Effectiveness and Safety of COVID-19 Vaccine among Pregnant Women in Real-World Studies: A Systematic Review and Meta-Analysis

We aimed to assess the effectiveness and safety of coronavirus disease 2019 (COVID-19) vaccines for pregnant women in real-world studies. We searched for observational studies about the effectiveness and safety of COVID-19 vaccines among vaccinated pregnant women from inception to 6 November 2021. A total of 6 studies were included. We found that vaccination prevented pregnant women from SARS-CoV-2 infection (OR = 0.50, 95% CI, 0.35–0.79) and COVID-19-related hospitalization (OR = 0.50, 95% CI, 0.31–0.82). Messenger-RNA vaccines could reduce the risk of infection in pregnant women (OR = 0.13, 95% CI, 0.03–0.57). No adverse events of COVID-19 vaccination were found on pregnant, fetal, or neonatal outcomes. Our analysis confirmed the effectiveness and safety of COVID-19 vaccines for pregnant women. Policy makers should formulate targeted strategies to improve vaccine coverage in pregnant women.


Introduction
Coronavirus disease 2019 , caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread rapidly worldwide, with a significant increase in the cases of infection. As of 22 December 2021, there have been more than 274.6 million confirmed cases of COVID-19 globally, including more than 5.4 million deaths, reported by WHO [1]. Among these cases of infection and death, many were pregnant women. According to Centers for Disease Control and Prevention (CDC), there were 152,682 total cases of pregnant women with COVID-19, and 253 deaths in the United States, from 22 January 2020 to 20 December 2021 [2]. Statistics from CDC also showed that compared to nonpregnant women, pregnant women are at an increased risk for severe outcomes from COVID-19, such as hospitalization, intensive care or requiring a ventilator or special equipment to help them breathe [3]. In addition, there is also an increased risk for preterm birth and stillbirth and a possible risk of developing other pregnancy complications among pregnant women infected with SARS-CoV-2 [4]. Thus, it is important to devote attention to the vaccination of pregnant women to protect them from SARS-CoV-2 infection and reduce their risk of severe illness during pregnancy.
In addition, some studies showed that some anti-SARS-CoV-2 immunoglobulin can be transferred to the newborn through placenta and breastmilk, so as to provide humoral immunity [8,10]. On the other hand, several studies also reported that COVID-19 vaccination during pregnancy did not lead to significant vaccine-related adverse events or adverse outcomes or obstetric, fetal, or neonatal adverse outcomes [8][9][10][11]13]. CDC confirmed that the benefits of receiving a COVID-19 vaccine outweigh any known or potential risks of vaccination during pregnancy and suggests people who are pregnant, breastfeeding, currently trying to get pregnant, or might become pregnant in the future undergo COVID-19 vaccination [13].
In terms of the COVID-19 vaccination strategy, WHO suggests vaccination for pregnant women only when the benefits of vaccination outweigh the potential risks [14][15][16][17][18][19][20], but current recommendations for pregnant women to be vaccinated against COVID-19 vary from country to country. For example, except for the US, Europe and the UK encourage pregnant women to be vaccinated against COVID-19 [21,22] but China does not [23]. Due to ethical and other reasons, evidence from randomized controlled trials (RCTs) on the safety and effectiveness of COVID-19 vaccines for pregnant women are scarce. Therefore, the real-world study (RWS) of the safety and effectiveness of COVID-19 vaccines for pregnant women can provide additional evidence. However, the results of several studies of pregnant women in the real world were inconsistent [8,24]. Furthermore, previous studies have found that compared with the general population, there is a higher rate of vaccination hesitation among pregnant women, mainly due to the concerns about the safety and effectiveness of vaccines for both mothers and infants [25,26]. Hence, it is urgent to carry out a systematic study and meta-analysis on the safety and effectiveness of COVID-19 vaccination for pregnant women, which would provide more scientific evidence for the protection of pregnant women, a population vulnerable during the COVID-19 pandemic.
In this systematic review and meta-analysis, we aimed to evaluate the effectiveness and safety of COVID-19 vaccines among pregnant women in the real world to provide evidence for an improved vaccine strategy for pregnant women during the COVID-19 pandemic.

Search Strategy and Selection Criteria
We searched published studies, without language restrictions, from inception to 6 November 2021 in PubMed, Embase, and ScienceDirect using the following search terms: (pregnant OR pregnancy) AND (effectiveness OR safety) AND (COVID-19 OR coronavirus OR SARS-CoV-2) AND (vaccine OR vaccination). We used EndNoteX8.2 (Thomson Research Soft, Stanford, USA) to manage records, screen, and exclude duplicates. This study was strictly performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). This study was registered on PROSPERO (CRD42021289924).
We included observational studies that examined the effectiveness and safety of COVID-19 vaccines among the pregnant women vaccinated with COVID-19 vaccine. The following studies were excluded: (1) irrelevant to the subject of the meta-analysis, such as studies that did not use COVID-19 vaccination as the exposure; (2) insufficient data to calculate the rate and outcomes for the effectiveness and safety of COVID-19 vaccines among the pregnant women; (3) duplicate studies or overlapping participants; (4) reviews, editorials, conference papers, case reports or animal experiments; and (5) studies that did not clarify the identification of COVID-19.
Studies were independently identified by two investigators (DJ and MYR) following the above criteria, and discrepancies were solved by consensus or with a third investigator (LQ).

Data Extraction
The primary outcome was the effectiveness of COVID-19 vaccines (including the BNT162b2 vaccine, mRNA-1273 vaccine, and adenovirus vector vaccine). The following data were extracted from the selected studies: (1) basic information of the studies, including first author, publication year, and study design; (2) characteristics of the study population, including sample sizes, age groups, trimester of pregnancy, and locations; (3) types of COVID-19 vaccines, the number of doses, the efficacy of vaccine; (4) outcomes for the effectiveness of COVID-19 vaccines: the number of SARS-CoV-2 infections, hospitalization for COVID-19, admission to the ICU for COVID-19, COVID-19-related death; and (5) outcomes for the safety of COVID-19 vaccines: the number and types of adverse pregnant, fetal or neonatal outcomes after vaccination.
Data extraction was conducted by two investigators (DJ and MYR) independently following the criteria above, and discrepancies were solved by consensus or with a third investigator (LQ).

Quality Assessment
We evaluated the risk of bias using the Newcastle-Ottawa quality assessment scale for cohort studies. Cohort studies were classified as having low (≥7 stars), moderate (5-6 stars), and high risk of bias (≤4 stars) with an overall quality score of 9 stars.
Quality assessment was independently conducted by two investigators (DJ and MYR), and discrepancies were solved by consensus or with a third investigator (LQ).

Data Synthesis and Statistical Analysis
We performed a meta-analysis with pooled data from cohort studies and assessed the effectiveness and safety of COVID-19 vaccines by clinical outcomes (incidence of the SARS-CoV-2 infection, COVID-19-related hospitalization, severe illness, admission to the ICU, death, and adverse pregnant, fetal, or neonatal outcomes after vaccination). Random-effects or fixed-effects models were used to pool the rates and adjusted estimates across studies separately based on the heterogeneity between estimates (I 2 ). Fixed-effects models would be used if I 2 ≤ 50%, which represents low to moderate heterogeneity and random-effects models would be used and tau-square would be estimated using the DerSimonian-Laird method if I 2 ≥ 50%, representing substantial heterogeneity. We analyzed data using Stata version 16.0 (Stata Corp, College Station, TX, USA).

Basic Characteristics
In the initial literature research, 413 potential articles were identified up to 6 November 2021 (145 in PubMed, 126 in Embase, 142 in Web of Science). A total of 230 duplicates were excluded. After reading the titles and abstracts, 156 articles were excluded based on the inclusion and exclusion criteria. Among the 27 studies under full-text review, 21 studies were excluded. Eventually, 6 studies were included in this meta-analysis based on the inclusion criteria [27][28][29][30][31][32]. The literature retrieval flow chart is shown in Figure 1.

Basic Characteristics
In the initial literature research, 413 potential articles were identified up to 6 Nove ber 2021 (145 in PubMed, 126 in Embase, 142 in Web of Science). A total of 230 duplica were excluded. After reading the titles and abstracts, 156 articles were excluded based the inclusion and exclusion criteria. Among the 27 studies under full-text review, 21 stu ies were excluded. Eventually, 6 studies were included in this meta-analysis based on t inclusion criteria [27][28][29][30][31][32]. The literature retrieval flow chart is shown in Figure 1.
The included studies were observational cohort studies that involved 40,978 pre nant women (19,108 Blakeway

Effectiveness of COVID-19 Vaccines among Pregnant Women
Five studies were assessed for the risk of infection after the injection of COVID-19 vaccines, involving 19,078 vaccinated pregnant women and 21,848 unvaccinated pregnant women. The pooled OR was 0.50 (95% CI, 0.35-0.70), which showed that the vaccines were protective against SARS-CoV-2 infection for the pregnant women. Two studies assessed the risk of hospital admission, involving 18,391 vaccinated pregnant women and 18,391 unvaccinated pregnant women. The pooled OR was 0.50 (95% CI, 0.31-0.82), which showed that the vaccine was protective for the pregnant women in terms of hospitalization. The risk of ICU admission and death were not assessable due to the low number of studies and insufficient data. However, we noticed that there were no deaths reported among the pregnant women in the included studies, regardless of whether they were vaccinated or unvaccinated. The results for analysis of COVID-19 vaccine effectiveness among pregnant women are shown in Table 5 and Figure 2.

Effectiveness of COVID-19 Vaccines among Pregnant Women
Five studies were assessed for the risk of infection after the injection of COVID vaccines, involving 19,078 vaccinated pregnant women and 21,848 unvaccinated pr nant women. The pooled OR was 0.50 (95% CI, 0.35-0.70), which showed that the vaccin were protective against SARS-CoV-2 infection for the pregnant women. Two studies sessed the risk of hospital admission, involving 18,391 vaccinated pregnant women a 18,391 unvaccinated pregnant women. The pooled OR was 0.50 (95% CI, 0.31-0.82), wh showed that the vaccine was protective for the pregnant women in terms of hospitali tion. The risk of ICU admission and death were not assessable due to the low number studies and insufficient data. However, we noticed that there were no deaths repor among the pregnant women in the included studies, regardless of whether they were v cinated or unvaccinated. The results for analysis of COVID-19 vaccine effectiven among pregnant women are shown in Table 5 and Figure 2.

Subgroup Analysis
We conducted subgroup analysis by location (USA, Qatar, Israel, and England), type vaccine (BNT162b2 vaccine; 2 types of vaccines, BNT162b2 vaccine, and Moderna vaccine well as 3 types of vaccines, BNT162b2 vaccine, Moderna vaccine, and adenovirus vector v

Safety of COVID-19 Vaccines among Pregnant Women
We assessed the risk of adverse pregnancy outcomes among vaccinated and unvaccinated pregnant women. . We found that there was not a direct association between vaccination and these adverse pregnancy outcomes in vaccinated pregnant women. The analysis results of adverse pregnancy outcomes among pregnant women with COVID-19 vaccination are shown in Table 7. We assessed the risk of 4 fetal outcomes among vaccinated and unvaccinated pregnant women, including 3 studies for abortion, 4 studies for preterm birth, 2 studies for term birth, and 4 studies for stillbirth. The pooled OR were 1.10 (95% CI, 0.86-1.42), 0.96 (95% CI, 0.74-1.24), 0.91 (95% CI, 0.50-1.65), and 0.74 (95% CI, 0.15-3.65), respectively, which showed there were no significant differences in fetal outcomes between vaccinated and unvaccinated pregnant women. The analysis results of adverse fetal outcomes among pregnant women with COVID-19 vaccination are shown in Table 8 and Figure 3.  We assessed the risk of adverse neonatal outcomes among vaccinated and unvaccinated pregnant women. A total of 2 studies involving 140 vaccinated pregnant women and 1862 unvaccinated pregnant women were assessed for the risk of low or very low birthweight (<2500 g) (OR = 1.35, 95% CI, 0.76-2.40), neonatal birth trauma (OR = 0.57, 95% CI, 0.03-9.77), hypoxic-ischemic encephalopathy (OR = 4.42, 95% CI, 0.18-108.91). A total of 3 studies involving 273 vaccinated pregnant women and 2261 unvaccinated pregnant women were assessed the risk of admission to the neonatal ICU (OR = 1.08, 95% CI, 0.48-2.42). We did not find any neonatal deaths among vaccinated and unvaccinated pregnant women. The results suggest that there is not an obvious connection between vaccination and adverse neonatal outcomes among vaccinated pregnant women. The analysis results pregnant women. The results suggest that there is not an obvious connection between vaccination and adverse neonatal outcomes among vaccinated pregnant women. The analysis results of adverse neonatal outcomes among pregnant women with COVID-19 vaccination are shown in Table 9.

Quality Evaluation and Publication Bias
We evaluated the quality of the included articles according to the Newcastle-Ottawa quality assessment scale, and all the included articles were of good quality (≥7 stars).

Discussion
To our knowledge, this is the first systematic review and meta-analysis assessing effectiveness and safety of COVID-19 vaccine among pregnant women based on real-world studies that reports the incidence of clinical status of COVID-19 and adverse events on pregnant, fetal, or neonatal outcomes. This meta-analysis consisted of a total of 6 observational studies involving 40,978 pregnant women. We found that COVID-19 vaccination caused the risk of SARS-CoV-2 infection and COVID-19-related hospitalization to both decrease by 50%. Moreover, no adverse events of COVID-19 vaccination were found on pregnant, fetal, or neonatal outcomes. Nowadays, data about the safety and effectiveness of vaccines given to pregnant women has been growing. These data suggest that the benefits of vaccination to the pregnant women outweigh the known or potential risks, and some regions or countries such as the USA, Europe, the UK, Australia, Canada, and France have adjusted their strategies to encourage pregnant women to get vaccinated against COIVD-19 [21,22,[33][34][35][36]. Hence, our results confirm the effectiveness and safety of COVID-19 vaccine for pregnant women, which can allay pregnant women's fears about the uncertainty of COVID-19 vaccines and serve as a reference for the relevant departments to formulate policies to improve the acceptance of vaccines among pregnant women.
Analysis of the available data shows that vaccination with COVID-19 mRNA vaccines (including BNT162b2 and Moderna vaccines) reduces the risk of SARS-CoV-2 infection in pregnant women (OR = 0.13, 95% CI, 0.03-0.57). The BNT162b2 vaccine alone also decreased the risk of SARS-CoV-2 infection (OR = 0.56, 95% CI, 0.48-0.66). The BNT162b2 and Moderna vaccines are mRNA vaccines encapsulated in lipid nanoparticles, which encode the viral spike protein of SARS-CoV-2. Both are given in two doses. BNT162b2 is recommended for individuals aged 12 and above, and Moderna is recommended for those aged 18 and above. Previous studies have shown that these two vaccines reduce the risk of SARS-CoV-2 infection in nonpregnant people, and the efficacy of both vaccines is ≥90%, which is consistent across age, sex, race, and ethnicity, and results regarding their safety are reassuring [37][38][39][40]. In addition, a meta-analysis showed that two doses of COVID-19 vaccine were 85% or more effective in preventing any clinical status of COVID-19 in general population [41]. Similar results were observed in pregnant women. Dagan found that within 7-56 days of the second dose of BNT162b2 vaccine for pregnant women aged ≥16, the vaccine was 96% effective against recorded infections and 97% effective against symptomatic infections, and that the double-dose vaccine was more effective for pregnant women than the single dose [30]. This is related to the level of antibodies in the serum of pregnant women after vaccination. Gray quantified SARS-CoV-2 spike and receptor-binding domain (RBD) immunoglobulin G (IgG), immunoglobulin A (IgA), and immunoglobulin M (IgM) in 131 vaccine recipients of child-bearing age. He found vaccine-induced antibody titers were comparable to those of nonpregnant women during pregnancy and lactation (pregnant: median 5.59 and interquartile range 4.68-5.89; lactating: median 5.74 and interquartile range 5.06-6.22; nonpregnant: median 5.62 and interquartile range 4.77-5.98). Besides, all titers caused by vaccine were significantly higher than those caused by natural infection of SARS-CoV-2 in pregnant women [42]. IgM, IgG, and IgA levels rose significantly in pregnant women after receiving the first dose of BNT162B2 vaccine, and IgG levels further increased after the second injection. Two weeks after the second dose, the main antibody response in the serum of pregnant, lactating, and nonpregnant women was dominated by IgG [42,43].
After COVID-19 vaccination, the vaccine's protection and ability to prevent infection with new strains may decrease over time. Timely booster shots can allow production of neutralizing antibodies that have been gradually reduced grow rapidly or rebound to produce better results. At present, various countries differ with respect to recommendations to get a booster shot. Israel, China, the UK, and the EU have all actively recommended booster vaccination for priority groups (such as elderly people with low immunity, highrisk groups of SARS-CoV-2 infection, etc.) [44][45][46]. The US recommends that those aged 16 or above get a booster shot [47]. However, WHO believes that there is insufficient evidence to justify the need for widespread booster vaccination and, instead, focus should be on improving global primary vaccination coverage to alleviate serious inequities in vaccine distribution [48]. Therefore, it is important to determine whether pregnant women are regarded as a priority group for booster vaccination. There is currently insufficient evidence to support the need for booster vaccination in pregnant women.
We found a lower risk of COVID-19-related infections in younger age groups. Studies have shown that advanced maternal age (≥35 years) is an independent risk factor for pregnancy complications, delivery complications, and adverse pregnancy outcomes [49]. To our knowledge, the immune system plays an important role in defending against infections, though previous studies have found that aging influences immune response to coronavirus infection. For instance, immunosenescence can inhibit adaptive immunity mediated by T and B cells, with increasing susceptibility to infection and clinical outcomes thereafter [50]. In addition, the literature has shown that pregnancy is a special state of immune tolerance in which cell-mediated immunity is attenuated through a range of mechanisms to prevent fetal rejection during pregnancy, thus leading to unique susceptibility to infectious disease pandemics and increased severity of virus-related diseases. As a result, infectious diseases such as COVID-19 make pregnant women vulnerable to adverse pregnancy outcomes, not only increasing the risk of maternal and perinatal morbidity but even leading to maternal and perinatal death [12,[51][52][53]. A systematic review based on 63 observational studies reveals that maternal age in combination with other factors can predict adverse pregnancy outcomes associated with COVID-19, and that older women infected with SARS-CoV-2 during the third trimester of pregnancy may have the highest rates of morbidity and mortality [54]. In our study, we did not observe a higher risk SARS-CoV-2 infection in older age groups, but aging remains a suspected risk factor for pregnant women. However, we were not able to assess the risk of COVID-19-related hospitalizations in the older age group due to insufficient data. Moreover, we did not have data available to determine accurately whether the hospitalization was due to SARS-CoV-2 infection or COVID-19related factors combined with pregnancy-related indicators. Therefore, studies about the impact of maternal age on the safety and effectiveness of vaccination as well as the correlation between pregnancy, age, and immunization should be conducted in the future.
In the subgroup analysis, among the pregnant women, we have found the protection of SARS-CoV-2 infection in retrospective cohort studies as well as the protection of SARS-CoV-2 infection in prospective cohort studies. Because there are so few data, we cannot assess the impact of prospective studies on COVID-19-related hospitalization. Retrospective and prospective studies are both observational cohort studies. The difference lies in that the former are collated and analyzed based on previous data, while the latter are carried out by researchers according to the requirements of topic selection and design. Both assume that researchers will follow the population over time, measure several major and minor exposure factors and outcomes, and evaluate the correlation between multiple exposures and multiple outcomes, both with high accuracy and efficiency [55][56][57]. A study testing the comparability between retrospective life history data and prospective birth cohort study data showed a high degree of similarity [58]. Therefore, no statistic difference in vaccine effectiveness was found between the two cohort analyses in our analysis.
In the subgroup analysis, the group of England did not show any difference as for other location groups, which may be due to differences in the risk of infection between different countries. Although some kind of interaction with regard to vaccine effectiveness could be expected in different countries, their safety characteristics should be the same [24]. CDC has summarized growing evidence from countries and regions about the safety and effectiveness of COVID-19 vaccination during pregnancy: First, COVID-19 vaccines do not cause COVID-19 infection, including in people who are pregnant or their babies. Second, early data on the safety of receiving an mRNA COVID-19 vaccine (Moderna or Pfizer-BioNTech) during pregnancy are reassuring. Third, early data suggest receiving an mRNA COVID-19 vaccine during pregnancy reduces the risk of infection. Fourth, vaccination during pregnancy leads to the production of antibodies that might protect the baby. Fifth, no safety concerns were found in animal studies [59]. Consistent with previous studies [24,60,61], we found no adverse effects of COVID-19 vaccination on pregnancyrelated, fetal, or neonatal outcomes. In addition, studies have found that Pfizer vaccine can induce effective maternal to neonatal transfer of IgG [29,43,62]. The longer the time interval from vaccination to delivery, the higher the maternal and neonatal antibody levels and the cord-to-maternal ratio [63,64]. After the receipt of the second vaccine dose, the maternal and neonatal antibody levels change by −10.9% and −11.7% per week [63]. This suggests that maternal vaccination protects infants.
Our study has some limitations. First, the population we included was limited to a few specific regions or countries, and the effectiveness and efficacy of vaccines for pregnant women worldwide cannot be completely and accurately assessed. Second, the vaccination status we included was limited to 2 doses and ≥1 dose, which overlapped, and there was no evaluation of the effectiveness of COVID-19 vaccine after the first injection in pregnant women. Third, due to the limited available data and the low hospitalization admission threshold for pregnant women, we could not precisely determine whether these hospitalizations were due to SARS-CoV-2 infection or COVID-19 combined with pregnancy indicators. Fourth, we evaluated the publication bias based on Harbord's modified test, and p values for the meta-analysis were all more than 0.05; however, they were limited for potential publication as the number of studies was too small. Fifth, the DerSimonian-Laird method we used to combine the effect size and assess the heterogeneity might underestimate the uncertainty due to the few numbers of studies involved the meta-analysis. In addition, we did not adopt the Hartung-Knapp method to adjust our analysis results, which may cause the potential risk of underestimating the between-study variability and even the risk of false positive results. Sixth, the results of the subgroup analysis for hospitalization were not informative as this outcome was evaluated for just two studies, so we removed them. Seventh, the mRNA + adenovirus vector vaccine group did not show differences as the data source studies focused on the effect of vaccination, not vaccine type, on the outcomes of pregnant women, which causes difficulties for a separate discussion of the effectiveness of adenovirus vector vaccine.

Conclusions
Our results suggest that COVID-19 vaccines are effective in reducing the incidence of SARS-CoV-2 infection and COVID-19-related hospitalization among pregnant women. No adverse effects of COVID-19 vaccination were found on pregnant, fetal, or neonatal outcomes. Our results confirm the effectiveness and safety of COVID-19 vaccination for pregnant women. Our findings can serve as a reference for relevant policy makers to formulate targeted strategies to improve the COVID-19-related vaccine policy for pregnant women. Moreover, reducing hesitancy regarding COVID-19 vaccines is also helpful for improving vaccination coverage and protect pregnant women from SARS-CoV-2 infection toward ending the pandemic. Funding: This study was funded by the National Natural Science Foundation of China (72122001; 71934002) and the National R&D Key project (2021ZD0114101, 2021ZD0114104, 2021ZD0114105). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the paper. No payment was received by any of the co-authors for the preparation of this article.
Institutional Review Board Statement: Not applicable.