Coronavirus Disease 2019 (COVID-19) Vaccination in Pregnancy

Coronavirus disease 2019 (COVID-19) vaccination is safe, effective, and recommended in pregnancy. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in pregnancy is associated with significant maternal morbidity and mortality, and its risks can be mitigated with coronavirus disease 2019 (COVID-19) vaccination. Vaccination against COVID-19 in pregnancy results in protection against both maternal and neonatal SARS-CoV-2 infection, as well as maternal critical illness. Vaccination during pregnancy is safe, with no documented risks of pregnancy loss, preterm delivery, congenital anomalies, or other adverse perinatal outcomes. For these reasons, COVID-19 vaccination is recommended in pregnancy by the Centers for Disease Control and Prevention, the American College of Obstetricians and Gynecologists, and the Society for Maternal-Fetal Medicine, as well as other national and international professional organizations. In this review, we will summarize the published literature demonstrating the benefit and safety of these vaccines.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in pregnancy is associated with significant maternal morbidity and mortality, and its risks can be mitigated with coronavirus disease 2019 (COVID- 19) vaccination. Vaccination against COVID-19 in pregnancy results in protection against both maternal and neonatal SARS-CoV-2 infection, as well as maternal critical illness. Vaccination during pregnancy is safe, with no documented risks of pregnancy loss, preterm delivery, congenital anomalies, or other adverse perinatal outcomes. For these reasons, COVID-19 vaccination is recommended in pregnancy by the Centers for Disease Control and Prevention, the American College of Obstetricians and Gynecologists, and the Society for Maternal-Fetal Medicine, as well as other national and international professional organizations. In this review, we will summarize the published literature demonstrating the benefit and safety of these vaccines. T he rapid development of coronavirus disease 2019  vaccines and the limited prospective data on COVID-19 vaccination in pregnancy has re-sulted in individuals, including pregnant individuals, being fearful of potential risks. The uptake of vaccination has been lower among pregnant individuals as compared with reproductive-aged nonpregnant individuals, with notable disparities by race and ethnicity. 1,2 The most recent data from the Centers for Disease Control and Prevention (CDC) (as of December 31,2022) show that 72% of pregnant individuals are fully vaccinated with the primary vaccine series. 3 These findings are despite unequivocal data demonstrating increased risks of maternal adverse outcomes (intensive care unit [ICU] admission, mechanical ventilation, death) and fetal or neonatal adverse outcomes (preterm delivery, stillbirth) with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during pregnancy. 4 The primary goal of coronavirus disease 2019 (COVID-19) vaccination is to prevent severe disease, hospitalization, and death due to COVID-19. Initial randomized controlled trial data for the Pfizer-BioNTech (BNT162b2) and Moderna (mRNA-1273) mRNA vaccines demonstrated 91% and 93% efficacy, respectively, against laboratory-confirmed SARS-CoV-2 infection, with some decline in vaccine efficacy with time elapsed since the last dose. 5,6 These initial studies were completed before the development of novel SARS-CoV-2 variants. Over the past 2 years, realworld experience and subsequent data have demonstrated lower vaccine efficacy against infection; thus, a bivalent booster targeting the native SARS-CoV-2 strain as well as the Omicron strain was developed.
In this narrative review, we provide evidencebased answers to common questions faced by clinicians caring for pregnant individuals. We discuss the efficacy of COVID-19 vaccines by summarizing the published literature on the maternal antibody response to vaccination and on the decreased risks of SARS-CoV-2 infection during pregnancy with vaccination, present the neonatal benefit of maternal vaccination, and highlight the documented safety profile of vaccination during pregnancy. We will focus primarily on mRNA-based vaccines, because these are the most available vaccines in the United States.

WHAT ARE THE CURRENT RECOMMENDATIONS FOR COVID-19 VACCINATION IN PREGNANT INDIVIDUALS?
The American College of Obstetricians and Gynecologists, the Society for Maternal-Fetal Medicine (SMFM), and the CDC all recommend COVID-19 vaccination at any point for individuals who are pregnant or may be pregnant in the future. 7-9 mRNA vaccines are preferred, although any COVID-19 vaccine platform with U.S. Food and Drug Administration approval or emergency use authorization is acceptable.
For individuals who have not been vaccinated against COVID-19 before or during pregnancy and are not immunocompromised, an initial two-dose mRNA vaccine series constitutes the primary series. The primary series can be administered at any point in pregnancy. For individuals who previously have received a primary vaccine series with or without a monovalent booster outside of pregnancy, a bivalent booster dose should be administered 2 months after the completion of a primary series or 2 months after the last (monovalent) booster dose, regardless of the total number of COVID-19 vaccine doses a patient has received (Fig. 1). 10,11 Special circumstances exist in which the COVID-19 vaccination schedule deviates from that described above. In immunocompromised patients (such as individuals with organ transplant, use of immunosuppressing medications, congenital immunosuppressing conditions, and other similar conditions), the primary vaccine series is a three-dose mRNA series, with the third dose administered 4 weeks after the second dose. A bivalent booster is recommended 2 months after completion of the three-dose primary series. 10,11 During pregnancy, influenza and Tdap (tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis) vaccinations are routinely recommended. Timing of COVID-19 vaccine administration is independent of the timing of influenza and Tdap vaccine administration, and co-administration is appropriate. Initial recommendations to separate COVID-19 vaccination from other vaccinations were motivated by the need to document COVID-19 vaccine-specific side effects and adverse effects. At present, only for recent vaccination against mpox (formerly monkeypox) is a delay of 4 weeks before a COVID-19 vaccine suggested. 11 Up-to-date recommendations regarding COVID-19 vaccination can be found on the CDC website: https://www.cdc.gov/vaccines/covid-19/downloads/ COVID-19-immunization-schedule-ages-6monthsolder.pdf. 10 COVID-19 vaccination is directed against the SARS-CoV-2 spike (S) protein, and the vaccine-induced antibody is the anti-S antibody. SARS-CoV-2 infection also induces anti-S antibodies, in addition to other antibodies, such as anti-nucleocapsid (N) antibodies, that are not generated after vaccination alone. The typical response to an antigenic stimulus (vaccine or infection) is to initially produce immunoglobulin (Ig)M antibodies, followed by IgG antibodies as the immune response matures. Immunoglobulin A antibodies are also produced in response to an antigenic stimulus, but, because these are most commonly mucosal antibodies, most of the data on COVID-19 vaccination pertain to anti-S IgG.
Several studies have evaluated the maternal anti-S response to vaccination during pregnancy. Initial studies of third-trimester vaccination among 122 individuals who delivered at or near term demonstrated that vaccine-induced antibodies are identified in umbilical cord blood as early as 16 days after the first dose of an mRNA vaccine. 12 Other data have identified a linear correlation between maternal IgG levels at delivery and umbilical cord or neonatal IgG levels. 12,13 When examining the antibody response to vaccination across all trimesters of vaccination, a cohort study of 1,359 vaccinated individuals who delivered term and late preterm neonates found that anti-S antibodies are detectable at delivery regardless of gestational age at the time of vaccine initiation, as long as individuals were fully vaccinated (defined as at least 2 weeks elapsed since the last vaccine dose) at delivery. The peak maternal and umbilical cord anti-S antibody at delivery was identified with vaccine initiation in the early third trimester, findings that are substantiated in another cohort study (Fig. 2). 14,15 These data should not be interpreted to suggest that third-trimester vaccination is the optimal time of vaccination. One study excluded deliveries at less than 34 weeks of gestation, and the other excluded deliveries at less than 37 weeks. Importantly, in the clinical setting, gestational age at birth cannot be predicted. Waiting for thirdtrimester vaccination only delays maternal protection, the primary indication for vaccination in pregnancy, and may also result in suboptimal neonatal protection.
Another question is whether the immediate and long-term antibody responses to COVID-19 vaccination are affected by the pregnant state. In one cohort study of pregnant and reproductive-aged nonpregnant individuals, the initial anti-S IgG antibody response was not different between the groups. 16 Another study, however, has noted some subtle differences in the initial immunologic response that may be attributable to pregnancy. 17 Longitudinal data regarding how the anti-S IgG antibody response wanes over time demonstrate no differences over 6-8 months for individuals vaccinated in pregnancy compared with reproductive-aged nonpregnant individuals. Differences are noted in the IgA peak and longitudinal response by pregnancy state, but the implications of these findings are unknown because clinical follow-up was not included in these studies. 16

DOES COVID-19 VACCINATION IN PREGNANCY PREVENT MATERNAL COVID-19?
In pregnancy, COVID-19 vaccination decreases the risks of and complications arising from SARS-CoV-2 infection. In a study of 10,000 pregnant individuals cared for in a single health system in Louisiana during the peak of the Delta variant, COVID-19 vaccination significantly reduced the risk of severe or critical COVID-19 illness, from 0.66% to 0.08%. 18 Specifically, none of the 1,332 vaccinated pregnant individuals in the study required supplemental oxygen or ICU admission; however, there was one maternal death, five ICU admissions, and six stillbirths among the 8,760 unvaccinated pregnant individuals with COVID-19.
Population-based data from other countries have similarly demonstrated the maternal benefit of vaccination in pregnancy. In Scotland, where most patients had an mRNA-based vaccine, the relative burden of COVID-19 fell on unvaccinated pregnant individuals. Whereas 77% of all COVID-19 cases occurred in unvaccinated pregnant individuals, 91% of all hospital admissions occurred in unvaccinated individuals, and 98% of all critical care admissions occurred in unvaccinated individuals. 19 In a cohort of 28,000 Israeli pregnant individuals, the efficacy of mRNAbased COVID-19 vaccination was estimated to be 96% in the first 2 months after individuals were considered to be fully vaccinated (at least 7 days after the second dose). Vaccine efficacy against hospitalization due to COVID-19 was approximately 89% at a time in which the circulating SARS-CoV-2 variants were the original strain and the Alpha variant. 20 In a recent study of 4,517 COVID-19-related emergency department or urgent care visits by pregnant individuals in the United States, COVID-19 vaccination reduced the risk of needing medical evaluation by 75-85% during the Delta wave, with more variable protection observed during the Omicron wave. 21 These authors also demonstrate efficacy of COVID-19 vaccination (primary series with or without a monovalent booster) against COVID-19-related hospitalization, with 96-99% efficacy during the Delta wave and 86% efficacy during the Omicron wave among individuals who received the last COVID-19 vaccine dose within 150 days.
An outstanding question is whether the efficacy of vaccination is different in pregnant individuals com-pared with postpartum or nonpregnant individuals. In a study of almost 20,000 individuals in Norway during the Delta and early Omicron periods, the risks of COVID-19 were not different among individuals fully vaccinated in pregnancy, fully vaccinated postpartum after receiving one dose of vaccine in pregnancy, or fully vaccinated outside of pregnancy and postpartum. 22 The overall benefits of COVID-19 vaccination in pregnancy are illustrated in Box 1. Unauthorized reproduction of this article is prohibited.
Data generated both from real-world efficacy as well as antibody response to booster doses in pregnancy demonstrate the importance of boosting and remaining up-to-date with vaccine-schedule recommendations. Much of the available data regarding the benefit attributable to a booster dose in pregnancy have been generated with the monovalent booster. Two studies have investigated the effects of receiving a booster dose in the third trimester, with completion of the initial vaccination series in pregnancy or prepregnancy. Both studies demonstrate that the highest maternal antibody levels are generated with third-trimester boosting, higher than completing the primary series in pregnancy, and result in effective transfer to the neonate. 14,23 Similar findings are also noted with boosting in the second trimester. 24 Whether the higher neonatal antibodies correlate with lower risks of SARS-CoV-2 infection or longer time of protection for the neonate has yet to be determined, because the level of protective antibody needed is unknown.
However, the primary goal of receiving a booster dose remains for maternal protection, and a retrospective cohort study from Israel provides the greatest argument for the benefit of a booster dose in pregnancy. This nationwide cohort study examined hospitalizations during pregnancy for symptomatic SARS-CoV-2 infections in both the Delta and Omi-cron waves, stratified by vaccinations received: none, primary series completed, or primary series and booster completed. The authors demonstrate several key findings. First, although completion of the primary vaccine series decreased the risks of hospitalization during the Delta wave, this benefit was eliminated during the Omicron wave. Recipients of three doses of a COVID-19 vaccine had the lowest rates of hospitalization for any symptomatic disease as well as for severe disease during both variant waves. Finally, during the Omicron period, receiving a third vaccine dose resulted in significantly improved vaccine effectiveness against hospitalization compared with two doses only. 25 (Fig. 3).
Finally, recent data from the CDC also demonstrate the clinical effectiveness of the bivalent booster in nonpregnant adults. Compared with adults aged 18-49 years who have received at least two doses of an mRNA-based COVID vaccine but have not received a bivalent booster, adults who are up-todate with the bivalent booster recommendation had an approximately 50% lower risk of symptomatic COVID-19 illness. 26

DOES COVID-19 VACCINATION IN PREGNANCY PREVENT COVID-19 IN INFANTS?
The passive transfer of antibodies across the placental circulation results in protection against COVID-19 in infants. In a large U.S. cohort of infants younger than age 6 months spanning the Delta and Omicron waves, achieving a status of full vaccination while pregnant (delivery at least 2 weeks after the second dose of an mRNA-based vaccine) decreased the risk of infant hospitalization due to COVID-19 by approximately 50%. 27 Vaccination at more than 20 weeks of gestation further decreased the risk of infant hospitalization up to 69%. 27 These findings have been corroborated in a large Norwegian cohort of infants, where maternal full vaccination decreased the risk of any COVID-19 illness in infants by 70% during the Deltapredominant period and by 33% during the Omicron-predominant period 28 (Box 1).
One question that may arise when counseling patients is whether SARS-CoV-2 infection in pregnancy confers a similar antibody-transfer benefit. One study comparing durability of passively transferred antibodies elicited from maternal vaccination (without natural SARS-CoV-2 infection in pregnancy) or maternal infection (without subsequent vaccination) demonstrated that 57% of 6-month-old infants of vaccinated individuals had detectable antibodies as compared with only 8% of infants of individuals with SARS-CoV-2 infection in pregnancy. These data do not address the incidence of clinical COVID-19 illness in infants, but they do indicate more durable antibodies, which likely translates to lower burden of disease among infants born to individuals vaccinated during pregnancy compared with those who had a natural SARS-CoV-2 infection. 29

IS COVID-19 VACCINATION ASSOCIATED WITH AN IMPROVEMENT IN PERINATAL OUTCOMES?
In addition to decreasing the risk of acquiring SARS-CoV-2 infection or developing severe COVID-19, receipt of a COVID-19 vaccine has also been associated with decreased risks of stillbirth or preterm delivery. Whether these improvements in perinatal outcomes are due to avoiding COVID-19 or whether vaccination is a marker for other healthy behaviors during pregnancy is unclear but deserves further study. 30 A meta-analysis has demonstrated similar findings, with a 15% reduction in risk of stillbirth noted and a non-statistically significant decrease in preterm delivery (spontaneous and medically indicated both included) of up to 10%. 31 Overall, the data are clear that COVID-19 vaccination is not associated with worsening of perinatal outcomes. Whether it improves perinatal outcomes, beyond avoiding the adverse outcomes associated with COVID-19 in pregnancy, is not well-established (Box 1).

WHEN IS THE OPTIMAL TIME IN PREGNANCY TO RECEIVE A COVID-19 VACCINATION?
Given the data available, the primary benefit of vaccination remains maternal protection and prevention of COVID-19 during pregnancy, averting the risks of severe maternal disease and risks of preterm delivery or stillbirth. Achieving this goal requires that individuals be fully vaccinated against COVID-19 as soon as possible, especially because no data exist to suggest that maternal protection is superior with vaccination at a particular gestational age. Although the absolute number of antibodies transferred to the neonate varies based on both maternal gestational age at vaccination and gestational age at delivery, the highest number of antibodies transferred to the neonate arises from first-trimester or prepregnancy vaccination and third-trimester booster dose. 14,32 Because patients cannot predict their gestational age at delivery, deferring vaccination to the second or third trimester to optimize neonatal antibody levels at delivery is ill-advised and not supported by the available literature. One study has demonstrated that Unauthorized reproduction of this article is prohibited.
neonates born to fully vaccinated individuals, including those with first-trimester vaccination, have similar or higher umbilical cord antibodies than neonates born to individuals who initiated vaccination in the third trimester but are not fully vaccinated before delivery. 14 Finally, many patients inquire about the utility of measuring anti-S antibodies generated from prior vaccination or infection to inform the timing of COVID-19 vaccination in pregnancy. Because there is no known level of anti-S antibody that is protective against COVID-19 (also known as the immune correlate of protection), and because the immunologic response to vaccination and a SARS-CoV-2 challenge extends beyond a quantitative amount of anti-S antibody, this approach is not recommended. In addition, the role of mucosal (IgA) immunity or T cell immunity in long-term protection is not clearly defined either. Therefore, the vaccine schedule as set by the CDC, informed by clinical trials and real-world data, is the optimal approach to determining timing of vaccination both during and outside of pregnancy.

DOES HAVING A HISTORY OF SARS-CoV-2 INFECTION ALTER THE RECOMMENDATIONS FOR THE PRIMARY VACCINATION SERIES OR A BOOSTER DOSE IN PREGNANCY?
The CDC recommends consideration for waiting up to 3 months to receive a dose of a COVID-19 vaccine after confirmed SARS-CoV-2 infection. 11 This waiting period should be informed by personal risk of severe COVID-19 (for which pregnancy is a risk factor, in addition to any patient-specific comorbidities), community transmission levels of SARS-CoV-2 infection, and circulating SARS-CoV-2 variants in the community. The rationale for deferring vaccination up to 3 months is based on the low re-infection rate documented across many populations within 3 months of confirmed SARS-CoV-2 infection. However, this is not a recommended or mandatory waiting period, and antibodies produced from natural infection wane quickly. In a large cohort of adult patients hospitalized with COVID-19, vaccination 3-6 months before hospitalization provided more protection against hospitalization than natural SARS-CoV-2 infection 3-6 months prior. 33 Primary vaccination or boosting in pregnancy after prior SARS-CoV-2 infection results in high maternal and umbilical cord antibody levels at delivery. 14,34 Therefore, administration of a primary dose or a booster dose, even after SARS-CoV-2 infection, is recommended for optimal protection against COVID-19 in pregnancy.

WHAT DO WE KNOW ABOUT THE SAFETY OF COVID-19 VACCINATION IN PREGNANCY?
A wealth of data has accumulated to demonstrate the safety of COVID-19 vaccination in pregnancy, with most of the data reflecting the use mRNA-based vaccines. Areas of theoretical concern have included the effects of vaccination on risks of miscarriage, stillbirth, preterm delivery, congenital anomalies, and small-for-gestational-age neonates. These concerns have been refuted with data. Risks of miscarriage at less than 20 weeks of gestation are not different among individuals who did and did not receive COVID-19 vaccination in the 4 weeks before miscarriage. 35 Data from v-safe, a CDC registry created to capture patient-reported adverse outcomes after COVID-19 vaccination, show a miscarriage rate of 14% between 6 and 20 weeks of gestation among individuals who received at least one dose of a COVID-19 vaccine, a rate that is consistent with population-based rates of miscarriage. 36 These data have been substantiated with additional data from Norway and Scotland. 37,38 Vaccination against COVID-19 is also not associated with stillbirth, preterm delivery, small-forgestational-age neonates, or congenital anomalies. [39][40][41] Data on adverse pregnant outcomes after a monovalent booster are similarly reassuring. 42 Finally, adverse peripartum outcomes resulting from COVID-19 vaccination in pregnancy also have not been demonstrated. 43 Patients may also inquire about the frequency of vaccine side effects. A large study of more than 12,000 pregnant individuals enrolled in the v-safe registry reported that the most common side effect after each mRNA dose was injection-site pain (88% after dose 1, 92% after dose 2). 44 Self-reported fever occurred in 4% after dose 1 and in 35% after dose 2. Although this frequency may seem high, a fever of 38.0°C (100.4°F) or higher occurred among only 8% of all participants. In another study of almost 8,000 individuals selfreporting side effects, some of whom may also have contributed data to the v-safe study, fever occurred in approximately 5% of individuals after dose 1 and, at most, in 20% of individuals after dose 2. 45 In that study, the highest mean temperature was 38.1°C (100.6°F) after dose 1 and 38.2°C (100.7°F) after dose 2. Followup data from a similarly designed study of monovalent booster doses demonstrated that more than 90% of pregnant individuals receiving booster doses had local injection-site reactions but were less likely to report fevers, myalgias, and headache as compared with nonpregnant or lactating individuals. 46 Rare adverse events after COVID-19 vaccination have also been tracked. A large study from the Vaccine Safety Datalink registry of more than 45 Unauthorized reproduction of this article is prohibited. demonstrated that fewer than 1% of vaccinated individuals have had an acute event, most commonly fever, malaise or fatigue, local reactions, or lymphadenopathy or lymphadenitis. Serious acute events, such as venous sinus thrombosis, encephalitis or myelitis, Guillain Barre syndrome, myocarditis or pericarditis, or pulmonary embolism, did not occur more frequently in pregnant vaccinated individuals than in pregnant unvaccinated individuals. 47

CONCLUSION
The data on COVID-19 vaccination in pregnancy clearly demonstrate that vaccination averts maternal morbidity from COVID-19. Vaccination also decreases the risk of stillbirth, may decrease the risk of preterm delivery, and decreases the risk of neonatal COVID-19 and resultant hospitalization. Vaccination against COVID-19 during pregnancy is safe, with no increased risks of adverse events and a side-effect profile that is comparable with that in the general population. No documented adverse pregnancy outcomes, such as miscarriage, stillbirth, or preterm delivery, have been attributed to COVID-19 vaccination. COVID-19 vaccination is safe, effective, and a powerful tool to prevent maternal and neonatal morbidity.