COVID-19 Vaccination and Pregnancy

Objectives : A review to assess the safety, efficacy, COVID-19 vaccination acceptance and awareness in pregnant women. Machanism : Pregnant women diagnosed with COVID-19 are characterized by more frequent hospitalization in intensive care units and are at three times higher risk of preterm; their newborns more often need invasive ventilation. Vaccination is the most effective preventive measures against SARS-CoV-2, but there are still questions about safety and immune response. Pregnant women were not included in study groups during phase III clinical trials. Findings in Brief : Vaccination during pregnancy is not associated with an increased risk of obstetric or neonatal complications; scientific communities recommend vaccination for pregnant women, those planning for pregnancy and those who are breastfeeding. Unfortunately, knowledge regarding COVID-19 vaccination and willingness to take vaccine during pregnancy is low. Conclusions : General practitioners and obstetricians have a large role in increasing public awareness of COVID-19 vaccination. No evidence of teratogenicity of the vaccine has been found.


Introduction
It has been 2 years since COVID-19, caused by SARS-CoV-2, was declared a pandemic in March 2020 [1].Despite the fact that the infection is asymptomatic in twothirds of pregnant women, the symptomatic course of the disease is more severe compared to that in nonpregnant women.Pregnant women diagnosed with COVID-19 are characterized by more frequent hospitalization in intensive care units, need for mechanical ventilation and extracorporeal membrane oxygenation, and death rate, and the risk of severe course of the disease is the highest in the third trimester [2][3][4][5].Fortunately, they usually require symptomatic treatment.Women who are infected with SARS-CoV-2 and present disease symptoms have less favorable obstetric outcomes than healthy women or infected women without infection symptoms.Symptomatic patients are at three times higher risk of preterm delivery (mainly iatrogenic), and intrauterine fetal demise.Moreover, the newborns of affected mothers more often need invasive ventilation and admission to the neonatal intensive care unit which is related to a higher percentage of preterm births (mainly iatrogenic-urgent cesarean section performed to save the mother) [2,5,6].
The most effective approach to prevent the severe course of COVID-19 seems to be preventive measures against SARS-CoV-2, which includes hand hygiene, avoidance of close contact with an infected person, and vaccination [7].Analyses of the effectiveness of preventive vac-cinations should take into account the type of vaccine, the number of doses administered, the variant/subvariant of the virus, the existence of comorbidities and medications taken, especially immunosuppressive ones, and the time elapsed since the administration of individual doses [8].
Currently, vaccination with mRNA vaccines is recommended for pregnant women, both by researchers evaluating the safety of these vaccines and by internationally recognized scientific societies that monitor the health status of particular social groups [9][10][11][12][13][14].
The position statement published by the Polish Society of Gynecologists and Obstetricians in April 2021 also indicated the advisability of vaccination for pregnant women.However, due to the lack of data on evidencebased medicine during the time, it was suggested that unless there is an emergency to administer the vaccine, vaccination should be postponed until the completion of organogenesis in the fetus [15].In Poland, preparations based on mRNA technology were highly preferred, as a larger number of published observational studies have demonstrated safety of using this sort of vaccination among pregnant women [15].
COVID19 vaccines should be offered to pregnant and lactating women.[...] each vaccination should be consulted with the obstetrician in charge of the pregnancy.However, we suggest that, if there is no indication for urgent vaccination of the pregnant woman, the above procedure be performed after the period of organogenesis.
Due to the existence of far more observations and safety evaluations of vaccination of pregnant women with mRNA vaccines, they are the preferred ones to be used first in the fight against COVID-19 pandemic in pregnant women.April 26, 2021 Current Strategic Advisory Group of Experts on Immunization (SAGE) of WHO [16] WHO has identified pregnant women as a priority-use group for COVID-19 vaccination, given the increased risk of severe outcomes.WHO recommends the use of all available type of vaccines in pregnant women when the benefits of vaccination to the pregnant woman outweigh the potential risks.

Safety of Vaccines
Pregnant women were not included in study groups during phase III clinical trials.Similarly, immunocompromised individuals were also not included.Nevertheless, COVID-19 vaccines are still recommended for immunocompromised individuals because they are not live vaccines [17] and provide substantial protection against severe infection.
Bleicher et al. [18] performed a comparative study analyzing the effect of vaccination during pregnancy on complications such as genital tract bleeding, gestational diabetes, gestational hypertension, fetal growth disorders, miscarriage, and preterm delivery [18].Their study included 326 patients, both vaccinated and unvaccinated.Both groups had a similar percentage of obstetric complications.However, vaccinated individuals were found to have a significantly lower risk of COVID-19 infection (1.5% vs 6.5%, p = 0.024, odds ratio 4.5, 95% confidence interval 1. 19-17.6).
A study published in The New England Journal of Medicine analyzed obstetric outcomes and side effects in more than 35,000 pregnant women [10].The analysis included women who were vaccinated at least 30 days before their last menstrual period and women in different stages of pregnancy.The data used for the study were obtained from the v-safe application for reporting adverse reactions to COVID-19 vaccines and the VAERS (Vaccine Adverse Event Reporting System).VAERS is a vaccine safety surveillance system established by the Centers for Disease Control and Prevention (CDC) and the US Food and Drug Administration (FDA) in 1990 [19].Of the early adverse events that possibly occur after vaccination, pregnant women slightly more likely experienced injectionsite pain than nonpregnant women, but less likely reported symptoms such as myalgia, chills, headache, or fever.To assess obstetric outcomes, randomly selected patients who were indicated on the app as currently pregnant were contacted.About 4000 women agreed to further analysis and were included in the study.Of these, 2.3% were vaccinated during the periconceptional period without knowing that they were pregnant, 28.6% were vaccinated in the first trimester of pregnancy, 43.3% in the second trimester, and 25.7% in the third trimester.The frequency of preterm deliveries and fetus growth disturbances in this studied population of pregnant women was similar to that of the general population (9.4% and 3.2%, respectively).Spontaneous miscarriage was the most common complication, but its frequency was not higher than that in the general population (12.6%).Congenital malformations were found in 2.2% of term pregnancies; however, the cases did include any woman who received the vaccine before pregnancy or in the first trimester.
The published studies on side effects reported by pregnant women have not shown complications other than those observed in the general population [20].Injection-site pain and fatigue after vaccination were the most common complications reported by pregnant women [21].Among almost 8000 women included in the study, these complaints were reported by 91.4% and 31.3%, respectively.One study described a case of immune thrombocytopenia that occurred after 13 days of vaccination (Moderna mRNA-1273 vaccine) in the first trimester of pregnancy [22].However, after treatment with corticosteroids, the patient was discharged from the hospital in good condition, with no further complications.Another similar case was described in Qatar [23].Pregnant women in the 8th week of pregnancy had a relapse of immune thrombocytopenia purpura (ITP) after the introduction of the first dose of Pfizer SARS-CoV2 vaccine, which worsened further after the second dose.Fortunately, without serious complications.The authors suggest, that women with history of ITP should have delayed the second dose of vaccine in pregnancy.Mendes-de-Almeida et al. [23] present more fatal case.A pregnant woman in the 23th week of pregnancy developed intracerebral hemorrhage localizated in the left temporal lobe associated with vaccine-induced thrombotic thrombocytopenia (VITT) 12 days after the ChAdOx1 nCOVID-19 vaccination [24].She underwent urgent neurosurgery for hematoma drainage and decompressive craniectomy.Unfortunately, after these procedures, obstetric ultrasound detected fetal death.The patient died 17 days after vaccination with refractory intracranial hypertension.To the best of our knowledge, abovementioned study was only one which has shown an association between vaccination during pregnancy and increased risk of maternal or neonatal complications.Fu et al. [25] presented a systematic review of 23 studies where they shown safety, high efficacy and no significant vaccine-related adverse events.A large multicenter study analyzed the potential impact of the vaccine on the risk of preterm delivery and fetal growth abnormalities [26].The study included over 36,000 unvaccinated and only 10,000 vaccinated pregnant women.The subjects received different types of vaccines.There was no evidence showing that the vaccinated group had a higher rate of preterm births or babies with too low a weight for gestational age (i.e., SGA).In another study, Kharbandy et al. [27] assessed whether COVID-19 vaccination was associated with an increased risk of miscarriage.This study included over 100,000 pregnant women who received both mRNA and vector vaccines.In the studied population, only 13,000 had a miscarriage.However, no correlation between pregnancy loss and earlier vaccination (in the 28 days preceding miscarriage) was found.An important piece of evidence supporting that vaccines do not affect the fetus is a paper demonstrating that IgM antibodies are not detected in cord blood [28].This confirms that vaccination has no effect on the fetal immune system.Both this study and another one which showed that Spike protein was not found in the placenta and cord blood indicate that the vaccine does not penetrate the placental barrier [29].The summary of   Only 41% reported they would get a vaccine; Receipt of influenza vaccine during the previous season was associated with higher odds of vaccine acceptability (aOR 2.1, 95% CI, 1.5-3.0) Non-Hispanic Black and Hispanic women had lower odds of accepting a vaccine compared with non-Hispanic White women The most frequently cited concern was vaccine safety for their pregnancy (82%) Huddleston et al. [36] 2506 USA Survey study given to pregnant women 57.4% getting vaccinated during pregnancy; among the unvaccinated, only 35.7% reported vaccine acceptance The predictors of lower odds of vaccination were being of the Black race compared with White race and being counseled by a provider not to vaccinate compared with no counseling

No information
The predictors of higher odds of vaccination were increasing education and income, living in a metropolitan area, and worry over COVID-19, being counseled about vaccination by a provider was a strong predictor of getting vaccinated compared with receiving no counseling Townsel et al. [37] 4379: pregnant, breastfeeding, trying to conceive and other women of a reproductive age USA Cross-sectional, opt-in online survey of the entire employee workforce at an academic medical center in the U.S. Primary outcome was receipt of or intent to receive the COVID-19 vaccine, classified as: received, delayed or declined Compared to other women of reproductive age, pregnant participants were six times more likely to delay COVID-19 vaccination and twice as likely to decline, those who were trying to conceive had nearly three times the odds of delaying and declining the vaccine compared to the referent.Very few physicians delayed or declined the vaccine Allied health professionals were slightly more likely to reject the vaccine compared to nurses.Non-Hispanic Black participants had a fourfold increased chance of both declining and delaying, whereas Non-Hispanic Asian participants were significantly less likely to decline and delay the vaccine compared to non-Hispanic White participants 33.2% (n = 1456) of all participants and 44.5% (n = 113) of pregnant participants expressed at least one concern.The highest rates of concern were observed for safety and effectiveness of the vaccine, which were highest among pregnant and trying to conceive participants The trust of pregnant and breastfeeding women and women who have offspring in government, in healthcare professionals, in scientific authorities, and sound scientific data is strongly associated with vaccine acceptance and may influence an individual's decision to perceive recommended actions as beneficial to the society as a whole.Pregnant women are 4 times more likely to trust government health information than non-pregnant women (OR = 4.150; p = 0.009) Breastfeeding women declared that they vaccinate their children as opposed to nonbreastfeeding women (p = 0.001) No information Therefore, they were determined to get vaccinated themselves (p = 0.006) Women aged 35-40 believed less that vaccinations were safe and effective in opposite to 30-35 Women with lower education think less that vaccinating children is safe and effective in preventing infectious diseases compared to women with higher education (p = 0.055) abovementioned reviews and studies are presented in the Table 2 (Ref.[10,18,21,[25][26][27][28][29]).

Immune Response and Efficacy
Many studies have analyzed the immune response after vaccination in pregnant women.A majority of these showed that the response in these women was the same as that in nonpregnant women.One study confirmed that the immune response, as measured by the increase in both IgG antibodies (humoral immunity) and T lymphocytes (cellular response), is identical in nonpregnant, pregnant, and breastfeeding women [30].Similar findings were reported by Gray et al. [31], who indicated that the immunogenicity of the vaccine was comparable in pregnant, nonpregnant, and breastfeeding groups.The authors also detected IgG antibodies in cord blood and breast milk.An analysis performed at a large academic center in New York revealed that antibody production starts 5 days of vaccination in pregnant women, and the antibodies are found in the cord blood after 16 days of vaccination [32].This suggests that vaccination up to 2 weeks before delivery provides passive protection to the newborn.Halas et al. [33] evaluated the need for hospitalization of children under 6 months of age who were diagnosed with COVID-19.The authors found that children of mothers who were vaccinated before 20 weeks of gestation had a 32% lower risk of hospital treatment than children born to women who were not vaccinated.In contrast, vaccination after the 20th week minimized the risk of hospitalization by as much as 80%.These differences are probably due to the decrease in antibody concentrations with increasing time since vaccination and seem to suggest that women who were vaccinated in early pregnancy should receive a booster dose.However, it is important to remember that vaccination is primarily intended to protect the woman from the severity of the disease and it is not advisable to postpone it in order to maximize the possible benefits to the newborn.Table 3 (Ref.[30][31][32][33]) summarized abovementioned studies.

Vaccination Acceptance and Awareness among Pregnant Women
Studies analyzing the willingness of pregnant women to be vaccinated have not shown promising results.A majority of them indicate a low acceptance of vaccination, ranging between 30% and 58% [34][35][36].In a review by Battarbee et al. [35], 41% of pregnant women expressed a willingness to get vaccinated.The main reason for refusal stated by participants was concern about the safety of the vaccine (82% of respondents).Women who had previously received the influenza vaccine were significantly more willing to be vaccinated for COVID-19.However, it seems comforting that women who received information on the vaccine from their doctors were more likely to agree to vaccination.The US study attributed the low acceptance of vaccination among pregnant women to a lack of confidence in the efficacy of the vaccine and fear of side effects, especially on the fetus [34,37].Among different populations, vaccination rates were lower among African-American and Latino pregnant women.The rates were also shown to be the lowest in the youngest age group [38].It was found that only 5.5% of women aged 18-24 years had received the vaccine.According to a Polish study, the faith of pregnant and breastfeeding women in the vaccine is strongly related to the opinions of the government, medical authorities, and health care workers [39].Thus, the dissemination of accurate information on vaccination by medical personnel and social campaigns is very important.This can significantly increase the level of trust and awareness regarding the effectiveness and safety of the vaccine and consequently increase the percentage of vaccinated pregnant women.The abovementioned studies and reviews are summarized in the Table 4 (Ref.[34][35][36][37][38][39]).

Summary
This study indicates that pregnant women must be vaccinated to protect against COVID-19.This population is at a higher risk of more severe disease and is more susceptible to infection compared to the general population.Vaccination during pregnancy is not associated with an increased risk of obstetric or neonatal complications, and no evidence of teratogenicity of the vaccine has been found.Scientific communities around the world, including the American College of Obstetricians and Gynecologists (ACOG), the Royal College of Obstetricians and Gynecologists (RCOG), the Society for Maternal-Fetal Medicine (SMFM), as well as the World Health Organization (WHO) and CDC, recommend vaccination for pregnant women as well as those planning for pregnancy and those who are breastfeeding.Knowledge regarding COVID-19 vaccination and willingness to take vaccine during pregnancy is low; information campaigns and, above all, general practitioners and obstetricians have a large role in increasing public awareness of COVID-19 vaccination.Every pregnant woman should be informed of the possibility, and indeed the necessity, of vaccination, and refusal should be recorded in the medical file.Vaccine for COVID-19 can also be given with other vacci-nations; however, an interval of 14 days between other vaccines is recommended, with the exception of the seasonal influenza virus vaccine which can be given concurrently.
The earliest detection of antibodies in women occurred 5 days post-vaccine dose 1, and the earliest detection of antibodies in cord blood occurred 16 days post-vaccine dose 1. Maternal IgG levels were significantly higher, week by week, starting 2 weeks after the first vaccine dose (p = 0.005 and 0.019, respectively), as well as between the first and second weeks after the second vaccine dose (p = 2e-07).Maternal IgG levels were linearly associated with cord blood IgG levels (R = 0.89, p < 2.2e-16).The placental transfer ratio correlated with the number of weeks elapsed since maternal vaccine dose 2 (R = 0.8, p = 2.6estudy at 20 pediatric hospitals in 17 states, to assess effectiveness of maternal completion of a 2dose primary mRNA COVID-19 vaccination series during pregnancy against COVID-19 hospitalization in infants Among 379 hospitalized infants aged <6 months (176 with COVID-19 [case-infants] and 203 without COVID-19 [control-infants]), the median age was 2 months, 21% had at least one underlying medical condition, and 22% of caseand control-infants were born premature (<37 weeks gestation).Effectiveness of maternal vaccination during pregnancy against COVID-19 hospitalization in infants aged <6 months was 61% (95% CI, 31%-78%) mRNACOVID-19 vaccineInfants of vaccinated during pregnancy and non-vaccinated women

Table 2 . The safety of COVID-19 vaccination in pregnant women.
Fu et al. [25] 23 studies Canada A systematic search of MEDLINE, Embase, PubMed, medRxiv, and bioRxiv COVID-19 vaccination in pregnant and lactating individuals is immunogenic, does not cause significant vaccine-related adverse events or obstetrical and neonatal outcomes Pfizer-BioNTech BNT162b2, Moderna mRNA-1273, Johnson & Johnson and AstraZeneca vaccine