Background
Coronavirus disease 2019 (COVID-19) during pregnancy is associated with severe maternal morbidity, mortality, and neonatal complications [
1]. Vaccines against infectious diseases are crucial, given that mRNA vaccines such as BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna) have reportedly reduced the risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and prevented the incidence of severe COVID-19 [
2,
3]. Moreover, several studies and a recent meta-analysis have reported the safety and efficacy of mRNA vaccines in pregnant women [
4‐
6].
However, given the differences in medical systems and national vaccination policies, vaccination coverage varies across different countries [
7], especially in pregnant women [
8]. In Japan, mRNA vaccination was initiated on February 17, 2021, with the Pfizer-BioNTech vaccine, and Moderna and AstraZeneca vaccines were introduced later. The Japan Society of Obstetrics and Gynecology recommends vaccination of all pregnant women [
9]. However, mRNA vaccination of pregnant women is not compulsory in Japan and is based on individual preference. A survey of 202 pregnant women from a multi-ethnic population in north London reported that 56.9% of pregnant women refused to get the COVID-19 vaccine. Various factors, such as age and ethnicity, have been reported to influence the decision of getting vaccinated [
10]. In Japan, more than 80% of the population has received at least one vaccination as of March 2022; however, information on the vaccination status, especially of pregnant women, is lacking [
11]. Thus, the availability of information on vaccination and related issues in pregnant women in Japan is limited. The severity of COVID-19 varies according to the genetic factors of the human host and the SARS-CoV-2 variant [
12]; therefore, it is necessary to collect data on the impact of COVID-19 on Japanese pregnant women.
In Japan, the trust of the public in the safety and effectiveness of vaccines is low because of the history of the onset of functional somatic syndromes in young Japanese women who had received the human papillomavirus vaccination [
13,
14]. Hence, we hypothesized that mRNA vaccination during pregnancy may be less acceptable to pregnant women in Japan than in other countries, owing to concerns about the effect of vaccination on the fetus. Therefore, this study aimed to examine the perinatal outcomes, coverage, adverse effects, and short-term safety of mRNA vaccination among pregnant women in Japan as primary outcomes and vaccine hesitancy as a secondary outcome.
Discussion
In this study, we assessed the status of COVID-19 mRNA vaccination, COVID-19 prevalence, and perinatal outcomes among pregnant Japanese women. Approximately 80% of the pregnant women had received at least one dose of vaccination against COVID-19. A high proportion of pregnant women who did not receive an mRNA vaccine had a history of asthma and food or drug allergies. The vaccinated group had a significantly lower incidence of SARS-CoV-2 infection and COVID-19-related pneumonia than the unvaccinated group. No association was observed between mRNA vaccination and adverse perinatal outcomes or the incidence of congenital diseases, including malformations. Adverse reactions were more frequent with the second dose of the mRNA vaccine than with the first dose, although no significant difference was noted in the incidence of serious adverse reactions according to the dose. More than 90% of pregnant women who did not receive an mRNA vaccine during pregnancy were concerned about its potential adverse effects on the fetus; more than 50% were concerned about the effects on themselves, and 15% were unwilling to receive a COVID-19 vaccine. Notably, a small number of pregnant women could not be vaccinated even if they wanted to.
The proportion of pregnant women with a history of asthma and allergies was higher in the vaccinated group than in the unvaccinated group. Given that asthma and allergy have similar background factors, some women may not have been vaccinated because of concerns about possible allergic reactions against mRNA vaccination. Although the incidence of allergies due to mRNA vaccines is very low, 11.1 of 1 million people receiving the BNT162b2 vaccine develop an allergic reaction [
16]. One prospective cohort study found that the incidence of allergy increased among those at particularly high risk of allergy after receiving the BNT162b2 vaccine [
17]. In one case report from Japan, a patient developed life-threatening acute asthma exacerbation after BNT162b2 vaccination [
18]. As the risk of allergic reactions is higher in individuals with a history of allergies than in individuals without a history of allergies and as patients with asthma may be at increased risk as well, the advantages and disadvantages of vaccinating high-risk individuals should be fully explained to the patients to support their decision-making process.
The present study included a cross-sectional design, and although it was difficult to verify the results of vaccine efficacy, previous reports [
4,
5,
19] have shown that mRNA vaccinations are effective in reducing both the incidence and severity of COVID-19. However, SARS-CoV-2 undergoes frequent mutation. Even if the current vaccines were effective against the then prevalent strains in Japan (Delta, BA.1; or Omicron, BA.2) [
11], it is unclear whether similar results would be obtained against other variants that are associated with reduced neutralizing antibody activity [
20,
21]. Further research is necessary to determine the effectiveness of vaccination against other variants. It is critical to collect information on each prevalent variant, vaccine type, and vaccination coverage by country and region.
Consistent with the findings of a previous study [
22], birth weight, and length at birth did not differ between the vaccinated and unvaccinated groups in our study. No neonatal deaths were reported in the vaccinated group. A previous study found that mRNA vaccination during pregnancy did not affect the incidence of congenital diseases, including malformations [
22]. Similarly, in women in the vaccination group in our study, vaccination showed no effect on the incidence of congenital diseases, including malformations, during the first trimester of pregnancy, and the incidence was similar to that of the general population in both groups [
23]. In this study, the preterm delivery and cesarean section rates in the vaccinated group were lower than those in the unvaccinated group. The preterm delivery rate among patients with COVID-19 in the unvaccinated group was slightly higher than that of the entire unvaccinated group (17.6% and 13.7%), but the cesarean section rate was rather low (41.2% and 42.2%). Moreover, it was challenging to establish a causal relationship between the higher COVID-19 infection rates observed in the non-inoculated group and the higher rates of preterm delivery or cesarean section in this study. On the other hand, high levels of anxiety are reportedly associated with premature birth and increased cesarean section rates [
24,
25]. Vaccination for SARS-CoV-2 infection is reportedly associated with a reduced risk of anxiety and depressive symptoms [
26], possibly contributing to the reassurance that vaccination protects the mother from SARS-CoV-2 infection. However, as the study design and subject matter differ from the previous study, there remains some uncertainty as to the validity of the hypothesis. Moreover, preterm birth and cesarean section rates are associated with several factors, and it is unclear why these rates were lower in the vaccinated group than in the unvaccinated group in our study. Further research is needed in this regard in the future.
Our study confirmed that the overall incidence of adverse effects due to mRNA vaccines was higher after the second dose than after the first dose, as reported previously for the general population and pregnant women [
2,
27,
28]. A few reports have stated that myocarditis may occur as a severe adverse effect of mRNA vaccination [
29]. In this study, no severe adverse effects of vaccination were reported, confirming that there are no major safety concerns regarding mRNA vaccines. In Japan, three or more vaccinations are now being administered as boosters; however, the effects of receiving additional doses of vaccine on perinatal outcomes, the frequency of adverse reactions in pregnant women, and the long-term effects during pregnancy on the fetus are not fully understood. As observed in this study, pregnant women are hesitant to receive the vaccine mainly because of concerns about adverse effects on the fetus. Large-scale studies investigating not only the short-term effects on the fetus but also the long-term effects are needed.
This study has some limitations. The study was retrospective in nature, and the number of participants was relatively small despite the multicenter study, and some data were missing. Furthermore, the detailed clinical course, including indications and reasons for premature births, and the precise period between vaccination and SARS-CoV-2 infection are unknown. Participating facilities were mainly university hospitals around Tokyo, which care for many high-risk pregnant women; therefore, women with high-risk pregnancies may have been over-represented, and this may explain the relatively high cesarean section rate. At the time that the protocol was developed, the policy was to administer two doses of mRNA vaccine in Japan; however, during the study, the circumstances changed, and three or more doses of vaccinations were being recommended. Despite these limitations, our study provides critical data on the current epidemic caused by the SARS-CoV-2 Delta and Omicron variants and, to the best of our knowledge, this is the first study to report the perinatal outcomes of women who received mRNA vaccination during pregnancy in Japan.
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