COVID-19 vaccine acceptance among pregnant women worldwide: A systematic review and meta-analysis

Background The COVID-19 pandemic has led to the death of many people worldwide. The World Health Organization (WHO) has declared vaccine resistance as one of the greatest health threats in the world even before the COVID-19 epidemic. The aim of this study was to evaluate the acceptance of COVID-19 vaccine in pregnant women. Method We performed this systematic review and meta-analysis in accordance with the PRISMA guidelines. We applied the standard search strategy to the PubMed/Medline, Web of Science (ISI), Scopus, Science Direct, Cochrane Library, EMBASE, and EBSCO databases, and the Google Scholar search engine. Heterogeneity between studies was relatively high and therefore meta-analyses were performed based on random effects model with 95% CI using STATA version 16. Results In 16 articles with a sample size of 19219 pregnant women, the acceptance of COVID-19 vaccine was estimated 53.46% (95%CI: 47.64%-59.24%). Subgroup analysis was performed based on continent (p = 0.796), data collection method (p = 0.450) and meta-regression based on the month of the study (P<0.001), and only meta-regression was significant based on the month of the study. The effect of some variables such as graviad (OR = 1.02 [95%CI: 0.90–1.16]), maternal age was (OR = 1.02 [95%CI: 0.93–1.11]) and history of influenza vaccination (OR = 0.87 [95%CI: 0.71–1.06]) on COVID-19 vaccine acceptance was evaluated, which was not significant. Conclusion The prevalence of COVID-19 vaccine acceptance in pregnant women was 53.46%, which was much lower than the general COVID-19 vaccination. Therefore, necessary interventions should be taken to increase the acceptance of the vaccine, address safety concerns and educate about it.


Conclusion
The prevalence of COVID-19 vaccine acceptance in pregnant women was 53.46%, which was much lower than the general COVID-19 vaccination. Therefore, necessary a1111111111 a1111111111 a1111111111 a1111111111 a1111111111 interventions should be taken to increase the acceptance of the vaccine, address safety concerns and educate about it.
we conducted a systematic review and meta-analysis to combine the findings from existing studies in this area and provide a clearer picture of its prevalence in the world [21].

Study protocol
Before beginning this study, in the assessment of protocol registry for systematic reviews, it was found that the review protocol was not recorded in any database. We performed this systematic review and meta-analysis in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines [22]. Each of the research stages, including search, selection of articles, data extraction, and qualitative evaluation of selected studies, was performed independently by at least two authors (M.A, R.R, and M.P) and the contradictions were resolved by consensus.

Search strategy
We did our initial literature search in October 2021. We applied the standard search strategy to the PubMed/Medline, Web of Science (ISI), Scopus, Science Direct, Cochrane Library, EMBASE, and EBSCO databases, and the Google Scholar search engine. We reviewed reference lists of identified articles to find other related articles. Searches were last updated in November 2021.
The search was performed using the following Mesh terms: "Coronavirus"

Inclusion and exclusion criteria
The included articles had the following inclusion criteria: English articles based on a cross-sectional design with short abstract that examined vaccine acceptance in pregnant women. Articles were excluded if: 1) they used a selective sampling (e.g., interventional trials after group allocation), 2) their samples included groups other than pregnant women, 3) they had sample size of � 50, 4) their subject was not related to our target subject, 5) they were duplicate studies, 6) they were case reports, review articles, congress, letters to the editor without quantitative data, and dissertations, 7) they had low quality in qualitative evaluation, and 8) they did not separate pregnant women from lactating women.

Article selection
Titles and abstracts of all identified reports were reviewed. The full text of the articles was then evaluated based on inclusion and exclusion criteria.

Data extraction
The following data were extracted from each article: First author, year of publication, month of study, study design, number of participants (total, based on pregnancy trimester, based on group, based on history of influenza vaccine injection, based on age [below and above 35 years]), Data collection tools, acceptance of COVID-19 vaccine (total, based on pregnancy trimester, based on history of influenza vaccine injection, based on age) and odds ratio (OR) and 95% confidence interval (CI) for variables.

Quality assessment
The adapted version of Newcastle-Ottawa Scale was used to assess the quality of nonrandomized studies [23]. The maximum attainable score was 9. Three categories were defined for the quality of articles: low quality (score less than 5), medium quality (score 6-7) and high score (score 8-9).

Statistical analysis
Heterogeneity between studies was relatively high and therefore meta-analyses were performed based on random effects model with 95% CI using STATA version 13. Heterogeneity was assessed using I 2 with thresholds � 25%, � 50% and � 75%, indicating low, medium and high heterogeneity, respectively [24]. We used the OR s index and 95% CI to show the effect of variables such as age, history of influenza vaccine and gravid on COVID-19 vaccine acceptance. Finally, we reported the results as OR and 95% CI. In studies that did not report OR s index and 95% CI, we obtained case and control cases based on the total sample size of each group as well as the rate of COVID-19 vaccine acceptance in each group. Sensitivity analysis examined whether prevalence estimates were influenced by study design. Publication bias was assessed using Begg's and Egger's tests [25,26]. P-value less than 0.05 were considered statistically significant.

Search results and features of articles
In the initial search, 2,324 articles on vaccine acceptance in the world were found. After reviewing the title and abstract, 29 articles were identified as relevant and after reviewing the full text, 13 articles were omitted due to lack of necessary criteria and finally 16 articles were entered into qualitative synthesis and among them, 16 eligible articles (related to acceptance of vaccine in pregnant women) entered the meta-analysis stage (Fig 1). Table 1 shows the specifications of each study.

Acceptance of COVID-19 vaccine and sensitivity analysis
In 16 articles with a sample size of 19219 pregnant women, the acceptance of COVID-19 vaccine was estimated at 53.46% (95% CI: 47.64-59.24) (Fig 2A). Furthermore, the sensitivity analysis with the omission of one study at a time showed that the results are still robust and the omission of one study does not affect the overall results ( Fig 2B).  64-59.24) and heterogeneity between subgroups was not significant (p = 0.796) (Fig 3A).

Effect of maternal age on COVID-19 vaccine acceptance
COVID-19 vaccine acceptance among pregnant women fewer than 35  Heterogeneity: I 2 = 0, P = 0.798), which indicates that the relationship between vaccine acceptance in pregnant women and the age of pregnant women is not significant (Fig 4C).

The effect of influenza vaccination history on COVID-19 vaccine acceptance
The prevalence of COVID-19 vaccine acceptance among pregnant women with a history of influenza vaccination was 61.13% (95% CI: 57.24-64.95) and without a history of influenza

Meta-regression between vaccine acceptance variable and month of studies
Significant heterogeneity of vaccine acceptance for the month of the study was detected in meta-regression (P<0.001) ( Table 2).

Publication bias
Egger's test has more power to detect publication bias and is close to one according to the results of Kendall correlation coefficient in Begg's test and is not statistically significant (p = 0.82), and is also insignificant in Egger's test (p = 0.888) and its confidence interval ranges from -8.67 to 7.58, and since it includes zero, it indicates that no publication bias has occurred (Fig 6).

Discussion
This study is the first systematic review and meta-analysis on COVID-19 vaccine acceptance in pregnant women worldwide. The total prevalence of COVID-19 vaccine acceptance in pregnant women was estimated at 53.4%, with the lowest and highest rates being 37% and 84.5%, respectively. To investigate the cause of heterogeneity between studies, subgroup analysis was performed based on continent, data collection method and meta-regression based on the month of the study, and only meta-regression was significant based on the month of the study. The effect of some variables such as gravid, maternal age and history of influenza vaccination on COVID-19 vaccine acceptance was evaluated, which was not significant. It was not possible to examine other causes, but it seems that the possible explanation for these differences may be differences in access to health care services and awareness about the severity of COVID-19. Widespread vaccination is the most promising strategy to end this global pandemic. COVID-19 vaccination started in February 2021 and the World Health Organization has approved more than three COVID-19 vaccines to reduce the incidence and potential threat of the disease [40][41][42][43]. Nevertheless, it is believed that the resistance of people, especially pregnant women, is high despite rapid preparation of the vaccine [44][45][46][47] and researchers attribute it to the extraordinary advances in the development of effective and safe vaccines against COVID-19 in a short time [48,49]. In a systematic review and meta-analysis, COVID-19 vaccine acceptance in the general population was over 70%, and gender, education level, history of influenza vaccination, and trust in government were strong predictors of COVID-19 vaccination [50] but our estimate in the general population was much lower. We also compared COVID-19 vaccine acceptance among pregnant women with previous infectious diseases such as the H1N1 flu pandemic; COVID-19 vaccine acceptance in this study was higher than H1N1 vaccine acceptance in 2009 (47%) among pregnant women in the United States [51]. Other systematic reviews on the acceptance of influenza and pertussis vaccines during pregnancy shows that concerns about vaccine safety are one of the most important factors influencing the decision to receive the recommended vaccines during pregnancy [19, [52][53][54][55]. Thus, resistance to COVID-19 vaccine may be a limiting factor in global efforts to control the present pandemic, and have a negative impact on health and socio-economic aspects of society [55]. A previous systematic review also found that women were less likely to be vaccinated during the global influenza pandemic in 2009 [56]. This may be due to the fact that men show more risky behaviors than women [57]. Based on the Model of Health Belief, anticipated benefits (people who want to get the vaccine see a lot of anticipated benefits in receiving the COVID-19 vaccine to protect themselves and other people), cues to action (noteworthy predictors which elevated the intention to COVID-19 vaccine were suggestions provided by the Ministry of Health and GP or conducting the vaccination at workplace), and anticipated severity (severity of disease shows that the people that want to receive the vaccine see themselves as a person who is at high risk of notable pain or experiencing side effects if they are infected with COVID-19, as compared to people that do not want to receive the vaccine) were the most important predictors of the intention to get COVID-19 vaccine [58,59]. Another reason for resistance to vaccine is the widespread anti-vaccination campaign in cyberspace. Johnson et al. argue that the internet has increased the audience of the anti-vaccine movement, and that it is possible that the explosive growth of anti-vaccination perspectives will hinder the development and acceptance of vaccines [60].
In the present study, the effect of some variables such as gravida, maternal age and history of influenza vaccine on COVID-19 vaccine was not significant. The results of a systematic review and meta-analysis demonstrated that high income, gender, marital status, influenza vaccine in the previous season, fear of COVID-19, confidence in the health system, higher education, chronic illness, and perceived risk are effective factors in COVID-19 vaccine acceptance [61]. The COVID-19 pandemic had great effects not only on vaccination against this sickness but also on readiness to get other vaccines, for instance against influenza. As a matter of fact, a huge anxiety for the upcoming winter is the combination of COVID-19 and influenza. Previous research has shown how an influenza pandemic can raise the acceptance of vaccination for seasonal influenza [62].
This study showed that sociodemographic variables have an effect on the rate of COVID-19 vaccine acceptance in Botswana. The older people (55 and older) had the highest acceptance rate for vaccine and this may be related to the fact that people in this age group pay attention to news provided by government sources, while younger groups often use social media and internet, which is full of unverified information and also the fact that this population has a higher risk of developing a severe case of the disease. On the contrary, a study in China demonstrated that middle-aged people (30-49 years) were more willing to receive the vaccine compared to other age groups. As authors mentioned, factors that influence willingness to receive the vaccine included paying much attention to the latest news related to the vaccine, among other factors [63].
Moreover, according to a systematic review and meta-analysis by Kilich et al., which examined factors influencing vaccination decisions among pregnant women, these women believe  that vaccination can cause birth defects, injuries, long-term effects and anxiety [46], and this has important implications for public health messages about COVID-19 vaccination during pregnancy [64].
The present study showed that vaccine acceptance among pregnant women has increased significantly over time, which may be due to communication strategies such as positive orientations for action, being encouraged by close and trusted people such as doctors and religious leaders, sharing personal experiences, and peer pressure [65]. It should also be noted that similar to the influenza vaccine, the definitive recommendation of obstetricians to pregnant women to inject the vaccine is likely to increase the acceptance of COVID-19 vaccine [66,67]. On the other hand, other evidences indicate that doctors' advice for vaccination is the most important factor in the mother's decision, regardless of geographical or social background. Furthermore, during the pandemic, pregnant women's anxiety about the health of the fetus and its health has a negative impact on their well-being. Numerous studies have also shown that health professionals, including midwives, can reduce the level of anxiety in pregnant women by supporting them [8,19,68].
Changes in acceptance levels among pregnant women during a pandemic disease may be influenced by socio-demographic factors such as age, gender, and income status, individual factors such as personal beliefs, political views, risk perception, and social or organizational factors such as social media [69]; many factors affecting COVID-19 vaccine acceptance, such as geographical or socio-economic factors, hardly change and preliminary studies have not examined such variables.
Systematic strategies should be implemented to improve the acceptance of the COVID-19 vaccine among pregnant women. Previous research has shown that several combination interventions, including training sessions, easy access to vaccines, and vaccination rewards, can increase influenza vaccine acceptance [70]. We suggest that better health education and public health messaging can be used to address pregnant women's concerns about fetal health and their own health. In addition, pregnant women should be informed about the benefits of protecting themselves, their family and friends after vaccination. We also recommend that national and individual interventions be performed to improve the COVID-19 vaccine acceptance among pregnant women in the future. At the national level, governments should instill public confidence in vaccines through scientific vaccine programs. In addition, governments need to be cautious and aware of potential anti-vaccine movements. In a part, it will be achieved by the integration of new emerging approaches and sciences to develop more reliable COVID-19 vaccine with minimum side effects in the future [71][72][73][74].

Limitations
One of the limitations of the present study is the lack of analysis in specific demographic subgroups due to the small number of articles.

Conclusion
The prevalence of COVID-19 vaccine acceptance in pregnant women was 53.46%, which was much lower than the general COVID-19 vaccination, but is consistent with the acceptance of other vaccines recommended in pregnancy such as influenza and tetanus, diphtheria and pertussis. Therefore, necessary interventions should be taken to increase the acceptance of the vaccine, address safety concerns and educate about it.