Monitoring vaccine safety using the vaccine safety Datalink: Assessing capacity to integrate data from Immunization Information systems.

BACKGROUND: The Vaccine Safety Datalink (VSD) uses vaccination data from electronic health records (EHR) at eight integrated health systems to monitor vaccine safety. Accurate capture of data from vaccines administered outside of the health system is critical for vaccine safety research, especially for COVID-19 vaccines, where many are administered in non-traditional settings. However, timely access and inclusion of data from Immunization Information Systems (IIS) into VSD safety assessments is not well understood. METHODS: We surveyed the eight data-contributing VSD sites to assess: 1) status of sending data to IIS; 2) status of receiving data from IIS; and 3) integration of IIS data into the site EHR. Sites reported separately for COVID-19 vaccination to capture any differences in capacity to receive and integrate data on COVID-19 vaccines versus other vaccines. RESULTS: All VSD sites send data to and receive data from their state IIS. All eight sites (100%) routinely integrate IIS data for COVID-19 vaccines into VSD research studies. Six sites (75%) also routinely integrate all other vaccination data; two sites integrate data from IIS following a reconciliation process, which can result in delays to integration into VSD datasets. CONCLUSIONS: COVID-19 vaccines are being administered in a variety of non-traditional settings, where IIS are commonly used as centralized reporting systems. All eight VSD sites receive and integrate COVID-19 vaccine data from IIS, which positions the VSD well for conducting quality assessments of vaccine safety. Efforts to improve the timely receipt of all vaccination data will improve capacity to conduct vaccine safety assessments within the VSD.

Assessing misclassification of vaccination status: Implications for studies of the safety of the childhood immunization schedule.

BACKGROUND: To address public concern about the safety of the childhood immunization schedule, the Institute of Medicine recommended observational studies comparing adverse health outcomes of fully vaccinated children to children under-vaccinated due to parental choice. Misclassification of vaccination status could bias such studies. OBJECTIVE: To assess risk of misclassification of vaccination status within the Vaccine Safety Datalink (VSD). DESIGN/METHODS: A retrospective cohort study was conducted in three phases. In phase 1, electronic health record (EHR) data were used to identify patterns of under-vaccination during the first 24months of life potentially due to parental choice. In phase 2, a random sample of records of under-vaccinated children was manually reviewed. In phase 3, a separate sample of parents were surveyed to assess whether EHR data accurately reflected their child's vaccination status. Phases 1 and 2 were conducted at 6 VSD sites, phase 3 at 1 site. RESULTS: The study cohort included 361,901 children born 2004 through 2012. By 24months of age, 198,249 (54.8%) were fully vaccinated with no delays, 84,698 (23.4%) experienced delays but were fully vaccinated by 24months of age, 4865 (1.3%) received no vaccines, 3789 (1.0%) delayed starting vaccination until ≥4months of age, 4781 (1.3%) had consistent vaccine-limiting (≤2 vaccines per visit), and the remaining 65,519 (18.1%) were missing vaccine series or doses. When a diagnosis code for vaccine refusal was present in EHR data, encounter notes confirmed vaccine refusal as the reason for under-vaccination for nearly 100% of sampled records. Parent surveys confirmed these findings. Parents of under-vaccinated children were more likely to report visiting an alternative medical provider than parents of fully vaccinated children. CONCLUSIONS: Specific groups of children, under-vaccinated due to parental choice, can be identified with relatively low likelihood of misclassification of vaccination status using EHR-based vaccine data and diagnosis codes.

Cumulative and episodic vaccine aluminum exposure in a population-based cohort of young children.

BACKGROUND: In addition to antigens, vaccines contain small amounts of preservatives, adjuvants, and residual substances from the manufacturing process. Some parents have concerns about the safety of these ingredients, yet no large epidemiological studies have specifically examined associations between health outcomes and vaccine ingredients, other than thimerosal. This study examined the extent to which the Vaccine Safety Datalink (VSD) could be used to study vaccine ingredient safety in children. METHODS: Children born 2004-2011 were identified in VSD data. Using immunization records, two cohorts were identified: children who were up-to-date and children who were undervaccinated before age 2 years. A database was also created linking vaccine type and manufacturer with ingredient amounts documented in vaccine package inserts. Thirty-four ingredients in two or more infant vaccines were identified. However, only amounts (in mg) for aluminum were consistently documented and commonly contained in infant vaccines. Analyses compared vaccine aluminum exposure across cohorts and determined the statistical power for studying associations between aluminum exposure and hypothetical vaccine adverse events. RESULTS: Among 408,608 children, mean cumulative vaccine aluminum exposure increased from 1.11 to 4.00 mg between ages 92-730 days. Up-to-date children were exposed to 11-26% more aluminum from vaccines than undervaccinated children. Power analyses demonstrated that safety studies of aluminum could detect relative risks ranging from 1.1 to 5.8 for a range of adverse event incidence. CONCLUSIONS: The safety of vaccine aluminum exposure can be feasibly studied in the VSD. However, possible biological mechanisms and confounding variables would need to be considered before conducting any studies.

Association of Tdap Vaccination With Acute Events and Adverse Birth Outcomes Among Pregnant Women With Prior Tetanus-Containing Immunizations.

IMPORTANCE: The Advisory Committee on Immunization Practices (ACIP) recommends the tetanus, diphtheria, and acellular pertussis (Tdap) vaccine for pregnant women during each pregnancy, regardless of prior immunization status. However, safety data on repeated Tdap vaccination in pregnancy is lacking. OBJECTIVE: To determine whether receipt of Tdap vaccine during pregnancy administered in close intervals from prior tetanus-containing vaccinations is associated with acute adverse events in mothers and adverse birth outcomes in neonates. DESIGN, SETTING, AND PARTICIPANTS: A retrospective cohort study in 29,155 pregnant women aged 14 through 49 years from January 1, 2007, through November 15, 2013, using data from 7 Vaccine Safety Datalink sites in California, Colorado, Minnesota, Oregon, Washington, and Wisconsin. EXPOSURES: Women who received Tdap in pregnancy following a prior tetanus-containing vaccine less than 2 years before, 2 to 5 years before, and more than 5 years before. MAIN OUTCOMES AND MEASURES: Acute adverse events (fever, allergy, and local reactions) and adverse birth outcomes (small for gestational age, preterm delivery, and low birth weight) were evaluated. Women who were vaccinated with Tdap in pregnancy and had a prior tetanus-containing vaccine more than 5 years before served as controls. RESULTS: There were no statistically significant differences in rates of medically attended acute adverse events or adverse birth outcomes related to timing since prior tetanus-containing vaccination. [table: see text]. CONCLUSIONS AND RELEVANCE: Among women who received Tdap vaccination during pregnancy, there was no increased risk of acute adverse events or adverse birth outcomes for those who had been previously vaccinated less than 2 years before or 2 to 5 years before compared with those who had been vaccinated more than 5 years before. These findings suggest that relatively recent receipt of a prior tetanus-containing vaccination does not increase risk after Tdap vaccination in pregnancy.

Safety of Tetanus Toxoid, Reduced Diphtheria Toxoid, and Acellular Pertussis and Influenza Vaccinations in Pregnancy.

OBJECTIVE: To evaluate the safety of coadministering tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) and influenza vaccines during pregnancy by comparing adverse events after concomitant and sequential vaccination. METHODS: We conducted a retrospective cohort study of pregnant women aged 14-49 years in the Vaccine Safety Datalink from January 1, 2007, to November 15, 2013. We compared medically attended acute events (fever, any acute reaction) and adverse birth outcomes (preterm delivery, low birth weight, small for gestational age) in women receiving concomitant Tdap and influenza vaccination and women receiving sequential vaccination. RESULTS: Among 36,844 pregnancies in which Tdap and influenza vaccines were administered, the vaccines were administered concomitantly in 8,464 (23%) pregnancies and sequentially in 28,380 (77%) pregnancies. Acute adverse events after vaccination were rare. We found no statistically significant increased risk of fever or any medically attended acute adverse event in pregnant women vaccinated concomitantly compared with sequentially. When analyzing women at 20 weeks of gestation or greater during periods of influenza vaccine administration, there were no differences in preterm delivery, low-birth-weight, or small-for-gestational-age neonates between women vaccinated concomitantly compared with sequentially in pregnancy. CONCLUSION: Concomitant administration of Tdap and influenza vaccines during pregnancy was not associated with a higher risk of medically attended adverse acute outcomes or birth outcomes compared with sequential vaccination. LEVEL OF EVIDENCE: II.

Timely versus delayed early childhood vaccination and seizures.

BACKGROUND: Little is known regarding the timing of childhood vaccination and postvaccination seizures. METHODS: In a cohort of 323 247 US children from the Vaccine Safety Datalink born from 2004 to 2008, we analyzed the association between the timing of childhood vaccination and the first occurrence of seizure with a self-controlled case series analysis of the first doses of individual vaccines received in the first 2 years of life. RESULTS: In infants, there was no association between the timing of infant vaccination and postvaccination seizures. In the second year of life, the incident rate ratio (IRR) for seizures after receipt of the first measles-mumps-rubella vaccine (MMR) dose at 12 to 15 months was 2.65 (95% confidence interval [CI] 1.99-3.55); the IRR after an MMR dose at 16 to 23 months was 6.53 (95% CI 3.15-13.53). The IRR for seizures after receipt of the first measles-mumps-rubella-varicella vaccine (MMRV) dose at 12 to 15 months was 4.95 (95% CI 3.68-6.66); the IRR after an MMRV dose at 16 to 23 months was 9.80 (95% CI 4.35 -22.06). CONCLUSIONS: There is no increased risk of postvaccination seizure in infants regardless of timing of vaccination. In year 2, delaying MMR vaccine past 15 months of age results in a higher risk of seizures. The strength of the association is doubled with MMRV vaccine. These findings suggest that on-time vaccination is as safe with regard to seizures as delayed vaccination in the first year of life, and that delayed vaccination in the second year of life is associated with more postvaccination seizures than on-time vaccination.

Association between undervaccination with diphtheria, tetanus toxoids, and acellular pertussis (DTaP) vaccine and risk of pertussis infection in children 3 to 36 months of age.

IMPORTANCE: Undervaccination is an increasing trend that potentially places children and their communities at an increased risk for serious infectious diseases. OBJECTIVE: To examine the association between undervaccination and pertussis in children 3 to 36 months of age. DESIGN: Matched case-control study with conditional logistic regression analysis. SETTING: Eight managed care organizations of the Vaccine Safety Datalink between 2004 and 2010. PARTICIPANTS: Each laboratory-confirmed case of pertussis (72 patients) was matched to 4 randomly selected controls (for a total of 288 controls). The case patients were matched to controls by managed care organization site, sex, and age at the index date. The index date was defined as the date of pertussis diagnosis for the case patients. EXPOSURE: Undervaccination for the diphtheria, tetanus toxoids, and acellular pertussis (DTaP) vaccine. Undervaccination was defined as the number of doses of DTaP vaccine that was either missing or delayed by the index date. Case patients and controls could be undervaccinated by 0, 1, 2, 3, or 4 doses of DTaP vaccine. Children undervaccinated by 0 doses were considered age-appropriately vaccinated by the index date. MAIN OUTCOME AND MEASURE: Pertussis. RESULTS: Of the 72 case patients with pertussis, 12 (16.67%) were hospitalized, and 34 (47.22%) were undervaccinated for DTaP vaccine by the date of pertussis diagnosis. Of the 288 matched controls, 64 (22.22%) were undervaccinated for DTaP vaccine. Undervaccination was strongly associated with pertussis. Children undervaccinated for 3 or 4 doses of DTaP vaccine were 18.56 (95% CI, 4.92-69.95) and 28.38 (95% CI, 3.19-252.63) times more likely, respectively, to have received a diagnosis of pertussis than children who were age-appropriately vaccinated. CONCLUSIONS AND RELEVANCE: Undervaccination with DTaP vaccine increases the risk of pertussis among children 3 to 36 months of age.

Mortality rates and cause-of-death patterns in a vaccinated population.

BACKGROUND: Determining the baseline mortality rate in a vaccinated population is necessary to be able to identify any unusual increases in deaths following vaccine administration. Background rates are particularly useful during mass immunization campaigns and in the evaluation of new vaccines. PURPOSE: Provide background mortality rates and describe causes of death following vaccination in the Vaccine Safety Datalink (VSD). METHODS: Analyses were conducted in 2012. Mortality rates were calculated at 0-1 day, 0-7 days, 0-30 days, and 0-60 days following vaccination for deaths occurring between January 1, 2005, and December 31, 2008. Analyses were stratified by age and gender. Causes of death were examined, and findings were compared to National Center for Health Statistics (NCHS) data. RESULTS: Among 13,033,274 vaccinated people, 15,455 deaths occurred between 0 and 60 days following vaccination. The mortality rate within 60 days of a vaccination visit was 442.5 deaths per 100,000 person-years. Rates were highest in the group aged ≥85 years, and increased from the 0-1-day to the 0-60-day interval following vaccination. Eleven of the 15 leading causes of death in the VSD and NCHS overlap in both systems, and the top four causes of death were the same in both systems. CONCLUSIONS: VSD mortality rates demonstrate a healthy vaccinee effect, with rates lowest in the days immediately following vaccination, most apparent in the older age groups. The VSD mortality rate is lower than that in the general U.S. population, and the causes of death are similar.

A population-based cohort study of undervaccination in 8 managed care organizations across the United States.

OBJECTIVES To examine patterns and trends of undervaccination in children aged 2 to 24 months and to compare health care utilization rates between undervaccinated and age-appropriately vaccinated children. DESIGN Retrospective matched cohort study. SETTING Eight managed care organizations of the Vaccine Safety Datalink. PARTICIPANTS Children born between 2004 and 2008. MAIN EXPOSURE Immunization records were used to calculate the average number of days undervaccinated. Two matched cohorts were created: 1 with children who were undervaccinated for any reason and 1 with children who were undervaccinated because of parental choice. For both cohorts, undervaccinated children were matched to age-appropriately vaccinated children by birth date, managed care organization, and sex. MAIN OUTCOME MEASURES Rates of undervaccination, specific patterns of undervaccination, and health care utilization rates. RESULTS Of 323 247 children born between 2004 and 2008, 48.7% were undervaccinated for at least 1 day before age 24 months. The prevalence of undervaccination and specific patterns of undervaccination increased over time (P < .001). In a matched cohort analysis, undervaccinated children had lower outpatient visit rates compared with children who were age-appropriately vaccinated (incidence rate ratio [IRR], 0.89; 95% CI, 0.89- 0.90). In contrast, undervaccinated children had increased inpatient admission rates compared with age-appropriately vaccinated children (IRR, 1.21; 95% CI, 1.18-1.23). In a second matched cohort analysis, children who were undervaccinated because of parental choice had lower rates of outpatient visits (IRR, 0.94; 95% CI, 0.93-0.95) and emergency department encounters (IRR, 0.91; 95% CI, 0.88-0.94) than age-appropriately vaccinated children. CONCLUSIONS Undervaccination appears to be an increasing trend. Undervaccinated children appear to have different health care utilization patterns compared with age-appropriately vaccinated children.

Secular trends in diagnostic code density in electronic healthcare data from health care systems in the Vaccine Safety Datalink project.

Large observational vaccine safety studies often use automated diagnoses extracted from medical care databases to identify pre-specified potential adverse events following immunization (AEFI). We assessed the secular trends and variability in the number of diagnoses per encounter regardless of immunization status referred as diagnostic code density, by healthcare setting, age, and pre-specified condition in eight large health care systems of the Vaccine Safety Datalink project during 2001-2009. An increasing trend in diagnostic code density was observed in all healthcare settings and age groups, with variations across the sites. Sudden increases in diagnostic code density were observed at certain sites when changes in coding policies or data inclusion criteria took place. When vaccine safety studies use an historical comparator, the increased diagnostic code density over time may generate low expected rates (based on historical data) and high observed rates (based on current data), suggesting a false positive association between a vaccine and AEFI. The ongoing monitoring of the diagnostic code density can provide guidance on study design and choice of appropriate comparison groups. It can also be used to ensure data quality and allow timely correction of errors in an active safety surveillance system.

Accuracy of influenza vaccination status in a computer-based immunization tracking system of a managed care organization.

Influenza vaccine safety and effectiveness studies conducted using electronic medical records rely on accurate assessment of influenza vaccination status. However, influenza immunization in non-traditional settings (e.g., the workplace) may not be captured in patient immunization tracking systems. We compared influenza vaccination status from electronic records with self-reported vaccination status for five hundred and two 50-79 years olds enrolled in a large managed care organization. Influenza vaccination status in the medical record had a high positive predictive value and specificity (both >99%). The negative predictive value was 80% and sensitivity was 78%. These data suggest that an electronic record of influenza vaccination reliably indicates immunization, while the absence of such a record is only moderately accurate, partly due to vaccines received in non-traditional settings.

Air pollution and hospital admissions for ischemic heart disease in persons with congestive heart failure or arrhythmia.

We examined whether ischemic heart disease (IHD) hospital admissions were associated with air pollutants in those with and without secondary diagnoses of arrhythmia (ARR) or congestive heart failure (CHF). We assessed the occurrence of increased vulnerability among persons with these conditions to daily variations in ozone, carbon monoxide, nitrogen dioxide, or particulate matter less than or equal to 10 micro m in aerodynamic diameter (PM10). The study population consisted of members of a large health maintenance organization residing in the South Coast Air Basin of California from 1988 to 1995. After adjustment for day of week, study year, and smoothing splines for day of study, temperature, and relative humidity, CO and NO2 were both associated with admissions with the greatest effects for CO. A 1-ppm increase in 8-hr average CO was associated with a 3.60% [95% confidence interval (CI), 1.62-5.63%] increase in same-day IHD admissions in persons with a secondary diagnosis of CHF, a 2.99% (95% CI, 1.80-4.19%) increase in persons with a secondary diagnosis of ARR, and a 1.62% (95% CI, 0.65-2.59%) increase in IHD admissions in persons without either secondary diagnosis. Air pollution was most strongly associated with myocardial infarction hospital admissions. The vulnerability of the secondary CHF subgroup may be due to a greater prevalence of myocardial infarction primary diagnoses and not the modifying effect of CHF. This study suggests that people with IHD and accompanying CHF and/or ARR constitute a sensitive subgroup in relation to the effects of criteria ambient air pollutants associated with motor vehicle combustion.