questionnaires provided data on 666 homeschool children. Table 1 shows the characteristics of the survey respondents. Mothers averaged about 40 years of age, were typically white, college graduates, with household incomes between $50,000 to $100,000, Christian, and married. The reasons for homeschooling for the majority of respondents (80-86%) were for a moral environment, better family relationships, or for more contact with their child or children.