ABSTRACT

Vaccination is an effective way to prevent infectious diseases. However, parental resistance to childhood immunizations has recently been a growing trend due to various factors. This systematic review and meta-analysis study focused on randomized controlled trials to investigate interventions for preventing parental vaccine refusal/hesitancy. This study was conducted according to the preferred reporting items for systematic review and Meta-analysis Protocols. PubMed, Science Direct, Web of Science, MEDLINE, Cochrane Library, Ovid, CINAHL, and ProQuest databases were screened with no year restriction. Two researchers each used the Cochrane risk-of-bias tool to determine the quality of the trials. Data were synthesized using a meta-analysis package. The study population consisted of 3,302 articles. The sample consisted of 22 randomized controlled trials, which implemented the interventions of text message reminders, digital training in vaccination, training in physician communication, training in parental decisionmaking, web-based activities, perinatal training in vaccination, immunization reminder and follow-up bracelets, and mother-daughter training. The results showed that slightly more parents agreed to get their children vaccinated after the interventions. The trials were moderately heterogeneous due to differences in sample size, country, and year. This paper investigated the effect of interventions on parental vaccine refusal/hesitancy and provided level-A evidence to suggest such interventions can be used to change parents’ vaccination comprehension and decisions.

Introduction

Vaccination has proven to be a cost-effective method for reducing mortality and morbidity rates caused by infectious diseases. However, recently, global childhood vaccination rates have declined. Sociocultural, environmental, economic, and individual factors play a role in parental vaccine refusal/hesitancy (1-3).

Recent outbreaks of vaccine-preventable diseases, such as measles and pertussis, demonstrate the dangers of low vaccination rates (4,5). For instance, Europe observed an eightfold increase in measles cases in 2018 (41,000 cases) compared to 2016 (5,000 cases; (6), and 87% of cases are attributed to those who refuse to be vaccinated (3,7). Diphtheria-tetanus-pertussis immunization rates have dropped to 92% and 91% in Europe and the United States, respectively. Therefore, the World Health Organization (WHO) identified vaccine refusal/hesitancy as one of the 10 threats to global health in 2019 (8,9). Moreover, the anti-vaccination trend has extended beyond childhood immunizations to campaigns against COVID-19 vaccines, a virus that has claimed millions of lives worldwide (10).

Many researchers have devoted their efforts to understanding and preventing parental refusal of childhood vaccinations (11-18). Specifically, some researchers have investigated interventions for the prevention of parental vaccine refusal/hesitancy. For example, some researchers sent vaccine-hesitant parents short texts a few days or more before a vaccination program to persuade them to get their children vaccinated (19-26). Other researchers implemented training-focused interventions, such as digital training in vaccination (27), training in physician communication (28), web-based interventions (29,30), and perinatal training in vaccination (31).

However, no comprehensive meta-analysis research exists assessing the overall effectiveness of interventions tailored to the prevention of parental vaccine refusal/hesitancy and identification of standards to inform further research on this topic. We aimed to fill this gap in the literature by determining the best intervention(s) against vaccine refusal/hesitancy so that healthcare professionals can use them to increase immunization rates.

Aims

This systematic review and meta-analysis focused on randomized controlled trials to determine the effectiveness of interventions for increasing parental vaccine acceptance rates.

The research questions were as follows:

-What kind of interventions are implemented to prevent parental vaccine refusal/hesitancy?

-Which interventions can help persuade parents to get their children vaccinated?

-How effective are interventions for increasing vaccine acceptance rates?

Methods

Search Strategy and Outcomes

The study followed the Preferred Reporting Items for Systematic Review and Meta-analysis Protocols (PRISMA-P). Figure 1 shows the flow diagram. This study satisfied all items recommended by the PRISMA-P checklist (32) and was recorded in the International Prospective Register of Systematic Reviews (PROSPERO; code: CRD42020157785).

Figure 1

Two researchers each searched the Science Direct, Web of Science, Springer Link, Ovid, CINAHL, PubMed, Cochrane Library, and ProQuest databases (August 2020) with no year restriction based on the four elements of PICOS (patient/population, intervention, comparison, outcome and study design). They screened the databases using the keywords of “vaccine,” “refusal,” “hesitancy,” “parent,” “intervention,” and “clinical trials” alone or in combination. They also used keywords/MeSH terms within articles from search alerts in PubMed. They compared the articles they accessed independently. They discussed the articles and reached a consensus on which articles to include in the study.

The literature review based on the search strategy yielded 3,302 articles, which were transferred to the EndNote 9 package. First, duplicates were removed (n=228), after which irrelevant articles by title or abstract were removed (n=2,899). The remaining 175 articles were reviewed based on the inclusion and exclusion criteria (Table 1), and 143 were removed. The full texts of the remaining 32 articles were reviewed and 10 were removed. One of the remaining 22 articles was regarded as two different articles because it involved two different interventions. Therefore, some sections and tables include 23 articles.

Table 1

Risk of Bias and Quality Appraisal

The researchers each used the Cochrane risk-of-bias assessment tool (RoB 2) to evaluate the risk of bias of the articles based on the following bias domains (33) (Figure 2). GRADE was used to grading quality of evidence and the strength of recommendation of studies.

Figure 2

Data Extraction and Analysis

The researchers each extracted the data based on (a) author, year, country, (b) participant characteristics, (c) intervention, (d) intervention details, (e) control group, (f) outcome measures, (g) results, and (h) certainty of the evidence (GRADE).

The data were analyzed using the Comprehensive Meta-analysis (version 2.0). The main outcome was pre- and postintervention vaccine acceptance rates. The data were prepared for meta-analysis using Microsoft Excel. The effect size (ES) was calculated using Borenstein and Hedges (34), which were rated as small (d=0.20), medium (d=0.50), and large effects (d=0.80) between the intervention and control groups (35). Cochran’s Q test and I² statistics were employed to determine heterogeneity (36). A significance level of less than <.05 indicated heterogeneity for Cochran’s Q test. I² of 25%, 50%, and 75% were classified as low, moderate, and high heterogeneity, respectively (37). The random-effects model was used to show the average difference and to calculate the weighted average difference (38). Publication bias was determined using Egger’s test, Begg and Mazumdar’s test for rank correlation, and Duval and Tweedie’s Trim-and-Fill test (39,40). Analog ANOVA and meta-regression analysis were performed to identify the cause of heterogeneity (41-44).

Results

Research Characteristics

The sample consisted of 22 randomized controlled trials, with a sample size of 57 to 15,786 (n=55,138). The trials were conducted between 2011 and 2020 in the United States (n=14), the United Kingdom (n=2), China (n=1), Australia (n=1), the Netherlands (n=1), Japan (n=1), Pakistan (n=1), and Guatemala (n=1).

Most trials implemented the intervention of sending parents short reminder messages (SMS alerts) before scheduled immunization visits for their children (19-26,45-49). The other trials provided digital training in vaccination [DTV; n=1; (27)], training in physician communication [TPC; n=1; (28)], training in parental decision-making [TPDM; n=1; (50)], perinatal training in vaccination [PTV; n=1; (31)], web-based interventions [WBI; n=2; (29,30], office-based educational brochure [OBEB; n=1; (51)], immunization reminder and follow-up bracelets [IRFB; n=1; (52)], and mother-daughter training [MDT; n=1; (53)].

The details of the interventions differed among trials. The SMS trials (19-26,45-49) involved sending parents short reminder messages just before scheduled immunization visits, or 4 days, 1 week, 4 weeks, 1 month, 2 months, or 4 months before the visits. The frequency of the SMS alerts depended on the dose of vaccination. The DTV trial (27) used only reinforcement messages depending on the parents’ views or administered training in vaccination within the scope of a program. The TPC trial (28) administered physicians 45-minute training and examined its effect on parental vaccine hesitancy. The TPDM trial (50) provided training to parents eight times for 2 months. One WBI trial (30) provided online training (via email) only once, while the other WBI trial (29) administered intervention six times with intervals of 2, 4, and 6 weeks. The PTV trial (31) presented two sessions (10 minutes per session) of training to parents in the perinatal period. The OBEB trial (51) used brochures laid out in the waiting room for visitors to take. The 1-year IRFB trial provided vaccinated children with bracelets that had a symbol for each vaccination (52). The MDT trial held 11 dinner meetings for mother-daughter training (53). The control groups in all trials received standard procedures (Table 2).

Table 2

Risk of Bias

In the domain of randomization process, 16 trials were at low risk of bias (19,23,25-31,45,47-51,53), five trials raised some concerns (21,22,24,46,52), and the remaining one was at high risk (20). All trials were at low risk of bias for deviations from intended interventions and missing outcome data. Five trials raised some concerns in the domain of bias in the measurement of the outcome (20,24,47,51,53), while the others were at low risk. Eight trials were at low risk in the domain of bias in the selection of the reported result, while the others raised some concerns. Six trials were at low risk in the domain of general bias, 16 raised some concerns, and one was at high risk (Figure 2).

Figure 2

Study Outcomes

This paper focused on 22 trials to investigate the effect of interventions on vaccine acceptance rates. Meta-analysis results showed that interventions for vaccine acceptance were effective [p<0.001, Hedge’s g=0.10, 95% CI (0.06, 0.14)]. The Cochran’s Q test results showed a moderate level of heterogeneity (Q=61.26, p<.001, I²=64.09%; Figure 3). The moderating variables of intervention type (Q=11.114, df=9, p=0.268) and vaccine type (Q=4.467, df=4, p=0.347) had no significant effect on the effect size between subgroups. The moderating variable of country significantly affected the heterogeneity (Q=32.891, df=7, p<0.001). The meta-regression analysis showed that sample size significantly affected the ES (Q=61.26, df=22, p<0.001), suggesting a negative correlation between sample size and ES. The variable of year also significantly affected the heterogeneity (Q=61.26, df=22, p<0.001).

Figure 3

Publication bias was determined using a funnel plot, Begg and Mazumdar’s test, and Egger’s test. The funnel plot presents the standard error for the Y-axis and the ES for the X-axis (Figure 4). The Begg and Mazumdar’s tau with continuity (tau=0.34, Z=2.32 p=0.02) and Egger’s regression test results indicated publication bias. Therefore, Duval and Tweedie’s Trim-and-Fill test was used to calculate publication bias again. The results indicated that nine studies be added to avoid publication bias, which would result in a general ES of 0.04 [95% CI (0.04, 0.11); Figure 4].

Figure 4

Discussion

This systematic review and meta-analysis focused on 22 randomized controlled trials to examine the effectiveness of interventions for promoting vaccine acceptance rates. The results indicated that interventions helped reduce vaccine refusal/hesitancy and increase vaccine acceptance rates, albeit insignificantly (Hedge’s g=0.10). We believe the difference in sample size, intervention, and outcome across the trials affected the ES of the interventions. Twelve trials showed interventions resulted in increased vaccine acceptance rates (19,20,23,25-27,30,31,48-51), while the remaining 11 found no significant difference in vaccine acceptance rates between the intervention and control groups (21-24,28,29,45-47,52,53).

The results showed that the trials had moderate heterogeneity, which was affected by sample size, intervention, and outcome (54,55). The ANOVA and meta-regression analysis results showed that the difference in sample size, year, and country caused the heterogeneity. The trials with large samples had insignificant ESs, adversely affecting both overall ES and heterogeneity. We suggest researchers employ the right statistical methods and consider missing data and errors when determining the right number of participants for accurate results in terms of ES and effectiveness. Differences in the country also affected the heterogeneity of the trials. Hofstede et al. (56) attributed cultural differences to vertical-collectivism and horizontal-individualism. They argued that horizontally individualistic cultures are the source of heterogeneity because they have loose social ties, resulting in high heterogeneity.

Most trials implemented the intervention of SMS alerts. Their results indicate that texting reminder messages to parents before their scheduled visits for their children’s vaccination reduces their vaccine refusal/hesitancy (19,23,26,48,49). However, texting messages sent too early before the scheduled visits or texting multiple messages did not affect vaccine acceptance rates. Face-to-face training, decision-making processes (30,31,50,51), and tech-based interventions (27) were most effective, increasing the overall ES. Given recent advances in technology and low health literacy rates, we believe it is of paramount importance to provide tech-based training in vaccination to the public. However, the training should be short and occasional given that trials of long (28) and frequent training (29,52,53) found no difference in vaccine acceptance rates between the intervention and control groups. If an intervention should be administered more than once, it should be implemented in multiple sessions over an extended period rather than short intervals (50).

The trials had a low or uncertain risk of bias, which was affected by differences in the number of samples and research content. We can state that the trials addressed the risk of methodological thinking and bias and met standards for randomizing and blinding. Most trials generated CONSORT flow charts, which should be used for accurate randomization, low risk of bias, and high research quality (57).

Although the trials reported different results, researchers and practitioners should take interventions as a whole and set standards regarding the frequency, duration, and application of interventions tailored to reduce vaccine refusal/hesitancy and increase vaccine acceptance rates. Such interventions should be short and occasional with tech-based interventions administered face to face right before visits for vaccinations. Researchers should be more careful when determining the right sample size. Future studies should consider these suggestions when it comes to designing interventions tailored to reduce parental vaccine refusal/hesitancy rates.

Strengths and Limitations

This research has several strengths. First, it is a comprehensive systematic review and meta-analysis on vaccine hesitancy in children. Second, a protocol based on Cochrane principles was followed. Another strength was that databases were scrupulously scanned and the Cochrane tools manual was followed to minimize bias. Further, the review was conducted by two authors independent of screenings and bias controls.

Concerning limitations, gray literature, such as conference papers, research, and committee reports, was not included. We wanted to keep the evidence to the highest level. Gray literature can be added to future studies, considering the risks of lowering the level of evidence.

Conclusion

This systematic review and meta-analysis focused on 22 randomized controlled trials to determine the effect of interventions on the reduction of parental vaccine refusal/hesitancy rates. The results show that interventions can be used to persuade parents to get their children vaccinated. Our results will be of considerable value to physicians, nurses, academics, primary healthcare staff, and the public. Overall, the results indicate that interventions should be short tech-based interventions administered face to face. We believe that the results can help primary healthcare staff develop new interventions to reduce parental vaccine refusal/hesitancy rates and provide high-quality care. The results introduce Level-A evidence that can pave the way for further research on the topic. We recommend that more researchers undertake more detailed and specific national and international trials concerning the effectiveness of interventions for promoting parental vaccine acceptance rates.

Ethics

Conflict of Interest: No conflict of interest was declared by the authors.

Financial Disclosure: The authors declared that this study received no financial support.

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The Effect of Interventions on the Prevention of Parental Vaccine Refusal and Hesitancy: A Systematic Review and Meta-analysis of Randomized Controlled Trials