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Evaluation of vaccination coverage is a key health indicator that is crucial to ensure that vaccination programs are reaching their objectives. In jurisdictions lacking a regional vaccine registry, studies that evaluate changes in coverage and timeliness, provide valuable information for targeted immunization strategies among specific groups . Under the provincial immunization program, all recommended childhood vaccines are offered free of charge in public health clinics (CLSC), hospitals, and in physicians’ offices. More than 75% of vaccinated children 0-4 years are vaccinated by public health nurses [2, 3]. Proof of vaccination or vaccination exemption is not required in Quebec to enter the education system. When looking at the most recent Canadian childhood National Immunization Coverage Survey (cNICS), vaccination uptake by vaccine type at age 2 years in 2013 varied from 72%-91%. A 2014 proportionally representative survey study from Québec estimated full coverage at 24 months to be between 71%-85% .
Vaccination coverage is the standard measure to assess if recommended threshold for herd immunity has been met, by vaccine type. Coverage often does not consider the timeliness of doses and may underestimate periods of sub-optimal protection or absence of protection against vaccine preventable diseases, leaving children susceptible to illness in the event of an outbreak [4-9]. Age-appropriate vaccination can be assessed by determining the age at vaccine dose, while the measure of delay may be categorized by cumulative time under-immunized . Coverage often does not distinguish unvaccinated from undervaccinated children. This lack of distinction ignores the refusal of all vaccines, having received some, but not all, age-appropriate vaccines, and those who are fully vaccinated for age, but experienced serious delays . Arguably, children who are not up-to-date (UTD) or under-immunized represent a more important group to target than those who receive no immunization at all, and likely represent entirely different populations [3, 12].
Several factors have been reported to influence complete immunization for age. Maternal age, marital status, low level of education, and large family size have been associated with a delay in complete vaccine coverage [13-19]. In contrast, higher levels of education and daycare attendance have been positively associated with complete immunization for age [13, 20]. Additionally, variables that relate to timing such as timely initiation of immunization and failure to co-administer 18 months vaccines (2nd dose MMR and 4th dose DTaP-IPV-Hib) are associated with immunization status at 2 years [17, 21, 22].
As determinants of vaccine uptake are context specific , we aimed to describe vaccination coverage and factors associated with complete immunization coverage at 24 months of age in pre-schoolers consulting in 3 hospitals in the province of Quebec [23, 24]. Our secondary objective was to evaluate the average number of days under-immunized for four vaccines: diphtheria and tetanus toxoids, acellular pertussis vaccine, poliovirus vaccine and Haemophilus influenzae type b vaccine (DTap-IPV-Hib), pneumococcal conjugate vaccine (PCV-7,10 or 13), Measles, Mumps, and Rubella with one containing varicella (MMR (v)), and meningococcal type C vaccine (Men-C-C). Finally, we determined factors associated with delay of more than 6 months for one or more vaccines.
This was a secondary analysis of a prospective, active surveillance study of children 8 weeks to 3 years of age, presenting to the emergency department for acute gastroenteritis (AGE) at 3 tertiary pediatric hospitals in the province of Quebec [1, 25, 26]. Recruitment and data collection took place between February 2012 and December 2014 with a total of 937 patients recruited. Patient selection has been previously described .
Data collection and variables
Participant demographics, medical information and vaccination history were systematically collected via phone interview with the child’s caretaker. Vaccination history (vaccine type and date) was collected from the participant’s immunization booklet. If the booklet was not available, parental permission was sought to contact vaccination provider to review records. History of prematurity (<37 weeks gestation) and presence of underlying conditions were coded as binary variables. The number of children in the home under the age of 18 years, in addition to the index child, was categorized as only index child, 2 children (index + 1) and, ≥2 (at least 2 + index). The age of parents at index child’s birth was categorized into three groups, based on distribution, <26, 26-39, and >39 years as the reference. Parents’ highest level of education was coded as <12 years of education, college, university and, graduate degree, the latter was used as the reference category.
We selected covariates for our model based on factors found in the literature to be associated with immunization practice in high-income countries. The first three characters (forward sortation area, FSA) of the residential postal code were used to determine the median household income using 2006 census data. Two hospitals were located in the Montreal Census Metropolitan Area (CMA) with a population ~4 million and in the Sherbrooke CMA, with a population of >200,000. Two binary variables were created to assess initiation of vaccination at 2 months (with one month grace period) and to assess whether co-administration of the two recommended 18-month vaccines were associated with an UTD status at 24 months in accordance with the Quebec Immunization Protocol (PIQ) [14, 27-30].
To allow all children equal time to receive vaccinations, only children 24 months and older were included. Patient’s age was determined at phone call date, when immunization data was collected or if missing, at consent date. Patients were excluded if they reported underlying inherited immunodeficiency and neoplasm of any kind past or present, as this population’s immunization needs differs from those of the healthy preschool population. We also excluded children with complete vaccination refusal, as they were likely to represent a different population.
The two outcome variables were UTD for age for all recommended vaccines and delayed for ≥6 months for one or more vaccines . We examined the UTD status regardless of timeliness of 4 vaccines during the first 24 months of life. Children were defined as being UTD by 24 months if they received the recommended number of vaccine doses, as per the PIQ during the study time frame (4 doses of DTap-IPV-Hib, 3 doses PCV 13, 2 doses MMR(v), and 1 dose Men-C-C). The Hepatitis B vaccine was not included in our analysis, as newborn vaccination was added to the PIQ after our study time frame. Rotavirus vaccine was not included, as it was introduced during our study. Results of uptake from this cohort have been previously described . The influenza vaccine was also excluded due to its nonspecific timing in the recommended series. Children with missing immunization dates were considered unvaccinated for that vaccine.
To determine days under-immunized as per PIQ guidelines, we considered a valid schedule where all 4 recommended vaccines were administered, with a 30-day grace period. Cumulative days under vaccinated were calculated according to the recommended schedule. Therefore, if vaccination was initiated late, e.g. at 4 months instead of 2, the child would be 30 days under-immunized. The next expected immunizations would be within 2 months + 30 days grace and if late for the next immunization, those days would be added to the initial 30 days for a final cumulative number days sub-optimally immunized by vaccine type. If vaccination was initiated after 12 months of age, the PIQ catch-up calendar for 1 to 3 years of age was used where the minimal acceptable intervals between vaccines was applied and the first year counted as time under-immunized . Required minimum intervals between doses were not counted as days under-immunized. We reported the mean number of days that children were under-immunized during the first 24 months of life, by vaccine type. We further categorized duration of under-immunization as less than 6 vs. 6 months or more, for at least one vaccine to determine the importance of timeliness within the standard measures of vaccination status.
Descriptive statistics were performed by first examining the summary of the data covariates.
A chi-square test was run for all categorical variables. Covariates with a p-value of ≤0.20 in univariate logistic regression or recognized as an important variable, as drawn from the literature, were considered for inclusion in the final logistic model. Interaction was assessed based on what the literature identifies as plausible two-way interactions; no significant interaction was found [32, 33].
Three multivariable logistic models were generated for each outcome, including sensitivity analysis: factors associated with incomplete immunization at 24 months and factors associated with cumulative delay ≥6 months. Model 1 included all independent variables related to the outcome. Model 2 included all variables from Model 1 with the addition of the variables “initiating vaccination on time” and “simultaneous vaccination at 18 months”. Model 3 included all variables in Model 2 and adjusted for recruitment site using random effects. Model fit was assessed by calculating the index of concordance, or c-index, which in logistic regression models is equivalent to the area under the receiver operator curve (AUC) . The population attributable fraction (PAF), accounting for missed vaccination opportunity in the source population, was calculated using the formula, PAF = pe+ * (OR – 1) / OR where pe+ is the exposed population. All analyses were done with Stata v.14 software (StataCorp. 2015. Stata Statistical Software: Release 14. College Station, TX: StataCorp LP).
A total of 246 subjects were included in the analysis. We excluded subjects <24 months of age, non-vaccinated children (n=20) and immunocompromised children (n=3). The distribution of parental age at child’s birth was consistent with that of Montreal’s fertility rate by age group for 2014 . Mean age of mothers and fathers at the index child’s birth was 30.5 (±5.62) and 30 (±6.16) years respectively.
Determinants for UTD status at 24 months of age
The overall UTD status was 73%. Subjects from hospitals A and B had an UTD status of 75% compared to only 61% of subjects at hospital C, indicating a different source population. Subjects who were UTD in their immunization schedules at 24 months of life differed from those not UTD (Table 1). Those who received simultaneous 18-month immunizations had the overall greatest vaccination coverage at 81%. Families with ≥3 children represented 36% of families where the index child was not UTD, compared to 24% of families where the index child was UTD. Low UTD status was seen in children who were ever breastfed (58%), whose fathers had a graduate degree (58%), and whose parents were divorced (62.5%), although no statistical significance was found.
In the multivariable analysis, factors associated with not being UTD at 24 months were: having 3 or more siblings (OR=0.50; 95% CI: 0.28-0.86) and not receiving the 18-month vaccines simultaneously (OR= 0.15; 95% CI: 0.11-0.21). Maternal education at a level of high school equivalent or less was associated with an UTD immunization status, (OR=1.70; 95% CI: 1.09-2.65). Timely initiation of the immunization schedule at 2 months of age was highly associated with an UTD status at 24 months of life (OR= 5.85; 95% CI: 2.80-12.22). The final model had a c-index of 0.76 (Table 2). The etiological fraction was 0.35: 35% of children not UTD could be attributed to missed opportunities to co-administer vaccines at 18 months.
Children were more likely to be UTD for each individual vaccine than for the series as a whole (Table 3). The percentage of children in the cohort with any delay ranged from 54% for the recommended doses of MMR vaccine and 35% for pneumococcal conjugate vaccine, to 27% for the meningococcal type C vaccine and to less than 25% for the DTap-IPV-Hib vaccines. However, a number of children remained under vaccinated for each vaccine for a substantial portion of their first 24 months of life. Of the mean cumulative number of days under-immunized, children spent the largest amount under-immunized for the antigen components of the pentavalent DTap-IPV-Hib vaccine (mean duration of 227 days) for 34% of 22 months of expected coverage. The mean cumulative days under-immunized was 209 days for PCV, 145 days for Men-C-C, and 107 days for MMR. Almost 50% of children with vaccination delay were under vaccinated for 6 months or more for DTap-IPV-Hib and PCV-13 vaccines. For MMR and meningococcal type C vaccine, the total possible delay was considerably shorter. Nevertheless, 17% were delayed for at least 6 of the possible 11 months for MMR and almost 32% for Men-C-C. Approximately 12% of our cohort was late to initiate their immunization schedule at 2 months of age. Of those who were late to initiate DTap-IPV-Hib, the median start time was 106 days (IQR 102-155) and the median start days for PCV 7, 10 or 13 was 113 (IQR 102-300).
Determinants for delay ≥6 months under-immunized
In multivariable analysis, subjects with 2 or more siblings were 3 times more likely to be under- immunized for ≥ 6 months (OR= 2.99; 95% CI: 1.45-6.22) (Table 4).Having a mother younger than 39 years at subject’s birth was also associated with a delay of ≥ 6 months (OR= 2.13-2.77; 95% CI: 1.73-3.60). Location where subjects were usually seen when ill was associated with a vaccination delay of ≥ 6 months: subjects who attended a walk-in clinic (OR= 1.69; 95% CI: 1.13-2.52) or an emergency department (OR=1.39; 95% CI: 1.02-1.90) when ill were more likely to present with delay. Non-simultaneous vaccination at 18 months represented an almost 4-fold increased odds of having a delay ≥ 6 months for one or more vaccines (OR =3.61; 95% CI: 2.47-4.39). Factors associated with an absence of delay or delays < 6 months included mothers and fathers with a high school education or less compared to a graduate degree (OR= 0.43; 95% CI: 0.22-0.83 and OR=0.50; 95% CI: 0.35-0.70, respectively). Having a household income < $75,000 annually was associated with less delay compared to high-income earners. Having access to a family physician, with the possibility for urgent consultation when ill was also associated with a delay of < 6 months (OR= 0.63; 95% CI: 0.44-0.91). Timely initiation of the immunization schedule was found to be protective against delays in immunization by 24 months of age (OR= 0.13; 95% CI: 0.07-0.24). The final model had a c-index of 0.76.
Immunization coverage is not yet optimal in the province of Quebec. Yet, children in our study cohort seemed to have higher coverage, by vaccine type, compared to the Canadian average, with the exception of the MMR vaccine (81% coverage compared to 89%, respectively), but comparable to the 2014 Quebec survey  , in particular when compared to data stratified by region (65.8% for the Greater Metropolitan Montreal and 73.8% for regions with >100,000 inhabitants). The proportion of non-vaccinated children in our cohort was comparable to results from previously described studies.
A recent globally inclusive systematic review by Larson et al. suggests that to be most efficient, vaccination programs must be tailored at the community level with adapted, targeted strategies that will improve immunization among specific groups [23, 24]. Between 2004 and 2013, five new vaccines were introduced in the Quebec pediatric schedule, which may have led to scheduling constraints for some parents and may have placed a higher demand on healthcare services resulting in unintentional delays in immunization .
Several factors were associated with immunization status. Children from families in the lower income categories and with parents with the lowest levels of education spent less time under-immunized and had an increased UTD status. These findings were consistent with results from Dummer et al., a Canadian study that showed higher immunization rates in poorer, less educated families [5, 13, 14]. The distribution of parental education levels in our population was similar to provincial statistics, except for a slighter higher proportion of parents having graduate degrees, compared to the rest of the province . Maternal age at child’s birth influences vaccination uptake: mothers 39 years of age and older were more likely to have children with an UTD status, although this was not significant at 24 months; while mothers younger than 39 years had a higher risk of having children with ≥ 6 months delays for specific vaccines. This could suggest that older parents may experience less constraint for timely vaccination, such a smaller family size.
The impact of non-simultaneous immunization of the two recommended vaccines at 18 months and timely initiation of the immunization schedule were important findings. Missed opportunity at 18 months represented 35% of the population attributable fraction. This percentage was smaller than estimated by Boulianne et al. in 2003 (46%), hopefully demonstrating an improvement in this area. We observed that 70% of our cohort who were not UTD at 24 months still received 3 doses of the DTap-IPV-Hib vaccine and 1 dose of MMR; very little was missing for these children to complete their vaccination schedule. More precisely, 31 (12%) children did not receive their 4th dose of the DTap-IPV-Hib vaccine. Several studies, including the cNICS 2013 survey, have identified dose 4 of DTaP as the most frequently missed vaccine for children not adequately immunized [5, 39-43]. For a majority of our study population, the time interval between 19 and 24 months represented an important catch-up period: the overall completion rate at 18 months was 46% compared to 73% by 24 months, for the same cohort, representing a 60% increase in coverage. Most children in our study were immunized on time: 77% to 87% of children had between none to 2 months delay by vaccine type. However, half of the children under-immunized had significant delay of ≥ 6 months during their first 24 months of life. Finally, 12% of our study cohort was late to start their immunization schedule, an important predictor of UTD status as previously reported [3, 17, 44-46].
Children in large families were not UTD for age, but also experienced important time under-immunized [4, 19, 47-49]. Efforts to schedule children in the same family simultaneously and emphasis on the importance of multiple vaccine co-administration will reduce the under immunized status of the majority of our target population. Furthermore, providing families with access to family practice care seemed associated with a better immunization status . Initiatives in some regions, which offer scheduling of childhood vaccinations through a web application as well as a tool to determine immunization needs, help families proactively schedule immunizations into their busy lives . A recent Cochrane review of patient-reminder studies in the US, Australia, Canada, Denmark, New Zealand, and the UK found that reminder and recall interventions increased the number of children who were vaccinated or UTD with their immunisations. A reminder during a vaccination visit remains a low cost and easy way to effectively encourage parents to present to their next vaccination appointment [52, 53].
The main study strength was reduced selection bias. Unlike studies where the primary aim is to determine coverage, our subjects were enrolled based on their presentation to the ED or hospitalization with acute gastroenteritis and were thus less likely to self-select based on immunization status, improving external validity. All immunizations were verified against booklet or provider, reducing chances of misclassification and increased study precision. This study also had several limitations. Our sample was not proportionately representative of the provincial population in terms of cultural background and locality (mostly metropolitan). As this was a secondary analysis, we were not able to collect all relevant variables associated with immunization such as employment, health, and mobility status of recruited families. Finally, we cannot rule out selection bias associated with health seeking behaviours.
Risk of disease due to immunization delay varies by disease circulation, transmissibility and likelihood of importation and severity of outcome. Vaccination timeliness is important for diseases that have the potential to cause large outbreaks and for diseases currently circulating such as measles, mumps and pertussis. Time spent under-immunized underlines that the standard measure of coverage does not capture this public health indicator. Timely initiation of the immunization schedule, close follow-up and simultaneous vaccination at 18 months will bridge a large gap between completeness for age and appropriate coverage at all ages.