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Pilot comparative study on the health of vaccinated and unvaccinated 6- to 12-year-old US children
Anthony R Mawson1 *, Brian D Ray2, Azad R Bhuiyan3 and Binu Jacob4
- Professor, Department of Epidemiology and Biostatistics, School of Public Health, Jackson State University, Jackson, MS 39213, USA
- President, National Home Education Research Institute, PO Box 13939, Salem, OR 97309, USA
- Associate Professor, Department of Epidemiology and Biostatistics, School of Public Health, Jackson State University, Jackson, MS 39213, USA
- Former graduate student, Department of Epidemiology and Biostatistics School of Public Health, Jackson State University, Jackson, MS 39213, USA
Received: March 22, 2017; Accepted: April 21, 2017; Published: 24 April 2017
Thanks to vaccines it has been possible to prevent millions of cases of infectious diseases, hospitalizations and death among American children, yet the long-term effects that the vaccination calendar has on health are still uncertain. For this reason, the American Institute of Medicine recommended the publication of studies that could answer this question. The present study aimed to 1) compare vaccinated and non-vaccinated children on a wide range of health outcomes and 2) determine if, in the case of an ascertained connection between vaccine and neurodevelopmental disorders (NDD), this remained significant after any adjustments statistics of other measurement factors. A cross-sectional study was conducted on mothers of children receiving parental education in collaboration with homeschooling associations in four states: Florida, Louisiana, Mississippi and Oregon. Mothers had to complete an anonymous online questionnaire about their biological children aged between 6 and 12 years, in relation to factors related to pregnancy, birth history, vaccinations, diagnosed diseases, use of medicines and health services. Regarding neurodevelopmental disorders (NDD), considered as a general diagnostic category, they had one or more of the following three related diagnoses: learning disabilities, Attention Deficit Hyperactivity Disorder and Autism Spectrum Disorder. Data from 666 children were collected, of whom 261 (39%) were unvaccinated. Vaccinated children were less likely to be diagnosed with chickenpox or whooping cough, but were more likely to receive pneumonia, otitis media, allergies and NDD. After the statistical adjustment, vaccines, male sex and preterm birth remained significantly associated with the onset of NDD. However, in a final model adjusted with the interaction, vaccinations, but not premature birth remained associated with the onset of NDD, while the interaction of preterm birth and vaccination was associated with a 6.6 increase in the risk factor of NDD (95% CI: 2.8, 15.5). In conclusion, vaccinated homeschooler children had higher rates of allergies and neuro developmental disorders (NDD) than unvaccinated. While vaccination remained significantly associated with NDD after controlling for other factors, vaccine-associated preterm birth had an apparent synergistic increase in the probability of developing NDD. It is therefore necessary to conduct further studies involving larger and independent samples and based on a more solid research project to verify and understand these unexpected discoveries, in order to optimize the impact of vaccines on children's health.
Vaccines are one of the greatest discoveries in biomedical science and among the most effective public health interventions made in the twentieth century . Vaccinations among American children born between 1995 and 2013 are estimated to have prevented 322 million diseases, 21 million hospitalizations and 732000 premature deaths, with total savings of $ 1,38 trillion. About 95% of American children aged 0-6 years receive all the recommended vaccinations, being a requirement for the attendance of kindergartens and playrooms [3,4], in order to prevent the development and spread of diseases infectious covered . Advances in biotechnology contribute to the development of new vaccines for large-scale use .
According to the current recommended vaccination schedule , American children receive up to 48 vaccine doses for 14 diseases from birth to six years, a number that has been growing since the 50s, mainly thanks to the Pediatric Vaccinal Program established in 1994. Initially, the vaccination program included nine vaccines against diphtheria, tetanus, pertussis, polio, haemophilus influenzae type B, hepatitis B, measles, mumps and rubella. Between 1995 and 2013 vaccines against five other diseases were added for children up to six years old: chicken pox, hepatitis A, pneumococcus, flu and rotavirus.
Prior to approval by the US Food and Drug Administration, vaccine safety tests and short-term immunological tests are performed, but the long-term effects of individual vaccines and the vaccine program itself are unknown . Vaccines are known to carry the risk of serious acute and chronic adverse effects, such as neurological complications and even death , but such risks are considered rare, while the vaccination schedule is believed to be safe and virtually effective for all. children .
There are only a few randomized trials on recommended pediatric vaccines, both in terms of morbidity and mortality, in part due to ethical reasons related to denying vaccination to children in the control group. The only exception, the high-titration measles vaccine, was withdrawn after several randomized trials in West Africa showed that it interacted negatively with the diphtheria-tetanus-pertussis vaccine, causing a significant 33% increase in infant mortality [ 11]. Safety tests based on observation studies include a limited number of vaccines, for example the measles-mumps-rubella vaccine or the hepatitis B vaccine, but no studies have been conducted on the vaccine program itself. There is also little knowledge about the effects of vaccines that have a long record of safety and protection against contagious diseases . The safety levels and long-term effects of ingredients used in vaccines, such as adjuvants and preservatives, are also unknown.  Other concerns concern the safety and cost-effectiveness of new vaccines against diseases that are potentially lethal for some individuals, but which have a minor impact on the health of the whole population, such as the type B meningococcal vaccine [14 ].
Information on adverse events following vaccinations is based primarily on voluntary complaints to the Vaccine Adverse Events Reporting System (VAERS) by doctors and parents. Unfortunately, the reporting rate of serious vaccine damage is estimated to be below 1% . These considerations led the then Institute of Medicine (which became the National Academy of Medicine today) in 2005 to recommend the establishment of a five-year vaccine safety research plan by the Centers for Disease Control and Prevention (CDC) [16 , 17]. The tests on the adverse effects of vaccines conducted in 2011 and 2013 by the Institute of Medicine have led to the conclusion that there are few health problems that can be caused or linked to vaccines and no evidence has been found that the vaccination schedule is unsafe [18, 19]. Another systematic review, commissioned by the Agency for Healthcare Research and Quality to identify any gaps in the safety tests of the pediatric vaccination program, led to the conclusion that post-vaccination adverse events are extremely rare . However, the Institute of Medicine noted that studies had to be conducted to compare the health of vaccinated and unvaccinated children, examine the long-term cumulative effects of vaccines, the timing based on the age and condition of the child, the total load and the number of vaccines to be administered in a single solution, the effects of the ingredients of the vaccines in relation to health, the mechanisms of diseases associated with vaccinations .
What makes the evaluation of a vaccination program complex is the fact that vaccines against infectious diseases have complex non-specific effects on morbidity and mortality that go beyond the prevention of the target disease. The existence of such effects calls into question the claim that individual vaccines influence the immune system independently of each other and that they have no other physiological effect other than protection against the targeted pathogen . The non-specific effects of some vaccines appear to be beneficial, while in others it appears that both morbidity and mortality increase [22, 23]. For example, both the measles vaccine and Bacillus Calmette-Guérin (against tuberculosis) are said to reduce overall morbidity and mortality , while diphtheria-tetanus-pertussis vaccines  and hepatitis B  have the opposite effect. The mechanisms responsible for these non-specific effects are unknown, but could include among others: interactions between vaccines and their ingredients, for example if viruses are alive or attenuated; the most recently administered vaccine; micronutrient supplements, such as vitamin A; the sequence of administration; and finally their combined and cumulative effects . One of the main ongoing controversies concerns the question of whether vaccinations play a role in neurological development disorders (NDDs), which generally include Attention Deficit Hyperactivity Syndrome (ADHD) and autism spectrum disorder (ASD). The issue was fueled by the fact that what has been called the "silent pandemic" of developmental neurotoxicity of a mainly subclinical nature, in which about 15% of children suffer from learning disorders, sensory deficits and developmental delays [27, 28]. In 1996 the estimate of ASD prevalence was 0,42%. In 2010 it had risen to 1,47% (one in 68), with one boy in 42 and one girl in every 189 suffering from these diseases . More recently, based on a CDC survey of parents between 2011 and 2014, 2,24% of children (1 in 45) are estimated to have ASD. While the percentages of other disabilities such as intellectual disability, cerebral palsy, hearing loss and impaired vision, had decreased or remained unchanged . The prevalence rates of Attention Deficit Hyperactivity Syndrome (ADHD) have increased significantly in recent decades . The initial increase in prevalence of learning disabilities was followed by a decrease in percentages in most states, probably due to changes in diagnostic criteria . The main reason for the increase in the diagnosis of NDD in recent decades is thought to be due to increased awareness of autism and more accurate diagnostic tools, as well as to a greater number of children with milder autistic symptoms. But such factors cannot be the only cause of such an increase . The geographical spread of the increase in ASD and ADHD suggests a role of the environmental factors to which children are virtually exposed.
A possible role of vaccines in increasing the diagnosis of NDD remains unknown due to the lack of data on the health of vaccinated and unvaccinated children. The need for this type of study is suggested by the fact that the Vaccine Injury Compensation Program has paid $ 3,2 billion to compensate for vaccine damage since it was created in 1986 . A study of the compensation made by the Vaccine Injury Compensation Program for complaints of encephalopathies and convulsive disorders caused by vaccine, found 83 cases recognized as due to brain damage. In all cases, it has been noted by the Court of Federal Claims, or indicated in the compensation agreements, that the children were suffering from autism or ASD . On the other hand, many epidemiological studies have found no relationship between the intake of selected vaccines (in particular the combined against measles, mumps and rubella) and autism [10, 40-45] and there is no established mechanism for which vaccines can cause autism .
An important contribution given by the comparison between vaccinated and unvaccinated children was given by the identification of an accessible group of unvaccinated children, since the majority of American children are vaccinated. Homeschooling children are suitable for such a study as they are mostly unvaccinated in relation to children attending public schools . Families who choose parental education have approximately the same average salary as families made up of married couples at a national level, a higher level of education and a greater number of children (more than three), compared to the national level which is on average two children [48-50]. Families who choose home schooling are slightly more present in the south, about 23% are not white-skinned and the age of children receiving parental education for all school grades is similar to that of children nationwide  . About 3% of the school-age population received parental education in the 2011-2012 school year .
The aim of the present study was to: 1) compare vaccinated and non-vaccinated children on a wide range of data on their health, including acute and chronic conditions, as well as the use of drugs and the health service; 2) determine whether a possible correlation between vaccinations and NDD remains significant after the adjustment of other measurement factors.
The study was implemented by creating a partnership with the National Home Education Research Institute (NHERI), an organization that has been involved in educational research on home schooling for many years and has close and extensive contacts with the community that has chosen the homeschooling across the nation (www.nheri.org). The study protocol was approved by the Jackson State University Institutional Review Board.
The study was designed as a cross-sectional survey of mothers who had chosen home schooling on their biological children aged 6 to 12, both vaccinated and unvaccinated. As the contact details of these families were not available, it was not possible to establish a defined population or a sampling structure to conduct a randomized study and from which it was possible to determine response rates. However, the object of our pilot study was not to obtain a representative sample of children receiving parental education, but to obtain a sample of unvaccinated children of a size that could analyze significant differences in the results between the two groups.
We proceeded to select 4 states (Florida, Louisiana, Mississippi and Oregon) for detection (Part 1). NHERI has provided a list of national and local parental education organizations, for a total of 84 in Florida, 18 in Louisiana, 12 in Mississippi and 17 in Oregon. The first interviews began in June 2012. NHERI contacted the heads of each state organization via email to request their support. A second e-mail was then sent, explaining the purpose of the study and the reasons, asking the managers to forward it to the members of their association (Part 2). A link was provided to an online questionnaire in which no personal data that could have identified the person would have been requested. With funds limited to 12 months, we tried to get as many answers as possible by contacting families through parental education organizations. The questionnaire was addressed to the biological mothers of children between 6 and 12 years of age, in order to obtain information also on factors related to pregnancy and birth, which could be decisive for the current health conditions of children. Age 6-12 was chosen because most of the recommended vaccinations should have already been administered.
Engagement and informed consent
Those responsible had to sign a memorandum of understanding from their associations and had to communicate the number of families that were part of it. Those who did not respond were contacted again, but only a few produced the requested information. When they were contacted by telephone at the end of the investigation, they replied that they had informed all members of the association about the ongoing study. Both in the letter sent to the parents and in the interview text, questions regarding vaccines were asked in a neutral way. The letter to the parents begins like this:
“Dear parent, this study concerns an important and current public health issue, that is, whether vaccinations are related in any way to children's health in the long run. Vaccination is one of the most important medical discoveries, but too little is known about its long-term impact to date. The aim of this study is to evaluate the effects of vaccines by comparing vaccinated and non-vaccinated children based on a series of results on their health ... "
The interviewees had to confirm their consent to participate, provide information on the state of residence and the postal code, as well as confirm that they would answer questions about their biological children aged between 6 and 12 years. The online questionnaire was published in the communication company Qualtrics (http://qualtrics.com). The questionnaire included only closed-ended questions, yes or no, in order to optimize both the answers and the completion rates.
Some mothers offered to collaborate as volunteers to assist NHERI in promoting the study in their parental education groups. Even some associations have worked to promote the study in the states to which they belonged. The investigation remained open for three months in the summer of 2012. No financial incentives were given for completing the investigation because they are not available.
Definitions and measurements
The vaccination status was divided into "unvaccinated" (who did not receive any vaccinations), "partially vaccinated" (received some, but not all recommended vaccinations) and "fully vaccinated" (to which all vaccines were administered recommended for age), as reported by mothers. These categories were developed on the assumption that any long-term effects of vaccines would have been much more evident in fully vaccinated children than in partially vaccinated and rare or absent in unvaccinated children. Mothers were asked to rely on vaccination records to indicate which vaccines and how many doses had been administered to the baby. The dates of the vaccinations were not requested in order not to overload those who had to answer the test and to reduce the probability of incorrect reports; we weren't even asked to give information about vaccine-related adverse events, because that wasn't our goal. Furthermore, the dates of the diagnoses were not requested because chronic diseases are often gradual and it takes a long time for the first symptoms to appear. Since most vaccinations are administered before the age of six, they should be prior to the recognition and diagnosis of most chronic diseases. Mothers were asked to indicate, on a list of more than 40 chronic and acute diseases, all those for which their baby (s) had received a diagnosis from a doctor. Other questions included the use of health services and protocols, dental check-ups, medical examinations for illness, medicines used, insertion of ventilation ear tubes, hospitalization days, amount of physical activity (number of hours in which the child energizes physical activity during the week), family income and the highest level of education of the mother or father and social relationships of children away from home (time spent playing with other children away from home). Other specific questions for mothers were about pregnancy-related conditions and birth history, the use of medications during pregnancy and exposure to an unfavorable environment (defined as living within 1-2 miles of a furniture factory, site of hazardous waste or timber processing factory). NDD, a derived diagnostic theory, has been defined as having one or more of the following three overlapping diagnoses: a learning disability, Attention Deficit Hyperactivity Syndrome (ADHD) and Autism Spectrum Disorder (ASD)  .
Unadjusted bivariate analyzes with chi-square tests were conducted to test the null hypothesis of no association between vaccination status and health outcomes, i.e. medical diagnosis of acute or chronic disease, medications and use of health services. In most analyzes, fully or partially vaccinated children were grouped together under the heading "vaccinated", while the unvaccinated were the control group. The second objective of the study was to determine whether the identification of any association between vaccine and neuro developmental disorders remained significant after a check based on other measurement factors. Descriptive statistics were calculated on all variables to determine frequencies and percentages for categorical variables and means (± SD) for continuous variables. The strength of the associations between vaccination status and health outcomes were tested using odds ratios (OR) and 95% confidence intervals (CI). The odds ratios describe the strength of the association between two categorical variables measured simultaneously and are the appropriate measure of this relationship in a cross-sectional study . Regularized and non-regularized logistic regression analyzes were conducted using the Statistical Analysis System (version 9.3) to determine the association factors with NDD.
Socio-demographic characteristics of the interviewees The information contained in the 415 questionnaires produced data concerning 666 children receiving parental education. Table 1 shows the characteristics of the people who participated in the survey. The mothers were about 40 years old, fair-skinned, graduated from college and with a family income between $ 50000 and $ 100000, Christian and married. The choice of parental education, in the majority of respondents (80-86%), was made to guarantee a morally valid environment, better family relationships and greater contact with one's own or one's children. The group of children was similarly made up of mostly white children (88%), with a slight preponderance of females (52%) and an average age of 9 years. Regarding the vaccination status, 261 (39%) were unvaccinated, 208 (31%) partially vaccinated and 197 (30%) had received all the recommended vaccinations. All statistical analyzes are based on these numbers.
Vaccinated children (N = 405), a group consisting of both partially and fully vaccinated, had contracted chickenpox with a significantly lesser probability (7.9% vs. 25.3%, p <0.001; Odds Ratio = 0.26, 95% Confidence interval: 0.2, 0.4) and canine cough (pertussis) (2.5% vs. 8.4%, p <0.001; OR 0.3, 95% CI: 0.1, 0.6) and, less likely, but not significantly, rubella (0.3 % vs. 1.9%, p = 0.04; OR 0.1, 95% CI: 0.01, 1.1). However, the vaccinated children were more likely diagnosed with otitis media (19.8% vs. 5.8%, p <0.001; OR 3.8, 95% CI: 2.1, 6.6) and pneumonia (6.4% vs. 1.2%, p = 0.001; OR 5.9, 95% CI: 1.8, 19.7). There were no differences in hepatitis A or B, high fever in the past six months, measles, mumps, meningitis (viral or bacterial), flu or rotavirus (Table 2).
Vaccinated children were significantly more likely diagnosed with the following diseases than unvaccinated children: allergic rhinitis (10.4% vs. 0.4%, p <0.001; OR 30.1, 95% CI: 4.1, 219.3), other allergies (22.2% vs. . 6.9%, p <0.001; OR 3.9, 95% CI: 2.3, 6.6), eczema / atopic dermatitis (9.5% vs. 3.6%, p = 0.035; OR 2.9, 95% CI: 1.4, 6.1), one disability in learning (5.7% vs. 1.2%, p = 0.003; OR 5.2, 95% CI: 1.6, 17.4), ADHD (4.7% vs. 1.0%, p = 0.013; OR 4.2, 95% CI: 1.2, 14.5 ), ASD (4.7% vs. 1.0%, p = 0.013; OR 4.2, 95% CI: 1.2, 14.5) other neurodevelopmental disorders (i.e. learning disability, ADHD, or ASD) (10.5% vs. 3.1%, p <0.001; OR 3.7, 95% CI: 1.7, 7.9) and other chronic diseases (44.0% vs. 25.0%, p <0.001; OR 2.4, 95% CI: 1.7, 3.3). No differences were found with respect to cancer, chronic fatigue, conduct disorder, Crohn's disease, depression, type 1 or 2 diabetes, encephalopathy, epilepsy, hearing loss, high blood pressure, inflammatory bowel disease, juvenile rheumatoid arthritis, obesity, seizures, Tourette's syndrome, or services received through the Individuals with Disabilities Education Act (the law governing the right to education and inclusion for students with disabilities) (Table 3).
Partial versus complete vaccination
Partially vaccinated children are in an intermediate position compared to children who have received all vaccines or who have not been vaccinated, compared to many, but not all results. For example, as shown in Table 4, partially vaccinated children are in an intermediate (apparently disadvantageous) position with regards to allergic rhinitis, ADHD, eczema and learning disabilities.
Gender differences in chronic disease
Among the vaccinated children (group formed by both partially and fully vaccinated), males had more likely been diagnosed with chronic disease than females. This is particularly significant in the case of allergic rhinitis (13.9% vs. 7.2%, p = 0.03; OR 2.1, 95% CI: 1.1, 4.1) ASD (7.7% vs. 1.9%, p = 0.006; OR 4.3, 95 % CI: 1.4, 13.2) and any neurodevelopmental disorder (14.4% vs. 6.7%, p = 0.01; OR 2.3, 95% CI: 1.2, 4.6) (Table 5).
Use of medicines and health services
The vaccinated (group consisting of both partially and fully vaccinated), had more likely used allergy drugs (20.0% vs. 1.2%, p <0.001; OR 21.5, 95% CI: 6.7, 68.9), antibiotics in the 12 months prior to the survey (30.8% vs. 15.4%, p <0.001; OR 2.4, 95% CI: 1.6, 3.6) and at least once on antifebrile drugs (90.7% vs. 67.8%, p <0.001; OR 4.6 , 95% CI: 3.0, 7.1). They were also more likely to have been seen by the doctor for a routine check-up in the previous 12 months (57.6% vs. 37.2%, p <0.001; OR 2.3, 95% CI: 1.7, 3.2), that they had had a dental visit ( 89.4% vs. 80.5%, p <0.001; OR 2.0, 95% CI: 1.3, 3.2), or who had undergone a specialist visit due to illness in the past year (36.0% vs. 16.0%, p <0.001 ; OR 3.0, 95% CI: 2.0, 4.4) that tympanic ventilation tubes had been applied (3.0% vs. 0.4%, p = 0.018; OR 8.0, 95% CI: 1.0, 66.1) or that they had been hospitalized or more nights in hospital (19.8% vs. 12.3%, p = 0.012; OR 1.8, 95% CI: 1.1, 2.7) (Table 6).
Factors associated with neurodevelopmental disorders
The second objective of the study is focused on a specific health outcome and was designed to determine whether vaccination can be associated with neurodevelopmental disorders (NDD) and, if so, whether this association remains significant after the adjustment of other measured factors. As already mentioned, due to the relatively low number of children with specific diagnosis, NDD is a derived variable, which includes children with a diagnosis of one or more disorders among ASD, ADHD and learning disabilities.
The close association and overlap of these diagnoses in the study is depicted in the figure just above (Figure 1). As can be seen in the figure, the largest diagnostic group is made up of learning disabilities (n = 15), followed by ASD (n = 9) and ADHD (n = 9), then to a lesser extent a combination of the three diagnoses.
Table 7 shows the factors associated with NDD in unadjusted logistic regression analyzes: vaccination (OR 3.7, 95% CI: 1.7, 7.9); male sex (OR 2.1, 95% CI: 1.1, 3.8); unfavorable environment, defined as such if you live 1-2 miles from a furniture factory (OR 2.9, 95% CI: 1.1, 7.4), a hazardous waste landfill, or a carpentry shop (OR 2.9, 95% CI: 1.1, 7.4) ; use of antibiotics during pregnancy (OR 2.3, 95% CI: 1.1, 4.8); preterm birth (OR 4.9, 95% CI: 2.4, 10.3). Two factors of particular statistical relevance are vaccination during pregnancy (OR 2.5, 95% CI: 1.0, 6.3) and having had three or more ultrasound scans (OR 3.2, 95% CI: 0.92, 11.5). factors not associated with the development of NDD in this study are: mother's education, family income and religious beliefs; the use of acetaminophen, alcohol and antacids during pregnancy; gestational diabetes; pre-eclampsia; Rhogham (immunoglobulin) injections during pregnancy; and breastfeeding (data not shown).
After adjusting for all other significant factors, those that have remained significantly associated with the development of NDD are: vaccines (OR 3.1, 95% CI: 1.4, 6.8); male sex (OR 2.3, 95% CI: 1.2, 4.3); and preterm birth (OR 5.0, 95% CI: 2.3, 11.1). The apparently strong association between vaccines and preterm birth with the development of NDD has suggested the possibility of an interaction between these three factors.
In a final model adjusted and designed to test this possibility, i.e. to verify the interaction between preterm birth and vaccination, the following factors remained significantly associated with NDD: vaccination (OR 2.5, 95% CI: 1.1, 5.6), non-white breed (OR 2.4, 95% CI: 1.1, 5.4), and male (OR 2.3, 95% CI: 1.2, 4.4). While premature birth was not significantly associated with the development of NDD, interaction with vaccinations was associated with the development of NDD with a 6,6 times greater probability (95% CI: 2.8, 15.5)
Following a recommendation from the Institute of Medicine  to produce studies that compared the health outcomes of vaccinated and unvaccinated children, the present study focuses on children receiving parental education, between the ages of 6 and 12 years and is based on anonymous reports from mothers on conditions during pregnancy, the history of birth, diseases diagnosed by the doctor, drugs and health care. Those who replied to the questionnaire were mainly white, married, college-educated, high-income women who were contacted and invited to participate in the study by leaders of the parental education organizations they were part of. The data collected in the survey were also used to determine whether vaccinations could be specifically associated with the development of NDD, a derived diagnostic category including diagnoses of learning disabilities, ASD and / or ADHD.
Regarding chronic or acute conditions, the vaccinated children had less likely than the non-vaccinated chickenpox and whooping cough, but had more likely, contrary to expectations, a diagnosis of otitis media, pneumonia, allergic rhinitis, eczema and NDD . They were also more likely to take antibiotics, allergy medications and anti-febrile drugs; they had been fitted with ventilation ear tubes and had been visited by a doctor for health reasons or had been hospitalized. The reason for hospitalization and the age of the child at that time were not recorded, but the latter figure appears to be consistent with an investigation in which 38801 complaints are reported to the VAERS of children who had been hospitalized or who had died after vaccination . This survey denounces a direct relationship between the number of doses of vaccine administered at one time and the rate of hospitalization or death; furthermore, the smaller the child was when the vaccine was administered, the higher the hospitalization or death rate . The hospitalization rate increases from 11% for two doses of vaccine, to 23,5% for 8 doses (r2 = 0.91), while the mortality rate increases significantly from 3,6% for those who received 1-4 doses at 5,4 , 5% for those who received 8-XNUMX doses.
In support of the hypothesis that the number of vaccines administered may be involved in the risk of chronic diseases associated with them, the comparison between fully, partially or not at all vaccinated children made in the present study showed that partially vaccinated children were more likely to have chronic diseases, but to an intermediate extent between completely and not at all vaccinated, in particular as regards allergic rhinitis, ADHD, eczema, learning disabilities, and NDD in general.
National ADHD and LD rates are similar to those of the survey. The rate of ADHD in the United States in subjects aged 4 to 17 years (double the age range of children in the present study) is 11% . The ADHD rate that emerged in the study, for children aged 6 to 12 years, is 3,3% and 4,7% if only vaccinated children are considered. The national LD rate is 5% , while data from the study show a rate of 3,9% for all groups and the
5,6% considering only children vaccinated. However, the prevalence of 2,24% ASD established in a survey done by the CDC to parents is lower than that established by the survey, with a rate of 3,3%. Male vaccinates were more likely to be diagnosed with allergic rhinitis or NDD than the female sex. The percentage of males vaccinated with an NDD in the present study (14,4%) is in line with national findings based on responses from parents to questionnaires, which indicate that 15% of American children between 3 and 17 years of age in years 2006-2008 had an NDD . Males are more likely than females to be diagnosed with NDD, especially ASD .
Vaccination has been strongly associated with both otitis media and pneumonia, which are among the most common complications of measles infection [56, 57]. The odds of otitis media were approximately four times higher among the vaccinated (OR 3.8, 95% CI: 2.1, 6.6) and the probabilities of myringotomy with trans tympanic drainage were eight times higher than those of unvaccinated children (OR 8.0 , 95% CI: 1.0, 66.1). Acute otitis media (OMA) is a very common childhood infection, causing up to 30 million medical visits to the United States each year and being the most frequent reason for prescribing antibiotics to children [58, 59]. The peak incidence of OMA is between 3 and 18 months and 80% of children have had it at least once before the age of three. OMA rates have increased in recent decades . Worldwide, the incidence of OMA is 10,9% with 709 million cases each year, of which 51% are children under 5 years of age . Pediatric OMA is a significant health problem in the US, resulting in an annual expenditure of $ 2,88 billion in medical care .
Numerous AOM reports have been archived in the VAERS database. If you do a search by typing "Cases where the age is less than 1 and the onset interval is 0 or 1 or 2 or 3 or 4 or 5 or 6 or 7 days and the symptom is otitis media"  revealed that 438.573 cases were reported between 1990 and 2011, often with fever and other signs and symptoms of inflammation and central nervous system involvement. A study  evaluated the nasopharyngeal colonization of S. pneumoniae, H. influenzae and M. catarrhalis during OMA in children fully or partially vaccinated with 0 or a dose of hepta-valent pneumococcal conjugate vaccine (PCV7) and a "Historical control group" composed of children belonging to the era prior to PCV7, finding a higher frequency of M. catarrhalis in the vaccinated group compared to the group of partially vaccinated and control (76% against 62% and 56% respectively). A high colonization rate from Moraxella catarrhalis is associated with a higher risk of OMA . An effective vaccination against pneumococcal infections can lead to the replacement of the latter in the nasopharyngeal cavity by serotypes and non-vaccine pneumococcal diseases . Vaccination with PCV-7 has a marked effect on the composition of the upper respiratory tract microbiota in children, going beyond changes in the distribution of pneumococcal serotypes and known potential pathogens and causing an increase in anaerobes, gram-positive bacteria and species gram-negative bacteria. The administration of PCV7 is also associated with the onset and expansion of types of oropharyngeal species. These observations suggested that the eradication of the pneumococcal serotype of the vaccine could be followed by the colonization of other bacterial species in the nasopharyngeal cavity remained empty, leading to an imbalance in the bacterial composition (dysbiosis) and an increased risk of otitis media. Long-term monitoring was recommended in order to understand all the implications of changes in the structure of the microbiota caused by vaccination . The second goal of the study was focused on a specific health outcome, trying to determine if vaccination could remain associated with the development of neurodevelopmental disorders (NDD) after a check based on other measurement factors. Following adjustment, the factors that remained significantly associated with NDD were: vaccination, non-white race, male gender and preterm birth.
The apparently strong association between vaccines and preterm birth with the development of NDD has suggested the possibility of an interaction between these three factors. This has been demonstrated in an interaction-adjusted final model (designed to verify the interaction between preterm birth and vaccination). In this vaccination model, non-white race and male remained associated with NDD, while premature birth alone was no longer associated with the development of NDD. However, the interaction between preterm birth and vaccinations has been associated with the development of NDD with a probability greater than 6,6 times. In summary, vaccinations, non-white race and male gender have been significantly associated with NDD after control over other factors. Premature birth, although significantly associated with NDD in unadjusted and adjusted analyzes, was no longer associated with NDD in the final model with interaction. However, preterm birth and combined vaccines were strongly associated with NDD in the interaction-adjusted final model, more than doubling the chances of NDD compared to vaccination alone. Premature birth has long been known as one of the main factors of NDD [68, 69], but since preterm babies are regularly vaccinated, the effects of preterm birth and vaccination have not been examined separately. The present study suggests that vaccination may be a contributing factor to the pathogenesis of NDD and that preterm birth alone may have a minor and reduced role in NDD (defined here as ASD, ADHD and / or learning disability) than believe currently. Research results also suggest that vaccination combined with premature birth may increase the chances of NDD compared to vaccination alone.
Our goal was not to test a specific hypothesis on the association between vaccination and health. The aim of the study was to determine whether the health outcomes of vaccinated children were different from those of unvaccinated children who received parental education, taking as a given that vaccines have nonspecific effects on morbidity and mortality as well as protection against pathogens. targeted . This comparison was based on testimonies made by mothers on factors related to pregnancy, medical history, vaccinations, diseases diagnosed by the doctor, drugs and use of health services. We tested the null hypothesis of no difference in results using chi-square tests, and then used the odds ratios and 96% confidence interval to determine the strength and weight of the association. If the effects of vaccination on health were limited to protection against targeted pathogens, as is assumed to be the case , one would not expect a difference in outcomes between vaccinated and unvaccinated groups except for reduced rates of target infectious diseases . However, impressive differences in different health outcomes between the two groups were found in this homogeneous sample of 666 children. Vaccinates were less likely to have had chickenpox or whooping cough, as expected, but were more likely to have been diagnosed with pneumonia, otitis, as well as allergies and NDD. What credibility can these results have? The study was not designed to be based on a representative sample of children receiving parental education, but on a convenience sample of sufficient size to test significant differences in outcomes. Homeschooling children were chosen because their vaccination rates are lower than those in the general population. In this respect, our pilot survey was a success, since data on 261 unvaccinated children were made available.
To avoid the possibility of too subjective or opinion-based data, only real information was requested, and questionnaires only asked for memorable events such as illnesses diagnosed by a doctor on the child. To minimize potential bias in information provided by mothers, all communications with mothers were made with an emphasis on vaccination neutrality and vaccine safety. To minimize memory-induced bias, respondents had to use their children's vaccination records. To improve reliability, closed-ended questions were used and all questions had to be answered to proceed with the test. To improve validity, he was asked to write only diseases diagnosed by the doctor. The answers could not be validated with the production of medical certificates, as the survey had to remain anonymous. However, self-reports of significant events are considered officially valid when medical or administrative documents are not available . If mothers had to produce copies of medical certificates for their babies, it would no longer be an anonymous survey and only a few would have completed questionnaires. We were advised by the leaders of parental education associations that if we made the production of medical certificates a requirement to participate in the survey, the recruitment efforts would not be successful. A further potential limitation is the underestimation of the disease in unvaccinated children. Could it be that unvaccinated children, as they are seen more rarely by doctors, have a lower rate of disease because they are less likely to be diagnosed? Indeed, vaccinated children show that they had been visited by a doctor in the previous 12 months for a routine visit more frequently than unvaccinated children (57.5% vs. 37.1%, p <0.001; OR 2.3, 95% CI: 1.7, 3.1).
During these visits children are normally vaccinated, and families opposed to vaccinations therefore tend to avoid them so as not to have to openly refuse vaccination. However, fewer doctor visits do not necessarily mean that unvaccinated children are less likely to be seen by a doctor if their condition justifies it. In fact, since unvaccinated children were more likely to receive a diagnosis of chicken pox or whooping cough, which requires a pediatric visit, differences in health outcomes are unlikely to be caused by an underestimation. The study's strengths include the study's unique design, which involves mothers who practice homeschooling as respondents, and the relatively large sample of unvaccinated children, which made it possible to compare health outcomes across the spectrum of vaccination coverage. Furthermore, the recruitment of biological mothers as respondents allowed us to test the hypotheses on the role of factors related to pregnancy and birth history, as well as vaccinations in the onset of NDD and other specific conditions. It is also a survey carried out within a demographic homogeneous population group: mainly white people, with high income and level of education, families practicing parental education and children aged between 6 and 12. the information was collected on the basis of anonymous answers given by biological mothers, who are obviously well informed about the vaccination and health status of their children, making their reports more reliable.
Evaluations of the long-term effects of the vaccination program on morbidity and mortality are limited . In this pilot survey of vaccinated and unvaccinated children receiving parental education, lesser chances of contracting chickenpox and whooping cough in vaccinated children were found, as expected, but unexpectedly more likely for other conditions diagnosed by a doctor. Although the transversal form of the study limits its causal interpretation, the strength and consistency of the results, the apparent "dose-response" relationship between vaccinations and many forms of chronic diseases and the significant association with neurodevelopmental disorders, all these data support the possibility that some aspects of the current vaccination program may contribute to the risk of childhood morbidity. Vaccination remained significantly associated with NDD even after controlling other factors, while preterm birth alone, long considered one of the greatest risk factors for NDD, was not associated with these disorders after controlling the interaction between birth premature and vaccination. Still, this factor together with vaccination has been associated with an apparent synergistic increase in NDD rates, higher than those of vaccination alone. Nonetheless, the results of the investigation should be interpreted with caution. First, further research is needed to replicate these results in studies based on larger samples and with a stronger research project. Second, subject to being replicated, the potentially harmful factors of the vaccination program should be identified, addressed and understand the mechanisms that cause them. Such studies are critical to optimizing the impact of vaccinations on children's health.
The authors declare that they have no financial interests that have any bearing on any aspect of the conduct or conclusions of the study and the manuscript presented.
Contributions of the author
AM designed the study, contributed to the analysis and interpretation of the data and drafted the document. BR designed the study, contributed to the data collection and modified the document. AB contributed to the data analysis and modified the document. BJ contributed to the analysis and processing of the data. All authors have read and approved the final version of the article.
This study was supported by grants from Generation Rescue, Inc. and the Children's Medical Safety Research Institute, charities that support research on children's health and safety. The funders had no role or influence on the design and conduct of the research or on the preparation of the reports.
The authors thank everyone who provided critical comments, suggestions and financial support for the project. We also thank the homeschool collaborative organizations and in particular the mothers who participated in the survey.
This study was approved by the Jackson State University Institutional Review Board and completed before Dr. Mawson's appointment at Jackson State University.
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