The Impact of the Number of Injections per Visit on the Likelihood of Human Papillomavirus Immunization

Abstract

Objective

To test whether adolescents, who are injection limited, that is, receiving only a limited number of immunization injections per visit, are less likely to complete the human papillomavirus (HPV) immunization series.

Study design

For Oregon adolescents age 13-17 years, HPV series completion rates were assessed based on never receiving >1 injection per visit from age ≥9 years. Among a study subset born and resident in Oregon through adolescence, HPV series rates were assessed based on never receiving >1 or 2 injections per visit from age ≥4 years. Cox proportional hazards regression was used to assess delays owing to limiting injections, controlling for sex and rural location.

Results

Among 241 453 study adolescents, 16.3% had only single-injection visits from age ≥9 years. Their HPV completion rate was 7.7% as compared with 61.7% for those with no limitations of number of injections. Among study adolescents born in Oregon, 10.2% never received >1 or 2 injections per visit from age ≥4 and were less than half as likely to complete the HPV series (28.4% vs 59.1%).

Conclusions

Limiting the number of injections per visit is associated with decreased completion of HPV immunization. As larger cohorts of young children with early injection-limiting characteristics age into adolescence, progress on HPV immunization rates may be challenged.

A recent modification of the immunization schedule allows teens in most instances to be counted as up-to-date with only 2 HPV immunizations; that is, dose one at <15 years of age and the interval to dose 2 being ≥5 months. Despite the boost this provided, HPV immunization series completion rates remains low in the US.¹ A further challenge to improving HPV immunization rates is that known interventions, such as reminder/recall or after presumptive, “ready to immunize” practice models, seem to yield only modest increases in HPV series completion rates.^2,3 One barrier to starting and finishing adolescent HPV immunization is the limited number of timely preventive care visits that most adolescents have at the ages when HPV immunization is recommended.^4,5 Many adolescents also have predictable immunization encounters tied to school requirements for tetanus-diphtheria-acellular pertussis immunization (Tdap), which is required in all US states for attendance in the seventh grade.^6,7 Attention to date on improving HPV immunization rates has in part focused on whether HPV is co-administered at Tdap or other immunization visits.^8,9

Missed HPV opportunities may result when the lack of a strong provider recommendation is matched against parent or teen reluctance to receive more than a single injection at a time, when multiple vaccines are due. Formalizing the presentation and negotiation of immunization recommendations is a key element of the presumptive model for HPV improvement, along with asking teens and parents to schedule HPV in the future if it was not agreed to at the current visit.³

Adolescents who never receive >1 injection at any provider encounter should be described as injection limited. For many, given the small number of visits expected during the period when adolescent immunizations are due, every visit is a missed opportunity. Tdap, quadrivalent meningococcal strain A/C/W/Y immunization (MenACWY), and HPV vaccines typically are due at the Tdap visit, although frequently only 1 or 2 of these vaccines are given simultaneously. In light of the attention paid recently to meningococcal disease outbreaks in teens, a finding of MenACWY preference over HPV in order of receipt at the Tdap visit is not surprising.⁹

Adolescent injection-limiting choices as defined here is analogous to prior use of the term for infants and young children, where parental choice of alternative immunization schedules may result in limiting the number of injections per visit. Prior work has found sharply increasing numbers of young children who consistently have limits on the number of injections per visit. As these young children age, preferences for limiting injections per visit are likely to impact HPV completion.¹⁰ Whether limiting behavior reflects a true vaccine hesitancy instead of needle avoidance issues or a reluctance to be “poked” multiple times is also unclear. On the provider side, a reluctance to push multiple injections at a visit with hesitant-appearing parents or teens also may apply.¹¹

Using Oregon's ALERT Immunization Information System (ALERT IIS), the primary purpose of this study was to assess the prevalence of consistent, single injection per visit behavior among a teen population and its relation to completion of the HPV series. Second, we sought to examine whether earlier childhood patterns of injection limitations also were related to decreased HPV immunization and series completion.

Methods

The primary study population consisted of Oregon adolescents 13-17 years of age as of May 1, 2019. For assessing trends, a similar population of teens also was assessed for the prior years of 2015-2018. Study teens were required to have a record in the ALERT IIS and to have their last known address in Oregon. The ALERT IIS is Oregon's statewide, lifespan immunization registry; it receives immunization reports from almost all Oregon providers, health plans, pharmacies, and billing exchanges. ALERT IIS is populated by Oregon birth records as well as provider and health plan reporting and includes children without immunizations. Oregon providers and clinic groups who vaccinate any patients under the Vaccines For Children program are required to report all immunizations to ALERT IIS, regardless of patient age or individual patient Vaccines For Children use. Adolescent records were, for aggregate analysis, weighted based on the time since last immunization to ensure accurate population representation and to decrease the effects of unreported mobility.¹²

For this study, injection-limiting adolescents were defined as those who never received >1 immunization injection on any single visit from age 9 years. The ALERT IIS natively tracks immunizations through CVX codes, where each CVX code reflects a single injection event. The total of injections per visit was calculated based on the count of CVX codes per visit. Age 9 years was chosen because it is the earliest age at which HPV may be given. ALERT IIS data also show that substantial numbers of study teens received immunizations other than seasonal influenza at 9 and 10 years of age, including HPV and catch-up vaccines. As evidence that being injection-limited is a relevant concept for 9- and 10-year-olds, among those receiving any immunizations at 9 years of age, 22.8% had received >1 immunization per year, and 53.9% of these were spaced out into multiple, single-injection visits; at 10 years of age, 31.5% had >1 immunization, and 51.4% of these were spaced out into multiple, single-injection visits. Beyond this early period, for injection-limited adolescents age 13-17 years, almost all would have had multiple injections due with Tdap, so that virtually all injection-limited adolescents had ≥1 missed opportunity. HPV series completion was based on either having 3 total vaccine doses, or 2 doses with the first dose given at <15 years of age and the second ≥5 calendar months after the first. County-level rates of injection-limited teens were determined based on the last residence address in ALERT IIS.

A further concern is whether observable injection limiting is plausibly linked to parents, providers, or both. One check on parental influence is to assess whether injection-limiting adolescents also had prior immunization histories with injection limiting at earlier ages. In Oregon, injection limiting for early childhood immunizations strongly increased among birth cohorts from 2007 onward but was rare before 2007.¹⁰ For this reason we chose the age of ≥4 years as most relevant to current HPV immunization.

Evidence of early injection-limiting behavior was determined by assessing the maximum number of injections received on any single visit from study adolescents' fourth birthday onward. Early injection limiting was defined as never receiving more than either 1 or 2 injections per visit. To avoid incomplete immunization registry records owing to mobility and coming into the system at older ages, analysis was restricted to adolescents age 13-17 years who were born in Oregon and had ≥1 early childhood immunization visit to an Oregon provider reported to ALERT IIS. Additionally, inclusion required that adolescents had a Tdap immunization from an Oregon provider reported to ALERT IIS. This process ensured that any HPV immunizations would be reported to ALERT IIS as well.

Analyses

The ratio of HPV series completion was calculated for adolescents who were and were not injection limiting for having either only single injection visits from age ≥9 years, and for the subset of adolescent who were born in Oregon and who had or had not a limited number of injections per visit from age ≥4 years. A secondary concern was with missed HPV opportunities at Tdap visits, because in Oregon Tdap is the only adolescent immunization on the school required schedule. To determine the degree of clustering of injection limiting among providers, the percentage of injection limited adolescents age 13-17 years was calculated for each Oregon clinic. Adolescents were assigned to clinics based on the site of receipt of the most recent immunization. School-based health centers, hospitals, public clinics, and pharmacies were excluded.

To assess whether early injection limiting was associated with a lesser likelihood of HPV completion, a survival analysis was performed through a Cox proportional hazards regression. For this regression, the hazard ratio (HR) of HPV completion was assessed per day of age for study adolescents from age 11 years to either the date of their HPV completion, or until the study end date of May 1, 2019. Sex and rural-urban locations were also included as variables in the regression. Risk ratios and confidence intervals were calculated using paired data routines in WinPepi, and survival analysis was performed through Cox proportional hazard regression in STATA (StataCorp, College Station, Texas).

Results

In total, 93.5% of the study population (n = 241 453) had a Tdap record in ALERT IIS, 79.7% had received ≥1 MenACWY vaccines, 70.5% had initiated the HPV series, and 51.4% had completed the HPV series. Of those who completed the HPV series, 32.3% had 2 doses of HPV vaccine and 67.7% had 3 doses. Overall, 16.4% of study adolescents never received >1 immunization per visit from age ≥9 years, meeting the study definition of being injection limited. Of these, 36.8% had only 1 immunization, a Tdap, reported to ALERT IIS. For adolescents with ≥1 visit where multiple immunizations were given, 62.2% completed the HPV series, whereas among injection-limited adolescents, only 7.7% completed the HPV series. Among adolescents who completed the HPV series, 98.4% had ≥1 provider encounter in which HPV was co-administered with another immunization.

The outcomes of Tdap visits when other immunizations were due are presented in Table I. At Tdap visits, MenACWY generally was preferred when only 1 immunization was given in addition to Tdap. Those receiving only MenACWY with Tdap were less likely to complete the HPV series as those receiving HPV and MenACWY at the Tdap visit (RR, 0.48; 95% CI, 0.47-0.49). Overall 76.1% of study adolescents who were not up to date for HPV immunization either were injection-limited or did not receive HPV at their Tdap visit.

Table I.

Immunization delivered at Tdap visit in Oregon, for teens age 13-17 years, 2019

Received at Tdap visits	Teens (%)	HPV initiation (ever) (%)	Subsequent HPV completion (%)	Tdap + MenACWY (ever) (%)
Tdap + HPV + MenACWY	39.7	100.0	76.6	100.0
Tdap + HPV	8.3	100.0	76.7	51.5
Tdap + MenACWY	27.6	54.8	37.1	100.0
Tdap alone	24.4	37.0	24.6	42.1

The prevalence of early injection limiting from age ≥4 years and its relation to HPV are presented in Table II. Overall, 10% of study adolescents had never received >1 or 2 injections per visit from age ≥4 years; these early injection-limiting adolescents were less than one-half as likely to complete the HPV series. Although screening by early shot limiting is not particularly sensitive to lack of HPV completion (10.2%) it is highly specific (94.8%), with a positive predictive value of 77.9% and a negative predictive value of 63.1%. The 2% of study adolescents who never received >1 injection per visit from age 4 years had substantially fewer immunization visits (mean, 2.6 visits) and 3.9% HPV series completion. The 8% of study adolescents with a limit of ≤2 injections per visit had a mean of 6.4 visits and a 34.2% HPV series completion. The 90% who were not injection limited had mean of 6.8 visits and a 59.1% HPV completion rate.

Table II.

Association of limited numbers of injections per visit, age ≥4 years, with HPV immunizations at age 13-17 years, for Oregon-born adolescents

Maximum numbers of injections per visit∗	HPV status
	None	≥1	UTD	UTD (rate) (%)
1	4079	394	176	3.9
2	9465	9464	6467	34.2
≥3	43 306	162 813	121 911	59.1

UTD, up-to-date.

^∗For Oregon-born adolescents age 13-17 years as of May 1, 2019, with a reported Tdap and ≥1 immunization visit by age 2 years; maximum number of immunizations per visit from age ≥4 years; includes influenza immunization.

The analysis was repeated based solely on injection limiting observed from birth through 9 years of age. For Oregon-born children with ≥2 immunization visits by age 9 years, and a reported Tdap immunization, injection limiting was defined as receiving no >1 or 2 injections per visit at any time from birth through age 9 years, without consideration of injection limiting observed after age 9 years. Early injection limiting was compared against HPV receipt by age 13-17 years. Among 5135 adolescents with injection limiting from birth to age 9 years, 59.1% received ≥1 HPV immunization, and 39.6% were complete for the HPV series. Among 217 274 adolescents with >2 injections per visit on ≥1 occasions, the rate of HPV initiation was 74.1%, with a series completion rate of 55.1%. Those with early childhood injection limiting were 0.72 times (95% CI, 0.69-0.74) as likely to complete the HPV series as those who did not limit injections in early childhood.

Among the 36 counties in Oregon, rates of injection-limited adolescents varied from 11% to 45% (Figure 1). Injection-limited rates were higher in rural than in metropolitan counties. In regression analysis, county injection-limited rates were significantly and negatively associated with the log of adolescent age in the 13- to 17-year-old populations. Injection-limiting rates were negatively associated with county HPV up-to-date rates (R² = 0.772), and HPV initiation rates (R² = 0.820). Controlling for county injection limiting, the difference between urban and rural counties in HPV immunization series completion rates was not significant.

Figure 1.

Rates of teens age 13-17 years who only have single-injection immunization visits, by Oregon county, 2019.

Cox proportional hazards modeling, comparing injection limiting from age ≥4 years, sex, and rural location against the “risk” of completing the HPV series found all 3 variables significant at the 99th percentile. Injection limiting had a HR, representing HPV completion, of 0.363 (95% CI, 0.356-0.375); rural location had a HR of 0.687 (95% CI, 0.676-0.698), and sex (male) had a HR of 0.851 (95% CI, 0.841-0.860). Interactions between these variables were tested, with none found to be significant. HRs for HPV completion by day of age between 11 and 18 years of age are presented for injection-limited vs nonlimited adolescents in Figure 2. Those with prior histories of injection limiting have a lower odds of completing the HPV series at all ages.

Figure 2.

Cox regression smoothed hazard rates of HPV series completion per day, Oregon teens age 13-17 years, stratified by never receiving >1 or 2 injections per immunization encounter from age ≥4 years. Circled numbers represent years of age.

For individual immunization providers, the percentages of their adolescent populations age 13-17 years who were injection limited varied widely. In 41% of the 596 private practices that reported adolescent immunizations for the study population, more than one-quarter of the practice populations were injection limited, and in 13% of practices, more than one-half of the populations were injection limited (Figure 3).

Figure 3.

Percentage of injection-limited teens age 13-17 years by Oregon private practices reporting to ALERT IIS (n = 596 practices), 2019.

Discussion

This study confirms that unless multiple injections are given per visit, teens infrequently will complete the HPV series. Provider-mediated delivery of only 1 immunization per teen visit should be viewed as a failure that, regardless of best intentions to follow-up, is almost certain to lead to incomplete HPV immunization before adulthood.

These findings support that both practice and parent factors are relevant to lack of HPV immunization. This early injection-limiting pattern supports a role for parents in subsequent avoidance of multiple immunizations per encounter. This study also found clustering of injection-limited adolescent populations among private practices. Whether such clustering reflects practice patterns such as lack of recommendation for adolescent immunizations beyond Tdap or reflects accommodation to vaccine hesitant populations is unknown and is an area for further research. Tools for dealing with hesitant parents or improving adolescent practice patterns for immunizations have shown only small effect and should be considered as works in progress.13, 14, 15

Practice-based improvements to boost adolescent HPV up-to-date rates fall into 2 categories: either to use more effectively existing adolescent provider encounters to give HPV vaccine or to create new encounters for immunizations. One strategy for the latter is for providers to ask, when some injections are declined on a given visit, to agree to schedule the necessary follow-up visit. This step is the last in the presumptive approach to vaccination, and asking parents to sign agreements to immunize later when a due immunization is refused is a common practice.^3,16 Our findings challenge the efficacy of relying on this strategy compared with more strongly advocating for HPV immunization within existing encounters. Because injection limiting or schedule crowding were found in more than three-quarters of visits by teens who did not complete the HPV series, efforts to improve HPV immunization rates substantially also must focus on adherence with the recommended number of immunizations per visit.

The American Academy of Pediatrics extols the influence of providers on parent and teen decisions, and notes the increasing burden to providers to discuss vaccine issues with parents. The provider should posit the best strategy is to give all due injection according to the recommended schedule, and providers should not assume that parent or adolescent nonenthusiasm regarding HPV immunization is rooted in substantial vaccine hesitancy.^17,18 Accommodation of parent or child preferences for limiting the number of injections per visit reduces the chances of finishing immunization series on time as for HPV and can lead to long-term increases in disease risk.

Tdap immunization visits to meet school requirements are the only predictable provider encounter for most teens and are an opportunity to give multiple recommended immunizations. In our study population, only a minority of teens received Tdap, MenACWY, and HPV immunizations on the same date. When the interaction between providers, parents, and teens leads to the receipt of 2 rather than 3 immunizations at the Tdap visit, MenACWY was 3 times as likely as HPV to be given in our study sample. This finding is in line with national claims data observations of delayed HPV vs MenACWY.¹⁹ Although the reporting of the dramatic consequences of meningococcal disease may bias parents or providers to view MenACWY as a more immediate need than HPV immunization, the relatively rare event of meningococcal infections vs the long-term public health benefit of HPV immunization in later avoidance of cancer risk needs to be considered. Apart from use in meningococcal outbreak situations, HPV immunization is of greater value than meningococcal immunization. Studies to date of cost per life-years saved by vaccination strongly favor HPV over MenACWY immunization.^20,21 If forced to decide, providers should ensure that HPV becomes their priority for a second immunization after Tdap.

Because combination vaccines have been shown to increase the receipt of multiple antigens per visit among younger children and adolescents as well, a single, pentavalent vaccine combining tetanus, diphtheria, pertussis, MenACWY, and HPV could be a public health solution, rendering moot the problems of limiting injections per visit.^12,22

This study and suggested approach have limitations. Differential access to teen immunizations was not considered. Injection-limited teens may face greater barriers related to access to or cost of HPV immunization. The focus of many providers and special clinics is to provide immunizations that are required for school attendance—in Oregon, namely, Tdap. In these instances, injection limiting may reflect less on parental or teen choice. A protocol change is needed to consider and administer all recommended immunizations concurrently. Information regarding visits without immunizations also was not available, nor whether any additional immunizations were recommended by providers but refused at injection-limited visits. Acute care visits at which Tdap was given, for teens who do not have routine nonacute care visits, could bias our findings. Many adolescents who were 13-17 years old in 2018 started their HPV series under the 3-dose recommendation; the newer standard of just 2 doses with appropriate timing for those starting before age 15 is likely to weaken but not invalidate the strong relations described here between limited immunizations per visit and likelihood of becoming up to date. Finally, the pattern of being injection limited as an adolescent with being injection limiting earlier as shown in this study may increase jeopardy of lack of HPV protection in the future. In Oregon, a substantial increase in early childhood injection limiting occurred between 2007 and 2010.¹⁰ The experience of early shot limiting for the current population of adolescents who are 13-17 years of age does not yet reflect this increase so that further attention is needed for this issue as cohorts with stronger evidence of hesitancy and injection-limitation advance into the age range for HPV.

Providers should recognize that accommodation of parent or child preferences for limiting vaccine injections per visit at all ages carries a substantial risk of interfering with adolescent's time-critical protection against HPV that is dependent on immunization.