key: cord-0738596-ohlxjhjf
authors: Galanis, P. A.; Vraka, I.; Siskou, O.; Konstantakopoulou, O.; Katsiroumpa, A.; Kaitelidou, D.
title: Uptake of COVID-19 vaccines among pregnant women: a systematic review and meta-analysis
date: 2022-04-01
journal: nan
DOI: 10.1101/2022.04.01.22273296
sha: d16745318e11123a5e01e743e47f3143be530c64
doc_id: 738596
cord_uid: ohlxjhjf

Background: Mass vaccination against the COVID-19 is essential to control the pandemic. COVID-19 vaccines are recommended now during pregnancy to prevent adverse outcomes. Objective: To evaluate the evidence from the literature regarding the uptake of COVID-19 vaccination among pregnant women. Methods: We conducted a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. We searched PubMed, Medline, Scopus, ProQuest, Web of Science, CINAHL, and a pre-print service (medRxiv) from inception to March 23, 2022. We included quantitative studies reporting COVID-19 vaccination uptake among pregnant women, studies that examine predictors of COVID-19 vaccination uptake and studies that examine reasons for decline of vaccination. We performed meta-analysis to estimate the overall proportion of vaccinated pregnant women against the COVID-19. Results: We found 11 studies including 703,004 pregnant women. The overall proportion of vaccinated pregnant women against the COVID-19 was 27.5% (95% CI: 18.8-37.0%). The pooled proportion for studies that were conducted in Israel was higher than the proportion for studies that were conducted in USA and other countries. Predictors of COVID-19 vaccination uptake were older age, ethnicity, race, trust in COVID-19 vaccines, and fear of COVID-19 during pregnancy. On the other hand, mistrust in the government, diagnosis with COVID-19 during pregnancy, and worry about the safety and the side effects of the COVID-19 vaccines were reasons for decline of vaccination. Conclusions: The global COVID-19 vaccination prevalence in pregnant women is low. There is a large gap in the literature on the factors influencing the decision of pregnant women to be vaccinated against the COVID-19. Targeted information campaigns are essential to improve trust and build vaccine literacy among pregnant women. Given the ongoing high case rates and the known increased risks of COVID-19 in pregnant women, our findings could help policy makers to improve the acceptance rate of COVID-19 vaccines in pregnant women especially in vulnerable subgroups.

Pregnant women with COVID-19 are at increased risk for severe illness, adverse birth outcomes and mortality. In particular, hospitalized pregnant women with symptomatic COVID-19 were more likely to have iatrogenic preterm births, to be admitted to intensive care and to need invasive ventilation than pregnant women without COVID-19 (Khalil et al., 2020; Lokken et al., 2021; Vousden et al., 2021; Woodworth et al., 2020; Zambrano et al., 2020) . For instance, in United Kingdom, between February and September 2021, 98% of the 1714 pregnant women admitted to hospital with symptomatic COVID-19 were unvaccinated (Iacobucci, 2021) , while no fully vaccinated pregnant women were admitted to intensive care with COVID-19 (UK Health Security Agency, 2021).

Pregnant women were not included in the initial randomized controlled trials testing COVID-19 vaccines, leading to the lack of data on vaccination safety and pregnancy outcomes compared to the general population (Pogue et al., 2020; Polack et al., 2020) .

However, two systematic reviews found that reactogenicity is similar in pregnant women and the general population, abortion rate is similar in vaccinated and nonvaccinated pregnant women studied before the COVID-19 pandemic, and anti-SARS-CoV-2 immunoglobulins are transferred through the placenta and the breast milk to the newborns, providing protective immunity (Falsaperla et al., 2021; Fu et al., 2022) .

Moreover, according to a systematic review with studies in the USA, pregnant women have the same risk of adverse pregnancy or neonatal outcomes with unvaccinated pregnant women (Rawal et al., 2022) . In general, COVID-19 vaccination produces immune responses during pregnancy and does not cause major negative outcomes.

Thus, several organizations, such as the Center for Disease Control, the Society for

Gynecologists recommend now that pregnant women should receive vaccines to prevent severe maternal morbidity and adverse birth outcomes (American College of Obstetricians and Gynecologist (ACOG), 2021; Centers for Disease Control and Prevention, 2021; Rasmussen & Jamieson, 2021) .

To the best of our knowledge, none of the systematic reviews provided evidence about the uptake of COVID-19 vaccines among pregnant women. Therefore, the aim of this systematic review was to identify what is known about the uptake of COVID-. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 1, 2022. ; https://doi.org/10.1101/2022.04.01.22273296 doi: medRxiv preprint 5 19 vaccines among pregnant women. Also, we investigated predictors of COVID-19 vaccination uptake among pregnant women and reasons for decline of vaccination.

We conducted a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines (Moher et al., 2009) .

We searched PubMed, Medline, Scopus, ProQuest, Web of Science, CINAHL, and a pre-print service (medRxiv) from inception to March 23, 2022. We used the following strategy in all fields: ((pregnan*) AND (vaccin*)) AND (covid-19) .

Three independent authors applied a three-step procedure for studies selection: removal of duplicates, screening of title and abstract, and reading of full-text articles.

In particular, two independent authors performed study selection and a third, senior author resolved the differences. Moreover, we examined reference lists of all relevant articles. The population of interest was pregnant women and the outcome was the COVID-19 vaccination uptake. Thus, we included quantitative studies reporting COVID-19 vaccination uptake among pregnant women, studies that examine predictors of COVID-19 vaccination uptake and studies that examine reasons for decline of vaccination. We included any paper with information about COVIDvaccination uptake in pregnant women independently the semester of pregnancy.

Studies published in English were eligible to be included. We excluded reviews, protocols, posters, case reports, statements, letters to the Editor, expert opinions, and editorials.

Three reviewers independently extracted the following data from the studies: authors, country, data collection time, sample size, age of pregnant women, study design, . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted April 1, 2022. ; https://doi.org/10.1101 https://doi.org/10. /2022 sampling method, response rate, percentage of COVID-19 vaccination uptake among pregnant women, predictors of COVID-19 vaccination uptake, reasons for decline of COVID-19 vaccination, and type of publication (journal or pre-print service).

We used the Joanna Briggs Institute critical appraisal tool to assess risk of bias of studies (Santos et al., 2018) . The response options are the following: Yes when the criteria are clearly identifiable through the article; No when the criteria are not identifiable; Unclear when the criteria are not clearly identified in the article; and Not applicable when the criteria do not apply to the study. The risk of bias is ranked as "low", "moderate", and "high" according to the percentage of "Yes" responses.

The outcome variable was the COVID-19 vaccination uptake among pregnant women. We divided the number of vaccinated pregnant women by the total number of pregnant women to calculate the proportion of pregnant women that took a COVID-19 vaccine. Then, we transformed this proportion with the Freeman-Tukey Double Arcsine method and we calculated the respective 95% confidence intervals (CI) for the proportions (Barendregt et al., 2013) . We used I 2 and the Hedges Q statistics to assess heterogeneity between studies. I 2 value higher than 75% indicates high heterogeneity, and a p-value<0.1 for the Hedges Q statistic indicates statistically significant heterogeneity (Higgins, 2003) . Heterogeneity between results was very high; thus we applied a random effect model to estimate pooled proportion of COVID-19 vaccinated pregnant women (Higgins, 2003) . We considered country, data collection time, sample size, age of pregnant women, study design, sampling method, response rate, risk of bias, and publication type (journal or pre-print service) as prespecified sources of heterogeneity. Due to the scarce data and the high heterogeneity in the results in some variables (e.g. age of pregnant women), we decided to perform subgroup analysis for risk of bias, study design, and the country that studies were conducted. Also, we performed meta-regression analysis using sample size and data collection time as the independent variables. We treated data collection time as a continuous variable giving the number 1 for studies that were conducted in December 2020, the number 2 for studies that were conducted in January 2020, etc. We performed a leave-one-out sensitivity analysis to estimate the influence of each study . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted April 1, 2022. ; https://doi.org/10.1101 https://doi.org/10. /2022 on the overall proportion of COVID-19 vaccinated pregnant women. We used the funnel plot and the Egger's test to assess the publication bias. Regarding the Egger's test, a P-value<0.05 indicating publication bias (Egger et al., 1997) . We did not perform meta-analysis for the factors that affect pregnant women' decision to be vaccinated against the COVID-19 since the data was very scarce. We used OpenMeta[Analyst] for the meta-analysis (Wallace et al., 2009) . Table 1 . Four studies were conducted in Israel (Goldshtein et al., 2022; Rottenstreich et al., 2022; Taubman -Ben Ari et al., 2022; Wainstock et al., 2021) , three studies in the USA (Lipkind et al., 2022; Razzaghi et al., 2021; Siegel et al., 2021) , two studies in United Kingdom (Blakeway et al., 2022; UK Health Security Agency, 2021) , one study in Japan (Hosokawa et al., 2022) , and one study in Scotland (Stock et al., 2022) . Data collection time among studies ranged from December 2020 (Lipkind et al., 2022 Razzaghi et al., 2021) to October 2021 (Stock et al., 2022 . Sample size ranged from 473 (Siegel et al., 2021) to 355,299 pregnant women (UK Health Security Agency, 2021). Eight studies were cohort studies (Blakeway et al., 2022; Goldshtein et al., 2022; Lipkind et al., 2022; Razzaghi et al., 2021; Rottenstreich et al., 2022; Stock et al., 2022; UK Health Security Agency, 2021; Wainstock et al., 2021) and three studies were cross-sectional (Hosokawa et al., 2022; Siegel et al., 2021; Taubman -Ben Ari et al., 2022) . Two studies used national data (Stock et al., 2022; UK Health Security Agency, 2021) , . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 1, 2022. ; https://doi.org/10.1101/2022.04.01.22273296 doi: medRxiv preprint three studies used a convenience sample (Hosokawa et al., 2022; Siegel et al., 2021; Taubman -Ben Ari et al., 2022) , and six studies did not report the sampling method (Blakeway et al., 2022; Goldshtein et al., 2022; Lipkind et al., 2022; Razzaghi et al., 2021; Rottenstreich et al., 2022; Wainstock et al., 2021) . Ten studies were published in peer-reviewed journals (Blakeway et al., 2022; Goldshtein et al., 2022; Hosokawa et al., 2022; Lipkind et al., 2022; Razzaghi et al., 2021; Rottenstreich et al., 2022; Stock et al., 2022; Taubman -Ben Ari et al., 2022; UK Health Security Agency, 2021; Wainstock et al., 2021) and one study in a pre-print service (Siegel et al., 2021) . Table 1 about here (Goldshtein et al., 2022; Lipkind et al., 2022; Rottenstreich et al., 2022; Stock et al., 2022; Wainstock et al., 2021 ) and low in three cohort studies (Blakeway et al., 2022; Razzaghi et al., 2021;  UK Health Security Agency, 2021). The most common bias in cohort studies was the absence of strategies to address incomplete follow up. Also, only one cohort study (Blakeway et al., 2022) used multivariate analysis to eliminate confounding.

Regarding cross-sectional studies, risk of bias was low in two studies (Hosokawa et al., 2022; Siegel et al., 2021) and moderate in one study (Taubman -Ben Ari et al., 2022) .

The overall proportion of vaccinated pregnant women against the COVID-19 was 27.5% (95% CI: 18.8-37.0%) (Figure 2 ). COVID-19 vaccination uptake among pregnant women ranged from 7.0% (95% CI: 6.9-7.1%) (UK Health Security Agency, 2021) to 68.7% (95% CI: 68.2-69.3%) (Goldshtein et al., 2022) . The heterogeneity between results was very high (I 2 =99.98%, p-value for the Hedges Q statistic<0.001).

A leave-one-out sensitivity analysis showed that no single study had a disproportional effect on the overall proportion, which varied between 23.5% (95% CI: 18.5-28.8%), . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 1, 2022. vaccination uptake among pregnant women was independent sample size (p=0.07) and data collection time (p=0.34).

Predictors of COVID-19 vaccination uptake among pregnant women and reasons for decline of vaccination are shown in Table 2 . Five studies investigated factors that affect pregnant women' decision to vaccinate against the COVID-19 (Blakeway et al., 2022; Hosokawa et al., 2022; Razzaghi et al., 2021; Siegel et al., 2021; UK Health Security Agency, 2021) . Three studies (Blakeway et al., 2022; Hosokawa et al., 2022; Siegel et al., 2021) used multivariate analysis to eliminate confounding, and two studies (Razzaghi et al., 2021 ; UK Health Security Agency, 2021) used descriptive statistics to present relationships between factors and COVID-19 vaccination uptake among pregnant women.

Two studies (Razzaghi et al., 2021 ; UK Health Security Agency, 2021) found that increased age was related with increased probability of COVID-19 vaccination uptake. Also, two studies (Razzaghi et al., 2021; UK Health Security Agency, 2021) found that White women and Asian women were vaccinated for COVID-19 more . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 1, 2022. ; 1 0 often than Black women and Hispanic women, while one study (UK Health Security Agency, 2021) found that vaccination was highest among women lived in least deprived areas and lowest among women lived in most deprived areas. Trust in COVID-19 vaccines, fear of COVID-19 during pregnancy and pregestational diabetes mellitus were predictors of COVID-19 vaccination uptake among pregnant women (Blakeway et al., 2022; Siegel et al., 2021) , while mistrust in the government, diagnosis with COVID-19 during pregnancy, and worry about the safety and the side effects of the COVID-19 vaccines were reasons for decline of vaccination (Hosokawa et al., 2022; Siegel et al., 2021) .

To the best of our knowledge, this is the first systematic review and meta-analysis that estimates the COVID-19 vaccination uptake among pregnant women and examines predictors of uptake and reasons for decline of vaccination. Eleven studies met our inclusion and exclusion criteria and we found that worldwide the uptake prevalence of the vaccination against the COVID-19 is 27.5% in pregnant women. This prevalence is considerably lower than the prevalence of pregnant women who expressed the intention to be vaccinated against the COVID-19. In particular, two meta-analyses (Carbone et al., 2022; Nikpour et al., 2022) found that the global prevalence of pregnant women accepting the COVID-19 is about 49-54%. Moreover, in a survey with 5,282 pregnant women from 16 countries, 52% of them indicated an intention to receive a COVID-19 vaccine (Skjefte et al., 2021).

Our review provides evidence of low levels of vaccine uptake in pregnant women.

The situation is getting worse since the proportion of pregnant women that actually take a COVID-19 vaccine is even lower in studies with low risk of bias and in the cohort studies. Thus, our estimation is probably an overestimation of the true global prevalence of pregnant women accepting the COVID-19 since the quality and the type of study seems to have a significant impact on the results of the studies. Moreover, we found that the vaccination rate is much higher in Israel than in other countries. This great difference may be due to the fact that Israel was one of the first countries that . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Interestingly, the vaccine uptake rate did not improve even when data from studies have begun to demonstrate the safety and efficacy of COVID-19 vaccines in pregnant women (Shimabukuro et al., 2021; Trostle et al., 2021) . However, the number of studies carried out since the publication of this information is very small and not sufficient to draw firm conclusions.

Five out of the 11 studies in this review examined factors that are associated with COVID-19 vaccine uptake in pregnant women. Older age of pregnant women is associated with vaccine uptake. This finding is confirmed by studies that investigated the intention of pregnant women to accept a COVID-19 vaccine. Several studies found that older age is related with higher acceptance of COVID-19 vaccines (Levy et al., 2021; Skjefte et al., 2021; Stuckelberger et al., 2021) . This finding is plausible since it is well known that pregnancy at advanced maternal age is a risk factor for adverse outcomes, such as higher rate of neonatal intensive care unit admission, preterm deliveries, spontaneous miscarriage, pre-eclampsia, low birthweight babies, preterm labor, worse Apgar scores, and cesarean deliveries (Glick et al., 2021; Pinheiro et al., 2019) . Moreover, older age is associated with higher COVID-19 mortality (Mehraeen et al., 2020; Sepandi et al., 2020; Yanez et al., 2020) . It is probable that older pregnant women confront COVID-19 with more fear resulting on a higher COVID-19 vaccination uptake (Skjefte et al., 2021; Tao et al., 2021) .

According to our review, COVID-19 vaccination rate was highest among White and Asian pregnant women, and lowest among Black and Hispanic pregnant women.

Hispanic ethnicity and Black or African American race is related with refusal of COVID-19 vaccination in pregnancy (Battarbee et al., 2022; Huddleston et al., 2022; Levy et al., 2021; Razzaghi et al., 2021; Townsel et al., 2021) . A systematic review found that white individuals have a higher rate of COVID-19 vaccine uptake than black individuals (Galanis et al., 2021) . Also, similar racial and ethnic disparities have been reported for the acceptance of other recommended vaccinates in pregnancy, such . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 1, 2022. ; https://doi.org/10.1101/2022.04.01.22273296 doi: medRxiv preprint 1 2 as tetanus, influenza and acellular pertussis, with Black and Hispanic women have the lowest vaccination coverage (Razzaghi et al., 2020) . 

Our review and meta-analysis is subject to some limitations. Data taken from databases may not provide the most up-to-date evidence regarding COVID-19 vaccination uptake among pregnant women due to publication process. This limitation is of particular importance in the present review, as the data on vaccination of pregnant women are constantly increasing. Moreover, data collection time among studies ranged from December 2020 to October 2021, while evidence regarding safety and efficacy of COVID-19 vaccines in pregnant women is increasing significantly on an ongoing basis. Thus, we should interpret the results of this review with care since they may not directly predict future behavior of pregnant women. Additionally, we could not generalize our results since the number of relevant studies included in this review is low and these studies were conducted only in five countries.

Only five studies examined the factors that affect pregnant women decision to take a COVID-19 vaccine. Moreover, these studies investigated mainly demographic factors, e.g. age, ethnicity, race, etc. For instance, psychological factors and social media variables that could affect women' attitudes towards COVID-19 vaccination uptake are not investigated so far.

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 1, 2022. ;

Regarding meta-analysis, we applied a random effects model and we performed subgroup and meta-regression analysis to overcome the high level of the statistical heterogeneity. However limited number of studies, high heterogeneity in the results in some variables, and scarce data forced us to perform subgroup and meta-regression analysis for a few variables. At least, the leave-one-out sensitivity analysis confirmed the robustness of our results.

We found that the global COVID-19 vaccination prevalence in pregnant women is low. Given the ongoing high case rates and the known increased risks of COVID-19 in pregnant women, high vaccination rate in this vulnerable population is paramount to reduce adverse outcomes, morbidity and mortality. An understanding of the factors related with increased COVID-19 vaccine uptake in pregnant women is essential to improve trust and build vaccine literacy. Moreover, there is a need for different public health messages and targeted information campaigns to improve COVID-19 vaccination acceptance especially in minority groups. Policy makers and healthcare professionals should reduce the fear and anxiety of pregnant women regarding the safety and efficacy of the COVID-19 vaccines. Education about the COVID-19 vaccines with strong and more informative messages is important to increase the acceptance of a COVID-19 vaccine in pregnant women.

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 1, 2022. is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 1, 2022. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 1, 2022. ; (2021). Disease severity, pregnancy outcomes, and maternal deaths among pregnant . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 1, 2022. ; . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 1, 2022. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 1, 2022. is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 1, 2022. is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 1, 2022. .

It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 1, 2022. 

Items for Systematic Reviews and Meta-Analysis.

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted April 1, 2022. ; https://doi.org/10.1101/2022.04.01.22273296 doi: medRxiv preprint

American College of Obstetricians and Gynecologist (ACOG). (2021). ACOG and SMFM Recommend COVID-19 Vaccination for Pregnant Individuals

Metaanalysis of prevalence

Attitudes Toward COVID-19 Illness and COVID-19 Vaccination among Pregnant Women: A Cross-Sectional Multicenter Study during

COVID-19 vaccination during pregnancy: Coverage and safety

COVID-19 vaccination in pregnancy: Early experience from a single institution

COVID-19 vaccine surveillance report week 47

The incidence, characteristics and outcomes of pregnant women hospitalized with symptomatic and asymptomatic SARS-CoV-2 infection in the UK from

Prenatal maternal COVID-19 vaccination and pregnancy outcomes

Meta-Analyst: Software for meta-analysis of binary, continuous and diagnostic data

Birth and Infant Outcomes Following Laboratory-Confirmed SARS-CoV-2

Infection in Pregnancy-SET-NET, 16 Jurisdictions

CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity

is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 1, 2022. is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 1, 2022. is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 1, 2022. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 1, 2022. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)The copyright holder for this preprint this version posted April 1, 2022. ; https://doi.org/10.1101/2022.04.01.22273296 doi: medRxiv preprint