Safety of COVID-19 vaccination in pregnant women and their neonatal outcome: a narrative Review

Abstract Background Even through the fact that pregnant women are more and more severely infected with COVID-19 disease, there are still doubts about vaccinating these people due to the lack of sufficient evidence base information. So in this systematic review, we decided to study vaccinated and unvaccinated pregnant women regarding maternal, fetal and neonatal complications and outcomes. The strategy of searching Between 30 December 2019 and 15 October 2021, electronic searches were performed on the databases of PubMed, Scopus, Google Scholar, and Cochrane library by searching in English and free full text. Keywords searched included these: maternal outcome, neonatal outcome, pregnancy, and COVID-19 vaccination. Among 451 articles, finally, seven studies were included to study pregnancy outcomes in vaccinated women compared to unvaccinated for systematic review purposes Results In this study 30257 vaccinated women in their third trimester compared to 132339 unvaccinated women in terms of age, the root of delivery, neonatal adverse outcomes. There were no significant differences between two groups in terms of: IUFD, and 1 min Apgar score, C/S rate, and NICU admission between the two groups, however, the rate of SGA, IUFD, and also neonatal jaundice, asphyxia, and hypoglycemia was more significant in the unvaccinated group comparing to the vaccinated group as a result. Among them, the chance of preterm labor pain was reported more among vaccinated patients. Emphasizing that, except 7.3% of the case population, everyone in the second and third trimesters had been vaccinated with mRNA COVID-19 vaccines Conclusion COVID-19 vaccination during the second and third trimesters appears to be the right choice due to the immediate impact of COVID-19 antibodies on the developing fetus and formation of neonatal prophylaxis, as well as the absence of adverse outcomes for both the fetus and mothers.


Introduction
Despite all the efforts to control COVID-19 pandemic it causes losses of lives and leaves long-lasting morbidity behind in the survivors [1]. The goal of all countries is to control COVID-19 by vaccinating all citizens at the same time in a short period time, including pregnant women [2]. But, in Carbone's study, 71.8% of women had refused to receive the COVID-19 vaccine, and among them, 69.7% of women considered being pregnant as the reason for refusing the vaccine injection, while 52.8% of these pregnant women had received Influenza and DTap vaccine during their pregnancy [3].
Vaccines without living viruses appear to be safe for injection [4]. None of the mRNA vaccines were prescribed or used during pregnancy [5]. Thus, there is little data on the efficacy, effectiveness, and safety of these vaccines during pregnancy On the other hand, pregnant women infected with COVID-19 are more likely to require ICU admission and mechanical ventilation. Besides, side effects of pregnancy and childbirth such as premature delivery, IUFD (intrauterine fetal death), IURG (intrauterine growth retardation), and SGA (small for gestational age) are reported more in this group [6,7]. The level of antibody in pregnant recipients of the COVID vaccine was the same as that in non-pregnant women and higher than that of those infected with SARS-COV. This antibody is evident in their infant cord blood [8,9].
In the RCTs which analyzed the long-term and shortterm effects of anti-Corona virus vaccines with MRNA on the general population, pregnant women were omitted because no animal reproductive toxicology study was conducted in this field. There were 1800 followable pregnant women at the time the study was conducted, and 45% had a child during this period [10,11].
Because of concerns about the COVID-19 vaccination and its undefined effects on pregnancy outcomes, we decided to compare the outcome of pregnancy and newborns between vaccinated and unvaccinated pregnant women in the mini-review. However, prescribing vaccination to pregnant women, especially high-risk pregnant women regarding severe infection is recommended despite not knowing whether it is safe or not in the long term [10][11][12].
A few studies have examined the outcome of pregnancy in these women who received the vaccine during the preconception period or their first trimester of pregnancy, so the results of maternal and fetal complications of the vaccine are often reported in mothers who received the vaccine in the third trimester of pregnancy.
In this systematic review, we studied vaccinated pregnant women, most of whom were MRNA vaccinated by Pfizer or Moderna, and unvaccinated pregnant women regarding maternal, fetal, and neonatal complications.

Inclusion criteria
The articles selected focused on pregnant women who had received either one or two doses of mRNA vaccination and had delivered their babies at the time of the study. This group and the unvaccinated group as a control group were studied for fetal and neonatal complications, which include: fetal abnormality, IUFD, SGA, method of birth, abortion rate, neonatal death, premature delivery, Apgar score minutes 1 and 5, NICU hospitalization, meconium, Neonatal encephalopathy, ICH, hypoglycemia, newborn convulsions, mechanical ventilation, Infant jaundice, and TTN.

Exclusion criteria
Studies published before 30 December 2019 or non-English studies were excluded.

Searching strategy
Between 30 December 2019 and 15 October 2022, electronic searches were performed on the databases of PubMed, Scopus, Google Scholar, and Cochrane library by searching in English and free full text. Keywords searched included these: maternal outcome, neonatal outcomes, pregnancy, and COVID-19 vaccination. Two reviewers independently analyzed the titles and abstracts of 451 articles, excluding those that did not meet the desired criteria. Finally, seven studies were included to study pregnancy outcome in vaccinated women compared to unvaccinated for systematic review purposes (Table 1).

Results
From the seven articles, 30257 pregnancies and deliveries in the vaccinated group and 132339 in the unvaccinated group were compared from the standpoint of maternal and fetal complications. Details are shown in Table 2.
In this study, most of the 30257 vaccinated women were in their second and third trimesters with a mean age of 33.05 years and 132339 unvaccinated women with a mean age of 33.63, were compared regarding delivery and newborn complications. Only 7.3% of women were vaccinated in the first trimester of pregnancy in only one study [13].
Those who received two doses of the vaccine were older and had a higher level of employment than the unvaccinated group. In addition, these women had already a history of repeated previous Cesarean sections, and previous abortions and received infertility drugs. The white race was more flexible in receiving vaccinations than the black race [14,15].
Most studies included singleton pregnancies except two which studied 12 and 24 multi-gestational pregnancy cases among 827 and 2002 population [11,16]. All the studies compared the effects of the inactive vaccine with or without a booster dose. In most of the studies, Pfizer and Moderna vaccines were used which are both inactive mRNA vaccines.
In each study control groups were selected from the same local population. Patients' and infants' follow-up was from vaccination till maximum of 28 days after delivery. All fetal and neonatal outcomes were compared between the two groups and summarized in Table 3.

Congenital malformation
In Shimabukuro et al. study six congenital anomalies from 726 vaccinated women were reported [11]. In the Blakeway study, just three cases of congenital anomalies (2.4%) were reported [14]. Other studies had no record of congenital anomalies in vaccinated groups.

Preterm labor pain
74 preterm delivery cases were reported in the group which was vaccinated in their second or third trimester. In the Bookstein et al. study, they focused on the uterine contractions after the first and second dose [5]. Approximately 1.3% of the women after the first dose and 6.4% after the second dose had experienced uterine contractions. 60% of these women were over 34 weeks pregnant. These uterine contractions did not lead to preterm delivery. However, our results show premature birth and premature rupture of the amniotic membrane in vaccinated women rather than in the control group. The risk of premature delivery (<37 weeks of gestation) was similar in both groups based on Theiler et al. study (9.2% in vaccinated women v/s 8.5% in the unvaccinated group, p ¼ .702) [16].

The root of delivery
The Cesarean section rate was reported 0.60% in the unvaccinated group and 0.69% in the vaccinated group (p ¼ .0735). Natural Vaginal Delivery (NVD) rate was 0.61% in the vaccinated group and 1.1% in the unvaccinated group (p < .0001). There was more instrumental delivery rate in the vaccinated group. (p ¼ .0902) Thus, it seems that receiving a vaccine does not affect the method of delivery. The patients did not go through cesarean section due to the increased chance of fatal distress. It should be mentioned that the vaccinated group in the Rottenstreich et al. study had more records of previous cesarean section delivery (p ¼ .04), abortion rates (p ¼ .01), and use of infertility drugs (p ¼ .01) than the unvaccinated group [15].
In all studies, the patients in both groups were similar regarding diabetes, gestational hypertension, and multi-fetal pregnancy, and obesity except for study number two in which the patients who had received the vaccine were older and the rate of diabetes, gestational hypertension was higher [14].

Early neonatal outcome
The chance of SGA in all 7 studies was reported 7.53% in the vaccinated group and 8.40% in the unvaccinated group (p < .0001). The chance of IUFD was significantly higher in the unvaccinated group with a prevalence of 2.35% and the vaccinated group with a prevalence of 2.0%% (p ¼ .002) [5,11,[14][15][16].
Apgar score minute 5 7 was reported 0.08% in the vaccinated group and 0.05% in the unvaccinated group (p ¼ .045). There was no significant difference between both groups for Apgar score 1 min after delivery (p ¼ .313). However, the Apgar score was examined only in the two studies [15,16].
Mechanical ventilation was examined in the three studies [5,9,15], which showed no significant difference between two groups; 0.026% in the vaccinated and 0.011% in the unvaccinated group (p ¼ .045).
Some newborns have very fast or labored breathing in the first few hours of life because of a lung condition called transient tachypnea of the newborn (TTN). "Transient" means it doesn't last long-usually, less than 24 h. "Tachypnea" (tak-ip-NEE-uh) means to breathe quickly.
Transient Tachypnea of the Newborn (TTN) was examined in the 3 studies with 0.020% prevalence in the vaccinated group and 0.006% prevalence in the unvaccinated group [5,9,15] The chance of neonatal jaundice, newborn convulsions, hypoglycemia right after birth, sepsis, and birth asphyxia were examined only in the one study [15], which showed no significant differences between the two groups except the rate of neonatal hypoglycemia which was increased in the vaccinated group 0.040% vs 0.017% (p ¼ .013).

Discussion
There are few studies on the outcome of pregnancy despite close contact of pregnant women and positive COVID-19 patients [11,17]. The immunity level of pregnant women is much lower than other normal women due to immunocompromisation health conditions [18]. The infection rate in this group is 70% higher than in other women of the same age [19,20]. Furthermore, pregnant women are in close contact with their families and children. As a result of their intense condition, their disease will place more strain on the healthcare system. Despite these problems, this group also has the lowest level of vaccination rate. Despite resistance to vaccine injection in the pregnant population in recent years, 21.7% influenza vaccination and 25.7% DPT vaccination among 323,622 pregnant women in New Zealand between 2013 and 2018 [22], now, according to the COVID-19 pandemic, vaccination of pregnant women during this time has increased to 40%, for example, in Israel. This item shows the need for more studies on the pros and cons of vaccination in this group [10]. In London, it is reported at 28.5% of pregnant women avoid vaccination because there is not enough reliable information on maternal and fetal effects [14]. In the 2021 Carbone Systematic Review, the willingness of pregnant and breastfeed women to inject the COVID-19 vaccine was reported as 49.1% and 61.1%, respectively, and these results are due to the lack of sufficient and reliable information about the safety and effectiveness as well as the adverse effects of the COVID vaccination injection in this sensitive period [22][23][24].
Available studies have focused on the effects of the COVID-19 vaccination in the second and third trimesters of pregnancy. The impact of vaccination in the first trimester on the abortion rate and other complications is still unknown. Although in Dong's study, COVID vaccination did not make a difference in the pregnancy rate of infertile couples, and in Calvert's study, the chances of miscarriage or ectopic pregnancy in vaccinated women did not increase compared to the period before the COVID-19 pandemic [25,26].
According to the study of Rotrinrish, the level of IgG created in the blood of the mothers after vaccination is higher than that of the infected mothers [15]. IgG makes its way through the umbilical cord to the fetus, just as the IgG created by influenza does. Therefore, the fetus is immune to COVID-19 as a result [9,21,27]. Using the V-safe application, the European Center for Disease Prevention and Control determined that there was no significant or specific complication among pregnant women who received the vaccination in their second or third trimester compared to women in the general population [15]. According to the present study, as it was explained in the test results, no case led to preterm delivery except for uterine contractions after the second dose at 34 weeks. Early neonatal complications, cesarean section, congenital malformations, decrease in Apgar score at minute 1, NICU admission, need for mechanical ventilation, asphyxia, and newborn jaundice complications were not more prevalent in the vaccinated group.
We have concerns about vaccination-induced fever in pregnant women, especially after the second dose compared to the unvaccinated group (in up to 32% of pregnant vaccinated women). The level of risk is still controversial. Because fever lasts only 24 to 36 h and is included wide CI in studies, it does not appear to affect on fetal development or neonatal complications as a result [14].
As of now, the RCOG does not specify an extreme age for COVID-19 vaccination. Due to conflicts regarding vaccination in the first trimester, it recommends postponing vaccination till 13 weeks of pregnancy for the low-risk women [17,28]. This is because the most common complication associated with mRNA vaccination for influenza in 2009 was first-trimester abortion [29].
According to our study, the chance of congenital anomalies in the vaccinated group is 2.14 to 2.2%, which is relatively close to the 3% of the unvaccinated group. It seems that based on the mothers age, race, and gestational age in recent decades the chance of congenital anomalies has remained stable in metropolitan, Atlanta, Georgia [30,31].
In this study, the chance of SGA was 7.53% in the vaccinated group. Because this study was conducted on a population with better social and economic conditions than south Asians and coastal Africans. Yet the risk is not greater than the unvaccinated group. The risk of SGA was significantly lower in the unvaccinated group. The results of this study are very similar to those of Mark et al. reported in 2012, which showed that vaccinations reduced the risk of SGA during the Influenza pandemic 44.8% vs 25.9% [31] (p ¼ 0.03).
In a systematic review by Deshayne et al., the chance of cesarean section, preterm delivery, IUGR, and IUFD among influenza-vaccinated women between 2008 and 2010 were compared, and only one RCT in the third trimester showed a significant reduction in SGA risk in the vaccinated group. Other studies have shown that the influenza vaccination in the second and third trimesters does not increase fetomaternal complications [32].
Nevertheless, in Satako's 2020 perospective study, 641 unvaccinated women were compared with 356 vaccinated women who received the influenza vaccine in their first, second, and third trimesters. Not only the vaccinated group show no adverse effects on maternal and fetal outcomes, but also vaccination in the third trimester reduces adverse birth outcomes with odds ratio 0.70, and 95% CI (0.51-0.98) [33].
Similar to our findings, the safety and efficacy of the pertussis vaccine in pregnant women have also been confirmed in the systematic review by Desponia et al., respectively [34].

Conclusion
COVID-19 vaccination during the second and third trimesters appears to be the right choice due to the immediate impact of COVID-19 antibodies on the developing fetus and the formation of neonatal prophylaxis, as well as the absence of adverse outcomes for both the fetus and mother. It is certainly possible to convince younger people to receive vaccinations using evidence-based adequate information like this study and other studies on mRNA vaccines.
Although more studies need to be done on the impacts of vaccination especially during the first trimester in the long term, as well as doing surveillance on the newborns, to confidently encourage mothers to have vaccinations. Even in high-risk mothers we can individually examine the case and interact with mothers to have vaccinations in the first trimester.

Disclosure statement
No potential conflict of interest was reported by the author(s).

Funding
The author(s) reported there is no funding associated with the work featured in this article.