Determinants of influenza vaccine hesitancy among pregnant women in Europe: a systematic review

Background Pregnant women are at high risk for severe influenza. However, maternal influenza vaccination uptake in most World Health Organization (WHO) European Region countries remains low, despite the presence of widespread national recommendations. An influenza vaccination reduces influenza-associated morbidity and mortality in pregnancy, as well as providing newborns with protection in their first months. Potential determinants of vaccine hesitancy need to be identified to develop strategies that can increase vaccine acceptance and uptake among pregnant women. The primary objective of the systematic review is to identify the individual determinants of influenza vaccine hesitancy among pregnant women in Europe, and how to overcome the hesitancy. Methods Databases were searched for peer-reviewed qualitative and quantitative studies published between 2009 and 2019 inclusive. Databases included PubMed via MEDLINE, Cochrane Central Register for Controlled Trials, PsycINFO, SAGE Journals, Taylor and Francis and Springer nature. These covered themes including psychology, medicine, and public health. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) approach, 11 studies were eligible and analyzed for significant determinants of influenza vaccine hesitancy among pregnant women in Europe. Results The most commonly reported factors were psychological aspects, for example concerns about safety and risks to mother and child, or general low risk perception of becoming ill from influenza. Doubts about the effectiveness of the vaccine and a lack of knowledge about this topic were further factors. There was also influence of contextual factors, such as healthcare workers not providing adequate knowledge about the influenza vaccine or the pregnant lady stating their antivaccine sentiment. Conclusion Health promotion that specifically increases knowledge among pregnant women about influenza and vaccination is important, supporting a valid risk judgment by the pregnant lady. The development of new information strategies for dialogue between healthcare providers and pregnant women should form part of this strategy.

Therefore, the goal of this review is to lay the groundwork for an evidence-based framework by identifying factors that drive influenza vaccine acceptance and demand among pregnant women in Europe. The findings can inform country-and regional-level policy decisions and complement health promotion activities.

Vaccine hesitancy
Vaccine hesitancy has been identified as one of the leading factors that contributes to low vaccination coverage [17]. It was identified by the World Health Organization as "one of the 10 greatest threats to global health in 2019" [18], and has been an important topic across COVID-19 vaccine development and roll-out [19,20]. People may accept some vaccines but reject others, and their beliefs may change over time. Hence, vaccine hesitancy is not always evident as a total refusal of all vaccines but as decision-making that can range between general rejection and acceptance of all vaccines [17,21]. The WHO Sage Working Group defines vaccine hesitancy as the "delay in acceptance or refusal of vaccination despite availability of vaccination services" [21]. Vaccine hesitancy is complex and context specific, varying across time, place and vaccines [22].
Determinants influencing vaccine hesitancy are multi-dimensional and vary across vaccines and target groups [23]. It is therefore important to understand that determinants of vaccine hesitancy cannot necessarily be generalized across different vaccines and contexts, as barriers to vaccine uptake can vary [24]. Seasonal influenza requires annual vaccination, but in some countries it is recommended only for certain population groups and may therefore be associated with specific attitudes and myths. Hence, these factors should be considered when investigating influenza vaccine hesitancy [25]. The Theory of Planned Behavior provides a framework for considering psychological insights around vaccine hesitancy, as used for example by Schmid et al. [25]. They incorporated different clusters of determinants that influence vaccination intention and behavior. Therefore, determinants can be categorized into physical, contextual, sociodemographic, and psychological determinants to identify possible barriers to vaccine uptake.

Objectives
Among the large body of evidence and numerous systematic reviews on influenza vaccine hesitancy [25][26][27], only a small number focus on pregnant women [28][29][30]. To the best of our knowledge, there is no specific European perspective on the topic. Analyzing the phenomena from a European perspective might offer relevant and geographically specific insights into Page 3 of 12 Adeyanju et al. Eur J Med Res (2021) 26:116 vaccine hesitancy, as evidence suggests that it is particularly common in countries with well-established health systems [31]. As the Sage Working Group suggests, factors leading to low vaccine acceptance can help to partially explain low vaccination rates in countries where immunization is easily accessible for the population. In countries where access to healthcare and vaccination services is more limited, vaccine acceptance is probably not the main driving force behind low vaccination coverage [21]. It is therefore reasonable to assume that determinants of vaccination hesitancy and acceptance vary across countries and settings. Thus, the primary objective of the systematic review is to identify the individual determinants of influenza vaccine hesitancy among pregnant women in Europe. Based on the framework by Schmid et al. [25], the secondary objectives include the identification of specific factors that predict vaccine hesitancy, such as psychological, sociodemographic, physical, and contextual factors.

Eligibility criteria
The study characteristics are generally based on the Population/Inter vention/Comparator/Outcome (PICO) approach [32]. The population under review (P) was pregnant women in WHO European Region member countries. Instead of an intervention (I), we assessed the determinants or factors influencing the outcome. There was no comparator (C), and lastly, the determined outcome (O) was influenza-vaccine hesitancy. Characteristics used as criteria for study eligibility are listed in Table 1. The main criteria were studies that focused on seasonal influenza vaccination, pregnant women in European countries, publications between 2009 and 2019 inclusive, and empirical studies that were peer reviewed and in English language. All studies relating to pregnant women and seasonal influenza vaccination were central to the review inclusion guideline. Guidelines for each database were created to ensure a systematic and transparent search procedure. These guidelines included a direct link to the website of the database, an adapted search string considering specific features and operators for each database, and the use of the inclusion and exclusion criteria, for instance, with filters. The analysis followed the PRISMA approach (Fig. 1). After duplicates were removed from the 1591 eligible papers, 1536 remaining articles were first scanned by title and abstract. Then, full texts of the 19 remaining articles were retrieved and assessed against the priori exclusion criteria, and 11 were finally included ( Table 1; Fig. 1).

Data extraction
Eleven studies met the inclusion criteria. For the data extraction, an Excel sheet was prepared by EE, LK, and TR, consisting of descriptive study characteristics, methodological aspects, and results of the studies ( Table 3). The answer categories followed the theoretical framework discussed above. Determinants were considered important if the authors of the original papers listed them in their discussion of the results. The studies were distributed among EE, LK, TR, IS, and GCA to complete the Excel sheet.

Synthesis of results
All data extracted were analyzed and used to inform classification of all determinants of influenza vaccine hesitancy, to address the goal of the review (see Table 4).

Quality assessment and risk of bias
Each study was assessed for risk of bias. The grading of the quality of each study was based on the study design using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework to either downgrade or upgrade the quality [33,34].

Interrater reliability
To assess the interrater reliability, from the 1,591 initially identified studies, 10 studies were chosen randomly. Each author of this systematic review rated the studies independently and decided whether the study should be included or excluded or whether there were any insecurities regarding this decision. The results of the rating are presented in Table 7 (see Appendix 3). Inconsistencies were discussed altogether to assure agreement and understanding of the selection criteria.
The overall study interrater reliability Kappa coefficient was K = 0.93 (where 1.0 is a perfect score) and therefore justified the approach of the subsequent screening process, meaning each author received a defined number of studies to screen by title and abstract [35]. Figure 1 presents the PRISMA flow diagram with the process of the selection of papers based on the four different phases: Identification, Screening, Eligibility, and Including. After removing the duplicates (55), 1536 potential studies remained. The remaining studies were screened based on title and abstracts. To decide if a study would be included or excluded, predefined eligibility criteria were applied. The screening resulted in the exclusion of 1442 studies, and therefore 94 studies remained. In the next screening comprising 75 studies, reasons for exclusion included: non-Europe region, not peer reviewed, pandemic H1N1 studies, study being a systematic review, etc. For the remaining 19 studies, full-text articles were retrieved and again assessed against the inclusion and exclusion criteria. As a result, 8 studies were excluded, and 11 studies met the final criteria. These studies were included in the data extraction.

Study characteristics
Within the timeframe of 2009-2019, 9 of 11 included publications were published between 2015 and 2019, one manuscript was published in 2012, and one in 2014. There were no studies from Eastern Europe. Publications mostly came from Northern, Western and Southern European countries, including Germany, Italy, Spain, Switzerland, Ireland, England, France, and Greece. All the studies were published in medical or public health-related journals, suggesting a potential lack of insight from other disciplines such as psychology and health communication.
Ten of eleven studies used a cross-sectional nonexperimental design, and in one case, a longitudinal study was conducted. Most of the studies followed a quantitative approach using standardized questionnaires. There were large differences in sample sizes between the studies, ranging from 198-11,752 participants (median participants 309, interquartile range 264-934).

Psychological factors Influenza risk perception
Seven studies described how risk perception influences vaccine hesitancy [36][37][38][39][40][41][42]. A low-risk perception can result from the denial of the threats from an influenza infection, and the perception that the personal risk is low. In a study conducted by Vila-Candel et al. [41], 23% believed that they were not at risk of contracting influenza while being pregnant. Some women not only underestimated their personal risk of getting the flu, but also thought that the risks of adverse events from the vaccine were higher compared to the effects of an influenza infection [15]. In an Italian study, 48.3% of the women stated that getting vaccinated was not a priority for them [39].

Concerns about safety and risks of the vaccine
When it comes to influenza vaccination, many pregnant women had concerns about the safety of the vaccine.  These concerns are related to the health of the mother as well as the unborn child, as pregnant women also fear that the vaccine could harm their children. These concerns are reflected in reported feelings of mistrust and insecurity. Five of the 11 studies identified these safety concerns as the most important factors contributing to vaccine hesitancy [36-38, 42, 43]. For example, a German study found that 60.4% of expectant mothers believe that the vaccine is unsafe during pregnancy and therefore mistrust the vaccine [36]. In a qualitative study conducted in Ireland, pregnant women who were hesitant to get vaccinated stated that they were afraid of possible risks of the vaccination, although unable to name specific dangers [44]. This shows that negative attitudes toward vaccination can result from poor knowledge or misconceptions.

Anti-vaccination attitude
Vaccine hesitancy can also result from negative attitudes toward vaccination in general. Maurici et al. [39] found that 28.8% of their sample refused all kinds of vaccinations for themselves or their children. While some women are opposed to vaccines in general, others specifically refuse to get vaccinated during pregnancy [43]. Furthermore, some women are susceptible to conspiracy theories that influence their decision against vaccination. In an Italian study, 6% of the women stated that vaccination is a business model motivated by the Pharma company's desire for more profit [15].

Low vaccine effectiveness
There were also concerns associated with the effectiveness of the vaccination itself. Some women stated that the vaccine was not effective in preventing an influenza infection and therefore refused to get vaccinated [15,42,43].

Contextual factors Information and recommendations given by health care providers
We observed that barriers against vaccination during pregnancy on the contextual level are partly due to the lack of information and adequate recommendations by health care providers. As a result, a significant number of pregnant women do not know about the general influenza vaccine recommendation in pregnancy at all. Reasons for the lack of knowledge include that healthcare workers also lack knowledge around influenza vaccination, and that information about vaccine accessibility is not available [15,43]. A Swiss study found a lack of support or recommendations from health care professionals that did not reflect the Swiss local public health guidance (43%) [43]. In a study conducted by Maurici et al. [39], 22.4% of the women sampled reported that the vaccine was not directly offered to them by physicians. Additionally, some health care providers even recommended against uptake of the influenza vaccine [39], although there was no clear medical or public health reason to do so. The results show that not knowing about the recommendation to get vaccinated was a relevant factor. In a German study, 44.1% of the unvaccinated women were unaware of the official vaccination recommendation [37]. Tuells et al. [40] found that nearly 30% of pregnant women in Valencia, Spain, did not know about the recommendation to get vaccinated against influenza.

Physical factors Proximity of childbirth
One of the reasons for not getting vaccinated was proximity to childbirth. Even though influenza vaccination is recommended for women in their second or third trimester of pregnancy, some women fear that getting vaccinated then can be dangerous or that it is not necessary because childbirth is close [41]. An additional factor is multiparity, possibly resulting from experiences of not having been infected with influenza during prior pregnancies [45].

Prior influenza vaccination
Other reasons for refusal of vaccination included the individual's experience with previous influenza vaccination and other vaccines. The experience of other people within the individual's network who had bad experiences also impacts influenza vaccination during pregnancy [15,36].

Sociodemographic factors
Determinants for not getting vaccinated by sociodemographic status included being an ethnic minority, having a lower educational level, and being an immigrant or refugee [45].

Other factors
Other factors mentioned were the need for time to think about a decision, as well as the fear of needles and drug objections [15].

Quality assessment and risk of bias
To assess the quality of the included studies, an overall benchmark was made based on the study design; thereafter, the downgrade/upgrade framework was applied using GRADE indictors [34,46]. Factors that described the quality of the study were assessed. Attention was paid to factors resulting in selection or reporting biases as well as sample size. The final quality assessment  26:116 showed that six studies were of moderate quality and five were assumed to be of low quality (see Table 5). See Appendix 2 for definitions (High/Moderate/Very Low/ Low).

Discussion
This review summarized relevant determinants of influenza vaccine hesitancy that 11 qualitative and quantitative studies identified among pregnant women in Europe. The most frequently reported factors were psychological determinants, such as low risk perception, concerns about the risks and safety of the vaccine, poor knowledge, and anti-vaccine attitudes [36][37][38][39][40]42].
Misperceptions about the vaccine exist in part because there is a lack of knowledge. Pregnant women are insufficiently informed about the risks of an influenza infection [36,37,40,41,44], which is directly related to existing negative attitudes toward vaccination [36][37][38][39]43]. The lack of information or recommendations from health care providers is one of the factors that contributed to vaccine hesitancy [39,43,44].
To decrease vaccine hesitancy, it is essential to increase knowledge on several areas including-the seasonal influenza itself, vaccine safety and effectiveness, when flu shots are recommended, and risk perceptions of influenza among pregnant women in Europe. Therefore, the low risks associated with the vaccine (both for the mother and the unborn child) should be better communicated, along with increased awareness of the risks associated with an influenza infection. Primary caregivers play a crucial role in women's decisions to get vaccinated because they are in direct contact with expectant mothers and can therefore provide the appropriate education. Health care providers should openly engage in discussions with pregnant women about vaccination and emphasize the evidence base around safety and effectiveness [42]. Vila-Candel et al. [41] stress that a combination of information materials and interpersonal recommendations from doctors or health care providers is the best solution to increase vaccine uptake. One of the problems identified here is the overall consistency and lack of information and recommendations from health care workers to pregnant women about the vaccination. Hence, interventions aimed at decreasing vaccine hesitancy should incorporate increasing knowledge and confidence of healthcare workers on the safety and effectiveness of vaccines and provide respective information material. To improve confidence, policy-makers should focus on interventions capable of invoking positive attitude toward vaccines, i.e., addressing issues such as vaccine adverse events, fear of needles, and disinformation about vaccines [24].
Mistrust and misinformation can be spread by healthcare providers. Thus, programs that assist health care providers in improving their vaccine communication skills as well as educate them about evidence-based responses to the most frequent concerns of pregnant mothers are necessary [47,48]. The important role of healthcare providers in increasing vaccination demand needs to be adequately leveraged, because caregivers of infants are more likely to be nudged by physician recommendations or other trusted sources [49,50].
Vaccine risk communication plays an essential role in addressing the psychological antecedence of vaccination behavior, especially risk perception [51]. Several studies have demonstrated risk beliefs and anticipated concern about vaccine-preventable diseases to correlate reliably with getting vaccinated [48]. Hence, proper identification of the causes of low-risk perception is important to design appropriate strategies. Those strategies are already applied in research on other target groups, such as childhood vaccination, HPV in adolescents, and vaccination in the elderly. Effective strategies that could be tested are, among others, education of health care workers for patient communication, evaluated misinformation debunking [52], and extended knowledge about preventable sequelae [53]. Also, although vaccine mandate has generated controversy overtime, but have been effective intervention toward population behavior change in some settings; hence, a consideration would be advised, especially for countries with high influenza infection rate with corresponding low vaccination demand [54].
Although influenza vaccination uptake in pregnant women differs across regions (US: 20%; Asia: 9.4-37.8%; South America: 3-97%; Australia 27%) [55][56][57][58], the reasons for vaccine uptake seem similar: confidence in their safety and effectiveness [25] and risk-perceptions for diseases and vaccines [59] are globally important. Most of the studies, worldwide and in this review, found several reasons for vaccine hesitancy, but only a few used systematically validated multidimensional models such as the 5C model [23]. Besides Confidence and Complacency (lack of risk perceptions), this model also includes Constraints (perceived structural barriers), Calculation (the process of information search during the vaccination decision), and Collective Responsibility (the value of community immunity and motivation to protect vulnerable others through one's own vaccination). Explicitly, the last determinant could be vital for prospective mothers and should be explored in future research.
Hence, to achieve increased uptake and overcome the low demand for seasonal influenza vaccines among pregnant women in Europe, in line with this review's primary objective, a stronger focus must be directed at addressing the identified individual determinants of influenza vaccine hesitancy.

Limitations
This review has several limitations, including the quality of included studies. Majority of the studies assessed self-reported vaccination status. The quality of selfreported data can be limited due to social desirability and false statements; therefore, we cannot rule out that the results of the review were affected by reporting biases. The findings may have further been affected by selection bias. Within the studies, there was an underrepresentation of women with a migration status. Additionally, women with high educational levels and those who are generally more interested in health topics were overrepresented. Also, there was geographical bias: there were no studies from Eastern Europe, as most of the studies were conducted in Northern, Western or Southern European countries. Additionally, the restriction of the search strategy to only articles in the English language may have produced biased search results and affected the above because it excluded articles from journals in other languages. Therefore, all the above limitations indicate that more evidence is required around vaccine confidence in pregnant women from underrepresented regions and populations. We considered determinants where the authors of the included  26:116 studies listed them in the discussion of their manuscripts, thus our findings may be influenced by the authors own perceptions of important determinants. The systematic distribution of reasons for vaccination decisions identified here will allow interventions for pregnant women to be more targeted, and hopefully also more effective, in the future.

Conclusion
This review highlighted several determinants of vaccine hesitancy in populations of pregnant women in Europe. Perceptions around safety issues and adverse events were common. We conclude that the education of healthcare providers is crucial to give stronger recommendations and address concerns effectively. Further research should focus on marginalized population groups, such as women with a migration background or other groups who struggle to access healthcare. Among these groups, specific social or cultural determinants may be particularly relevant. This review contributes to further research and practical applications of findings to address influenza vaccine hesitancy among pregnant women in Europe.

Funding
Open Access funding enabled and organized by Projekt DEAL.

Availability of data and materials
The datasets generated and/or analyzed are available at OSF.