Impact of vaccine delays at the 2, 4, 6 and 12 month visits on incomplete vaccination status by 24 months of age in Quebec, Canada

The present study is based on the data from six cross-sectional surveys conducted in Quebec in 2006, 2008, 2010, 2012, 2014 and 2016 [15, 19‐23]. With the authorization of the Quebec Access to Information Commission, children in these studies were randomly selected from the Quebec Universal Health Insurance database which includes all children from the province. Each survey included a “1-year cohort” and a “2-year cohort” with children aged 15 to 17 months and 24 to 26 months respectively at the time of the survey. With surveys conducted every other year and cohorts defined by year of birth (e.g. in the survey conducted at the beginning of 2006, the 2-year cohort included children born in 2003 and those in the 1-year cohort were born in 2004), the six surveys assessed the immunization data in 12 different birth cohorts (born between 2003 and 2014). The surveys invited approximately 1000 children in each cohort (only 600 for 2006), a number deemed sufficient to obtain a precision of ±3% in the vaccine coverage for each survey assuming a response rate of about 60% [24]. Were excluded children living in the two northern regions of the province.

Questionnaires were sent by mail and were filled out by parents or legal guardians. A postal reminder was sent to non-respondents 2 weeks and 4 weeks later. In the absence of response, parents were called directly 2 weeks after the last postal reminder and those with unknown phone number or not reached by phone received another questionnaire by mail. Respondents were invited to transcribe on the questionnaire the information available in their child’s vaccination booklet (i.e. vaccine names, date of vaccination and vaccine providers). The questionnaire also collected information on the characteristics of the child, the mother and the parents. For children without vaccination booklets and those with information incomplete or inconsistent with the provincial vaccine schedule, vaccine providers were contacted to collect/validate the information. Only written information on doses from parents or vaccine providers were accepted. Each survey was approved by the Ethic Board Committee of the CHU de Quebec-Université Laval Hospital and written consent was obtained from all the participants.

Since 2004, many new vaccines had been introduced in the Quebec’s vaccination schedule (Table 1).The pneumococcal conjugate vaccine (PCV) was introduced in December 2004 with 3 doses scheduled at 2, 4 and 12 months. A single dose of monovalent varicella vaccine at 12 months of age was introduced in 2006 and replaced in 2008 by the combined measles, mumps, rubella and varicella vaccine (MMRV). Since November 2011, children are receiving two doses of rotavirus vaccine at 2 and 4 months of age. Finally, in June 2013, hepatitis B vaccine program was launched and the combined vaccine against diphtheria, acellular pertussis, tetanus, polio, Haemophilus influenzae type b and Hepatitis B (DTaP-IPV-Hib-HB) replaced the pentavalent vaccine DTaP-IPV-Hib in the schedule at 2, 4 and 18 months of age.

Birth and vaccination dates were used to compute age at vaccination in days. A dose was administered on-time if received within 30 days of the recommended age and was considered delayed after this period (Table 1). Vaccine delays were assessed for each of the first three doses of the DTaP-containing vaccine (DTaP) recommended at 2, 4 and 6 months of age and for the first dose of the measles-containing vaccine (Measles) recommended at 12 months. As most recommended vaccines are administered at the same visit, these vaccines have been used as markers of all vaccines administered at each visit. A vaccine delay at one dose is frequently followed by a vaccine delay at the following dose(s). A new vaccine delay was defined as a delay occurring among children whose previous dose(s) were on-time (e.g. Delay at 4 months among children with no delay at 2 months).

Given the changes in the Quebec vaccination schedule over the study period, the vaccination status was defined for antigens common to all surveys (DTaP-IPV-Hib, Men C-C and measles-mumps-rubella). A complete vaccination status by 24 months of age was defined as having received 4 doses of DTaP-IPV-Hib, 1 dose of Men-C-C vaccine and 2 doses of MMR vaccine before 2 years of age. Otherwise, the vaccination status was incomplete.

All analyses were performed with Statistical Analysis System (SAS Institute Inc. Carry, NC, version 9.4). Proportions were compared using Chi-square test or Chi-square test for trend when appropriate. Missed opportunities at 2 and 12-month visits occurred when a vaccine-eligible child did not receive all recommended vaccines at the same vaccination date [25]. Other independent variables included data regarding the child, the family and the vaccine provider. The data on vaccine provider at the 2 month visit were used for the analysis of vaccine delays at 2, 4 and 6 months and the data on vaccine provider for all vaccination visits from 2 to 12 months were used for the analysis of vaccine delays at 12 months.

As vaccine delays occurred before 15 months of age, the analyses on factors associated with new vaccine delays included all participants to maximize the statistical power. In contrast, as children in the “1-year cohort” had not yet reached 2 years of age, the impact of new vaccine delays at 2, 4, 6 or 12 months on vaccination status by 24 months of age was estimated only with children in the “2-year cohort”.

The impact of new vaccine delays at 2, 4, 6 and 12 month on vaccination status by 24 months of age was estimated with a robust Poisson multivariable regression. This alternative to logistic regression for binary outcomes directly estimates relative risk without risking convergence issues associated with log-binomial regressions [26‐28]. The SAS GENMOD procedure was used with a log link and a robust estimator of the standard errors. All potential factors associated to incomplete vaccine coverage and to vaccine delay were included in the model without any selection procedure [29]. Risk-ratio modification by the survey year was assessed with an interaction term between vaccine delay and survey year in the model. A model based standardization approach was used to estimate adjusted risk difference (RD) in incomplete vaccination status by 24 months of age between children with and without vaccine delays [30]. Briefly, using predicted probabilities of the model, the standardized risk of outcome considering all children exposed (with vaccine delays) was estimated. The standardized risk considering all children unexposed (without vaccine delays) was also estimated similarly. The standardized RD was obtained as the difference between these two quantities. Adjusted attributable risks in the population (ARp) were estimated for delays at each dose also using a model based standardization approach. That is, ARp were estimated as one minus the ratio of the predicted risk of outcome considering all children unexposed over the observed risk of outcome [31]. Confidence intervals for RD and ARp were obtained through the percentile method by performing non-parametric bootstrap with 1000 samples [32, 33].

Of the 11,200 children invited to participate since 2006, the participation rate was 70% (844/1200) in 2006, 64% (1282/2000) in 2008, 62% (1233/2000) in 2010, 73% (1459/2000) in 2012, 69% (1384/2000) in 2014 and 65% (1295/2000) in 2016. Children born outside Quebec were excluded from the analysis because they were exposed to a different vaccine schedule (n = 140 for the 1-year cohorts and n = 174 for the 2-year cohorts). This left a total of 3675 children in the 1-year cohorts and 3508 children in the 2-year cohorts (95% of participants for both cohorts) for the analysis.

Forty-four percent of participant children were the first child in the family, 76.9% attending daycare and the majority were vaccinated in public health clinics (66.7%). Most parents lived with a partner (91.9%) and most mothers have completed a college or university degree (70.5%). Missed opportunities occurred in 3.1% of children at the 2-month visit for which two injections were to be administered and in 14.8% at the 12-month visit where three injections were recommended (from 31.1% in 2006 to 7.0% in 2016). All characteristics of children participants are presented in Additional file 1.

The proportion of children vaccinated by age in days for each dose is presented in Fig. 1. At 2 months, a greater proportion of children received their DTaP1 close to the recommended age compared to subsequent visits. At 6 months, 14.1% of children received DTaP3 after 227 days. The proportion of new vaccine delays increased from 5.4% at 2 months to 14.3% at 12 months (Fig. 2). Among children who experienced vaccine delays at 2 months (n = 386), 77.2% had vaccine delays at other visits (298/386) (Fig. 3) and 33.7% had vaccine delays at each of the next three visits. At 4 months there were 2.4 times more vaccine delays (n = 941) than at 2 months of which 66.6% (627) were new vaccine delays. Among these new vaccine delays, 84.1% experienced vaccine delays at subsequent visits (527/627). At 6 months, there were 4.2 times (1617) more vaccine delays than at the 2 month visit and 49.9% (807) were new vaccine delays. At 12 months, the number of vaccine delays was similar to that at 6 months (1624) and 60.7% (986) were new vaccine delays (Fig. 2 and Table 2). In children with a vaccine delay for DTaP doses, instead of using the minimum interval recommended for accelerated schedule to prevent additional vaccine delays, the majority received their next dose with 2-month intervals as recommended for routine schedule (see Additional file 2).

The characteristics of participants according to vaccine delays at 2, 4, 6 and 12 months of age are presented in Table 2. The proportion of children with a vaccine delay increased with age, from 5.4% at the 2-month visit to 23.1% at the 6-month visit and 23.6% at the 12-month visit. Among children with a vaccine delay, the interval between 30 days after the recommended age and the time they received their dose was a median of 17 days for DTaP1 at 2 months, 10 days for DTaP2 at 4 months, 13 days for DTaP3 at 6 months and 21 days for measles at 12 months. Overall, 39% of children experienced at least one vaccine delay at one of the four visits, decreasing from 50% in 2006 to 30% in 2016. In univariate analysis, all characteristics except the sex were associated with new vaccine delays for at least one of the visits (Table 2). Between 2006 and 2016, for children immunized in public health clinics, the proportion with new vaccine delays decreased from 9.1 to 3.6% at the first visit, from 13.7 to 6.5% at the 4 month visit, from 20.3 to 11.0% at the 6 month visit and from 31.0 to 11.2% at the 12 month visit. In contrast, no significant differences were observed for children vaccinated in medical clinic/hospital for the 4 and 6 month visits (see Additional file 3).

Among children with and without a vaccine delay for the DTaP1 at 2 months, 46.4 and 11.1% respectively had an incomplete vaccination status by 24 months for an unadjusted risk difference of 35.3% and a 27.7% adjusted risk difference (RD) (Table 3). The adjusted risk difference for incomplete vaccination status by 24 months was 13.8, 10.5 and 8.8% for new vaccine delays at 4, 6 and 12 months respectively. The relative risk of incomplete vaccination status by 24 months of age between children with and without a vaccine delay varied between 2.3 and 3.6 with overlapping confidence intervals. As computed with predicted probabilities from the multivariable models, 72.5% of 2-year children with an incomplete status by 24 months were attributable to a vaccine delay: 16.1% were attributable to a vaccine delay that first occurred at 2 months, 10.6% at 4 months, 14.0% at 6 months and 31.8% at 12 months. There was no risk-ratio heterogeneity for the survey year.

Compared to the firstborn, other children were more likely to have a new vaccine delay at 2, 4, 6 and 12 months (Table 4). Missed opportunity at the 2-month visit was the most important factor associated with vaccine delays for DTaP1 (RR 4.28 (IC 3.18; 5.77)). At 2 months, children who were not attending daycare (versus attending daycare) and children whose parent who completed the survey was living without a partner (versus with a partner) were more likely to experience delays. Vaccination in medical clinic/hospital (versus in public health clinics) at the 2-month visit was associated with lower risk of vaccine delay for DTaP2 and DTaP3. The risk of vaccine delays for DTaP1 and DTaP2 decreased with higher maternal education. Missed opportunity at the 12-month visit was the most important factor associated with vaccine delays for measles at 12 months. Gestational age at birth lower than 37 weeks (vs ≥ 37 weeks) was also associated with vaccine delays at 12 months. Finally, in contrast to results observed for DTaP2 and DTaP3, children vaccinated in medical clinic/hospital or in both settings for the 12-month visit were more likely to experience measles vaccine delays at 12 months compared with children vaccinated in public health clinics.