Worldwide Child Routine Vaccination Hesitancy Rate among Parents of Children Aged 0–6 Years: A Systematic Review and Meta-Analysis of Cross-Sectional Studies

Routine vaccine hesitancy is a major global health challenge observed in over 190 countries worldwide. This meta-analysis aims to determine the worldwide prevalence of routine vaccination hesitancy among parents of children aged 0–6. An extensive search was conducted in four scientific databases: PubMed, Scopus, Web of Science, and the Cochrane Library. Studies were included if they reported hesitancy related to WHO-recommended routine immunizations for children under 7 years of age. A single-arm meta-analysis was performed using the OpenMeta[Analyst] software. An initial search retrieved 5121 articles, of which only 23 publications, involving 29,131 parents, guardians, and caregivers from over 30 countries met the inclusion criteria and quality assessment. The cumulative prevalence of parental vaccine hesitancy was found to be 21.1% (95% CI = 17.5–24.7%, I2 = 98.86%, p < 0.001). When stratifying the prevalence of vaccine hesitancy per WHO region, significant variations were observed, ranging from 13.3% (95% CI = 6.7–19.9%, I2 = 97.72%, p < 0.001) in the Region of the Americas to 27.9% (95% CI = 24.3–31.4%) in the Eastern Mediterranean region. The study findings highlight the need for healthcare providers and governments to develop and improve comprehensive programs with communication strategies to reduce parental vaccine hesitancy.


Introduction
Vaccine hesitancy, recognized by the World Health Organization (WHO), is a serious global problem, particularly as the incidence of infectious diseases among children rises.Public health services face numerous challenges in addressing this issue, including the impact of the COVID-19 pandemic, which has significantly affected parental confidence in vaccination [1,2].Measles outbreaks occurring in various parts of the world also underscore the importance of monitoring and assessing the level of parental hesitancy regarding vaccinating children under 7 years of age [3][4][5].This phenomenon, defined as the reluctance to promptly accept or refuse vaccination despite the widespread availability of vaccination services, poses a threat to global public health [6].
Although vaccinations help to prevent life-threatening infectious diseases, annually saving over 4 million lives, vaccination coverage rates continue to decline across the globe [7,8].Recognizing the gravity of this issue, the WHO has designated a reduction in vaccine hesitancy as one of its foremost global priorities.Despite the significance of vaccine hesitancy, there are currently no universally effective interventions to address parental hesitancy and vaccine refusal [9].
Young children, especially infants and preschoolers, are at increased risk of illnesses and complications from infections that can be prevented by vaccination.According to the Vaccines 2024, 12, 31 2 of 20 WHO recommendations, the following list of vaccines is recommended for all immunization programs worldwide in order to facilitate the development of optimal immunization schedules: Bacillus Calmette-Guérin (BCG) for tuberculosis, hepatitis B vaccine, polio vaccine, diphtheria, tetanus, and pertussis-containing vaccine (DTPCV), Haemophilus influenzae type b (Hib) vaccine, pneumococcal conjugate vaccine, rotavirus vaccine, measles vaccine, rubella vaccine, and human papillomavirus vaccine (HPV) [10].According to the WHO-recommended immunization program, a significant portion of mandatory childhood immunization is administered before a child reaches the age of 7.This age category is the most suitable for assessing parental attitudes towards vaccination [11].
Vaccine hesitancy occurs in countries regardless of the varying levels of socioeconomic development.According to estimates, vaccine hesitancy is observed in over 190 countries worldwide, all of which are members of the WHO [12].In a comprehensive retrospective study of 149 countries that analyzed global trends in vaccine confidence and included data from 284,381 individuals, it was found that confidence in the importance of vaccines exhibited the strongest univariate association with vaccination coverage [13].Numerous research studies have aimed to identify parental hesitancy toward childhood vaccination [14 -19].Recent outbreaks of diseases preventable by vaccination have provided a stark reminder of the strong link between vaccine hesitancy and refusal.This highlights the importance of analyzing and monitoring the level of indecisiveness among parents, especially among parents of preschool-aged children [20,21].
Thus, this meta-analysis aims to synthesize data from various sources and use various assessment tools to create a more convincing, objective, and complete picture of the problem of parental hesitancy regarding compulsory childhood vaccination in general.Despite the presence of publications on the topic of indecision, no publications were identified that examined the general picture of indecision in parents of children under 7 years of age.Infants and young children are known to be more vulnerable to many infectious diseases.Identifying and understanding parental vaccine hesitancy in early childhood is critical to ensure the safety and health of children, prevent the spread of infections, and increase community confidence in vaccination.A subgroup analysis was conducted considering the type of data collection tool used, the world region, and the income level of the country.

Search Strategies
The study was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [22].An extensive search was performed in four scientific databases: PubMed, Scopus, Web of Science, and Cochrane Library.Data were searched for from the date of database inception until 30 June 2023.The following combination of keywords was used: "parental vaccination hesitancy", "vaccination hesitancy", "routine vaccination hesitancy", "child vaccination hesitancy", "routine vaccination attitude", "parental vaccination refusal"."The following search strategy was applied in PubMed: ("parental" OR "caregiver" OR "guardians") AND ("routine" OR "mandatory") AND ("child" OR "children" OR "childhood") AND ("vaccination" OR "immunization") AND ("hesitancy" OR "attitude" OR "refusal").Following that, we reviewed the abstracts and titles of all identified publications to ascertain if they satisfied the inclusion criteria.Subsequently, we examined the reference lists of all qualified articles to discover any pertinent articles.

Eligibility Criteria
To ensure the methodological quality of publications and adherence to the WHOrecommended list of vaccines for all immunization programs worldwide, inclusion and exclusion criteria were employed in the systematic review of articles.This was done to calculate the prevalence of hesitancy among parents, caregivers, and guardians (

Data Extraction
In the first stage of the study, the first author of the present review (M.B.) imported all identified studies from databases into the Rayyan.aiweb platform [23] to identify and remove duplicates.In the second stage, after removing duplicates, M.B. and A.S. independently conducted initial screenings of study titles and abstracts.All studies that did not meet the inclusion criteria were excluded from the study.During the secondary screening, full-text articles were assessed against the inclusion criteria.Articles that passed the two stages of screening were entered into a data extraction sheet.All additional questions and discrepancies regarding the acceptability of articles were resolved through discussion with another researcher (Yu.S.).The process of selection in accordance with PRISMA guidelines is presented in Figure 1.The following data were recorded for each study: author, year of publication, country, study period, type of study, sample size, targeted population, data collection tool, and vaccine hesitancy/refusal/delay rate.
passed the two stages of screening were entered into a data extraction sheet.All additional questions and discrepancies regarding the acceptability of articles were resolved through discussion with another researcher (Yu.S.).The process of selection in accordance with PRISMA guidelines is presented in Figure 1.The following data were recorded for each study: author, year of publication, country, study period, type of study, sample size, targeted population, data collection tool, and vaccine hesitancy/refusal/delay rate.

Quality Assessment
The Joanna Briggs Institute (JBI) checklist is a standardized and widely used tool for assessing research quality, developed by the Joanna Briggs Institute [24].It comprises a set of questions or criteria reflecting the key elements of a well-planned study, including studies with cross-sectional study designs.This tool enables the evaluation of studies by providing 4 response options: "yes", "no", "unclear", and "not available".Articles were categorized into three quality groups: low quality (scoring 1 and 2 out of 9), moderate

Quality Assessment
The Joanna Briggs Institute (JBI) checklist is a standardized and widely used tool for assessing research quality, developed by the Joanna Briggs Institute [24].It comprises a set of questions or criteria reflecting the key elements of a well-planned study, including studies with cross-sectional study designs.This tool enables the evaluation of studies by providing 4 response options: "yes", "no", "unclear", and "not available".Articles were categorized into three quality groups: low quality (scoring 1 and 2 out of 9), moderate quality (scoring 3-6 out of 9), and high quality (scoring 7-9) [24].Only studies demonstrating high methodological quality, scoring 7 and above on the JBI checklist, were considered in this review.

Statistical Analyses
A single-arm meta-analysis was conducted using the OpenMeta[Analyst] software, which had been developed at Brown University in Providence, Rhode Island, United States [25].ArcMap v.10.8.1 by ESRI, produced in Redlands, California, United States [26], was employed to perform the mapping of the included studies.The prevalence of vaccine hesitancy was determined using the random effects model and the restricted maximum likelihood method, incorporating 95% confidence intervals (CIs).The assessment of the heterogeneity level was carried out using the I 2 statistic test.I 2 values below 25% were indicative of low heterogeneity, while values between 25% and 75% suggested moderate heterogeneity, and values exceeding 75% indicated high heterogeneity [25].To calculate a weight based on the sample sizes of the studies, vaccine hesitancy rates from both the multi-country study with multiple outcomes and the vaccine hesitancy study at three time points were entered separately into the analysis.Subgroup analyses were undertaken when prevalence data were subdivided into categories based on World Bank country classifications by income level [27], data collection tool, and world region [28].

Overview of Included Studies
Searches across four databases (PubMed, Scopus, Web of Science, Cochrane Library) retrieved a total of 5121 articles.Out of these, only 23 met the inclusion/exclusion criteria and passed the quality assessment.These 23 studies involved 29,131 parents, guardians, and caregivers of children aged 0-6 years (see Table 1).The studies originated from various countries, including Italy, India, the USA, Canada, Turkey, Austria, Bulgaria, Croatia, Cyprus, Germany, Greece, Hungary, Israel, Lithuania, Malta, Moldova, the Netherlands, Poland, Portugal, Slovenia, Spain, Ukraine, Pakistan, Cameroon, Ethiopia, China, France, the Philippines, Brazil, England, and Malaysia.In several countries, multiple studies were conducted, with Italy having three studies, India having five studies, Turkey having three studies, and Brazil having two studies.The earliest study was carried out in Canada from March 2014 to February 2015, while the latest study was conducted in Turkey from September to December 2021.Sample sizes across the studies ranged from 99 to 3130 parents.
Five different assessment tools were employed in the included articles: Parent Attitudes About Childhood Vaccines (PACV), WHO Strategic Advisory Group of Experts Vaccine Hesitancy Scale (WHO SAGE VHS), a combination of both PACV and WHO SAGE VHS, Vaccine Confidence Index (VCI), and a self-structured questionnaire.The PACV questionnaire was applied in seven studies, encompassing a total of 5694 parents/caregivers in the countries of Italy [29], India [30,31], the USA [32], Canada [33], and Turkey [34][35][36].The highest number of studies utilized the WHO SAGE VHS, with eight studies involving a sample size of 10,417 parents/caregivers from Pakistan [37], India [38,39], Cameroon [40], Ethiopia [41], China [42], France [43], and the Philippines [44].A study conducted across 18 European countries employed a survey based on two sources, PACV and WHO SAGE VHS, with the participation of 5736 parents/caregivers [45].Self-administered questionnaires were applied in Brazil [46], England [47], India [48], Italy [49], and Malaysia [50], involving 6938 parents/caregivers.The Vaccine Confidence Index (VCI) was used in Brazil [51], involving 952 parents, of whom 352 were parents of children under 5 years of age.Out of the 32 countries examined in the study , 21 studies were carried out in countries categorized as high-income by the World Bank, 11 studies in upper-middleincome countries, 9 studies in lower-middle-income countries, and 1 study in a low-income country, specifically Ethiopia.Table 2 provides an overview of the characteristics of all the studies included in the meta-analysis.Figure 2      characteristics of all the studies included in the meta-analysis.Figure 2 depicts a world map showing the countries included in the systematic review.
The prevalence of vaccine hesitancy among parents of children aged 0-6 years varied

Discussion
Combining various studies into a unified analysis will yield a deeper and more comprehensive understanding of parental hesitancy toward routine vaccination.This can be pivotal in crafting targeted programs to enhance awareness and increase vaccination rates among children.Previous systematic reviews have often noted the lack of a single indicator capable of effectively measuring parental vaccine hesitancy.Therefore, we conducted this systematic review and meta-analysis of cross-sectional studies to

Discussion
Combining various studies into a unified analysis will yield a deeper and more comprehensive understanding of parental hesitancy toward routine vaccination.This can be pivotal in crafting targeted programs to enhance awareness and increase vaccination rates among children.Previous systematic reviews have often noted the lack of a single indicator capable of effectively measuring parental vaccine hesitancy.Therefore, we conducted this systematic review and meta-analysis of cross-sectional studies to determine the overall rate of hesitancy among parents or caregivers regarding mandatory vaccination for children under 7 years of age.Our meta-analysis revealed a cumulative prevalence of parental vaccine hesitancy at 21.1% (95% CI = 17.5-24.7%),which was statistically significant (p < 0.001).However, we observed a high level of heterogeneity (I 2 = 98.86%), signifying variations in the study outcomes included in the analysis, potentially distorting the assessment of the mean effect across studies.To address this heterogeneity and mitigate its impact on result interpretation, subgroup analyses were performed based on income level [27], data collection tools, and world region.Several potential reasons for this heterogeneity were identified, including differences in defining vaccine hesitancy, variations in tools used for its measurement, disparities in income levels among countries, and discrepancies in approved vaccination schedules.Moreover, differences in parental hesitancy toward childhood vaccination in countries such as high-income countries may be due to increased access to information and resources that allow parents to be more informed about vaccination decisions and choices.In addition, high levels of education and diversity of opinions and perspectives in society may also contribute to a greater diversity of views on vaccination among parents.This may lead to greater heterogeneity in decisions about childhood vaccinations, which in turn may affect the level of hesitancy among parents.However, the presence of these factors, in varying proportions, may be individual for each country or society [53,54].
According to the definition provided by the Strategic Advisory Group of Experts (SAGE) Working Group on Vaccine Hesitancy (VH), vaccine hesitancy (VH) refers to the delay in acceptance or refusal of vaccination despite the availability of vaccination services [1].However, different studies interpret this definition in various ways.Some studies solely focus on refusal rates and delayed or incomplete vaccination and do not employ a specific tool to identify hesitancy rates.Various questionnaires have been developed and are used to assess vaccine hesitancy.The diversity in definitions and assessment tools of vaccine hesitancy can lead to ambiguous result interpretations, complicating comparisons and comparability.The inability to compare datasets can result in information loss or incorrect amalgamation.Therefore, a unified strategy with stringent inclusion and exclusion criteria for studies is a crucial and necessary aspect for synthesizing results in future review articles.
This meta-analysis covers five different tools for evaluating parental vaccine hesitancy: the Parent Attitudes About Childhood Vaccines (PACV), the WHO SAGE Vaccine Hesitancy Scale (VHS), a combination of both PACV and WHO SAGE VHS, the Vaccine Confidence Index (VCI), and a self-structured questionnaire.The PACV questionnaire was originally developed by Opel et al. [7], while the SAGE VHS was formulated under the guidance of the WHO by Larson et al. in 2015 [1].Another tool in use is the VCI, which comprises three questions designed for the global assessment of vaccine confidence.One of the largest recent questionnaires in this area is "The Vaccine Confidence Project" [12], which collected 65,819 responses across 67 countries [37].Additionally, the 5C+ Model, used to measure vaccine hesitancy, incorporates dimensions such as confidence, complacency, constraints, calculation, and collective responsibility, particularly in relation to identifying psychological barriers to vaccination behavior.Valid instruments for assessing adherence [38] and willingness [39] for these vaccines are also available.However, our objective did not encompass these factors, and the studies we scrutinized primarily investigated hesitancy concerning childhood vaccinations.
It is important to acknowledge the diversity of vaccination schedules approved by different countries.To consolidate the findings and calculate a global vaccine hesitancy (VH) rate, this meta-analysis focused solely on the vaccines recommended by the WHO for global immunization programs.Consequently, we excluded studies that reported unified vaccine coverage rates for the routine WHO immunization program along with one or more additional vaccines.This exclusion criterion led to the removal of certain studies, including the one by Ngandjon et al. (2022) that examined yellow fever vaccine hesitancy alongside other mandatory vaccinations [40], the study by Napolitano et al. (2018) that assessed varicella vaccine hesitancy [41], and the study by Dasgupta et al. (2018) that explored Japanese encephalitis vaccine hesitancy rates [55].We do not discount the possibility of excluding a significant portion of studies from the meta-analysis due to the stringent inclusion and exclusion criteria employed in the study.However, applying this methodology enables us to identify generalized outcomes regarding parental hesitancy towards routine vaccination.
Reasons for VH vary according to geographic location, the economic status of the country, and the type of vaccination.According to Obohwemu et al. (2022), unfavorable attitudes and behavioral tendencies towards vaccination, such as reduced perceptions of vaccine effectiveness and mistrust of health authorities, were the most common barriers to vaccine uptake.The main determinants of VH include confidence and complacency, which encompass anxiety, a low perceived risk, a low severity of the disease, reduced confidence in the safety and effectiveness of vaccines, a lack of trust in healthcare providers and vaccination services, and fear of side effects [56].Misinformation on various media platforms and lack of knowledge are some of the reasons for vaccine refusals in many countries [57].Despite the significance of vaccine hesitancy, there are currently no universally effective measures to eliminate parental hesitancy and vaccine refusal [9].Public health services face numerous challenges in addressing this problem, including the impact of the COVID-19 pandemic, which has played a significant role in shaping parental confidence in vaccination.Current measles outbreaks around the world also highlight the importance of monitoring and measuring VH among parents of children aged under 7 years [5].Various countries actively employ comprehensive programs aimed at enhancing public knowledge and awareness through mass media utilization and training healthcare workers in communication tools.Interventions based on vaccination reminders are also employed to combat vaccine hesitancy [58,59].Considering the widespread prevalence of parental hesitancy toward childhood vaccination in different countries, as supported by research findings, there is a need to continually refine existing strategies to reduce parental hesitancy levels regarding mandatory childhood vaccination, especially among preschool-aged children.
This work has several limitations that should be acknowledged.Firstly, a high degree of heterogeneity among the studies included in this meta-analysis was identified.Variations in the definitions of VH across studies; the wide range of tools for detecting VH, income levels of the countries, and world regions; and disparities in approved vaccination schedules could contribute to the heterogeneity of the data.However, we mitigated these concerns by implementing rigorous inclusion and exclusion criteria for articles, as well as employing a validated tool for assessing publication quality, allowing us to exclude studies of low to moderate methodological quality.Second, the cross-sectional study design does not allow for the determination of cause-and-effect relationships in the studies.Third, we excluded studies not written in English, non-full-text articles, conference abstracts, and government reports.Given the substantial heterogeneity observed in studies, future research could address these limitations by adopting a unified vaccination schedule recommended by the World Health Organization for all countries in systematic reviews examining vaccine hesitancy in children.Additionally, conducting high-quality research is advised to identify the causal relationships existing with parental hesitancy regarding mandatory childhood vaccination.
To the best of our knowledge, this is the first meta-analysis aimed at analyzing VH among parents of children under 7 years of age.This age group of children is often at a higher risk of contracting infectious diseases due to their developing immune systems [8].In this study, we did not include HPV hesitancy in the analysis for two reasons: the timing of HPV vaccination (typically administered over the age of 7) and the likely differences in the nature of hesitancy related to HPV vaccination compared to routine childhood vaccinations.The study has several strengths, including extensive coverage, independent screening, and bias control.It also utilizes a validated research quality assessment tool.Despite not having restrictions on the year of publication, the studies included in the review had a research depth of less than 10 years (from 2014 to 2021).

Conclusions
In this meta-analysis, the cumulative prevalence of parental vaccine hesitancy was determined to be 21.1% (95% CI = 17.5-24.7%,I 2 = 98.86%, p < 0.001).While this meta-analysis included studies from over 30 different countries, it is important to note that this prevalence may not fully represent the global parental vaccine hesitancy rate.Nevertheless, identifying a pooled vaccine hesitancy rate can provide a consistent approach for monitoring and analyzing trends in vaccine hesitancy worldwide.This, in turn, could contribute to the development and enhancement of comprehensive programs with communication strategies for healthcare institutions and governments aimed at reducing parental vaccine hesitancy, ultimately leading to increased vaccination coverage and strengthened protection against vaccine-preventable diseases.Future research efforts should prioritize the development of a comprehensive indicator to assess parental vaccine hesitancy, taking into account the complexities and variations observed in our study.

Figure 1 .
Figure 1.PRISMA flowchart indicating the process of study identification, screening, and inclusion.

Figure 1 .
Figure 1.PRISMA flowchart indicating the process of study identification, screening, and inclusion.
depicts a world map showing the countries included in the systematic review.Vaccines 2024,12,31

Figure 5 .
Figure 5. Forest plot of prevalence of child routine vaccination hesitancy among parents of children aged 0-6 years depending on the income level of a country [29-41,43-52].

Figure 5 .
Figure 5. Forest plot of prevalence of child routine vaccination hesitancy among parents of children aged 0-6 years depending on the income level of a country [29-41,43-52].

Figure 5 . 18 Figure 6 .
Figure 5. Forest plot of prevalence of child routine vaccination hesitancy among parents of children aged 0-6 years depending on the income level of a country [29-41,43-52].Vaccines 2024, 12, x FOR PEER REVIEW 13 of 18

Figure 6 .
Figure 6.Forest plot of prevalence of child routine vaccination hesitancy among parents of children aged 0-6 years depending on the world region [29-41,43-52].

Table 1 .
Inclusion and exclusion criteria based on the provided information.

Table 2 .
Summarized characteristics of included studies.
* Absolute values were calculated based on the percentage of the final VH result.N/A-Not Applicable.Vaccines 2024, 12, 31 12 of 20 Vaccines 2024, 12, x FOR PEER REVIEW 6 of 18