ORIGINAL ARTICLE
Association of age-appropriate vaccination status at 24 months with all-cause hospitalizations: A retrospective cohort study
2025 年 7 巻 4 号 p. 113-119
詳細
2025 年 7 巻 4 号 p. 113-119
BACKGROUND
Childhood vaccinations can be effective for preventing not only infectious diseases but also other diseases and traumas. This is because vaccines may have nonspecific immunological effects. Additionally, visits for vaccinations may benefit doctors in promoting the overall health of children. We assessed whether vaccination status at 24 months was associated with the incidence of all-cause hospitalization.
METHODS
This retrospective cohort study used the vaccine records and healthcare claims from a Japanese city. We included children born between April 2014 and December 2020. Children who took all the following vaccine doses covered by the national immunization program at 24 months of age were defined as having an age-appropriate vaccination status: four doses of Hemophilus influenza type b, four of 13-valent pneumococcal conjugate, four of diphtheria, tetanus, acellular pertussis, and inactivated polio, three of hepatitis B virus, one of Bacille de Calmette et Guérin, one of measles and rubella, and one of varicella-zoster virus. A Cox regression model compared all-cause hospitalizations between children with and without age-appropriate vaccination, adjusting for sex, birth year, and comorbidities.
RESULTS
We identified 2,492 children: 1,689 were age-appropriate vaccinated, and 803 were not. There was no significant difference in all-cause hospitalizations (adjusted hazard ratio, 0.93; 95% confidence interval, 0.69 to 1.3; P = 0.65).
CONCLUSIONS
The effect of age-appropriate vaccinations on the overall health of children may be small.
In addition to the prevention of targeted vaccine-preventable diseases (VPDs), nonspecific effects of childhood vaccinations have been discussed1–9). A recent study suggested that vaccinations might induce nonspecific protective responses against various infections10). These findings suggest that childhood vaccinations may efficiently contribute to preventing not only targeted VPDs but also other infectious diseases. In addition, when children visit for vaccinations, even if the visit is not specifically for a health checkup, healthcare providers can assess the overall health of children or guide children and their caregivers on injury prevention. In other words, vaccination visits may aid children and their caregivers in the early detection of other illnesses and in the prevention of traumas.
Several studies have reported the effect of particular vaccines, such as the measles-containing vaccine, diphtheria-tetanus-pertussis vaccine, and Bacille de Calmette et Guérin (BCG) vaccine on all-cause mortality1–7). A previous systematic review showed that BCG and measles-containing vaccines were associated with improved all-cause mortality, whereas only diphtheria-tetanus-pertussis vaccines were associated with increased all-cause mortality; however, these associations were not significant2). In contrast, another systematic review did not provide conclusive evidence regarding the immunological effects, such as increased IFN-γ or lymphoproliferation of measles-containing vaccines, diphtheria-tetanus-pertussis vaccines, and BCG vaccines1). However, many of the previous studies have been conducted in low-income countries, and the follow-up period was relatively short. Moreover, previous studies have focused on the nonspecific effects of only a single vaccination (measles-containing vaccines, diphtheria-tetanus-pertussis vaccines, or BCG vaccines), although simultaneous vaccinations are currently recommended. In addition, the results of previous studies may have led to missing the possible effects of health guidance during vaccination visits. Thus, the evidence on the relationship between comprehensive childhood vaccination status and subsequent overall health condition is inadequate.
We hypothesized that an age-appropriate vaccination status would reduce the risk of all-cause hospitalizations. This study aimed to compare the incidence of all-cause hospitalizations between children with and without age-appropriate vaccination status at 24 months.
In this retrospective cohort study, we used data from vaccine records and the healthcare administrative claims database provided by a single Japanese city that collaborated with our research. This city, with a population of around 600,000, serves as an urban residential hub for commuters working in Tokyo. The healthcare administrative claims database contains data on hospital admissions and outpatient visits, including patient age, sex, and diagnoses recorded using the International Classification of Diseases 10th revision (ICD-10) codes. Because healthcare administrative claims data were obtained only from the National Health Insurance11), our database did not include children covered by other health insurance. Vaccine records include information on the administered vaccine type and vaccination dates. Healthcare administrative claims data and vaccine records were linked using unique identification numbers in the city office12).
STUDY PARTICIPANTSWe identified all children born between April 1, 2014 and December 31, 2020 in our database. We did not obtain data on vaccinations or health administration during the period without a resident registration certificate or insurance. We only included children who had consistently lived in the relevant city and remained enrolled in the National Health Insurance from birth to 24 months of age because the vaccination status at this age was assessed. Our observation period was between April 1, 2016 and December 31, 2022.
EXPOSURES AND OUTCOMESThe primary exposure variable was age-appropriate vaccination status at 24 months. We evaluated the Hemophilus influenza type b, 13-valent pneumococcal conjugate vaccine, diphtheria, tetanus, acellular pertussis, and inactivated polio, hepatitis B virus, BCG, measles and rubella, and varicella-zoster virus vaccines.
The vaccine doses recommended by the Japanese national immunization program were four of Hemophilus influenza type b vaccine, four of 13-valent pneumococcal conjugate vaccine, four of diphtheria, tetanus, acellular pertussis, and inactivated polio vaccine, three of hepatitis B virus vaccine, one of BCG vaccine, one of measles and rubella vaccine, and one of varicella-zoster virus vaccine before 24 months (Supplemental Table 1). Children who received all these vaccines at 24 months of age were defined as having an age-appropriate vaccination status. We did not evaluate the hepatitis B virus vaccination status of children born before April 1, 2016, because hepatitis B virus vaccine was included in the national immunization program in October 2016 for children born on or after April 1, 2016. Data on rotavirus vaccines, which were included in the national immunization program in October 2020, were not used because we included only children born until December 31, 2020. We did not evaluate the second dose of the VZV vaccine because it is recommended 6 to 12 months after the first dose at the age of 1 year. We did not assess the vaccination status of seasonal influenza or mumps because the national immunization program does not cover them as routine childhood vaccines. The number of evaluated vaccines was 15 for children born before April 1, 2016, or 18 for others. We set the group with an age-appropriate vaccination status as the control group.
The primary outcome was all-cause hospitalizations after 24 months of age. For sub-analyses, we analyzed hospitalizations for the VPDs we targeted with our estimated vaccines, respiratory infectious diseases, and trauma based on ICD-10 codes. Targeted VPDs were Hib (A41.3, A49.2, J14, and J20.1), Streptococcus pneumonia (A40.3, G00.1, J13, and J20.2), HBV (B16.2, B16.9, and B18.1), diphtheria (A36), tetanus (A35), pertussis (A37.0 and A37.9), polio (A80.9), tuberculosis (A15–19), measles (B05), rubella (B06), and varicella infection (B01). Respiratory infection diseases included acute upper respiratory tract infections (J00–06), influenza (J09–11), viral pneumonia (J12, J15–18), acute bronchitis (J20), acute bronchiolitis (J21), and acute lower respiratory tract infections (J22). Trauma includes injury, poisoning, and other consequences of external causes (S00–99 and T07–88). We did not include hospitalizations that crossed the second birthday as outcome.
We also analyzed secondary outcomes including the length of hospital stay irrespective of reasons for hospitalization, the number of outpatient visits, and the number of acetaminophen prescriptions after 24 months of age.
The covariates were sex, birth year (2014–2017 or 2018–2020), and chronic comorbidities diagnosed before 24 months of age (none or any). We divided the children into two categories according to their birth year (2014–2017 or 2018–2020) to ensure that the incidence of infectious diseases decreased during the COVID-19 pandemic. The chronic comorbidities were identified using the pediatric complex chronic conditions classification system version 213).
STATISTICAL ANALYSESContinuous variables are expressed as means and standard deviations or medians and interquartile ranges, and categorical variables are expressed as percentages (%).
The Cox regression model was used to compare the adjusted hazard ratios of the groups without and with (the control) age-appropriate vaccination status. The proportional hazard assumptions were tested using the Schoenfeld residual test, and no violations were found. We only treated the first hospitalization as the outcome if the children were hospitalized twice or more after 24 months of age. Observation was censored based on the earliest event, including outcome occurrence, death, completion of the observation period (December 31, 2022), or withdrawal from the relevant insurance.
We performed two sensitivity analyses. First, we focused exclusively on children born in 2020 because they were likely the most profoundly affected by the COVID-19 pandemic. We compared the adjusted hazard ratios of the groups without and with age-appropriate vaccination status using Cox regression model. In this analysis, birth year (2014–2017 or 2018–2020) was not adjusted as a covariate. In the second analysis, we considered all-cause hospitalizations as a count-based outcome and applied a Poisson regression model with an offset function.
For the analyses examining the length of all-cause hospitalizations, the number of all-cause outpatient visits, and the number of acetaminophen prescriptions as secondary outcomes, a general linear regression model was used adjusting for sex, birth year, and the presence of chronic comorbidities diagnosed before 24 months of age. Length of hospitalization was analyzed only for children who had been hospitalized, excluding those without hospitalizations during the study period. For outpatient visits, the follow-up period was included as an offset function.
Statistical analyses were performed using the Stata software (version 17.0; StataCorp LP, College Station, TX, USA). For all tests, the threshold for significance was set at P < 0.05.
Written informed consent was not required owing to the anonymity of the patients in the database. This study was approved by the Institutional Review Board of the University of Tokyo (approval no. 2021187NI-(3)).
A total of 45,272 children born between April 1, 2014 and December 31, 2020 were identified. Of these, 17,574 children who did not live in the relevant city throughout the study period and 25,206 not enrolled in the relevant health insurance program were excluded. After exclusion, 2,492 were identified. Among the children, 1,689 (67.8%) were fully vaccinated at 24 months of age, and 120 (4.8%) were previously diagnosed with chronic comorbidities. No children were diagnosed with congenital immunodeficiency (D80–84 and D89), and whose data on vaccination dates was unknown.
Table 1 presents the patient demographics (n = 2,492). There were no significant differences in age, sex, or presence of chronic comorbidities between the groups with and without age-appropriate vaccination status. Of the 15 or 18 evaluated vaccines, the median number of unadministered vaccines in the group without an age-appropriate vaccination status was 2 (interquartile range: 1–5). The coverage rates for each vaccine are presented in Supplemental Table 2.
| All patients | p | |||||
|---|---|---|---|---|---|---|
| With age-appropriate vaccine status (the control) (N = 1,689) |
Without age-appropriate vaccine status (N = 803) |
|||||
| Sex (male), n (%) | 887 | (52.5) | 426 | (53.1) | 0.80 | |
| Age (years), mean (SD) | 5.5 | (2.0) | 5.6 | (2.0) | 0.54 | |
| Birth year, n (%) | 2014 | 228 | (13.5) | 125 | (15.6) | 0.002 |
| 2015 | 297 | (17.6) | 99 | (12.3) | ||
| 2016 | 241 | (14.3) | 147 | (18.3) | ||
| 2017 | 251 | (14.9) | 124 | (15.4) | ||
| 2018 | 212 | (12.6) | 114 | (14.2) | ||
| 2019 | 225 | (13.3) | 87 | (10.8) | ||
| 2020 | 235 | (13.9) | 107 | (13.3) | ||
| Any comorbiditiesa), n (%) | No | 1,612 | (95.4) | 760 | (94.6) | 0.39 |
| Yes | 77 | (4.6) | 43 | (5.4) | ||
| The number of missed vaccinationsb), median (IQR) | 0 | 2 | (1–5) | <0.001 | ||
Abbreviations: IQR, interquartile range; SD, standard deviation
a) Comorbidities diagnosed before 24 months of age were defined using the pediatric complex chronic conditions classification system.
b) We evaluated 15 vaccines for children born before April 1, 2016, or 18 for the others.
The incidence of all-cause hospitalizations after 24 months of age was 8.4% (210 of 2,492) (Table 2). No patients were hospitalized for targeted VPDs. Of the hospitalized children, 23.8% (50 of 210) were diagnosed with upper respiratory tract infection, and 11.4% (24/210) had trauma. In crude comparisons, the median length of all-cause hospitalization was significantly longer in the group without age-appropriate vaccination status compared to the group with age-appropriate vaccination status (P = 0.001). Additionally, there were no significant differences between the two groups in the crude analyses of the number of all-cause outpatient visits per year, or the number of acetaminophen prescription visits per year (shown in Table 3).
| Reasons for hospitalizations, n(%) | All patients | p | |||
|---|---|---|---|---|---|
| With age-appropriate vaccine status (the control) (N = 1,689) |
Without age-appropriate vaccine status (N = 803) |
||||
| All reasons | 146 | 9.4 | 64 | 8.0 | 0.57 |
| Targeted VPDsa) | 0 | 0 | 0 | 0 | — |
| Respiratory infection diseases | 33 | 2.0 | 17 | 2.1 | 0.79 |
| Trauma | 19 | 1.1 | 5 | 0.6 | 0.23 |
Abbreviations: VPDs, vaccine-preventable diseases
a) These included Hib, Streptococcus pneumoniae, diphtheria, tetanus, pertussis, polio, tuberculosis, measles, rubella, and varicella infections.
| All patients | p | ||||
|---|---|---|---|---|---|
| With age-appropriate vaccine status (the control) |
Without age-appropriate vaccine status | ||||
| The length of all-cause hospitalization (days), median (interquartile ranges) | 3 | 2–5 | 4 | 2–8 | 0.001 |
| The number of all-cause outpatient visits (counts per year), median (interquartile ranges) | 2.50 | 0.29–11.10 | 3.02 | 0.39–13.30 | 0.71 |
| The number of acetaminophen prescriptions (counts per year), median (interquartile ranges) | 0.82 | 0.16–2.50 | 0.91 | 0.15–2.68 | 0.51 |
Table 4 presents the results of the Cox regression for all-cause hospitalizations after 24 months of age in the group without age-appropriate vaccination status, with reference to the control. There was no significant difference in all-cause hospitalizations between the group without age-appropriate vaccination status and the control (adjusted hazard ratio, 0.93; 95% confidence interval, 0.69 to 1.26; P = 0.65). In the Poisson regression model, the coefficient of age-appropriate vaccination status to all-cause hospitalization was −0.21; 95% confidence interval, −0.44 to 0.02; P = 0.07. Thus, analyzing the outcome as a count did not alter the results. There were no significant differences in hospitalizations for respiratory infection diseases and traumas (adjusted hazard ratio, 0.58; 95% confidence interval, 0.22 to 1.55; P = 0.28; adjusted hazard ratio, 1.10; 95% confidence interval, 0.61–1.99; P = 0.75, respectively). Also, among the 342 children born in 2020, there was no significant difference in all-cause hospitalizations between the groups (adjusted hazard ratio: 1.61; 95% confidence interval: 0.51–5.03; P = 0.41), consistent with the main findings.
| Adjusted hazard ratio (95% confidence interval) | p | |
|---|---|---|
| All reasons (all children, main analysis) (N = 2,492) | 0.93 (0.69 1.26) | 0.65 |
| Respiratory infection diseases | 1.10 (0.61, 1.99) | 0.75 |
| Trauma | 0.58 (0.22, 1.55) | 0.28 |
| All reasons (children born in 2020) (N = 342) | 1.61 (0.51, 5.03) | 0.41 |
| All reasons (children born between 2014 and 2019) (N = 2,150) | 0.91 (0.67, 1.24) | 0.54 |
In the sub analyses for secondary outcomes, not having age-appropriate vaccine status was significantly associated with longer hospital stays (coefficient: 5.9 days; 95% confidence interval: 1.9–9.8; P = 0.004) and increased outpatient visits (coefficient: 0.12; 95% confidence interval: 0.10 to 0.14; P < 0.001). On the contrary, it was not significantly associated with the number of acetaminophen prescriptions (shown in Table 5).
| Coefficient (95% confidence interval) | p | |
|---|---|---|
| The length of all-cause hospitalization (days) | 5.9 (1.9, 9.8) | 0.004 |
| The number of all-cause outpatient visits | 0.12 (0.10, 0.14) | <0.001 |
| The number of acetaminophen prescriptions | 0.05 (−0.04, 0.10) | 0.067 |
This study investigated all-cause hospitalizations following age-appropriate vaccination status at 24 months of age with adjustment for children’s demographic characteristics, using the vaccine records and healthcare administrative claims database of one city in Japan. The results demonstrated no demographic differences in patient characteristics between the group without an age-appropriate vaccination status and the control group. After adjusting for possible confounders, the group without age-appropriate vaccination status showed no significant increase in hospitalizations for all causes, specific diseases, or trauma. Additionally, the results were consistent even if we only focused on children born in 2020 during the COVID-19 pandemic. Moreover, age-appropriate vaccination status was not significantly associated with the number of hospitalizations.
Evidence of the nonspecific effects of a particular vaccine in high-income countries is inconsistent4–9). To our knowledge, there have been no studies on the association between age-appropriate vaccination status and all-cause hospitalizations. Therefore, we could not compare our findings with those of previous studies. We considered age-appropriate vaccination status as exposure. Age-appropriate vaccination status may have led to a comprehensive assessment of the nonspecific effects of multiple vaccinations. Similarly, comorbidities diagnosed before the index date were considered. The ‘healthy vaccine bias’, which arises from the tendency of healthier individuals to be more inclined to receive vaccinations and less likely to develop diseases, may have been mitigated14).
This study suggests that age-appropriate vaccinations may have a limited effect on preventing trauma or diseases other than VPDs. Although our study population was relatively large, the sample size was insufficient to detect the impact of nonspecific effects of childhood vaccinations. Furthermore, our study period encompassed the COVID-19 pandemic, during which the number of cases of various other infectious diseases decreased by COVID-19 prevention measures15),16). Accordingly, the total number of hospitalizations for any reason may have been low initially. The number of hospitalizations for trauma was also small, irrespective of the COVID-19 pandemic. This may explain the small impact of age-appropriate vaccination status on all-cause hospitalizations. In addition, the group without an age-appropriate vaccination status had a median of only 2 missed vaccinations (interquartile range: 1–5), indicating that the difference in vaccination status between the two groups was minimal.
However, age-appropriate vaccination status was significantly associated with shorter length of hospitalization stays, therefore, it may prevent more severe diseases or traumas requiring longer stay. The difference in the number of outpatient visits was small, although significant; therefore, the impact of age-appropriate vaccination status on outpatient visits, if any, may be minimal.
The pathway from vaccine administration to prevention of other diseases remains unknown. The nonspecific effects of vaccines in preventing other diseases may be attributed to the inherent effectiveness of the vaccines, or to interventions by healthcare providers during the vaccination process. In Japan, health checkups or injury prevention guidance at vaccination visits are neither mandatory nor recommended, but voluntary. Thus, these types of health promotion for children may rarely be provided, or their impact, if any, may not reduce the number of hospitalizations. Our findings imply that evaluating children’s overall health or offering injury prevention guidance for them and their caregivers might need to be addressed separately from vaccination opportunities to effectively prevent various diseases and injuries.
This study had some limitations. First, our database did not contain information on how frequently doctors provided children’s health checkups or injury prevention guidance simultaneously with vaccinations. In Japan, because the health guidance for children has no reimbursement, it was not recorded in our health administrative database to determine whether health guidance was provided. Second, only children who lived in the relevant city and had health insurance from birth to 24 months were included in our study. We did not analyze the association between vaccination status and health outcomes before the age of 24 months. Furthermore, the reasons for moving to or changing health insurance are unknown. The proportions of vaccination for each vaccine in our study were lower than those reported by the Ministry of Health, Labour and Welfare17) (detailed in Supplemental Table 3), suggesting that our study population may not be representative of the entire population of Japan because we were not able to track individuals who had moved or changed their health insurance. Finally, in countries where routine child health checkups are frequently provided, the impact of child vaccinations on child health checkups may be smaller than that in Japan. Thus, the external validity of our study may vary depending on the child healthcare system in each country.
Our analysis did not show that a child’s age-appropriate vaccination status was associated with subsequent hospitalization for any cause. The effect of age-appropriate vaccinations on enhancing the overall health of children by preventing trauma or other diseases than VPDs may be small. Further studies are warranted to reveal the significance of health guidance from health professionals during vaccination visits on children’s health.
The authors declare no conflicts of interest in relation to the work presented in the manuscript.
This study was supported by the Grants-in-Aid for Innovative Drug Discovery and Development Project from the Japan Agency for Medical Research and Development (grant number: 21nf0101636h0001).
W. M. study conception and design; S. A., S. O., N. M., and K.U. data curation; W. M. data analyses; H. Y. funding; W. M. writing-original draft; and all authors writing-review and editing.
Disclaimer: Hideo Yasunaga is one of the Editorial Board members of Annals of Clinical Epidemiology. This author was not involved in the peer-review or decision-making process for this paper.
