Parental Refusal of Pertussis Vaccination Is Associated With an Increased Risk of Pertussis Infection in Children

Setting and Study Population

The setting was Kaiser Permanente Colorado (KPCO), a Denver-based health plan with more than 430000 current members. KPCO members receive full coverage of all pediatric vaccines as recommended by the Advisory Committee on Immunization Practices.¹⁴ We conducted a case-control study among children ages 2 months to 18 years, who were members of the health plan between 1996 and 2007. The study was designed to determine if children who contracted pertussis infection were more likely to have parents who refused pertussis vaccinations than a similar group of children who did not develop pertussis infection. The study was reviewed and approved by the KPCO institutional review board.

Definition and Selection of Cases

All potential pediatric cases of pertussis in children were identified by using KPCO medical databases. Potential cases were selected if they had 1 or more of the following: a positive polymerase chain reaction (PCR) laboratory test for Bordetella pertussis, a positive pertussis culture result, or an International Classification of Diseases, Ninth Revision, Clinical Modification code for B pertussis (033.0, 033.1, 033.8, or 033.9). These diagnosis codes and laboratory tests represented medical encounters in the outpatient, emergency department, and inpatient settings. All potential cases were identified without knowledge of vaccination status.

The medical charts of potential cases were then reviewed by a trained abstractor, who was blinded to vaccination status. Details from the pertinent medical encounter and all records up to 14 days after this encounter were abstracted. The abstractor recorded pertussis PCR and culture results, clinical diagnoses of pertussis, duration of cough, presenting symptoms (paroxysms, posttussive emesis, whoop), sequelae of pertussis (apnea, pneumonia, seizures, encephalopathy), and previous exposures to close contacts infected with pertussis. A close contact was defined as someone at day care, school, or home with known pertussis. Additional variables included birth date, gender, home address, ethnicity, age, and medical setting of the qualifying encounter. Patients were classified as confirmed cases if they had a medical chart–verified positive PCR test or a positive culture for B pertussis.¹⁵ Confirmed cases between 2 months and 18 years of age were eligible for the final analyses, because infants are not immunized before 2 months of age.

Selection of Controls

For each case, the date of pertussis diagnosis represented the index date. Each case was matched to 4 randomly selected controls by gender, length of KPCO enrollment, and age at the index date (within 7 days). The controls were selected from a pool of pediatric members enrolled in the KPCO health plan between 1996 and 2007. Eligible controls did not have a record of pertussis infection before the index date. Vaccination status was ascertained retrospectively from the index date (see below). This matching scheme helped to simultaneously control for age and season.

Ascertainment of Vaccination Status

The medical charts of the cases and controls were reviewed by a trained medical charts abstractor to determine each child's vaccination status. Diphtheria, tetanus, and acellular pertussis vaccination is recommended at ages 2, 4, 6, 12 to 18, and 48 to 59 months.¹⁴ Before 1996, the diphtheria, tetanus, and whole-cellular pertussis vaccine was recommended on a similar schedule.¹⁶ The medical abstractor, who was blinded to pertussis case status, documented the types and dates of vaccinations received, and whether immunizations were refused by parents for personal, nonmedical reasons. Children were classified as “vaccine refusers” if it was explicitly documented in the medical chart that their parents had refused 1 or more pertussis immunizations for nonmedical reasons. Children were classified as “vaccine acceptors” if they were age-appropriately vaccinated against pertussis at the index date. Children were also classified as vaccine acceptors if they were partially vaccinated against pertussis at the index date and the reason for lack of vaccination was not vaccine refusal. In many instances, a child was partially vaccinated (or not up-to-date) because the physician delayed immunizations due to an acute illness or the parent scheduled his or her child's immunizations after the recommended ages. Cases and controls were excluded if they had a documented medical contraindication to vaccination or if the reason for lack of vaccination was not explicitly documented in the medical charts.

Statistical Analysis

The final case-control population was analyzed with conditional logistic regression to estimate matched odds ratios (ORs) and 95% confidence intervals (CIs). In the regression model, the dependent variable was pertussis case status and the independent variable was vaccine refuser status; each case and control was either a vaccine refuser or vaccine acceptor. The matched ORs from the conditional logistic regression models were then used to calculate the percentage attributable risk in the vaccine refusers and the attributable risk in the total population.^17,18

Secondary Analyses

Some of the children in our primary case-control analysis were not KPCO members during their first 20 months of life. These children were not continuously enrolled during the period in which they would have received the primary 4-dose series of pertussis vaccination in KPCO clinics. As a result, the immunization records for some of these children may have been incomplete. To address the potential for misclassification of vaccination status in our primary analysis, we conducted an additional analysis using a cohort of children who were continuously enrolled in the health plan from 2 to 20 months of age. Within this cohort, we conducted a case-control study of continuously enrolled children using the same methods as the primary case-control study. For this analysis, however, we matched 10 randomly selected controls for each case, because the cohort entry criteria limited the number of available cases and vaccine refusers for analysis.

We also explored 2 potential sources of bias in our study. First, parents who refuse or accept vaccinations may exhibit different health care–seeking behavior when their children are acutely ill. For example, when compared with vaccine-accepting parents, parents who refuse vaccinations may be less likely to bring their children to medical attention for acute illnesses.¹¹ This would decrease the likelihood of detecting pertussis among vaccine refusers, thereby underestimating the association between vaccine refusal and pertussis infection. Second, a child's vaccination status may influence a physician's decision to test for pertussis. For instance, a physician may be more likely to test unvaccinated than vaccinated children when they present with acute illnesses. An increase in testing of unvaccinated children would lead to an overestimate of the association between vaccine refusal and pertussis infection.

To examine these potential sources of bias, we conducted separate analyses using the cohort of children followed continuously from 2 to 20 months of age. We excluded laboratory-confirmed cases and patients with strong clinical suspicion for pertussis (cough at the date of the ordered laboratory test and 1 or more of the following: paroxysms, posttussive emesis, and a close contact with known pertussis), because these children should be tested for pertussis regardless of vaccination status. Among vaccine refusers and vaccine acceptors, the analyses compared the odds of visiting the clinic for an upper respiratory infection (URI) and the odds of receiving a pertussis laboratory test at a URI-related clinic visit. URIs were identified by International Classification of Diseases, Ninth Revision, Clinical Modification codes (460.xx, 464.xx, and 465.xx) in the automated databases.

Cases of Pertussis

We identified 439 patients with a diagnosis of pertussis in the automated databases. Of these, 178 (41%) had a medical chart–verified positive PCR or positive culture for pertussis, and 165 were between 2 months and 18 years of age. We excluded 9 (5%) patients who were either unvaccinated or partially vaccinated, because the reason for lack of vaccination was not documented in the medical charts. This resulted in a final study population of 156 laboratory-confirmed cases. The annual incidence rate of confirmed pertussis cases increased over time, with 78% of the cases occurring after year 2001. There was, however, no evidence of clustering of cases in a specific time period or geographic location.

In the final case population, 17 (11%) patients had parents who refused all pertussis immunizations and 1 (0.6%) had parents who refused 4 of the 5 recommended doses. Of these 18 refuser cases, 14 had parents who refused all routine immunizations. The parents of the remaining 4 cases refused some but not all of the following vaccinations: polio, H influenzae type b, hepatitis B, varicella, and measles-mumps-rubella. A majority of the parents were white, >30 years of age, and of higher socioeconomic status (based on median income for census tract of home address).

The mean age of the cases was 9 years, and 47% were female (Table 1). A majority of the cases presented in the clinic or emergency department; 6% were hospitalized. The mean reported duration of cough at time of diagnosis was 11.7 days, and 30% of the cases had clinical symptoms of pertussis other than cough documented in the medical charts (Table 2). There were no significant differences in the reported duration of cough, symptoms, or sequelae between the vaccine refusers and vaccine acceptors who contracted pertussis (data not shown).

Controls

Of the 624 controls, we excluded 29 (5%) children who were either unvaccinated or partially vaccinated, because the reason for lack of vaccination was not documented in the medical charts. This resulted in a final study population of 595 controls. The controls had similar gender and age distributions as the cases. In the final control population, 3 (0.5%) children had parents who refused 1 or more pertussis immunizations.

Secondary Analysis

In the secondary case-control analysis of continuously enrolled children, we identified a cohort of 27748 children who were continuously enrolled in KPCO from 2 to 20 months of age. In this cohort, we identified 31 laboratory-confirmed pertussis cases and 308 matched controls. The proportion of cases and controls with parents who refused all pertussis immunizations was 13.0% (n = 4) and 0.7% (n = 2), respectively.

Risk of Pertussis in Vaccine Refusers

In the primary case-control analysis, vaccine refusal was strongly associated with laboratory-confirmed pertussis (OR: 22.8 [95% CI: 6.7–77.5]) (Table 3). In the secondary case-control analysis of continuously enrolled children, vaccine refusal was also strongly associated with pertussis infection (OR: 19.3 [95% CI: 3.5–104.5]). The percentage attributable risk in the vaccine refuser population was 99.5% (95% CI: 98.1%–99.9%), and the total population attributable risk was 11.0% (95% CI: 5.8%–16.0%). These estimates suggest that all 18 of the unvaccinated pertussis cases were attributed to vaccine refusal, and 11% of the pertussis cases in the total population were associated with vaccine refusal.

Potential Diagnostic Bias

To evaluate the potential for a diagnostic bias, we compared the odds of receiving a laboratory test for pertussis between the vaccine refusers and vaccine acceptor study groups. Of the 27748 cohort members with continuous follow-up from 2 to 20 months of age, there were 161 (0.6%) medical chart–verified vaccine refusers. In total, 33 PCR- or culture-confirmed pertussis cases and 53 patients with strong clinical suspicion for pertussis testing were excluded from the cohort. In the remaining vaccine refuser and vaccine acceptor study groups, 73 (48%) and 17785 (65%) of the children had at least 1 URI visit during the follow-up period, respectively. Vaccine acceptors were twice as likely to visit the clinic for an URI than children of parents who refused pertussis vaccines (OR: 2.0 [95% CI: 1.5–2.8]). Conversely, among children who presented to the clinic with URI symptoms, vaccine refusers were >3 times as likely to be tested for pertussis than vaccine acceptors (OR: 3.2 [95% CI: 1.0–10.1]).