key: cord-1053868-e65r39k3 authors: Carbone, Luigi; Di Girolamo, Raffaella; Mappa, Ilenia; Saccone, Gabriele; Raffone, Antonio; Di Mascio, Daniele; De Vivo, Valentino; D'Antonio, Francesco; Guida, Maurizio; Rizzo, Giuseppe; Maria Maruotti, Giuseppe title: Worldwide beliefs among pregnant women on SARS-CoV-2 vaccine: a systematic review date: 2021-12-07 journal: Eur J Obstet Gynecol Reprod Biol DOI: 10.1016/j.ejogrb.2021.12.003 sha: 4bfe2b53a805d5f92fd1ff24129a120509dc945f doc_id: 1053868 cord_uid: e65r39k3 BACKGROUND: SARS-CoV-2 vaccine has been recommended to pregnant women, but survey studies showed contrasting findings worldwide in relation to the willingness to accept vaccination during pregnancy. OBJECTIVE: To evaluate the evidence from the literature regarding the acceptance rate of the SARS-CoV-2 vaccine in pregnant and breastfeeding women. Study design: We performed a systematic review on the main databases (MEDLINE (PubMed), Scopus, ISI Web of Science) searching for all the peer-reviewed survey studies analyzing the eventual acceptance rate of the SARS-CoV-2 vaccine among pregnant and breastfeeding women. To combine data meta-analyses of proportions and pooled proportions with their 95% confidence intervals (CI) were calculated. RESULTS: 15 studies including 25839 women were included in the analysis. The proportion of women actually willing to be vaccinated during pregnancy is 49.1% (95% CI, 42.3-56.0), and the proportion of breastfeeding women is 61.6% (95% CI, 50.0-75.0). CONCLUSION: The cumulative SARS-CoV-2 vaccine acceptance rate among pregnant women appear still low. Vaccinal campaign are urgently needed to drive more confidence into the vaccine to help reducing the spread of the infection and the possible consequences during pregnancy. It has been more than a year since SARS-CoV-2 pandemic was declared. At the time of writing more than 4 million and 400 thousand deaths have been registered worldwide. [1] Italy was the one of the first European countries to be severely hit by the spread of the pandemic. There, evidence and guidance on how to manage obstetrics and gynecology patients during this period have been soon released and taken as example by other nations [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] . Notably, pregnant women were soon considered a population at increased risk for complications and more severe COVID-19 course [16] [17] [18] [19] [20] [21] [22] . Very soon, it appeared as the vaccination could have been one of the most useful solutions to counteract the pandemic, but historically pregnant women have not been included into vaccine trials [23] , and therefore uncertainty about its safety in this specific population opened a debate on the need to administer SARS-CoV-2 vaccine during pregnancy [24] [25] [26] [27] [28] ; indeed, counseling becomes of striking value in such a context [29] [30] [31] [32] [33] . National and international societies endorsed this suggestion, initially considering the high-risk pregnancies and working as health practitioners as the main indications to the vaccine, as well as the need to include pregnant women into future vaccine trials, and then stating that pregnancy should not be considered a contraindication to the vaccine and that pregnant women are "de facto" a population at risk [34] [35] [36] [37] [38] [39] [40] [41] [42] . Preliminary data seem to reassure regarding safety issues and immunization properties of SARS-CoV-2 vaccines in pregnant women, demonstrating also that neonates born from vaccinated mothers possess antibodies against SARS-CoV-2 [43] [44] [45] . In this scenario, it is still unclear whether women are really likely to request vaccination during pregnancy. For this reason, we previously conducted two surveys in two Italian teaching hospitals to evaluate the willingness of women to undergo the SARS-CoV-2 vaccine, with contrasting findings [46, 47] . In light of the increasing number of surveys on the matter, the aim of this systematic review was to elucidate what pregnant women worldwide really think about the chance to receive the vaccine against COVID-19. We conducted a systematic search using the MEDLINE (PubMed), Scopus, ISI Web of Science databases to identify all relevant studies published before 22 August 2021. Combinations of the following keywords and MESH search terms were used: ("vaccine" OR "vaccination") AND ("SARS-CoV-2" OR "COVID-19" OR "coronavirus") AND ("pregnancy" OR "pregnant" OR "pregnant women" OR "during pregnancy" AND ("acceptance" OR "hesitancy" OR "belief" OR "perspectives" OR "willingness") AND ("survey"). Search strategy was limited to only English studies. The reference lists of relevant reviews and articles were also hand-searched to complement database search. We adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [48] , and provide its checklist (Supplementary material 1). Only studies reporting the willingness of pregnant women to receive anti-SARS-CoV-2 vaccine on a survey basis were included. We excluded studies on vaccines other than SARS-COV-2. We also excluded studies reporting the rate of currently SARS-CoV-2-vaccinated women in pregnancy. Two reviewers (LC, RDG) independently evaluated titles and abstracts. Duplications were removed using Endnote online software and also manually. Disagreements were resolved by discussion among authors, and if required, with the involvement of the most experienced authors (GR, GMM). Only studies published in peer-reviewed journals were evaluated. Data were extracted independently by two reviewers (RDG, VDV) using predefined data fields, and study quality indicators. In detail, we developed a data extraction sheet based on the Cochrane data extraction template for non RCTs (https://dplp.cochrane.org/data-extraction-forms). The risk of bias and quality assessment of the included studies were performed using the Quality Assessment Checklist for Survey Studies in Psychology (Q-SSP) [49] . This checklist is divided into 4 domains (Introduction: Rationale/Variables -4 items; Participants: Sampling/Recruitment -3 items; Data: Collection/Analyses/Measures/Results/Discussion -10 items; Ethics -3 items). Two authors (IM, GS) independently assessed the risk of bias for each study. If for more than 70% of items a YES response has been found, the study is considered of acceptable quality, otherwise questionable. The primary outcome was the evaluation of SARS-CoV-2 vaccine acceptance rate in pregnant or breastfeeding women. The main reasons declared as determinants for vaccine acceptance/refusal were also described. Prevalence of SARS-CoV-2 vaccine acceptance was calculated by the total number of women accepting to be vaccinated in that whole population group, then considering the number of women accepting to be vaccinated in pregnant and breastfeeding groups alone, respectively. Prevalence was calculated for each included study and as pooled estimate, and graphically reported on forest plots with 95% confidence interval (CI). Statistical heterogeneity among studies was assessed by the inconsistency index I 2 . Heterogeneity was categorized as: null for I 2 = 0%, minimal for I 2 < 25%, low for I 2 < 50%, moderate for I 2 < 75% and high for I 2 ≥ 75%. The association between the prevalence of socio-demographic and medical features and SARS-CoV-2 vaccine acceptance was assessed using odds ratio (OR) with 95% confidence interval (CI). In details, advanced maternal age, Caucasian ethnicity, medium-high education, occupation, health status features and trimesters of pregnancy were analyzed comparing with non-variables as reference groups. P value < 0.05 was considered significant. The random effect model of DerSimonian and Laird was adopted for all analyses. Egger's test was used to assess potential publication bias and funnel plots were created for visual inspection. Tests for funnel plot asymmetry were not used when the total number of publications included for each outcome was less than 10, as the tests lack power to detect real asymmetry in this case. The analysis was performed using Stats direct 3.0.171 (Stats Direct Ltd) and Revman 5.3 (The Nordic Cochrane Centre, The Cochrane Collaboration, 2014) statistical software. Initially, 232 articles were identified; of these, 84 articles were duplications and thus removed. The titles and abstracts of 148 articles were scrutinized and ultimately 32 were selected for full text retrieval and eligibility assessment. Finally, 15 articles [46, 47, [50] [51] [52] [53] [54] [55] [56] [57] [58] [59] [60] [61] [62] were included in the quantitative and qualitative analyses (Figure 1 ). Two of them were multicenter international surveys [50, 59] , two came from Italy [46, 47] , two from Ethiopia [53, 56] and three from USA [54, 57, 61] . In relation to the period of analysis, Ceulemans et al. [50] and were the first ones to ask for vaccine acceptance among pregnant women, followed by Skjefte et al. [59] , Mohan et al. [55] , Tao et al. [62] and Mappa et al. [47] , during a period in which there was still no vaccine or it was not yet widely proposed to pregnant women (Table 1 ). The study by Stukelberger et al. [60] is a part of Ceulemans et al. [50] , but it was included in the analysis since it was not possible to extract data for secondary analysis from Ceulemans et al. [50] ; however, in order not to duplicate the study population, we subtracted from the total cases of Ceulemans et al. [50] those of Stukelberger et al. [60] . When performing the quality assessment according to the Q-SSP checklist, it was decided to not take into consideration two items (n. 3 and n. 12). Item n. 3 is related to the definition of a proper hypothesis to guide the survey, while item n. 12 requests the use of validated instruments to perform the survey. In our opinion, given that the main aim of these surveys was to understand an epidemiological issue and not to prove some theory or hypothesis, and also just to know pregnant women's willingness to receive the SARS-CoV-2 vaccine (a simple and direct question, without the use of specific tools), this would have led to lower total scores since no studies but one clearly declared a hypothesis [52] , and only a study declared the use of a validated tool [55] . Finally, only 2 studies were considered of questionable quality (Table 2) . However, since the purpose of our study is to understand the worldwide attitude of pregnant women to receive the SARS-CoV-2 vaccine, we decided to include all of them into the systematic review. Overall, 25839 women have been included in the analysis. From the data reported by included studies, it appears that 50% of them (95% CI, 43.4-56.7) would accept the vaccine during pregnancy or breastfeeding (Table 3; Figure 2 ). When we analyzed pregnant women separately from breastfeeding women, it came out that the proportion of women actually willing to be vaccinated during pregnancy is 49.1% (95% CI, 42.3-56.0; Figure 3 ), but the proportion of breastfeeding women is higher, reaching the 61.6% (95% CI, 50.0-75.0; Figure 4) (Table 3) . Moreover, we observed increased acceptance rate in Caucasian women (OR 1.93, 95% CI 1.0-3.5) and women usually accepting influenza vaccine (also eventually when pregnant; OR 5.18, 2.6-10.1). No differences were noted in relation to advanced maternal age, civil status, education, occupation, trimester of pregnancy and other features (Table 4) . A potential publication bias could be found for the primary outcome (Egger's test: -6,762783, 95% Worldwide, the acceptance rate of the vaccination against SARS-CoV-2 is about 50% in pregnant women and 60% in breastfeeding women. This data show that vaccinal campaign should still be largely implemented to increase the proportion of women receiving the vaccine during pregnancy. Having received influenza vaccine is associated with an increased acceptance of anti-SARS-CoV-2 vaccine, demonstrating that people usually confident in vaccines do not avoid this one. Although not statistically significant, it appears that well-educated women would accept the vaccine compared with less educated women, as well as employed compared to unemployed, women with pre-existing disease or complications during pregnancy, and unmarried women compared to married ones. Since the launch of the vaccinal campaign against SARS-CoV-2, the issue of pregnant women has been raised by the scientific community and the most important Obstetrics and Gynecology societies released recommendations in favor of it, but on the basis of a free choice of the pregnant woman, given the lack of data. However, reports showed quite soon that the vaccines were able to induce a response in pregnant women [43] [44] , and that neither obvious safety issues were noticed in pregnant women and their fetuses or newborns [45] , nor a true change in pregnancy complications' rates [63] . Moreover, the vaccine during pregnancy has been shown to reduce the risk of SARS-CoV-2 infection [64] . Indeed, a retrospective analysis conducted in the United Kingdom showed that less than one third of women delivering between March and July 2021 received the vaccine against SARS-CoV-2, with a lower acceptance rate among younger women, non-white ethnicity, and lower socioeconomic background [65] . These data are consistent with the findings from our analysis and need a thorough attention, as pregnant women suffering from COVID-19 are at increased risk of severe course of the disease [66] . This is the first systematic review to evaluate the overall worldwide acceptance rate of SARS-CoV-2 vaccine among pregnant women. The review protocol was not registered a priori. Adherence to PRISMA guidelines and reporting of all peer-reviewed survey studies are among the strength of our analysis. Indeed, given that no specific tools or shared and uniform questionnaires have been distributed among the different populations, there is a wide heterogeneity of data both as evaluated and as reported, making it difficult to compare and unify the results. Furthermore, we did not plan any sensitivity analysis. In addition, having asked the willingness towards SARS-CoV-2 vaccination in different periods, before and during vaccines' distribution, could have provoked different reactions among respondents. A potential publication bias was found for the primary outcome, but not when only pregnant women were considered, excluding breastfeeding ones. Also, a selection bias may have skewed the results of many included surveys, due to the voluntary participation and the large inclusion and few exclusion criteria adopted by each study. Last but not least, we did not plan to perform an individual-patient-data meta-analysis asking raw data to authors of the included surveys, and therefore, an evaluation of potential confounders could not be performed. During pandemic and lockdown, it has been observed that the access to emergency units for obstetrical and gynecological issues was reduced compared to the previous year [67, 68] , mostly as a consequence of the anxiety to get the infection in public and crowded places [69] [70] [71] [72] . Currently, it seems that the anxiety of pregnant women is greater about receiving the vaccine than about contracting the infection, mainly in relation to unknown effects on the health of the fetuses and newborn as reported by various studies [46, 47, 52, 54, 56] . A recent study explored if the possibility of onsite vaccination against SARS-CoV-2 offered to a high-risk obstetric population would increase the uptake in pregnant women, with scarce results [73] , showing that vaccine hesitancy is the most important reason for refusal and not a limited vaccine access as claimed by Centers for Disease Control and Prevention (CDC) [74] . In this scenario, it is of paramount importance that governments adopt all the needed strategies to inform this subgroup of the population that the consequences of the disease may be significantly more severe than the potential and unproven consequences of the vaccine, which are causing pregnant women's avoidance. Furthermore, reporting of the acceptance/refusal of the vaccine against SARS-CoV-2 in all obstetrical and delivery settings will help to acquire more data on the safety of it, to be shared as soon as possible. Our systematic review showed that 49.1% of pregnant women and 61.6% of breastfeeding women would accept SARS-CoV-2 vaccination. These rates appear still too low given the high rate of complications associated with COVID-19 course during pregnancy. Therefore, different strategies with stronger and more informative messages regarding the pros and cons of getting vaccinated should be carried out, in order to reduce the spread of the infection. An online questionnaire on SurveyMonkey's platform was designed. The survey link was sent to participants by the research team, and the participants answered the questionnaire via their smartphones or tablets. The researchers stayed in the same room with participants to answer their questions or clarify unclear terminology. The survey had four components: 1) sociodemographic information; 2) maternal characteristics; 3) affected by COVID-19 pandemic; 4) willingness to receive and pay for COVID vaccine. Demographic information, maternal features and effect of COVID-19 epidemic during antenatal care were also collected. The primary outcomes acceptance to receive t COVID-19 vaccine, wi to pay for the vaccine a amount of money parti were willing to pay ("a WTP"). To measure th outcomes, we asked th following questions: "D want to get a COVID-1 vaccine?" and "Are yo pay for a COVID-19 v yourself and your hous members?" We asked t question because pregn women might perceive were not eligible for th vaccination but they w to pay for other family to be vaccinated. Those answered "No" were as provide their reasons. M pregnant women answe "Yes" were then asked amount of money they willing to pay for the C vaccination by asking " much do you want to p COVID vaccination?". Introduction Participants Data Ethics TOTAL Result Carbone et al., 2021 3/3 2/3 7/9 2/3 14/18 A Ceulemans et al., 2021 3/3 2/3 6/9 2/3 13/18 A Geoghegan et al., 2021 3/3 1/3 8/9 2/3 14/18 A Goncu Ayan et al., 2021 3/3 1/3 6/9 2/3 13/18 A Hailemariam et al., 2021 3/3 3/3 7/9 2/3 15/18 A Levy et al., 2021 3/3 3/3 7/9 2/3 15/18 A Mappa et al., 2021 3/3 2/3 7/9 2/3 14/18 A Mohan et al., 2021 3/3 2/3 7/9 2/3 14/18 A Mose et al., 2021 3/3 3/3 8/9 2/3 16/18 A Desai et al., 2021 3/3 1/3 5/9 1/3 10/18 Q Nguyen et al., 2021 3/3 2/3 8/9 2/3 15/18 A Skjefte et al., 2021 3/3 2/3 6/9 2/3 13/18 A Stuckelberger et al., 2021 3/3 2/3 7/9 2/3 14/18 A Sutton et al., 2021 3/3 2/3 6/9 2/3 13/18 A Tao et al., 2021 3/3 2/3 5/9 2/3 12/18 Q A, acceptable quality; Q, questionable quality. Pooled proportions (95% CI) for the main outcomes observed in the present systematic review. 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To combine data meta-analyses of proportions and pooled proportions with their 95% confidence intervals (CI) were calculated. To explore the determinant factors influencing vaccine acceptance rate, different anamnestic features between pregnant or breastfeeding women accepting SARS-CoV-2 vaccine and women refusing it were analyzed and the results were Results: 15 studies including 25839 women were included in the analysis. The proportion of women actually willing to be Conclusion: The cumulative SARS-CoV-2 vaccine acceptance rate among pregnant women appear still low. Vaccinal campaign are urgently needed to drive more confidence into the vaccine to help reducing the spread of the infection and the possible consequences during pregnancy. Keywords: SARS-CoV-2, COVID-19 in pregnancy, vaccine, prevention Conflicts of interests: The authors declare that they have no conflict of interest Acknowledgements: none. ☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.☐The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Authors' contributions: All authors contributed to the study. All authors read and approved the final manuscript.