Systematic Review: Safety and Efficacy of mRNA COVID-19 Vaccines in Pregnant Women

Abstract

Since pregnant women were excluded from clinical trials for vaccines against SARS-CoV-2, the novel coronavirus disease 2019 (COVID-19), there is limited data on the safety and efficacy of vaccines in this population. This systematic review explored the safety and efficacy of mRNA vaccines in pregnant women. A literature search was performed using Ovid databases through November 2021 for all studies evaluated efficacy and safety of mRNA COVID-19 vaccines in pregnant women. A total of five studies including 42,782 women were included in the systematic review. Humoral immunity to COVID-19 was detected in pregnant women who received the vaccine and no differences found in spike-specific T-cell responses. Incidence of high-grade chronic villitis is higher in the unvaccinated group with adjusted odds ratio of .31 (.1-.97), P < .05. Vaccination in pregnant women resulted in 12.6% spontaneous abortions (SAB) with 92.3% occurring in the first trimester, .1% stillbirth (>20 weeks gestation), 9.4% preterm birth (<37 weeks gestation), and 2.2% congenital abnormalities. The mRNA COVID-19 vaccines are immunogenic in pregnant women and no obvious safety concerns observed. There is no increased incidence of adverse reactions in pregnant women. Our finding supports that pregnant women should receive the vaccination at their earliest convenience regardless of trimester.

Keywords

COVID-19 vaccination pregnancy Pfizer-BioNTech Moderna

Background

On January 21, 2020, the Centers for Disease Control and Prevention (CDC) confirmed the first COVID-19 case in the United States.¹ COVID-19 is an infectious disease caused by a virus known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).² People who are infected with the virus will experience mild to moderate respiratory illness such as cough and sore throat, but there are some who will become seriously ill and require medical attention.² Severe symptoms include difficulty breathing or shortness of breath, loss of speech or mobility, and chest pain.² On March 11, 2020, the World Health Organization declared COVID-19 as a pandemic.¹ As of March 2022, there have been 473 million COVID-19 cases worldwide and over 6 million deaths as a result of the virus.³

To reduce the spread of the virus, Phase 1 trials for COVID-19 vaccines began as early as March 2020 and Phase 3 trials began as early as July 2020.¹ In December 2020, the FDA approved Emergency Use Authorizations (EUA) for both the Pfizer-BioNTech and Moderna COVID-19 vaccines⁴ and in February 2021, the FDA approved EUA for the J&J Janssen COVID-19 vaccine.⁵ In July 2022, FDA issued an EUA for the Novavax COVID-19 vaccine.⁶ The Pfizer-BioNTech and Moderna vaccines are mRNA vaccines that include at least two doses for full primary vaccination completion and available boosters. The Moderna vaccine is 2-dose primary series 4 weeks apart for ages 18 and older.⁷ The Pfizer-BioNTech vaccine is 2-dose primary series 3 weeks apart for ages 5 and older (COMIRNATY for ages 16+ and generic Pfizer-BioNTech vaccine label for ages 5-15).⁸ A third dose of the primary series of mRNA vaccines are authorized for certain individuals who have undergone solid organ transplantation, or who are diagnosed with conditions that are considered to have an equivalent level of immunocompromise.^7,8 The J&J Janssen vaccine is a viral vector vaccine and administered as one dose for ages 18 and older.⁹ The Novavax COVID-19 Vaccine, Adjuvanted is a protein subunit vaccine and administered as 2-dose series 3 weeks apart.⁶ This systematic review will only focus on the Pfizer-BioNTech and Moderna COVID-19 mRNA vaccines.

In the early stages of the pandemic where only one variant was known, the Moderna COVID-19 vaccine was shown to reduce the risk of COVID-19 infection by 94.5% in phase 3 trials and the Pfizer-BioNTech COVID-19 vaccine was shown to be 95% effective.^4,8 In October 2020, the earliest documented sample of the delta variant was found and in November 2021, the omicron variant was found.¹⁰ In a study between November 2021 and January 2022, the effectiveness of the COVID-19 vaccine against the delta and omicron variants was evaluated.¹¹ After the full 2-dose series, the Pfizer-BioNTech COVID-19 vaccine was shown to be 90.9% effective against the delta variant and 65.5% effective against the omicron variant.¹¹ After the full 2-dose series, the Moderna COVID-19 vaccine was shown to be 94.5% effective against the delta variant and 75.1% effective against the omicron variant.¹¹

Since pregnant women were not included in the clinical trials before EUAs were granted, data on vaccine safety and efficacy in this population remains limited.¹² As of early May 2021, only 16.3% of pregnant women in the US received >1 dose of a COVID-19 vaccine during pregnancy or prior to pregnancy.¹³ Vaccination was lowest among Hispanic (11.9%) and non-Hispanic Black women (6.0%) and women aged 18-24 years (5.5%) and highest among non-Hispanic Asian women (24.7%) and women aged 35-49 years (22.7%).¹³ As of November 2021, 63.2% of pregnant women received >1 dose of a COVID-19 vaccine during pregnancy or prior to pregnancy.¹⁴ Vaccination was lowest among non-Hispanic Black women (53.4%) and highest among non-Hispanic Asian women (88.7%).¹⁴ The hesitation of receiving the COVID-19 vaccine may be due to limited data on the safety of the vaccines for pregnant women since they were excluded from clinical trials.¹² Regardless of COVID-19 infection, birth defects affect one in every 33 babies in the US each year and account for 20% of all infant deaths.¹⁵ Spontaneous abortion (SAB), also known as miscarriage, occurs in up to 10% of clinically recognized pregnancies (80% occurs in the first trimester).¹⁶ Pregnant women with COVID-19 infection may be at an increased risk for these adverse pregnancy and neonatal outcomes (birth defects, SAB, preterm births) compared with pregnant women without COVID-19 infection.¹⁷ In addition, pregnant women with COVID-19 are at an increased risk for severe COVID-19 associated illness, which included admission to an intensive care unit (ICU), received extracorporeal membrane oxygenation, or received invasive mechanical ventilation, or increased risk of death.¹⁷ With the maternal and neonatal risks associated with COVID-19 infection in pregnant women, it is important to determine whether COVID-19 vaccination is safe and effective for this population.

As updated on March 3, 2022, the CDC recommends COVID-19 vaccination for people who are pregnant, breastfeeding, trying to get pregnant now, or might become pregnant in the future.¹⁴ There is still a lack of further research in this area which is evident in the low COVID-19 vaccination rate among pregnant women in the US despite the vaccine being available since December 2020. As of December 2022, there are only five studies that have been completed to evaluate the efficacy and safety of COVID-19 mRNA vaccines in pregnant women. This systematic review will demonstrate the safety and efficacy of COVID-19 mRNA vaccination in pregnant women based on the limited data available.

Methods

Data Sources and Search Strategy

A comprehensive literature search was performed using Ovid databases through November 2021. The key terms used in this systematic review included “coronavirus,” “pregnancy,” “COVID-19,” “vaccine,” “Pfizer-BioNTech,” “Moderna,” “Johnson & Johnson,” and “mRNA vaccine.” Figure 1 includes the Preferred Reporting Items for Systematic Reviews (PRISMA) flow diagram¹⁸ to illustrate the selection of articles for this systematic review.

Data Extraction

We extracted the following data from the studies: title, author, publication year, study design, study population, baseline characteristics, outcomes, results, and conclusions. We followed the PRISMA -) 2020 Checklist to select the final studies and perform this systematic review. PRISMA is a 27-item check list used to identify, select, appraise, and synthesize studies.¹⁸

Inclusion and Exclusion Criteria

During our search, we included full publications and abstracts of randomized controlled trials, cohort studies, and case-control studies which evaluated the efficacy or safety of COVID-19 mRNA vaccines in pregnant women. There were 11 total articles that included information about pregnancy and COVID-19 vaccine, but only five evaluated the efficacy and safety of mRNA vaccines. We selected five full text articles to conduct this systematic review. We excluded animal studies, case reports, editorials, and letters to editors. We excluded articles which were only informational and did not evaluate any outcomes.

Outcomes

The goal of these studies was to evaluate the efficacy or safety of mRNA COVID-19 vaccines, although primary outcomes for each study were different. The primary outcomes (Table 1) include humoral immunity to COVID-19, adverse reactions and neonatal outcomes, antibody responses, placental lesions, and SAB. There were no secondary outcomes evaluated in any of the studies. Adverse outcomes (Table 2) were also evaluated in some of the studies. The most frequently local and systemic reactions reported were injection-site pain, fatigue, headache, and myalgia.

Table 1.

Summary of Individual Studies.

	Outcome	Results	Conclusions
Collier et al,¹² May 2021	• SARS-CoV-2 receptor binding antibody responses from pregnant, lactating, and nonpregnant women • Humoral and cellular immune responses against original SARS-CoV-2 strain and B.1.1.7 and B1.351 variants	• Antibody responses: RBD-IgG binding antibody titers in NP (37 839), P (27 601), and L (23 497) after the 2nd dose were higher than baseline pre-vaccination titers; antibodies were found in cord blood and breast milk • Immune responses: No differences were found in spike-specific T-cell responses across the strains evaluated	• Vaccine-elicited antibodies were transported to infant cord blood and breast milk • Receipt of a COVID-19 mRNA vaccine was immunogenic in pregnant women • Pregnant and nonpregnant women who were vaccinated developed cross-reactive antibody responses and T-cell responses against SARS-CoV-2 variants of concern
Gray et al,¹⁹ Mar 2021	• Titers of SARS-CoV-2 spike and receptor-binding domain IgG, IgA, and IgM in participant sera, breastmilk, and umbilical cord sera	• Vaccine-induced maternal antibody titers in sera did not differ by trimester of vaccination • Higher levels of SARS-CoV-2 antibodies were observed in all vaccinated women compared with pregnant women with natural infection • Vaccine-induced IgG was transferred across the placenta to the fetus and also through breastmilk	• COVID-19 mRNA vaccines generated robust humoral immunity in pregnant and lactating women • Vaccine-induced immune responses were statistically significantly greater than the response to natural infection • Immune transfer to neonates occurred via placenta and breastmilk
Shanes et al,²¹ Jul 2021	• Placental lesions such as decidual arteriopathy, fetal vascular malperfusion, low/high-grade chronic villitis, or chronic histocytic intervillositis	• Incidence of high-grade chronic villitis higher in the control group than vaccinated group with adjusted OR of .31 (.1-.97), P < .05 • No statistically significant difference in other placental lesions evaluated	• No increased incidence of placental lesions in women with COVID-19 mRNA vaccination compared to women with no vaccination
Shimabukuro et al,¹⁷ Apr 2021	• Adverse reactions (v-safe) • Pregnancy and neonatal outcomes (v-safe pregnancy registry) • Pregnancy-related adverse events (VAERS)	• V-safe: injection-site pain, fatigue, headache, and myalgia were the most frequent local and systemic reactions • Pregnancy registry: 12.6% SAB, .1% stillbirth, 9.4% preterm birth, 2.2% congenital abnormalities • VAERS: 46 cases of SAB (37 in 1st trimester, 2 in 2nd trimester, 7 in unknown trimester)	• Preliminary findings did not show obvious safety concerns among pregnant women who received COVID-19 mRNA vaccines
Zauche et al,²⁰ Aug 2021	• Spontaneous abortion (defined as pregnancy loss occurring from 6 to <20 weeks’ gestation)	• Cumulative risk of SAB from 6 to 19 weeks’ gestation was 14.1% (95% CI: 12.1-16.1%) • Age-standardized cumulative risk of SAB was 12.8% (95% CI: 10.8-14.8%)	• Receipt of COVID-19 mRNA vaccine preconception or during pregnancy is not associated with an increased risk of spontaneous abortion

Table 2.

Adverse Outcomes of Individual Studies.^a

Collier et al,¹² May 2021	•Fever was reported in 27 NP (52%, SD 7%), 4 P (14%, SD 6%), 7 L (44%, SD 12%) women •No severe adverse events or pregnancy or neonatal complications were observed
Gray et al,¹⁹ Mar 2021		NP (n = 16)		P (n = 84)		L (n = 31)
		1st dose	2nd dose	1st dose	2nd dose	1st dose	2nd dose
	Injection-site soreness	75	75	88	57	67	61
	Fatigue	38	56	14	53	13	50
	Fever or chills	6	50	1	32	3	43
	Headache	31	38	8	32	30	39
Shanes et al,²¹ Jul 2021	Placental lesions	Vaccine group (n = 84)	Control group (n = 116)		aOR (95% CI)		P
	Decidual arteriopathy	10	12		.75 (.3-1.9)		.55
	Fetal vascular malperfusion	6	7		.85 (.27-2.7)		.78
	Low-grade chronic villitis	12	8		1.6 (.62-4.2)		.33
	High-grade chronic villitis	5	14		.31 (.1-.97)		.04
	Chronic histiocytic intervillositis	0	1.7
Shimabukuro et al,¹⁷ Apr 2021		Pfizer-BioNTech		Moderna		Total
		1st dose (n = 9052)	2nd dose (n = 6638)	1st dose (n = 7930)	2nd dose (n = 5635)	1st dose (n = 16 982)	2nd dose (n = 12 273)
	Injection-site pain	84.0	88.7	92.8	95.6	88.1	91.9
	Fatigue	26.6	63.7	33.0	80.6	29.6	71.5
	Headache	16.5	47.3	19.9	65.0	18.1	55.4
	Myalgia	8.8	43.9	14.7	66.1	11.6	54.1
Zauche et al,²⁰ Aug 2021	•Among 2456 pregnant women, 27.5% experienced at least one prior SAB and 9.1% had experienced at least two prior SABs•After vaccination, 165 (6.7%) women self-reported an SAB, of which 154 (93.3%) occurred prior to 14 weeks’ gestation^b

NP, nonpregnant; P, pregnant; L, lactating.

^aAll numbers are reported as percentage.

^bPrior to 14 weeks gestation means during the first trimester.

Statistical Analysis

We did not perform any statistical analyses on the outcomes of the studies since all outcomes were measured differently. Each study performed their own statistical analysis (Table 3), and their results are summarized.

Table 3.

Statistical Analysis of Individual Studies.

Collier et al,¹² May 2021	• Descriptive statistics were calculated using SAS 9.4 and GraphPad Prism 8.4.3• Data presented as median with interquartile range or proportion with standard deviation
Gray et al,¹⁹ Mar 2021	• Participant characteristics summarized with frequency statistics• Continuous outcomes reported as mean (standard deviation) or median (interquartile range) and correlation analyses were performed using Spearman coefficients.• Statistical significance was defined as P < .05• Statistical analyses were performed using GraphPad Prism 9 and Stat/IC version 16.1
Shanes et al,²¹ Jul 2021	• Performed with unpaired t tests or Fisher exact test for demographics and logistic regression with gestational age as a covariate for placental lesions (Python SciPy 1.6.1)• Post hoc power calculation was performed, demonstrating at least 80% power to identify a 2.5-fold or higher increased risk of any lesion with a baseline prevalence of >10% and a threefold or higher increased risk of any lesion with a baseline prevalence of >7%
Shimabukuro et al,¹⁷ Apr 2021	• Descriptive analyses were performed with the use of v-safe survey data for persons who identified as pregnant through February 28,2021; persons enrolled in the v-safe pregnancy registry who were vaccinated through February 28,2021; and vaccine adverse event reporting system (VARES) reports involving pregnant women received through February 28, 2021• Local and systemic reactogenicity was compared between persons who identified as pregnant and nonpregnant women• Descriptive analyses were conducted with the use of SAS 9.4• All activities were reviewed by the CDC and were conducted in accordance with applicable federal law and CDC policy
Zauche et al,²⁰ Aug 2021	• Descriptive analyses were performed• Gestational age at vaccination was calculated using self-reported date of vaccination, and either self-reported estimated due date or date of the first day of the last menstrual period• Life table methods were used to calculate the cumulative risk of SAB by gestational week• A sensitivity analysis was conducted to estimate the maximum possible risk of SAB

Results

Study Characteristics

A total of 5 studies were analyzed in this systematic review (Table 4). These studies were conducted between March and August 2021. Three studies (Gray et al,¹⁹ Shimabukuro et al,¹⁷ Zauche et al²⁰) focused on the vaccinated group whereas two studies (Collier et al,¹² Shanes et al²¹) compared a vaccinated group with an unvaccinated group. The Shimabukuro et al¹⁷ study evaluated three different groups where all women were pregnant. The groups included participants in the V-safe surveillance system, V-safe pregnancy registry, and vaccine adverse event reporting system (VAERS). V-safe is a new CDC smartphone-based active surveillance system where enrollment is necessary.¹⁷ A total of 42 782 participants were included in all five studies with 42 662 participants being pregnant at the time of evaluation. Figure 2 assesses the quality of each individual study using the Newcastle-Ottawa Quality Assessment Scale.²² All five studies did not demonstrate that the outcome of interest was not present at the start of the study and did not mention any loss of follow-up. Therefore, they did not receive a score for those two categories. Ascertainment of exposure was self-reported for all studies except for Collier et al.¹²

Table 4.

Baseline Characteristics of Individual Studies.

	Study type & design	Total participants (n)	Vaccinated (%)	Age^a (yr)	Pfizer-BioNTech^a (%)	Moderna^a (%)	Trimester of 1st dose (%)
Collier et al,¹² May 2021	FT; exploratory, descriptive, PC	131 (63 NP, 52 P, 16 L)	78.6	32.8	60 NP, 37 P, 69 L	40 NP, 63 P, 31 L	1st		17
							2nd		50
							3rd		33
Gray et al,¹⁹ Mar 2021	FT; PC	131 (16 NP, 84 P, 31 L)	100	35.7	50.3	49.7	1st		13
							2nd		46
							3rd		40
Shanes et al,²¹ Jul 2021	RL; RC	200	42	33.1	N/A	N/A	N/A
Shimabukuro et al,¹⁷ Apr 2021	FT; PC	V-safe: 35 691Registry: 3958VAERS: 221	100	>60% between 25 and 34	V-safe: 53.9Registry: 54.0	V-safe: 46.1Registry: 46.0	Peri^b	2.3
							1st	28.6
							2nd	43.3
							3rd	25.7
Zauche et al,²⁰ Aug 2021	FT; RC	2456	100	49% between age 30 and 34	52.7	47.3	Peri^b		15.5
							1st		50.1
							2nd		34.4

N/A, not available (information was not provided by the study). FT, full text; PC, prospective cohort; RL, research letter; RC, retrospective cohort; NP, nonpregnant; P, pregnant; L, lactating.

^aMedian Value; range is provided when median value is not provided.

^bPericonception is within 30 days before last menstrual period.

Primary Outcomes

Table 1 summarizes the primary outcomes, results, and conclusions of each individual study. Immunologic assays were used to measure humoral immune response and cellular immune response.¹² Receptor binding domain (RBD) IgG and IgA binding antibody is a measure of antiviral humoral immune response and can be used to assess cross-reactive serum IgG or IgA binding against viral variants of concern using mutated spike RBD protein.¹² Humoral immunity to COVID-19 was detected in pregnant women who received the vaccine and there were no differences found in spike-specific T-cell responses across different strains evaluated.¹² Vaccine-induced maternal antibodies were transferred across the placenta to the fetus and also through breastmilk.¹⁹ Incidence of high-grade chronic villitis is higher in the unvaccinated group than vaccinated group with adjusted OR of .31 (.1-.97), P < .05.²¹ No statistically significant difference in other placental lesions were found.²¹ Vaccination in pregnant women resulted in 12.6% SAB with 92.3% occurring in the first trimester, .1% stillbirth, 9.4% preterm birth, and 2.2% congenital abnormalities.¹⁷ Cumulative risk of SAB from 6 to 19 weeks’ gestation was 14.1% (95% CI: 12.1-16.1%).²⁰

Adverse Outcomes

Table 2 summarizes the adverse outcomes evaluated in the individual studies. The top four most reported adverse outcomes were selected for the Gray et al¹⁹ study and Shimabukuro et al¹⁷ study. Overall, there was no statistically significant difference between pregnant women and nonpregnant women in terms of adverse outcomes after vaccination with mRNA COVID-19 vaccines

Discussion

The goal of this systematic review is to evaluate the safety and efficacy of Pfizer-BioNTech and Moderna mRNA COVID-19 vaccines in pregnant women to provide an evidence-based recommendation on whether pregnant women should receive vaccination. Due to the exclusion of pregnant women from initial clinical trials, there was limited evidence to provide such recommendation to this population. This systematic review summarizes a total of five cohort studies which evaluated the safety and efficacy of the mRNA COVID-19 vaccines in pregnant women.

As of January 2022, the CDC recommends that all pregnant women receive the COVID-19 vaccination regardless of trimester. This recommendation may be based on two studies (Collier et al¹² and Gray et al¹⁹) which evaluated the immunogenicity of the vaccination in pregnant women. Both studies showed that immunity passes through the placenta to the fetus and through breastmilk. Gray et al¹⁹ also found that higher level of COVID-19 antibodies were found in all vaccinated women compared with pregnant women 4-12 weeks from natural COVID-19 infection. The result of these two studies illustrates that COVID-19 vaccination, specifically the mRNA vaccines, is effective in protecting pregnant women from COVID-19 infection.

Two studies (Gray et al¹⁹ and Shimabukuro et al¹⁷) evaluated the adverse outcomes after COVID-19 vaccination and found that injection-site pain, fatigue, and headache were the most commonly reported. These symptoms are listed as possible side effects of all COVID-19 vaccinations^7,8,12 and are typically reported in all populations. Gray et al¹⁹ compared pregnant, nonpregnant, and lactating women. There was no significant difference in adverse effects between all groups after vaccination. Shimabukuro et al¹⁷ found small differences in reporting frequency between pregnant and nonpregnant women. Pregnant women did not report having severe reactions more frequently than nonpregnant women, except for nausea and vomiting, which can be an ADE due to natural progression in pregnancy.¹⁷ The findings from these two studies illustrate that the mRNA COVID-19 vaccines are safe in pregnant women. Three out of the five studies evaluated pregnancy-related and neonatal adverse outcomes. First, Shanes et al²¹ evaluated the occurrence of placental lesions (Table 5) in pregnant women who were vaccinated and not vaccinated. The study found a statistically significant difference for high-grade chronic villitis²¹ which is inflammation of placental villi which could lead to complications such as intrauterine growth restriction, neurologic complications, stillbirth, neonatal death.²³ Pregnant women who were not vaccinated were more likely to experience high-grade chronic villitis compared to pregnant women who were vaccinated.²¹ However, there were no increased incidences for other placental lesions (Table 5) in vaccinated women compared to nonvaccinated women.²¹

Table 5.

Placental Lesions.

	Definition	Complications
Decidual Arteriopathy²⁵	Thickening or fibrinoid necrosis of the vessel wall, endothelial swelling and detachment	Pre-eclampsia, fetal growth restriction
Fetal vascular malperfusion²⁶	Applied to a group of placental lesions indicating reduced or absent perfusion of villous parenchyma by the fetus	Fetal growth restriction, CNS injury, stillbirth
Low-grade chronic villitis²³	Inflammation of placental villi with <10 contiguous villi in any one focus	Intrauterine growth restriction
High-grade chronic villitis²³	Inflammation of placental villi with >10 contiguous villi in at least one focus	Intrauterine growth restriction, neurologic complications, stillbirth, neonatal death
Chronic histocytic intervillositis²⁷	Infiltration of maternal macrophages into placenta	Spontaneous or recurrent abortion, fetal growth restriction, fetal death

Second, Zauche et al²⁰ evaluated the risk of SAB in pregnant women who received an mRNA COVID-19 vaccination. According to Zauche et al,²⁰ SAB is a common pregnancy outcome affecting 11 to 22% of recognized pregnancies. Of 2456 pregnant participants in their study, 27.5% had experienced at least one prior SAB and 9.1% had experienced at least two prior SABs.²⁰ All participants received at least one mRNA COVID-19 vaccine dose preconception or prior to 20 weeks’ gestation (during their first or second trimester).²⁰ After vaccination, 6.7% of the participants self-reported an SAB, of which 154 (93.3%) occurred prior to 14 weeks’ gestation (during the first trimester).²⁰ The cumulative risk of SAB from 6 to 19 weeks’ gestation was 14.1% (95% CI: 12.1-16.1%) and age-standardized cumulative risk of SAB was 12.8% (95% CI: 10.8-14.8%).²⁰ The week-specific SAB risk was higher in percentage in the first trimester than in the second trimester, although the risk of SAB post vaccination is still within acceptable general population limit of 11-22%.²⁰

Third, Shimabukuro et al¹⁷ evaluated pregnancy-related and neonatal adverse outcomes through the V-safe pregnancy registry and VAERS. Among 827 participants in the registry who had completed a pregnancy, the pregnancy resulted in a live birth in 86.1%, SAB in 12.6%, and stillbirth in 1 participant.¹⁷ 98.3% of the pregnancies that resulted in a live birth were among persons who received their first eligible vaccine dose in their third trimester.¹⁷ Among the live-born infants, there were no significant reports of neonatal outcomes or neonatal death.¹⁷ Through VAERS, there were 46 cases of SAB with 37 in the first trimester, 2 in the second trimester, and 7 in unknown. There were three cases each of stillbirth, premature rupture of membranes, and vaginal bleeding. There were no reports of any congenital anomalies.¹⁷ This sample consists of <1% of pregnant women in the v-safe program, so these adverse events are considered rare in the pregnant population who received COVID-19 vaccinations. Based on these results, it may be safe to recommend the mRNA COVID-19 vaccine to pregnant women in their second or third trimester.

In a recent development, vaccine associated myocarditis have been reported in 1.62% of the vaccinated population.⁶ This post vaccination adverse event have been reported in young male who have received second dose of mRNA vaccines (Modera & Pfizer-BioNTech). According to Britter et al,²⁴ post vaccination induced myocarditis have not been reported in pregnant patients.

After evaluating all five studies, this systematic review concludes that the Pfizer-BioNTech and Moderna mRNA COVID-19 vaccines are safe and effective in pregnant women. This systematic review has a couple of strengths. First, there are currently no published manuscripts which provide a summary of research performed on the pregnant population regarding COVID-19 vaccination. This systematic review provides an evidence-based recommendation which may potentially increase vaccination rates in pregnant women by reducing pregnant women’s fear of receiving the COVID-19 vaccination. Physicians and obstetricians may refer to this systematic review for a summary of results rather than evaluating individual studies to provide a recommendation to their pregnant patients. In addition, this systematic review can be used to identify what further research can be done. For example, since there is still a limited number of studies on the safety and efficacy of the COVID-19 vaccine in pregnant women, researchers can form more studies regarding the topic. The studies can go further into detail about the effectiveness of the vaccine in the newer variants of SARS-CoV-2 such as the delta and omicron variant.

However, there are a few limitations to this systematic review. Since the outcomes of each study were different from each other, statistical analysis was not performed to provide a median result from all studies. This systematic review only serves as a summary of results. Once there are more studies available in the future, it is highly recommended to gather similar data and perform statistical analysis for another systematic review. In addition, this systematic review only included studies which evaluated the Pfizer-BioNTech and Moderna mRNA COVID-19 vaccines. There are many vaccines available worldwide, including J&J’s Janssen COVID-19 vaccine which is available in the US. The decision to evaluate only mRNA COVID-19 vaccines was based on the availability of studies when searching the databases. Future studies should include evaluation of all available COVID-19 vaccines rather than limiting it to just mRNA vaccines. Another limitation to this systematic review is that three out of five studies had a relatively small study population. To provide more conclusive recommendations, a cohort study with a larger population should be conducted.

Conclusion

The Pfizer-BioNTech and Moderna mRNA COVID-19 vaccines are immunogenic in pregnant women and there were no safety concerns observed. There is no increased incidence of adverse reactions in pregnant women compared to nonpregnant women. According to the CDC, COVID-19 vaccination is recommended for women who are pregnant, breastfeeding, trying to get pregnant, or might become pregnant in the future. The CDC does not have any specific recommendations for which trimester to receive the vaccination. Our systematic review concurred with CDC recommendations that pregnant women should receive the mRNA COVID-19 vaccines from Pfizer-BioNTech or Moderna at their earliest convenience to reduce the risk of severe illnesses associated with COVID-19 infection, regardless of their pregnancy trimester status.

Footnotes

Author Contribution

The authors confirm contribution to the paper as follows: study conception and design: Julia Lam, Jeffrey Nehira, and Bin Deng. Data collection: Julie Lam; analysis and interpretation of results: Julie Lam, Jeffrey Nehira, Olivia Phung, Bin Deng; draft manuscript preparation: Julie Lam, Jeffrey Nehira, Olivia Phung, Bin Deng. All authors reviewed the results and approved the final version of the manuscript.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Bin Deng

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