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Temporal Association of Certain Neuropsychiatric Disorders Following Vaccination of Children and Adolescents: A Pilot Case–Control Study
Douglas L. Leslie, Robert A. Kobre, […], and James F. Leckman

Additional article information
Temporal Association of Certain Neuropsychiatric Disorders Following Vaccination of Children and Adolescents: A Pilot Case–Control Study
Douglas L. Leslie, Robert A. Kobre, […], and James F. Leckman

Additional article information

Abstract
Background
Although the association of the measles, mumps, and rubella vaccine with autism spectrum disorder has been convincingly disproven, the onset of certain brain-related autoimmune and inflammatory disorders has been found to be temporally associated with the antecedent administration of various vaccines. This study examines whether antecedent vaccinations are associated with increased incidence of obsessive–compulsive disorder (OCD), anorexia nervosa (AN), anxiety disorder, chronic tic disorder, attention deficit hyperactivity disorder, major depressive disorder, and bipolar disorder in a national sample of privately insured children.

Methods
Using claims data, we compared the prior year’s occurrence of vaccinations in children and adolescents aged 6–15 years with the above neuropsychiatric disorders that were newly diagnosed between January 2002 and December 2007, as well as two control conditions, broken bones and open wounds. Subjects were matched with controls according to age, gender, geographical area, and seasonality. Conditional logistic regression models were used to determine the association of prior vaccinations with each condition.

Results
Subjects with newly diagnosed AN were more likely than controls to have had any vaccination in the previous 3 months [hazard ratio (HR) 1.80, 95% confidence interval 1.21–2.68]. Influenza vaccinations during the prior 3, 6, and 12 months were also associated with incident diagnoses of AN, OCD, and an anxiety disorder. Several other associations were also significant with HRs greater than 1.40 (hepatitis A with OCD and AN; hepatitis B with AN; and meningitis with AN and chronic tic disorder).

Conclusion
This pilot epidemiologic analysis implies that the onset of some neuropsychiatric disorders may be temporally related to prior vaccinations in a subset of individuals. These findings warrant further investigation, but do not prove a causal role of antecedent infections or vaccinations in the pathoetiology of these conditions. Given the modest magnitude of these findings in contrast to the clear public health benefits of the timely administration of vaccines in preventing mortality and morbidity in childhood infectious diseases, we encourage families to maintain vaccination schedules according to CDC guidelines.

Keywords: anorexia nervosa, obsessive–compulsive disorder, anxiety disorder, tic disorder, vaccination, influenza, meningococcus
Introduction
There is a considerable body of scientific evidence indicating that the immune system plays a key role in normal brain development and in the pathobiology of several neuropsychiatric disorders (1). These include obsessive–compulsive disorder (OCD) (2, 3), anorexia nervosa (AN) (4), tic disorders (5), attention deficit hyperactivity disorder (ADHD) (6), major depressive disorder (7), and bipolar disorder (8). The precise role immune mechanisms play in these disorders remains to be determined.

In light of the role of the immune system in these central nervous system (CNS) conditions, the impact of vaccines on childhood-onset neuropsychiatric diseases had been considered and was mainly addressed with regards to the administration of the measles, mumps, and rubella (MMR) vaccine (and its various components) and the subsequent development of autism spectrum disorder (ASD). Although the controversy over MMR vaccination and ASD still exists for some members of the public, this association has been convincingly disproven (9, 10). On the other hand, the onset of a limited number of autoimmune and inflammatory disorders affecting the CNS has been found to be temporally associated with the antecedent administration of various vaccines (11). These disorders include idiopathic thrombocytopenic purpura, acute disseminated encephalomyelitis, and Guillain–Barré syndrome among others (12–16). More recently, data have emerged indicating an association between the administration of the H1N1 influenza vaccine containing the AS03 adjuvant and the subsequent new onset of narcolepsy in several northern European countries (17, 18). The immune mechanisms and host factors underlying these associations have not been identified or fully characterized, although preliminary data are beginning to emerge (18–23).

Given this growing body of evidence of immunological involvement in CNS conditions, and despite the controversy concerning the link between ASD and MMR and the clear public health importance of vaccinations, we hypothesized that some vaccines could have an impact in a subset of susceptible individuals and aimed to investigate whether there is a temporal association between the antecedent administration of vaccines and the onset of several neuropsychiatric disorders, including OCD, AN, tic disorder, anxiety disorder, ADHD, major depressive disorder, and bipolar disorder using a case–control population-based pediatric sample (children aged 6–15 years). To assess the specificity of any statistical associations, we also determined whether or not there were any temporal associations between antecedent vaccine administration and the occurrence of broken bones or open wounds.

Materials and Methods
Data were obtained from the MarketScan® Commercial Claims and Encounters database, which is constructed and maintained by Truven Health Analytics. Data from 2002 to 2007 were used for the study. MarketScan consists of de-identified reimbursed health-care claims for employees, retirees, and their dependents of over 250 medium

and large employers and health plans. Hence, individuals included in the database are covered under private insurance plans; no Medicaid or Medicare data are included. The database includes claims information describing the health-care experiences for approximately 56 million covered lives per year. The database is divided into subsections, including inpatient claims, outpatient claims, outpatient prescription drug claims, and enrollment information. Claims data in each of the subsections contain a unique patient identifier and information on patient age, gender, geographic location (including state and three-digit zip code), and type of health plan.

The inpatient and outpatient services subsections of the MarketScan database contain information on all services performed in an inpatient or outpatient setting. These data include information on dates of services, the diagnoses associated with the claim, and the procedures performed. The outpatient services subsection includes information for all services performed in a doctor’s office, hospital outpatient clinic, emergency room, or other outpatient facility. Previous studies have used the MarketScan database to examine health-care service use and costs for children (24–29).

Study Population
The study sample consisted of children aged 6–15 with a diagnosis of one of the following conditions (ICD-9 codes in parentheses): OCD (300.3), AN (307.1), anxiety disorder (300.0–300.2), tic disorder (307.20 or 307.22), ADHD (314), major depression (296.2–296.3), and bipolar disorder (296.0–296.2, 296.4–296.8). To test the specificity of the models, we also included children with broken bones (800–829) and open wounds (870–897). To identify new cases, we further limited the sample in each
Temporal Association of Certain Neuropsychiatric Disorders Following Vaccination of Children and Adolescents: A Pilot Case–Control Study
Douglas L. Leslie, Robert A. Kobre, […], and James F. Leckman

Additional article information

Abstract
Background
Although the association of the measles, mumps, and rubella vaccine with autism spectrum disorder has been convincingly disproven, the onset of certain brain-related autoimmune and inflammatory disorders has been found to be temporally associated with the antecedent administration of various vaccines. This study examines whether antecedent vaccinations are associated with increased incidence of obsessive–compulsive disorder (OCD), anorexia nervosa (AN), anxiety disorder, chronic tic disorder, attention deficit hyperactivity disorder, major depressive disorder, and bipolar disorder in a national sample of privately insured children.

Methods
Using claims data, we compared the prior year’s occurrence of vaccinations in children and adolescents aged 6–15 years with the above neuropsychiatric disorders that were newly diagnosed between January 2002 and December 2007, as well as two control conditions, broken bones and open wounds. Subjects were matched with controls according to age, gender, geographical area, and seasonality. Conditional logistic regression models were used to determine the association of prior vaccinations with each condition.

Results
Subjects with newly diagnosed AN were more likely than controls to have had any vaccination in the previous 3 months [hazard ratio (HR) 1.80, 95% confidence interval 1.21–2.68]. Influenza vaccinations during the prior 3, 6, and 12 months were also associated with incident diagnoses of AN, OCD, and an anxiety disorder. Several other associations were also significant with HRs greater than 1.40 (hepatitis A with OCD and AN; hepatitis B with AN; and meningitis with AN and chronic tic disorder).

Conclusion
This pilot epidemiologic analysis implies that the onset of some neuropsychiatric disorders may be temporally related to prior vaccinations in a subset of individuals. These findings warrant further investigation, but do not prove a causal role of antecedent infections or vaccinations in the pathoetiology of these conditions. Given the modest magnitude of these findings in contrast to the clear public health benefits of the timely administration of vaccines in preventing mortality and morbidity in childhood infectious diseases, we encourage families to maintain vaccination schedules according to CDC guidelines.

Keywords: anorexia nervosa, obsessive–compulsive disorder, anxiety disorder, tic disorder, vaccination, influenza, meningococcus
Introduction
There is a considerable body of scientific evidence indicating that the immune system plays a key role in normal brain development and in the pathobiology of several neuropsychiatric disorders (1). These include obsessive–compulsive disorder (OCD) (2, 3), anorexia nervosa (AN) (4), tic disorders (5), attention deficit hyperactivity disorder (ADHD) (6), major depressive disorder (7), and bipolar disorder (8). The precise role immune mechanisms play in these disorders remains to be determined.

In light of the role of the immune system in these central nervous system (CNS) conditions, the impact of vaccines on childhood-onset neuropsychiatric diseases had been considered and was mainly addressed with regards to the administration of the measles, mumps, and rubella (MMR) vaccine (and its various components) and the subsequent development of autism spectrum disorder (ASD). Although the controversy over MMR vaccination and ASD still exists for some members of the public, this association has been convincingly disproven (9, 10). On the other hand, the onset of a limited number of autoimmune and inflammatory disorders affecting the CNS has been found to be temporally associated with the antecedent administration of various vaccines (11). These disorders include idiopathic thrombocytopenic purpura, acute disseminated encephalomyelitis, and Guillain–Barré syndrome among others (12–16). More recently, data have emerged indicating an association between the administration of the H1N1 influenza vaccine containing the AS03 adjuvant and the subsequent new onset of narcolepsy in several northern European countries (17, 18). The immune mechanisms and host factors underlying these associations have not been identified or fully characterized, although preliminary data are beginning to emerge (18–23).

Given this growing body of evidence of immunological involvement in CNS conditions, and despite the controversy concerning the link between ASD and MMR and the clear public health importance of vaccinations, we hypothesized that some vaccines could have an impact in a subset of susceptible individuals and aimed to investigate whether there is a temporal association between the antecedent administration of vaccines and the onset of several neuropsychiatric disorders, including OCD, AN, tic disorder, anxiety disorder, ADHD, major depressive disorder, and bipolar disorder using a case–control population-based pediatric sample (children aged 6–15 years). To assess the specificity of any statistical associations, we also determined whether or not there were any temporal associations between antecedent vaccine administration and the occurrence of broken bones or open wounds.

Materials and Methods
Data were obtained from the MarketScan® Commercial Claims and Encounters database, which is constructed and maintained by Truven Health Analytics. Data from 2002 to 2007 were used for the study. MarketScan consists of de-identified reimbursed health-care claims for employees, retirees, and their dependents of over 250 medium and large employers and health plans. Hence, individuals included in the database are covered under private insurance plans; no Medicaid or Medicare data are included. The database includes claims information describing the health-care experiences for approximately 56 million covered lives per year. The database is divided into subsections, including inpatient claims, outpatient claims, outpatient prescription drug claims, and enrollment information. Claims data in each of the subsections contain a unique patient identifier and information on patient age, gender, geographic location (including state and three-digit zip code), and type of health plan.

The inpatient and outpatient services subsections of the MarketScan database contain information on all services performed in an inpatient or outpatient setting. These data include information on dates of services, the diagnoses associated with the claim, and the procedures performed. The outpatient services subsection includes information for all services performed in a doctor’s office, hospital outpatient clinic, emergency room, or other outpatient facility. Previous studies have used the MarketScan database to examine health-care service use and costs for children (24–29).

Study Population
The study sample consisted of children aged 6–15 with a diagnosis of one of the following conditions (ICD-9 codes in parentheses): OCD (300.3), AN (307.1), anxiety disorder (300.0–300.2), tic disorder (307.20 or 307.22), ADHD (314), major depression (296.2–296.3), and bipolar disorder (296.0–296.2, 296.4–296.8). To test the specificity of the models, we also included children with broken bones (800–829) and open wounds (870–897). To identify new cases, we further limited the sample in each diagnostic group to children who were continuously enrolled for at least 1 year prior to their first diagnosis for the condition (the index date). Next, a matched one-to-one control group was constructed for each diagnostic group consisting of children who did not have the condition of interest and were matched with their corresponding case on age, gender, date of the start of continuous enrollment, and three-digit zip code. Because vaccines tend to occur during certain times of year (such as before summer camps or the beginning of school), controls were also required to have an outpatient visit at which they did not receive a vaccine within 15 days of the date that the corresponding case was first diagnosed with the condition, in an effort to control for seasonality. The date of this visit was the index date for children in the control group.

For each diagnostic group and their corresponding controls, individuals who were vaccinated in the 3, 6, or 12 months before the index date were identified. Exposure to vaccines was measured using CPT codes (list available from the authors upon request) and ICD-9 codes (V03–V06 or V07.2). Exposure to specific vaccines, including influenza, tetanus and diphtheria (TD), hepatitis A, hepatitis B, meningitis, and varicella, was tracked.

Statistical Analysis
The analyses were performed for each diagnostic group (and their controls) separately. Children with multiple conditions (e.g., ADHD and tic disorder) were included in each of the corresponding analytic groups. First, the proportion of children who were exposed to vaccines in the period before the index date was compared across the case and control groups. Next, bivariate conditional logistic regression models were
Temporal Association of Certain Neuropsychiatric Disorders Following Vaccination of Children and Adolescents: A Pilot Case–Control Study
Douglas L. Leslie, Robert A. Kobre, […], and James F. Leckman

Additional article information

Abstract
Background
Although the association of the measles, mumps, and rubella vaccine with autism spectrum disorder has been convincingly disproven, the onset of certain brain-related autoimmune and inflammatory disorders has been found to be temporally associated with the antecedent administration of various vaccines. This study examines whether antecedent vaccinations are associated with increased incidence of obsessive–compulsive disorder (OCD), anorexia nervosa (AN), anxiety disorder, chronic tic disorder, attention deficit hyperactivity disorder, major depressive disorder, and bipolar disorder in a national sample of privately insured children.

Methods
Using claims data, we compared the prior year’s occurrence of vaccinations in children and adolescents aged 6–15 years with the above neuropsychiatric disorders that were newly diagnosed between January 2002 and December 2007, as well as two control conditions, broken bones and open wounds. Subjects were matched with controls according to age, gender, geographical area, and seasonality. Conditional logistic regression models were used to determine the association of prior vaccinations with each condition.

Results
Subjects with newly diagnosed AN were more likely than controls to have had any vaccination in the previous 3 months [hazard ratio (HR) 1.80, 95% confidence interval 1.21–2.68]. Influenza vaccinations during the prior 3, 6, and 12 months were also associated with incident diagnoses of AN, OCD, and an anxiety disorder. Several other associations were also significant with HRs greater than 1.40 (hepatitis A with OCD and AN; hepatitis B with AN; and meningitis with AN and chronic tic disorder).

Conclusion
This pilot epidemiologic analysis implies that the onset of some neuropsychiatric disorders may be temporally related to prior vaccinations in a subset of individuals. These findings warrant further investigation, but do not prove a causal role of antecedent infections or vaccinations in the pathoetiology of these conditions. Given the modest magnitude of these findings in contrast to the clear public health benefits of the timely administration of vaccines in preventing mortality and morbidity in childhood infectious diseases, we encourage families to maintain vaccination schedules according to CDC guidelines.

Keywords: anorexia nervosa, obsessive–compulsive disorder, anxiety disorder, tic disorder, vaccination, influenza, meningococcus
Introduction
There is a considerable body of scientific evidence indicating that the immune system plays a key role in normal brain development and in the pathobiology of several neuropsychiatric disorders (1). These include obsessive–compulsive disorder (OCD) (2, 3), anorexia nervosa (AN) (4), tic disorders (5), attention deficit hyperactivity disorder (ADHD) (6), major depressive disorder (7), and bipolar disorder (8). The precise role immune mechanisms play in these disorders remains to be determined.

In light of the role of the immune system in these central nervous system (CNS) conditions, the impact of vaccines on childhood-onset neuropsychiatric diseases had been considered and was mainly addressed with regards to the administration of the measles, mumps, and rubella (MMR) vaccine (and its various components) and the subsequent development of autism spectrum disorder (ASD). Although the controversy over MMR vaccination and ASD still exists for some members of the public, this association has been convincingly disproven (9, 10). On the other hand, the onset of a limited number of autoimmune and inflammatory disorders affecting the CNS has been found to be temporally associated with the antecedent administration of various vaccines (11). These disorders include idiopathic thrombocytopenic purpura, acute disseminated encephalomyelitis, and Guillain–Barré syndrome among others (12–16). More recently, data have emerged indicating an association between the administration of the H1N1 influenza vaccine containing the AS03 adjuvant and the subsequent new onset of narcolepsy in several northern European countries (17, 18). The immune mechanisms and host factors underlying these associations have not been identified or fully characterized, although preliminary data are beginning to emerge (18–23).

Given this growing body of evidence of immunological involvement in CNS conditions, and despite the controversy concerning the link between ASD and MMR and the clear public health importance of vaccinations, we hypothesized that some vaccines could have an impact in a subset of susceptible individuals and aimed to investigate whether there is a temporal association between the antecedent administration of vaccines and the onset of several neuropsychiatric disorders, including OCD, AN, tic disorder, anxiety disorder, ADHD, major depressive disorder, and bipolar disorder using a case–control population-based pediatric sample (children aged 6–15 years). To assess the specificity of any statistical associations, we also determined whether or not there were any temporal associations between antecedent vaccine administration and the occurrence of broken bones or open wounds.

Materials and Methods
Data were obtained from the MarketScan® Commercial Claims and Encounters database, which is constructed and maintained by Truven Health Analytics. Data from 2002 to 2007 were used for the study. MarketScan consists of de-identified reimbursed health-care claims for employees, retirees, and their dependents of over 250 medium and large employers and health plans. Hence, individuals included in the database are covered under private insurance plans; no Medicaid or Medicare data are included. The database includes claims information describing the health-care experiences for approximately 56 million covered lives per year. The database is divided into subsections, including inpatient claims, outpatient claims, outpatient prescription drug claims, and enrollment information. Claims data in each of the subsections contain a unique patient identifier and information on patient age, gender, geographic location (including state and three-digit zip code), and type of health plan.

The inpatient and outpatient services subsections of the MarketScan database contain information on all services performed in an inpatient or outpatient setting. These data include information on dates of services, the diagnoses associated with the claim, and the procedures performed. The outpatient services subsection includes information for all services performed in a doctor’s office, hospital outpatient clinic, emergency room, or other outpatient facility. Previous studies have used the MarketScan database to examine health-care service use and costs for children (24–29).

Study Population
The study sample consisted of children aged 6–15 with a diagnosis of one of the following conditions (ICD-9 codes in parentheses): OCD (300.3), AN (307.1), anxiety disorder (300.0–300.2), tic disorder (307.20 or 307.22), ADHD (314), major depression (296.2–296.3), and bipolar disorder (296.0–296.2, 296.4–296.8). To test the specificity of the models, we also included children with broken bones (800–829) and open wounds (870–897). To identify new cases, we further limited the sample in each diagnostic group to children who were continuously enrolled for at least 1 year prior to their first diagnosis for the condition (the index date). Next, a matched one-to-one control group was constructed for each diagnostic group consisting of children who did not have the condition of interest and were matched with their corresponding case on age, gender, date of the start of continuous enrollment, and three-digit zip code. Because vaccines tend to occur during certain times of year (such as before summer camps or the beginning of school), controls were also required to have an outpatient visit at which they did not receive a vaccine within 15 days of the date that the corresponding case was first diagnosed with the condition, in an effort to control for seasonality. The date of this visit was the index date for children in the control group.

For each diagnostic group and their corresponding controls, individuals who were vaccinated in the 3, 6, or 12 months before the index date were identified. Exposure to vaccines was measured using CPT codes (list available from the authors upon request) and ICD-9 codes (V03–V06 or V07.2). Exposure to specific vaccines, including influenza, tetanus and diphtheria (TD), hepatitis A, hepatitis B, meningitis, and varicella, was tracked.

Statistical Analysis
The analyses were performed for each diagnostic group (and their controls) separately. Children with multiple conditions (e.g., ADHD and tic disorder) were included in each of the corresponding analytic groups. First, the proportion of children who were exposed to vaccines in the period before the index date was compared across the case and control groups. Next, bivariate conditional logistic regression models were estimated to determine the hazard ratios (HRs) and 95% confidence intervals (95% CIs) associated with the effect of vaccine exposure on having the condition of interest. Separate models were run for the 3-, 6-, and 12-month periods preceding the index date for each diagnostic group. The study was approved by the Penn State College of Medicine Institutional Review Board.

Results
Characteristics of each of the diagnostic groups are presented in Table Table1.1. Sample sizes ranged from 551 children diagnosed with AN to 85,151 children with a broken bone. The average age ranged from 9.5 ± 2.5 for children with tic disorder to 13.3 ± 1.7 for children with AN. Not surprisingly, the distribution of sex varied considerably across diagnostic groups, with higher percentages of females in the AN (86.6%) and major depression (56.3%) categories and higher proportions of males in the tic disorder (76.4%), ADHD (66.8%), open wound (62.2%), broken bone (58.4%), OCD (56.6%), and bipolar disorder (54.1%) categories.

Table 1

Table 1
Characteristics of the sample.

Characteristic Broken bone Open wound OCD Anorexia nervosa Anxiety disorder Tic disorder ADHD Major depression Bipolar disorder
N % N % N % N % N % N % N % N % N %
N 85,151 73,290 3,222 551 23,462 2,547 46,640 13,295 5,892
Age, mean ± SD 11.1 ± 2.7 10.6 ± 2.9 11.1 ± 2.6 13.3 ± 1.7 11.3 ± 2.8 9.5 ± 2.5 10.3 ± 2.8 12.9 ± 2.2 12.3 ± 2.6
Gender
Male 49,689 58.4 45,562 62.2 1,825 56.6 74 13.4 11,357 48.4 1,945 76.4 31,170 66.8 5,811 43.7 3,185 54.1
Female 35,462 41.6 27,728 37.8 1,397 43.4 477 86.6 12,105 51.6 602 23.6 15,470 33.2 7,484 56.3 2,707 45.9
Receipt of vaccinea
Any vaccine 10,308 12.1 7,577 10.3 512 15.9 118 21.4 3,389 14.4 402 15.8 5,536 11.9 1,700 12.8 682 11.6
Influenza 3,550 4.2 2,783 3.8 246 7.6 42 7.6 1,418 6.0 214 8.4 2,366 5.1 548 4.1 247 4.2
TD 2,061 2.4 1,358 1.9 68 2.1 27 4.9 520 2.2 53 2.1 913 2.0 405 3.0 159 2.7
HepA 1,950 2.3 1,462 2.0 86 2.7 14 2.5 570 2.4 62 2.4 1,005 2.2 285 2.1 100 1.7
HepB 713 0.8 550 0.8 20 0.6 12 2.2 201 0.9 14 0.5 366 0.8 150 1.1 60 1.0
Meningitis 1,325 1.6 835 1.1 61 1.9 24 4.4 422 1.8 36 1.4 495 1.1 223 1.7 88 1.5
Varicella 1,002 1.2 750 1.0 52 1.6 8 1.5 323 1.4 44 1.7 577 1.2 93 0.7 42 0.7
aReciept of vaccine in the 6 months before first diagnosis of the disorder.

OCD, obsessive–compulsive disorder; ADHD, attention deficit hyperactivity disorder; TD, tetanus and diphtheria; Hep, hepatitis.
Temporal Association of Certain Neuropsychiatric Disorders Following Vaccination of Children and Adolescents: A Pilot Case–Control Study
Douglas L. Leslie, Robert A. Kobre, […], and James F. Leckman

Additional article information

Abstract
Background
Although the association of the measles, mumps, and rubella vaccine with autism spectrum disorder has been convincingly disproven, the onset of certain brain-related autoimmune and inflammatory disorders has been found to be temporally associated with the antecedent administration of various vaccines. This study examines whether antecedent vaccinations are associated with increased incidence of obsessive–compulsive disorder (OCD), anorexia nervosa (AN), anxiety disorder, chronic tic disorder, attention deficit hyperactivity disorder, major depressive disorder, and bipolar disorder in a national sample of privately insured children.

Methods
Using claims data, we compared the prior year’s occurrence of vaccinations in children and adolescents aged 6–15 years with the above neuropsychiatric disorders that were newly diagnosed between January 2002 and December 2007, as well as two control conditions, broken bones and open wounds. Subjects were matched with controls according to age, gender, geographical area, and seasonality. Conditional logistic regression models were used to determine the association of prior vaccinations with each condition.

Results
Subjects with newly diagnosed AN were more likely than controls to have had any vaccination in the previous 3 months [hazard ratio (HR) 1.80, 95% confidence interval 1.21–2.68]. Influenza vaccinations during the prior 3, 6, and 12 months were also associated with incident diagnoses of AN, OCD, and an anxiety disorder. Several other associations were also significant with HRs greater than 1.40 (hepatitis A with OCD and AN; hepatitis B with AN; and meningitis with AN and chronic tic disorder).

Conclusion
This pilot epidemiologic analysis implies that the onset of some neuropsychiatric disorders may be temporally related to prior vaccinations in a subset of individuals. These findings warrant further investigation, but do not prove a causal role of antecedent infections or vaccinations in the pathoetiology of these conditions. Given the
Table 1
Characteristics of the sample.
Rates of receipt of vaccines in the 6 months before the first diagnosis of the disorder are also reported in Table Table11 and varied considerably across diagnostic groups. Receipt of any vaccine in the previous 6 months was highest for children with AN (21.4%), followed by OCD (15.9%) and tic disorder (15.8%), and was lowest for children with
Temporal Association of Certain Neuropsychiatric Disorders Following Vaccination of Children and Adolescents: A Pilot Case–Control Study
Douglas L. Leslie, Robert A. Kobre, […], and James F. Leckman

Additional article information

Abstract
Background
Although the association of the measles, mumps, and rubella vaccine with autism spectrum disorder has been convincingly disproven, the onset of certain brain-related autoimmune and inflammatory disorders has been found to be temporally associated with the antecedent administration of various vaccines. This study examines whether antecedent vaccinations are associated with increased incidence of obsessive–compulsive disorder (OCD), anorexia nervosa (AN), anxiety disorder, chronic tic disorder, attention deficit hyperactivity disorder, major depressive disorder, and bipolar disorder in a national sample of privately insured children.

Methods
Using claims data, we compared the prior year’s occurrence of vaccinations in children and adolescents aged 6–15 years with the above neuropsychiatric disorders that were newly diagnosed between January 2002 and December 2007, as well as two control conditions, broken bones and open wounds. Subjects were matched with controls according to age, gender, geographical area, and seasonality. Conditional logistic regression models were used to determine the association of prior vaccinations with each condition.

Results
Subjects with newly diagnosed AN were more likely than controls to have had any vaccination in the previous 3 months [hazard ratio (HR) 1.80, 95% confidence interval 1.21–2.68]. Influenza vaccinations during the prior 3, 6, and 12 months were also associated with incident diagnoses of AN, OCD, and an anxiety disorder. Several other associations were also significant with HRs greater than 1.40 (hepatitis A with OCD and AN; hepatitis B with AN; and meningitis with AN and chronic tic disorder).

Conclusion
This pilot epidemiologic analysis implies that the onset of some neuropsychiatric disorders may be temporally related to prior vaccinations in a subset of individuals. These findings warrant further investigation, but do not prove a causal role of antecedent infections or vaccinations in the pathoetiology of these conditions. Given the modest magnitude of these findings in contrast to the clear public health benefits of the timely administration of vaccines in preventing mortality and morbidity in childhood infectious diseases, we encourage families to maintain vaccination schedules according to CDC guidelines.

Keywords: anorexia nervosa, obsessive–compulsive disorder, anxiety disorder, tic disorder, vaccination, influenza, meningococcus
Introduction
There is a considerable body of scientific evidence indicating that the immune system plays a key role in normal brain development and in the pathobiology of several neuropsychiatric disorders (1). These include obsessive–compulsive disorder (OCD) (2, 3), anorexia nervosa (AN) (4), tic disorders (5), attention deficit hyperactivity disorder (ADHD) (6), major depressive disorder (7), and bipolar disorder (8). The precise role immune mechanisms play in these disorders remains to be determined.

In light of the role of the immune system in these central nervous system (CNS) conditions, the impact of vaccines on childhood-onset neuropsychiatric diseases had been considered and was mainly addressed with regards to the administration of the measles, mumps, and rubella (MMR) vaccine (and its various components) and the subsequent development of autism spectrum disorder (ASD). Although the controversy over MMR vaccination and ASD still exists for some members of the public, this association has been convincingly disproven (9, 10). On the other hand, the onset of a limited number of autoimmune and inflammatory disorders affecting the CNS has been found to be temporally associated with the antecedent administration of various vaccines (11). These disorders include idiopathic thrombocytopenic purpura, acute disseminated encephalomyelitis, and Guillain–Barré syndrome among others (12–16). More recently, data have emerged indicating an association between the administration of the H1N1 influenza vaccine containing the AS03 adjuvant and the subsequent new onset of narcolepsy in several northern European countries (17, 18). The immune mechanisms and host factors underlying these associations have not been identified or fully characterized, although preliminary data are beginning to emerge (18–23).

Given this growing body of evidence of immunological involvement in CNS conditions, and despite the controversy concerning the link between ASD and MMR and the clear public health importance of vaccinations, we hypothesized that some vaccines could have an impact in a subset of susceptible individuals and aimed to investigate whether there is a temporal association between the antecedent administration of vaccines and the onset of several neuropsychiatric disorders, including OCD, AN, tic disorder, anxiety disorder, ADHD, major depressive disorder, and bipolar disorder using a case–control population-based pediatric sample (children aged 6–15 years). To assess the specificity of any statistical associations, we also determined whether or not there were any temporal associations between antecedent vaccine administration and the occurrence of broken bones or open wounds.

Materials and Methods
Data were obtained from the MarketScan® Commercial Claims and Encounters database, which is constructed and maintained by Truven Health Analytics. Data from 2002 to 2007 were used for the study. MarketScan consists of de-identified reimbursed health-care claims for employees, retirees, and their dependents of over 250 medium and large employers and health plans. Hence, individuals included in the database are covered under private insurance plans; no Medicaid or Medicare data are included. The database includes claims information describing the health-care experiences for approximately 56 million covered lives per year. The database is divided into subsections, including inpatient claims, outpatient claims, outpatient prescription drug claims, and enrollment information. Claims data in each of the subsections contain a unique patient identifier and information on patient age, gender, geographic location (including state and three-digit zip code), and type of health plan.

The inpatient and outpatient services subsections of the MarketScan database contain information on all services performed in an inpatient or outpatient setting. These data include information on dates of services, the diagnoses associated with the claim, and the procedures performed. The outpatient services subsection includes information for all services performed in a doctor’s office, hospital outpatient clinic, emergency room, or other outpatient facility. Previous studies have used the MarketScan database to examine health-care service use and costs for children (24–29).

Study Population
The study sample consisted of children aged 6–15 with a diagnosis of one of the following conditions (ICD-9 codes in parentheses): OCD (300.3), AN (307.1), anxiety disorder (300.0–300.2), tic disorder (307.20 or 307.22), ADHD (314), major depression (296.2–296.3), and bipolar disorder (296.0–296.2, 296.4–296.8). To test the specificity of the models, we also included children with broken bones (800–829) and open wounds (870–897). To identify new cases, we further limited the sample in each diagnostic group to children who were continuously enrolled for at least 1 year prior to their first diagnosis for the condition (the index date). Next, a matched one-to-one control group was constructed for each diagnostic group consisting of children who did not have the condition of interest and were matched with their corresponding case on age, gender, date of the start of continuous enrollment, and three-digit zip code. Because vaccines tend to occur during certain times of year (such as before summer camps or the beginning of school), controls were also required to have an outpatient visit at which they did not receive a vaccine within 15 days of the date that the corresponding case was first diagnosed with the condition, in an effort to control for seasonality. The date of this visit was the index date for children in the control group.

For each diagnostic group and their corresponding controls, individuals who were vaccinated in the 3, 6, or 12 months before the index date were identified. Exposure to vaccines was measured using CPT codes (list available from the authors upon request) and ICD-9 codes (V03–V06 or V07.2). Exposure to specific vaccines, including influenza, tetanus and diphtheria (TD), hepatitis A, hepatitis B, meningitis, and varicella, was tracked.

Statistical Analysis
The analyses were performed for each diagnostic group (and their controls) separately. Children with multiple conditions (e.g., ADHD and tic disorder) were included in each of the corresponding analytic groups. First, the proportion of children who were exposed to vaccines in the period before the index date was compared across the case and control groups. Next, bivariate conditional logistic regression models were estimated to determine the hazard ratios (HRs) and 95% confidence intervals (95% CIs) associated with the effect of vaccine exposure on having the condition of interest. Separate models were run for the 3-, 6-, and 12-month periods preceding the index date for each diagnostic group. The study was approved by the Penn State College of Medicine Institutional Review Board.

Results
Characteristics of each of the diagnostic groups are presented in Table Table1.1. Sample sizes ranged from 551 children diagnosed with AN to 85,151 children with a broken bone. The average age ranged from 9.5 ± 2.5 for children with tic disorder to 13.3 ± 1.7 for children with AN. Not surprisingly, the distribution of sex varied considerably across diagnostic groups, with higher percentages of females in the AN (86.6%) and major depression (56.3%) categories and higher proportions of males in the tic disorder (76.4%), ADHD (66.8%), open wound (62.2%), broken bone (58.4%), OCD (56.6%), and bipolar disorder (54.1%) categories.

Table 1
Table 1
Characteristics of the sample.
Rates of receipt of vaccines in the 6 months before the first diagnosis of the disorder are also reported in Table Table11 and varied considerably across diagnostic groups. Receipt of any vaccine in the previous 6 months was highest for children with AN (21.4%), followed by OCD (15.9%) and tic disorder (15.8%), and was lowest for children with open wounds (10.3%). Rates of receipt of specific vaccines were fairly low, ranging from 0.5% for the hepatitis vaccine among children with tic disorder to 8.4% for the influenza vaccine among children with tic disorder. In general, vaccination rates were highest among children in the AN, OCD, and tic disorder groups and were lowest for children in the open wound or bipolar disorder groups.

Table Table22

Table 2
Bivariate associations of receipt of vaccine with new diagnosis.a

Vaccine Broken bone N = 85,151 Open wound N = 73,290 OCD N = 3,222 Anorexia nervosa N = 551 Anxiety disorder N = 23,462 Tic disorder N = 2,547 ADHD N = 46,640 Major depression N = 13,295 Bipolar disorder N = 5,892
Hazard ratio (HR) 95% CI HR 95% CI HR 95% CI HR 95% CI HR 95% CI HR 95% CI HR 95% CI HR 95% CI HR 95% CI
Any vaccine
3 months 1.04 1.00 1.08 0.96 0.92 1.00 1.23 1.02 1.49 1.80 1.21 2.68 1.12 1.04 1.20 1.11 0.90 1.38 1.06 1.00 1.12 0.88 0.80 0.97 0.87 0.75 1.01
6 months 1.08 1.05 1.11 0.97 0.94 1.01 1.27 1.10 1.47 1.63 1.17 2.27 1.13 1.07 1.19 1.25 1.06 1.47 1.04 1.00 1.09 0.92 0.86 0.99 0.82 0.73 0.91
12 months 1.07 1.04 1.09 0.97 0.94 1.00 1.23 1.09 1.38 1.47 1.12 1.93 1.14 1.09 1.19 1.19 1.04 1.36 1.08 1.05 1.12 0.89 0.84 0.95 0.87 0.79 0.95
Influenza
3 months 1.03 0.96 1.11 0.93 0.86 1.01 1.36 1.02 1.82 2.20 1.10 4.38 1.23 1.10 1.38 1.24 0.91 1.67 0.98 0.91 1.07 0.81 0.68 0.96 0.71 0.55 0.92
6 months 1.07 1.02 1.13 0.96 0.91 1.02 1.48 1.21 1.83 1.83 1.07 3.15 1.24 1.14 1.35 1.27 1.02 1.58 0.97 0.91 1.02 0.89 0.79 1.00 0.84 0.70 1.00
12 months 1.06 1.02 1.09 0.97 0.93 1.01 1.35 1.16 1.59 1.52 0.99 2.34 1.27 1.19 1.35 1.28 1.08 1.50 1.04 0.99 1.09 0.93 0.84 1.02 0.87 0.76 1.00

presents HRs from the bivariate associations of receipt of vaccine within the 3-, 6-, and 12-month periods preceding the index date for each diagnostic group compared to their matched controls. Children with OCD, AN, anxiety disorder, or ADHD were more likely to have had a vaccination in each of the preceding periods than their matched controls, and children with tic disorder were more likely to have had a vaccination in the preceding 6- and 12-month periods than their matched controls. HRs associated with receipt of any vaccine were highest for children with AN, ranging from 1.47 (95% CI 1.12–1.93) for the 12-month preceding period to 1.80 (95% CI 1.21–2.68) for the 3-month preceding period, followed by OCD, which ranged from 1.23 for both the 12-month (95% CI 1.12–1.93) and 3-month (95% CI 1.02–1.49) preceding periods to 1.27 (95% CI 1.10–1.47) for the 6-month preceding period. However, children with broken bones were also more likely to have had a vaccination in the preceding period, although the HRs were smaller, ranging from 1.04 (95% CI 1.00–1.08) for the 3-month preceding period to 1.08 (95% CI 1.05–1.11) for the 6-month preceding period. The other control condition, open wounds, showed no increased incidence following vaccinations. In addition, children with major depression were less likely to have had a vaccination in all 3 preceding periods, and children with bipolar disorder were also less likely to have had a vaccination in the 6- or 12-month preceding periods.

There were fewer statistically significant results when looking at the effects of the individual vaccines. Children with OCD were more likely to have received the influenza vaccine in each of the preceding periods, or the hepatitis A vaccine in the previous 6 or 12 months. Children with AN were also more likely to have received the influenza vaccine in the preceding 3 or 6 months, or the TD vaccine in the previous 12 months. Children with anxiety disorder were more likely to have received the influenza vaccine in the previous 12 months. Children with tic disorder were more likely to have received an influenza or a meningococcal vaccine in the previous 6 or 12 months. However, children with broken bones were also slightly more likely to have received the influenza vaccine during the previous 3-, 6-, and 12-month intervals. In contrast, children with major depression were less likely to have received the influenza vaccine in the previous 3 months or the meningitis vaccine in the previous 12 months. Similarly, children with bipolar disorder were also less likely to have received the influenza vaccine in the previous 3 or 6 months. Antecedent vaccination with any vaccine and with the TD vaccine during the previous 12 months was very modestly associated with a decreased incidence of open wounds (Table (Table22).

Discussion
The principal findings of this study are as follows: (i) children with OCD, AN, anxiety disorder, and tic disorder were more likely to have received influenza vaccine during

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5244035/#B5