MMR vaccine study, Importance Despite research showing no link between the measles-mumps-rubella (MMR) vaccine and autism spectrum disorders (ASD), beliefs that the vaccine causes autism persist, leading to lower vaccination levels. Parents who already have a child with ASD may be especially wary of vaccinations.
Objective To report ASD occurrence by MMR vaccine status in a large sample of US children who have older siblings with and without ASD.
Design, Setting, and Participants A retrospective cohort study using an administrative claims database associated with a large commercial health plan. Participants included children continuously enrolled in the health plan from birth to at least 5 years of age during 2001-2012 who also had an older sibling continuously enrolled for at least 6 months between 1997 and 2012.
Exposures MMR vaccine receipt (0, 1, 2 doses) between birth and 5 years of age.
Main Outcomes and Measures ASD status defined as 2 claims with a diagnosis code in any position for autistic disorder or other specified pervasive developmental disorder (PDD) including Asperger syndrome, or unspecified PDD (International Classification of Diseases, Ninth Revision, Clinical Modification 299.0x, 299.8x, 299.9x).
Results Of 95 727 children with older siblings, 994 (1.04%) were diagnosed with ASD and 1929 (2.01%) had an older sibling with ASD. Of those with older siblings with ASD, 134 (6.9%) had ASD, vs 860 (0.9%) children with unaffected siblings (P < .001). MMR vaccination rates (≥1 dose) were 84% (n = 78 564) at age 2 years and 92% (n = 86 063) at age 5 years for children with unaffected older siblings, vs 73% (n = 1409) at age 2 years and 86% (n = 1660) at age 5 years for children with affected siblings. MMR vaccine receipt was not associated with an increased risk of ASD at any age. For children with older siblings with ASD, at age 2, the adjusted relative risk (RR) of ASD for 1 dose of MMR vaccine vs no vaccine was 0.76 (95% CI, 0.49-1.18; P = .22), and at age 5, the RR of ASD for 2 doses compared with no vaccine was 0.56 (95% CI, 0.31-1.01; P = .052). For children whose older siblings did not have ASD, at age 2, the adjusted RR of ASD for 1 dose was 0.91 (95% CI, 0.67-1.20; P = .50) and at age 5, the RR of ASD for 2 doses was 1.12 (95% CI, 0.78-1.59; P = .55).
Conclusions and Relevance In this large sample of privately insured children with older siblings, receipt of the MMR vaccine was not associated with increased risk of ASD, regardless of whether older siblings had ASD. These findings indicate no harmful association between MMR vaccine receipt and ASD even among children already at higher risk for ASD.
Two doses of measles-mumps-rubella (MMR) vaccine are currently recommended for children in the United States: the first at age 12 to 15 months and the second at age 4 to 6 years.1 Although a substantial body of research over the last 15 years has found no link between the MMR vaccine and autism spectrum disorders (ASD),2- 4 parents and others continue to associate the vaccine with ASD.5 Parents cite vaccinations, especially MMR, as a cause of ASD6 and have deferred or refused vaccinations for their children as a result.7,8 Lower vaccination levels threaten public health by reducing both individual and herd immunity and have been associated with several recent outbreaks of measles, with most cases occurring among unvaccinated individuals.9
Families with a child affected by ASD may be particularly concerned about reports linking MMR and ASD, despite the lack of evidence.10 Surveys of parents who have children with ASD suggest that many believe the MMR vaccine was a contributing cause.11 This belief, combined with knowing that younger siblings of children with ASD are already at higher genetic risk for ASD compared with the general population,12- 14 might prompt these parents to avoid vaccinating their younger children. In a recent survey of 486 parents of children with ASD, nearly 20% had declined or delayed MMR immunization in the younger siblings of these children.15 Furthermore, a Canadian study of 98 younger siblings of children with ASD found that younger siblings were less likely to be fully MMR immunized when compared with their older siblings with ASD. However, there were no statistically significant differences in rates of ASD diagnosis between immunized and nonimmunized children.10 To our knowledge, this very small study is alone in examining MMR immunization and ASD outcomes among the younger siblings of children with ASD.
Thus, we set out to report on ASD occurrence by MMR vaccine status in a large sample of US children having older siblings with ASD and to compare findings with those among children who have older siblings without ASD.
METHODS
ABSTRACT | INTRODUCTION | METHODS | RESULTS | DISCUSSION | CONCLUSIONS | ARTICLE INFORMATION | REFERENCES
A retrospective cohort study was conducted using an administrative claims database associated with a large US health plan (the Optum Research Database). The Optum Research Database includes more than 34 million individuals each year, containing both commercially insured individuals and Medicare managed care enrollees. The database consists of proprietary, deidentified health claims data from a geographically diverse US population (16% West, 20% Midwest, 36% South, and 27% Northeast). In addition, the age and sex distribution of the enrollees is similar to that reported by the US Census Bureau for both the commercially insured and the Medicare managed care populations. The New England Institutional Review Board waived the need for informed consent and deemed the study exempt based on its use of existing, deidentified16 data.
Index children were identified among commercially insured enrollees who had both medical and pharmacy coverage and included all children in the database born between January 1, 2001, and December 31, 2007, who were continuously enrolled in the health plan from birth to at least 5 years of age and who also had an older sibling continuously enrolled in the health plan for at least 6 months between the beginning and end of the study period (January 1, 1997-December 31, 2012). Older siblings of index children were identified using a family identifier variable associated with the insurance policy; siblings had to be between 6 months and 17 years older than the index child to be included.
ASD status in index children and older siblings was determined using a claims-based algorithm with a positive predictive value of 87%17 that required 2 or more claims on separate dates of service with an InternationalClassification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis code in any position for autistic disorder, other specified pervasive developmental disorder (PDD) including Asperger syndrome, or unspecified PDD (299.0x, 299.8x, and 299.9x). Both index child and older sibling ASD status were determined using their entire enrollment time that fell within the study period. Index children had to have at least 1 older sibling with 2 claims with ASD diagnoses or all older siblings with no ASD diagnoses. Children with an older sibling with only 1 claim with an ASD diagnosis were excluded. Index children with only 1 claim with an ASD diagnosis were also excluded.
MMR vaccine receipt was defined as having a Current Procedural Terminology (CPT) or ICD-9-CM procedure code indicating receipt of each component (measles, mumps, and rubella) between birth and 5 years of age (eTable 1 in the Supplement). The date of administration of the trivalent MMR (or the last-administered component of monovalent vaccines) was used to determine age at administration for each dose (first or second).
Because the recommended age of first MMR dose administration is 12 to 15 months, and 4 to 6 years for the second dose, relative risks (RRs) were estimated to compare ASD status in children receiving 1 dose of MMR at ages 2, 3, 4, and 5 years and 2 doses at age 5 years vs those who were unvaccinated at those ages (2-dose RRs at age 4 years would only include those children who received the second dose by their fourth birthday). Separate RRs were estimated for children with older siblings with and without ASD. Since no children were lost to follow-up before reaching age 5, unadjusted RRs were reported as cumulative incidence rate ratios by taking the ratio of the proportion of children who had an ASD diagnosis in an exposed group (either 1 MMR dose or 2 MMR doses) to the proportion of children who had an ASD diagnosis in the unvaccinated group at a given age.
Adjusted RRs were reported as hazard rate ratios estimated from a single Cox proportional hazard regression model that used age since birth as the time scale and included MMR receipt as a time-varying covariate ascribing follow-up time to either the unvaccinated group, the 1-dose group, or the 2-dose group, depending on immunization status at any given age. An interaction term between MMR receipt and older sibling ASD status was included to allow adjusted RRs to vary by older sibling ASD status. In addition, interactions between MMR receipt and age (to relax the proportionality assumption and allow hazard ratios [HRs] to vary by age), as well as a 3-way interaction between MMR receipt, age, and older sibling ASD status, were tested for possible inclusion in the final model.
Both time-varying and fixed covariates were also included in adjusted models to control for potential confounding. Separate claims-based indicators of the presence of seizures and vaccine-related allergies in the index child were included as time-varying covariates because they are possible contraindications to vaccines and are potentially associated with ASD status.18- 20 To capture aspects of the index child’s overall health status that might also be associated with both MMR receipt and ASD status, an indicator for preterm birth and a modified claims-based version21 of the childhood chronic conditions score (CCC)22 were included as fixed covariates. The modified CCC uses claims-based diagnosis codes to capture the presence of chronic conditions, excluding those associated with ASD, within 9 domains: neuromuscular, cardiovascular, respiratory, renal, gastrointestinal, hematologic or immunologic, metabolic, other congenital or genetic defects, and malignant neoplasms. The presence of at least 1 claim for a condition within each domain between birth and age 2 adds 1 point to the CCC score (range, 0-9). eTable 2 in the Supplement lists ICD-9-CM codes used to define conditions and variables.
Maternal and paternal educational level, household income, and race/ethnicity were also included as fixed covariates. These sociodemographic factors have been associated with both ASD status23 and vaccine receipt.24 Approximately 30% of the race/ethnicity data in this study were collected directly from public records (eg, driver’s license records), while the remaining data were imputed using commercial software (E-Tech by Ethnic Technologies) that uses algorithms developed with US Census data zip codes (zip + 4) and first and last names. This imputation method has been validated and demonstrates 97% specificity, 48% sensitivity, and 71% positive predictive value for estimating the race of black individuals.25 Individuals categorized as other/unknown for race/ethnicity were those whose race/ethnicity could not be assigned by the imputation algorithm or who were added to the data set after the imputation had been performed.
Other fixed covariates included in the adjusted models were sex of the index child, mother’s and father’s age at index child’s birth, geographic location defined by the 4 US Census regions, mental health benefits, and index child birth year, which was included to adjust for varying opportunity for ASD to develop or be diagnosed. Response categories were created for unknown or missing values of all covariates and included as such in regression models.
A series of sensitivity analyses were conducted to explore the influence of potential MMR or ASD status measurement error on results. Quantitative bias analyses were implemented for both exposure and outcome misclassification following the approach described by Lash et al.26 More detail on bias analysis methods is provided in the online supplement (eAppendix and eTable 3 in the Supplement). In addition, associations between MMR receipt and ASD risk were also reestimated using a less-restrictive 1-claim criterion for ASD diagnosis in younger siblings. An additional sensitivity analysis was also performed rerunning final models on the subset of children with no missing data on any covariates.
Statistical significance testing of unadjusted rate ratios was conducted using the Yates χ2 test, and statistical significance testing of hazard ratios estimated by maximum likelihood were conducted using Wald χ2 statistics. Likelihood ratio tests were used to test the statistical significance of Cox proportional hazards models with and without interaction terms. All statistical tests were 2-sided and the α level for all tests was .05. Analyses were performed using SAS statistical software, version 9.2.
RESULTS
ABSTRACT | INTRODUCTION | METHODS | RESULTS | DISCUSSION | CONCLUSIONS | ARTICLE INFORMATION | REFERENCES
Out of 95 727 children in the cohort, 1929 (2.01%) had an older sibling with ASD. Overall, 994 (1.04%) children in the cohort had ASD diagnosed during follow-up. Among those who had an older sibling with ASD, 134 (6.9%) were diagnosed with ASD, compared with 860 (0.9%) diagnosed with ASD among those with siblings without ASD (P < .001). The MMR vaccination rate (≥1 dose) for the children with unaffected siblings (siblings without ASD) was 84% (n = 78 564) at 2 years and 92% (n = 86 063) at age 5 years. In contrast, the MMR vaccination rates for children with older siblings with ASD were lower (73% at age 2 years [n = 1409] and 86% [n = 1660] at age 5 years).
Table 1 shows the clinical and sociodemographic characteristics of the 95 727 children, stratified by older sibling ASD status. Birth years were roughly equally distributed over 2001-2007, and slightly more than half of the sample was male. Approximately three-quarters of participants were white, 3% were black (vs 13% in the US population), and 9% were Hispanic (vs 17% in the US population).27 All 4 of the major geographic regions in the United States were represented, with somewhat more representation in the South (42% vs 38%) and less in the West (17% vs 24%) as compared with the overall US population.27 Approximately 3% had a potential contraindication to vaccine receipt and approximately 8% were preterm. The average length of continuous enrollment was slightly more than 7 years.
Design, Setting, and Participants A retrospective cohort study using an administrative claims database associated with a large commercial health plan. Participants included children continuously enrolled in the health plan from birth to at least 5 years of age during 2001-2012 who also had an older sibling continuously enrolled for at least 6 months between 1997 and 2012.
Exposures MMR vaccine receipt (0, 1, 2 doses) between birth and 5 years of age.
Main Outcomes and Measures ASD status defined as 2 claims with a diagnosis code in any position for autistic disorder or other specified pervasive developmental disorder (PDD) including Asperger syndrome, or unspecified PDD (International Classification of Diseases, Ninth Revision, Clinical Modification 299.0x, 299.8x, 299.9x).
Results Of 95 727 children with older siblings, 994 (1.04%) were diagnosed with ASD and 1929 (2.01%) had an older sibling with ASD. Of those with older siblings with ASD, 134 (6.9%) had ASD, vs 860 (0.9%) children with unaffected siblings (P < .001). MMR vaccination rates (≥1 dose) were 84% (n = 78 564) at age 2 years and 92% (n = 86 063) at age 5 years for children with unaffected older siblings, vs 73% (n = 1409) at age 2 years and 86% (n = 1660) at age 5 years for children with affected siblings. MMR vaccine receipt was not associated with an increased risk of ASD at any age. For children with older siblings with ASD, at age 2, the adjusted relative risk (RR) of ASD for 1 dose of MMR vaccine vs no vaccine was 0.76 (95% CI, 0.49-1.18; P = .22), and at age 5, the RR of ASD for 2 doses compared with no vaccine was 0.56 (95% CI, 0.31-1.01; P = .052). For children whose older siblings did not have ASD, at age 2, the adjusted RR of ASD for 1 dose was 0.91 (95% CI, 0.67-1.20; P = .50) and at age 5, the RR of ASD for 2 doses was 1.12 (95% CI, 0.78-1.59; P = .55).
Conclusions and Relevance In this large sample of privately insured children with older siblings, receipt of the MMR vaccine was not associated with increased risk of ASD, regardless of whether older siblings had ASD. These findings indicate no harmful association between MMR vaccine receipt and ASD even among children already at higher risk for ASD.
Two doses of measles-mumps-rubella (MMR) vaccine are currently recommended for children in the United States: the first at age 12 to 15 months and the second at age 4 to 6 years.1 Although a substantial body of research over the last 15 years has found no link between the MMR vaccine and autism spectrum disorders (ASD),2- 4 parents and others continue to associate the vaccine with ASD.5 Parents cite vaccinations, especially MMR, as a cause of ASD6 and have deferred or refused vaccinations for their children as a result.7,8 Lower vaccination levels threaten public health by reducing both individual and herd immunity and have been associated with several recent outbreaks of measles, with most cases occurring among unvaccinated individuals.9
Families with a child affected by ASD may be particularly concerned about reports linking MMR and ASD, despite the lack of evidence.10 Surveys of parents who have children with ASD suggest that many believe the MMR vaccine was a contributing cause.11 This belief, combined with knowing that younger siblings of children with ASD are already at higher genetic risk for ASD compared with the general population,12- 14 might prompt these parents to avoid vaccinating their younger children. In a recent survey of 486 parents of children with ASD, nearly 20% had declined or delayed MMR immunization in the younger siblings of these children.15 Furthermore, a Canadian study of 98 younger siblings of children with ASD found that younger siblings were less likely to be fully MMR immunized when compared with their older siblings with ASD. However, there were no statistically significant differences in rates of ASD diagnosis between immunized and nonimmunized children.10 To our knowledge, this very small study is alone in examining MMR immunization and ASD outcomes among the younger siblings of children with ASD.
Thus, we set out to report on ASD occurrence by MMR vaccine status in a large sample of US children having older siblings with ASD and to compare findings with those among children who have older siblings without ASD.
METHODS
ABSTRACT | INTRODUCTION | METHODS | RESULTS | DISCUSSION | CONCLUSIONS | ARTICLE INFORMATION | REFERENCES
A retrospective cohort study was conducted using an administrative claims database associated with a large US health plan (the Optum Research Database). The Optum Research Database includes more than 34 million individuals each year, containing both commercially insured individuals and Medicare managed care enrollees. The database consists of proprietary, deidentified health claims data from a geographically diverse US population (16% West, 20% Midwest, 36% South, and 27% Northeast). In addition, the age and sex distribution of the enrollees is similar to that reported by the US Census Bureau for both the commercially insured and the Medicare managed care populations. The New England Institutional Review Board waived the need for informed consent and deemed the study exempt based on its use of existing, deidentified16 data.
Index children were identified among commercially insured enrollees who had both medical and pharmacy coverage and included all children in the database born between January 1, 2001, and December 31, 2007, who were continuously enrolled in the health plan from birth to at least 5 years of age and who also had an older sibling continuously enrolled in the health plan for at least 6 months between the beginning and end of the study period (January 1, 1997-December 31, 2012). Older siblings of index children were identified using a family identifier variable associated with the insurance policy; siblings had to be between 6 months and 17 years older than the index child to be included.
ASD status in index children and older siblings was determined using a claims-based algorithm with a positive predictive value of 87%17 that required 2 or more claims on separate dates of service with an InternationalClassification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis code in any position for autistic disorder, other specified pervasive developmental disorder (PDD) including Asperger syndrome, or unspecified PDD (299.0x, 299.8x, and 299.9x). Both index child and older sibling ASD status were determined using their entire enrollment time that fell within the study period. Index children had to have at least 1 older sibling with 2 claims with ASD diagnoses or all older siblings with no ASD diagnoses. Children with an older sibling with only 1 claim with an ASD diagnosis were excluded. Index children with only 1 claim with an ASD diagnosis were also excluded.
MMR vaccine receipt was defined as having a Current Procedural Terminology (CPT) or ICD-9-CM procedure code indicating receipt of each component (measles, mumps, and rubella) between birth and 5 years of age (eTable 1 in the Supplement). The date of administration of the trivalent MMR (or the last-administered component of monovalent vaccines) was used to determine age at administration for each dose (first or second).
Because the recommended age of first MMR dose administration is 12 to 15 months, and 4 to 6 years for the second dose, relative risks (RRs) were estimated to compare ASD status in children receiving 1 dose of MMR at ages 2, 3, 4, and 5 years and 2 doses at age 5 years vs those who were unvaccinated at those ages (2-dose RRs at age 4 years would only include those children who received the second dose by their fourth birthday). Separate RRs were estimated for children with older siblings with and without ASD. Since no children were lost to follow-up before reaching age 5, unadjusted RRs were reported as cumulative incidence rate ratios by taking the ratio of the proportion of children who had an ASD diagnosis in an exposed group (either 1 MMR dose or 2 MMR doses) to the proportion of children who had an ASD diagnosis in the unvaccinated group at a given age.
Adjusted RRs were reported as hazard rate ratios estimated from a single Cox proportional hazard regression model that used age since birth as the time scale and included MMR receipt as a time-varying covariate ascribing follow-up time to either the unvaccinated group, the 1-dose group, or the 2-dose group, depending on immunization status at any given age. An interaction term between MMR receipt and older sibling ASD status was included to allow adjusted RRs to vary by older sibling ASD status. In addition, interactions between MMR receipt and age (to relax the proportionality assumption and allow hazard ratios [HRs] to vary by age), as well as a 3-way interaction between MMR receipt, age, and older sibling ASD status, were tested for possible inclusion in the final model.
Both time-varying and fixed covariates were also included in adjusted models to control for potential confounding. Separate claims-based indicators of the presence of seizures and vaccine-related allergies in the index child were included as time-varying covariates because they are possible contraindications to vaccines and are potentially associated with ASD status.18- 20 To capture aspects of the index child’s overall health status that might also be associated with both MMR receipt and ASD status, an indicator for preterm birth and a modified claims-based version21 of the childhood chronic conditions score (CCC)22 were included as fixed covariates. The modified CCC uses claims-based diagnosis codes to capture the presence of chronic conditions, excluding those associated with ASD, within 9 domains: neuromuscular, cardiovascular, respiratory, renal, gastrointestinal, hematologic or immunologic, metabolic, other congenital or genetic defects, and malignant neoplasms. The presence of at least 1 claim for a condition within each domain between birth and age 2 adds 1 point to the CCC score (range, 0-9). eTable 2 in the Supplement lists ICD-9-CM codes used to define conditions and variables.
Maternal and paternal educational level, household income, and race/ethnicity were also included as fixed covariates. These sociodemographic factors have been associated with both ASD status23 and vaccine receipt.24 Approximately 30% of the race/ethnicity data in this study were collected directly from public records (eg, driver’s license records), while the remaining data were imputed using commercial software (E-Tech by Ethnic Technologies) that uses algorithms developed with US Census data zip codes (zip + 4) and first and last names. This imputation method has been validated and demonstrates 97% specificity, 48% sensitivity, and 71% positive predictive value for estimating the race of black individuals.25 Individuals categorized as other/unknown for race/ethnicity were those whose race/ethnicity could not be assigned by the imputation algorithm or who were added to the data set after the imputation had been performed.
Other fixed covariates included in the adjusted models were sex of the index child, mother’s and father’s age at index child’s birth, geographic location defined by the 4 US Census regions, mental health benefits, and index child birth year, which was included to adjust for varying opportunity for ASD to develop or be diagnosed. Response categories were created for unknown or missing values of all covariates and included as such in regression models.
A series of sensitivity analyses were conducted to explore the influence of potential MMR or ASD status measurement error on results. Quantitative bias analyses were implemented for both exposure and outcome misclassification following the approach described by Lash et al.26 More detail on bias analysis methods is provided in the online supplement (eAppendix and eTable 3 in the Supplement). In addition, associations between MMR receipt and ASD risk were also reestimated using a less-restrictive 1-claim criterion for ASD diagnosis in younger siblings. An additional sensitivity analysis was also performed rerunning final models on the subset of children with no missing data on any covariates.
Statistical significance testing of unadjusted rate ratios was conducted using the Yates χ2 test, and statistical significance testing of hazard ratios estimated by maximum likelihood were conducted using Wald χ2 statistics. Likelihood ratio tests were used to test the statistical significance of Cox proportional hazards models with and without interaction terms. All statistical tests were 2-sided and the α level for all tests was .05. Analyses were performed using SAS statistical software, version 9.2.
RESULTS
ABSTRACT | INTRODUCTION | METHODS | RESULTS | DISCUSSION | CONCLUSIONS | ARTICLE INFORMATION | REFERENCES
Out of 95 727 children in the cohort, 1929 (2.01%) had an older sibling with ASD. Overall, 994 (1.04%) children in the cohort had ASD diagnosed during follow-up. Among those who had an older sibling with ASD, 134 (6.9%) were diagnosed with ASD, compared with 860 (0.9%) diagnosed with ASD among those with siblings without ASD (P < .001). The MMR vaccination rate (≥1 dose) for the children with unaffected siblings (siblings without ASD) was 84% (n = 78 564) at 2 years and 92% (n = 86 063) at age 5 years. In contrast, the MMR vaccination rates for children with older siblings with ASD were lower (73% at age 2 years [n = 1409] and 86% [n = 1660] at age 5 years).
Table 1 shows the clinical and sociodemographic characteristics of the 95 727 children, stratified by older sibling ASD status. Birth years were roughly equally distributed over 2001-2007, and slightly more than half of the sample was male. Approximately three-quarters of participants were white, 3% were black (vs 13% in the US population), and 9% were Hispanic (vs 17% in the US population).27 All 4 of the major geographic regions in the United States were represented, with somewhat more representation in the South (42% vs 38%) and less in the West (17% vs 24%) as compared with the overall US population.27 Approximately 3% had a potential contraindication to vaccine receipt and approximately 8% were preterm. The average length of continuous enrollment was slightly more than 7 years.
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