Covid-19 vaccination in pregnancy
BMJ 2022; 378 doi: https://doi.org/10.1136/bmj-2021-069741 (Published 10 August 2022) Cite this as: BMJ 2022;378:e069741
- Martina L Badell, associate professor1,
- Carolynn M Dude, assistant professor1,
- Sonja A Rasmussen, professor2 ,
- Denise J Jamieson, professor and chair1
- 1Department of Gynecology and Obstetrics, Emory University School of Medicine, Atlanta, GA. USA
- 2Departments of Pediatrics and Obstetrics and Gynecology, University of Florida College of Medicine, Gainesville, FL, USA
- Correspondence to: Denise J Jamieson djamieson{at}emory.edu
ABSTRACT
Pregnancy is an independent risk factor for severe covid-19. Vaccination is the best way to reduce the risk for SARS-CoV-2 infection and limit its morbidity and mortality. The current recommendations from the World Health Organization, Centers for Disease Control and Prevention, and professional organizations are for pregnant, postpartum, and lactating women to receive covid-19 vaccination. Pregnancy specific considerations involve potential effects of vaccination on fetal development, placental transfer of antibodies, and safety of maternal vaccination. Although pregnancy was an exclusion criterion in initial clinical trials of covid-19 vaccines, observational data have been rapidly accumulating and thus far confirm that the benefits of vaccination outweigh the potential risks. This review examines the evidence supporting the effectiveness, immunogenicity, placental transfer, side effects, and perinatal outcomes of maternal covid-19 vaccination. Additionally, it describes factors associated with vaccine hesitancy in pregnancy. Overall, studies monitoring people who have received covid-19 vaccines during pregnancy have not identified any pregnancy specific safety concerns. Additional information on non-mRNA vaccines, vaccination early in pregnancy, and longer term outcomes in infants are needed. To collect this information, vaccination during pregnancy must be prioritized in vaccine research.
Introduction
On 11 March 2020, the World Health Organization declared the SARS-CoV-2 outbreak a worldwide pandemic.1 To date, nearly 400 million cases of SARS-CoV-2 infection have been confirmed globally. Although stating the exact number of cases that have occurred in pregnant patients is difficult, recent statistics suggest that women of reproductive age make up more than 20% of the global population, and approximately 5% of women of reproductive age are pregnant at any given time.234 Therefore, several million cases of covid-19 during pregnancy are expected to have occurred in the past two years, making SARS-CoV-2 infection one of the most prevalent illnesses to affect this population.
Pregnant patients with symptomatic covid-19 infection are at increased risk for severe disease, with increased rates of hospital admission, intensive care unit (ICU) admission, intubation, and death.56 According to a recent systematic review, pregnant patients with covid-19 face higher rates of several adverse maternal outcomes as well as ICU admission (odds ratio 2.61, 95% confidence interval 1.84 to 3.71) and invasive ventilation (2.41, 2.13 to 2.7) compared with non-pregnant women of reproductive age with covid-19, and significantly higher rates of death (6.09, 1.82 to 20.38) compared with pregnant patients without covid-19.7 Given the risks faced by both pregnant patients and neonates, understanding the immunologic response to vaccination in pregnancy is critically important. More than 100 vaccines were tested in clinical trials, with 12 vaccines currently in use.8 Given that pregnancy was an exclusion criterion in early clinical trials of vaccines, obstetric patients and their providers initially were required to make decisions about vaccination with limited data. To help to fill this gap, this review aims to summarize available data on the immunogenicity, effectiveness, adverse effects, and perinatal outcomes of maternal covid-19 vaccination, as well as on vaccine hesitancy during pregnancy. This review is aimed at clinicians caring for pregnant patients and researchers involved in vaccine development or public health.
Sources and selection criteria
We considered studies reporting on adult human populations who received covid-19 vaccination in pregnancy for inclusion in this review. An additional topic of interest was vaccine hesitancy in pregnancy. We did a comprehensive literature search to identify relevant articles. An experienced medical librarian developed and conducted search strategies, with input from the research team. We searched four bibliographic databases between November 2019 and March 2022: EBSCO’s CINAHL (Cumulative Index of Nursing and Allied Health), Embase, MEDLINE via PubMed, and Web of Science Classic Core Collection (Science Citation Index Expanded, Social Sciences Citation Index, Arts and Humanities Citation Index, Conference Proceedings Citation Index-Science, Conference Proceedings Citation Index-Social Sciences and Humanities, Book Citation Index- Science, Book Citation Index-Social Sciences and Humanities, Emerging Sources Citation Index, Current Chemical Reactions, Index Chemicus).
The searches combined controlled vocabulary supplemented with keywords related to the concepts of vaccination (for example, immunization, immunogenicity), pregnancy (for example, gestation, breastfeeding), covid-19 (for example, SARS-CoV-2, coronavirus), empirical methods (for example, prospective trial, cohort study), vaccine hesitancy (for example, uptake, unwillingness), and ethics related to vaccination during pregnancy (for example, therapeutic orphan, patient selection). We included articles written in the English language. We did not review preprints, and we did not include case reports. Searches were carried out on 8 February 2022 and rerun for updates on 8 March 2022 (fig 1).
We identified 45 studies evaluating the use of covid-19 vaccines in pregnancy via our search. Of these studies, 20 investigated immunogenicity, 10 investigated vaccine efficacy, 12 evaluated adverse effects of vaccines, and 26 evaluated perinatal outcomes after prenatal vaccination. We also included two additional studies published after our search given that their large sample size substantially expanded the available data on pregnancy outcomes after covid-19 vaccination. We also added one study on risk of congenital fetal anomalies after the search, as it specifically evaluated the association of covid-19 vaccination during the highest risk period for teratogenicity. Of the 48 included studies, most reported the use of mRNA vaccines (43 included the Pfizer-BioNTech vaccine (BNT162b2); 28 included the Moderna vaccine (mRNA-1273)); only six reported use of the Johnson & Johnson-Janssen vaccine (Ad26.COV2.S), and five reported use of the Oxford-AstraZeneca vaccine (ChAdOx1-S). Some studies included multiple vaccine types, and some did not report the specific vaccine used. One study included two participants who received the Sinovac vaccine (CoronaVac; inactivated), three who received a combination of CoronaVac and Pfizer, and 78 who received Pfizer.9 The paper reported on infection rates during the era of the omicron variant, finding that fully vaccinated pregnant patients had milder illness, but did not break down the results by vaccine type. No other studies identified included inactivated vaccines. Vaccine hesitancy was evaluated in 42 studies. Several studies evaluated more than one outcome, so the total number of studies included in this review is 83.
Incidence/prevalence
Pregnancy is an independent risk factor for severe covid-19.5 Although the absolute risk for severe maternal morbidity and mortality is low, pregnancy remains a risk factor for hospital admission, ICU admission, and need for extracorporeal membrane oxygenation related to covid-19 compared with non-pregnant women.5 Covid-19 in pregnancy has also been associated with an increased risk of stillbirth and maternal death,71011 and comorbidities such as advanced maternal age, obesity, diabetes, and heart disease further increase these risks. Moreover, several cases of intrauterine transmission of SARS-CoV-2 have been carefully documented, although the risk seems to be low.12 Additionally, neonates have been shown to be susceptible to severe illness from SARS-CoV-2 infection,13 so providing protection to the neonate through maternal vaccination is important. Neonates rely on the active placental transfer of maternal IgG for their protection against pathogens during the first six months of life,1415 so vaccination during pregnancy has the potential to protect both mother and neonate.
Although vaccination with other respiratory viruses such as influenza during pregnancy has been shown to be highly successful and safe,161718 these vaccinations have been the subject of ongoing research in the pregnant population for decades. Despite the clear harm SARS-CoV-2 infection poses to pregnant patients and their neonates, the paucity of initial safety and efficacy data on covid-19 vaccines in pregnancy led countries around the globe to take different positions on whether people should be vaccinated during pregnancy. According to the Covid-19 Maternal Immunization Tracker (COMIT), a website that provides global information on countries’ public health policies regarding recommendations about covid-19 vaccines for pregnant and lactating people,19 106 countries recommend covid-19 vaccination for some or all pregnant or lactating people, whereas 15 countries specifically recommend against vaccination in this population. Given the wide diversity of recommendations worldwide, the prevalence of people vaccinated for covid-19 during pregnancy likely also varies considerably. In the US, all major professional health organizations, including the American College of Obstetricians and Gynecologists (ACOG) and the Society for Maternal Fetal Medicine (SMFM), have consistently recommended that everyone who is pregnant should be vaccinated against covid-19 since early 20212021; however, as of April 2022, the US Vaccine Safety Datalink estimated that only 69.4% of pregnant women aged 18-49 years had been fully vaccinated with covid-19 vaccines before or during pregnancy.22
Covid-19 vaccines
We identified four vaccines as having published data on their use in pregnancy: Pfizer-BioNTech, Moderna, Johnson & Johnson-Janssen, and Oxford-AstraZeneca (table 1). The Pfizer-BioNTech and Moderna mRNA vaccines had the most data in pregnancy. The mRNA vaccines work by releasing mRNA that encodes for the SARS-CoV-2 spike protein into cells, allowing the cell’s machinery to produce the spike protein. Once mRNA from the vaccine has been read, it is destroyed. The body’s immune cells then generate a response to the spike protein, creating the antibodies that provide immunity to SARS-CoV-2. The other two vaccines with data in pregnancy, the Oxford-AstraZeneca and Johnson & Johnson-Janssen vaccines, rely on an adenovirus vector to introduce DNA for the SARS-CoV-2 spike protein into the body’s cells. The DNA is first copied into mRNA, and then, as with the mRNA vaccines, the mRNA is used to produce copies of the spike protein, which then stimulate the immune system to create antibodies. Thus far, mRNA vaccines have shown better efficacy in the non-pregnant population than the viral vector vaccines for preventing symptomatic illness—with Pfizer and Moderna vaccines showing 95.0% and 94.1% efficacy, respectively, in the initial clinical trials—as well as severe disease, two weeks after the two dose series.2325 By contrast, the Johnson & Johnson-Janssen vaccine was 72% effective in preventing symptomatic infection and 85% effective in preventing severe disease in the non-pregnant population,27 and the AstraZeneca vaccine was 70.4% effective after two doses.29 However, some of these differences between vaccines might be due to the variants circulating at the time of the trials.
Covid-19 vaccines with data in pregnancy
As pregnancy was an exclusion criterion for these studies, which vaccine is the most effective in the pregnant population is unclear. More information on all vaccine types is needed, as many countries, including India, a country with approximately one sixth of the world’s pregnant population, have no mRNA vaccines available. However, given the high morbidity from SARS-CoV-2 infection in pregnancy, most countries surveyed recommend covid-19 vaccination for some or all pregnant or lactating individuals.19 Most advocate for covid-19 vaccination regardless of previous infection and state that serologic testing, a pregnancy test, or a letter from an obstetric provider should not be required before vaccination. No recommendation for specific timing of vaccination in pregnancy exists; however, given that the primary goal of vaccination is to prevent maternal infection, most countries recommend vaccination regardless of pregnancy trimester. Pregnancy need not be delayed after covid-19 vaccination, as none of the currently available vaccines is a live vaccine.
Despite these strong recommendations for universal vaccination, vaccine hesitancy in the pregnant population remains high. Many people cite concern for fetal/infant wellbeing as a reason to decline vaccination, so more information on perinatal outcomes and transplacental antibody transfer is needed. Efforts are ongoing to fill these gaps, as a recent review of the clinicaltrials.gov website (accessed 23 March 2022) showed that 11 trials investigating covid-19 vaccinations in pregnancy are ongoing, including several prospective observational trials that are evaluating maternal and infant outcomes after covid-19 vaccination in pregnancy. These trials will hopefully provide additional information on the safety and efficacy of these vaccines and on the optimal timing and frequency of vaccination in pregnancy to maximize maternal and neonatal benefit.
Covid-19 vaccines in pregnancy
Vaccination during pregnancy can reduce disease related morbidity and mortality for pregnant people and their infants. Patients are at higher risk of significant morbidity from viral illnesses such as influenza if contracted during pregnancy,31 and other viral infections, such as Zika, rubella, and varicella, can cause serious neonatal morbidity if the primary infection occurs during pregnancy.323334 Other viruses, such as pertussis, are relatively inconsequential for a pregnant person or a fetus, but pertussis infection in a young infant can be fatal. Immunizations have been shown to benefit all three populations—mother, fetus, and neonate—as any vaccine given to the mother can protect the neonate via the transplacental transport of IgG antibodies.14 However, although several vaccines are recommended in pregnancy, the optimal timing of the vaccination varies depending on the pathogen. Some vaccines, such as those for rubella and varicella, are recommended only during the preconception and postpartum period, as live vaccines theoretically could cause congenital infection if given during or just before pregnancy. By contrast, pertussis vaccination is recommended in every pregnancy, optimally between 27 and 36 weeks, to facilitate maximal placental antibody transfer for greatest protection of the neonate. Finally, influenza vaccines are recommended at any time in pregnancy during influenza season, as the priority is to prevent maternal infection. Current recommendations for covid-19 vaccines closely follow those for influenza vaccines—that is, the vaccine should be given as soon as possible in pregnancy for maternal benefit, given the significant increase in morbidity from SARS-CoV-2 infection seen in the pregnant population. Understanding how pregnancy affects response to covid-19 vaccination and subsequent placental antibody transfer is critical to guiding vaccine recommendations for this special population.
Covid-19 vaccine immunogenicity data in pregnancy
Available data on the humoral and functional immune response to covid-19 vaccines in pregnancy are observational. Our review identified 20 studies evaluating the immunogenicity of covid-19 vaccines in pregnancy (table 2).3536373839404142434445464748495051525354 Most studies evaluated immunogenicity of the Pfizer-BioNTech vaccine. A few studies did not clearly describe either the vaccine platform or the total number of participants; however, when described, this information is provided in table 2. Multiple studies support a robust maternal antibody response to covid-19 vaccination.40424344455154 A cohort study documented humoral immunity in pregnancy, with immunogenicity and reactogenicity similar to those observed in non-pregnant women; vaccine induced antibody titers were equivalent in pregnant and non-pregnant women.42 A few studies have found reduced immunogenicity in pregnancy compared with that observed in non-pregnant vaccinated women.3835 One study found that pregnant women (n=390) had significantly lower serum SARS-CoV-2 IgG concentrations than non-pregnant women (n=260) (signal to cut-off ratio 27.03 v 34.35; P<0.001).38 A smaller study observed a delay in the evolution of Fc receptor binding and functional antibody responses during pregnancy after initial vaccination; the response improved after the second dose but was still lower than in non-pregnant women.35 An increase in maternal SARS-CoV-2 IgG antibody response with a second dose in pregnancy was also documented by a study that found significantly higher maternal IgG concentrations, week by week, starting two weeks after the first vaccine dose, as well as between the first and second weeks after the second vaccine dose (P<0.005 and P=0.019, respectively).47 Another study also found higher antibody concentrations during pregnancy after two doses compared with one dose of Moderna vaccine.52
Immunogenicity data on covid-19 vaccines in pregnancy
Two studies evaluated the maternal immunogenicity after a third trimester booster vaccination.4954 A prospective cohort study found considerable antibody waning throughout pregnancy in those vaccinated in the first trimester, with a boosting effect of a third vaccine dose.49 Booster dose administration was associated with significantly increased maternal and neonatal antibody concentrations compared with those who completed the two dose vaccine series in the first trimester without a booster dose (P<0.001). In a retrospective study of 1359 pregnant women, completion of the vaccination course, history of SARS-CoV-2 infection, and a third trimester booster dose were associated with the highest maternal and umbilical cord antibody concentrations.54 These immunogenicity studies highlight the importance of adherence to full vaccination recommendations in pregnancy and additionally support the benefit of a booster dose in pregnancy to optimize immunity.
Several studies documented a more robust maternal antibody response to vaccination than to previous infection.363940424346 One found significantly higher SARS-CoV-2 IgG concentrations in maternal serum and cord blood among fully vaccinated women (n=64) (P<0.001) compared with 11 previously infected pregnant women.46 Vaccination during pregnancy may also provide protection for the newborn. We identified 16 studies that documented presence of SARS-CoV-2 antibodies in cord blood after maternal vaccination.353640414243444546474849515253 Additionally, several studies have shown a positive correlation between maternal serum and cord blood antibody concentrations, which is generally described as the placental transfer ratio.36404546484952 With regard to timing of antibody production, one study found maternal antibody production as early as five days after a first vaccine dose and transplacental transfer as early as 16 days after a first dose.47 Some variability exists, however, and lack of transfer was seen in one neonate who was delivered six weeks after the second dose. Another study found that the three of 28 cord samples that were IgG negative all came from deliveries with less than three weeks between the time of first dose and delivery.45 Maternal IgG concentrations and placental IgG transfer ratios increased over time, suggesting that time between vaccination and birth may be an important factor.
The degree of maternal protection via placental transfer of antibodies likely depends on maternal antibody concentration, which is related to timing of vaccination and delivery. In one study, early third trimester (27-31 weeks) vaccination was associated with higher neonatal anti-SARS-CoV-2 antibody and serum neutralizing activity. This may support early third trimester as the optimal timing for a booster vaccination to optimize maternal to fetal antibody transfer for neonatal protection.49 In general, transplacental antibody transfer starts in the second trimester; however, transfer is most efficient in the third trimester.5556
More studies of factors affecting placental antibody transfer are needed, along with better understanding of the degree of protection provided. Although we identified 20 studies evaluating the immunogenicity of covid-19 vaccines in pregnancy, they were primarily on mRNA vaccines. These limited data highlight the importance of fully understanding the immunology of pregnancy to develop evidence based, pregnancy specific vaccine recommendations. Overall, the immunogenicity data in pregnancy illustrate a robust immune response to vaccination and maternal transfer of antibodies to the neonate via cord blood.
Covid-19 vaccines in prevention of maternal and infant infection
We identified nine articles evaluating risk of maternal SARS-CoV-2 infection after maternal vaccination.95758596061626364 The data overwhelming support maternal vaccination as being effective at reducing the risk for infection and severe illness. A large national prospective cohort study in Scotland of 18 399 vaccinated and 126 149 unvaccinated pregnant women found that 77.4% (3833/4950; 95% confidence interval 76.2% to 78.6%) of SARS-CoV-2 infections, 90.9% (748/823; 88.7% to 92.7%) of SARS-CoV-2 associated hospital admissions, and 98% (102/104; 92.5% to 99.7%) of SARS-CoV-2 associated critical care admission occurred in those who were unvaccinated.63 In Israel, a large observational cohort of 10 861 vaccinated pregnant women matched to 10 861 unvaccinated pregnant controls found an estimated vaccine effectiveness from seven through 56 days after the second dose of 96% (95% confidence interval 89% to 100%) for any documented infection, 97% (91% to 100%) for infections with documented symptoms, and 89% (43% to 100%) for covid-19 related hospital admission.60
These results reflect effectiveness mainly against the original SARS-CoV-2 reference strain and the B.1.1.7 (alpha) variant, as these were the dominant strains circulating during the study period. This is similar to the vaccine effectiveness estimated in the general population in Israel. A retrospective cohort study in the US of 1332 vaccinated pregnant patients and 8760 incompletely vaccinated or unvaccinated pregnant patients found that vaccinated patients had lower odds of severe covid-19, defined as SpO2 <94% on room air, PaO2/FiO2 ratio <300 mm Hg, respiratory rate >30 breaths per minute, or lung infiltrates >50%, or critical covid-19, defined as respiratory failure, septic shock, or multiple organ failure (0.08% v 0.66%; adjusted odds ratio 0.10, 95% confidence interval 0.01 to 0.49) and covid-19 of any severity (1.1% v 3.3%; 0.31, 0.17 to 0.51).62 These and the other smaller studies show an association between maternal SARS-CoV-2 vaccination and lower odds of covid-19 illness. Overall, covid-19 vaccines have been found to be highly effective in preventing severe illness, hospital admission, and death; these data support similar effectiveness in pregnancy.
Additionally, one study evaluated the effectiveness of maternal vaccination during pregnancy against covid-19 related hospital admission in infants during the first six months of life.65 Of 176 infants admitted with covid-19, 16% of their mothers had been vaccinated compared with 32% of 203 infants admitted without covid-19 (P<0.01). Effectiveness of maternal vaccination during pregnancy against covid-19 related hospital admission in infants aged <6 months was found to be 61% (31% to 78%). Effectiveness of a two dose covid-19 vaccination series was 32% (–43% to 68%) in the first 20 weeks of pregnancy and 80% (55% to 91%) after 21 weeks through 14 days before delivery. This gestational age breakdown has wide confidence intervals and should be interpreted with caution. Overall, completion of a two dose mRNA covid-19 vaccination series during pregnancy seems to reduce covid-19 related hospital admissions among infants aged <6 months, but the duration of clinical protection remains uncertain. A smaller study evaluating antibody response in infants found that most infants (98%; 48/49) had detectable anti-S IgG antibodies at 2 months of life after maternal vaccination and 57% (16/28) still had detectable concentrations at 6 months.66 This was compared with only 8% (1/12) with detectable antibodies after SARS-CoV-2 infection during pregnancy. The concentrations of antibodies needed to provide protection in infants is unknown, so clinical data in correlation with titer information are needed. However, given the burden of SARS-CoV-2 in infants and that covid-19 vaccines are not planned for infants <6 months, these findings provide support that babies receive protective benefits from maternal vaccination.
COVID-19 vaccines and perinatal outcomes
On the basis of 26 studies describing perinatal outcomes after covid-19 vaccination in pregnancy, the overall rates of adverse perinatal outcomes were not increased after maternal vaccination (table 3). The rates of preterm birth, fetal growth restriction, cesarean delivery, and neonatal intensive care unit (NICU) admission varied across studies, which is likely explained by different patient populations; however, in the studies with a comparison group of unvaccinated pregnant patients, the rates were not significantly increased. Some challenges in evaluating perinatal outcomes after exposure during pregnancy include understanding the baseline risk of the outcome, the timing of the exposure in pregnancy related to the outcome, and the necessary sample size needed to detect a difference. Additionally, common sources of bias in maternal vaccination observational studies including healthy vaccinee bias and confounding by indication, immortal time bias, and cohort truncation must be considered.79
Perinatal outcome data with covid-19 vaccines in pregnancy
A large registry based study of births in Sweden and Norway (28 506 vaccinated; 129 015 unvaccinated) found no significant increased risk of adverse pregnancy outcomes including preterm birth, stillbirth, small for gestational age, or NICU admission in people vaccinated against SARS-CoV-2 during pregnancy.74 The results were similar for vaccinations during the second or third trimester, with one or two doses of vaccine, and with different mRNA vaccine types. A large (>10 000 people vaccinated during pregnancy) US based multisite retrospective cohort with a diverse population and comprehensive data on vaccination did not find an increase in preterm birth or small for gestational age birth.73 Additionally, a large (913 vaccinated; 3486 unvaccinated) retrospective cohort in Israel found no differences in pregnancy, delivery, or newborn complications, including gestational age at delivery, incidence of small for gestational age birth, and newborn respiratory complications.76
Another important perinatal outcome of interest after maternal vaccination is risk of spontaneous abortion. Studies evaluating this risk should ideally include a control group and document timing of maternal vaccination. We identified four studies on risk of spontaneous abortion after covid-19 vaccinations in pregnancy.67686970 One used the Vaccine Safety Datalink to analyze the odds of receiving a covid-19 vaccine in the 28 days before a spontaneous abortion.67 It found that pregnancies ending in a spontaneous abortion did not have an increased odds of exposure to a covid-19 vaccination in the previous 28 days compared with ongoing pregnancies (adjusted odds ratio 1.02, 0.96 to 1.08). Results were consistent for Moderna and Pfizer vaccines and by gestational age group. Additionally, a case-control study from Norwegian registries of 13 956 women with ongoing pregnancies (958 vaccinated) found adjusted odds ratios of 0.91 (0.75 to 1.10) for covid-19 vaccination in the previous three weeks following a spontaneous abortion and 0.81 (0.69 to 0.95) for vaccination in the previous five weeks, showing no evidence of an increased risk for early pregnancy loss after covid-19 vaccination.69
Six studies evaluated the risk of fetal anomalies after maternal vaccination (table 3).575861707177 A large Israeli study of 16 738 infants prenatally exposed to the Pfizer vaccine compared with 7452 unexposed infants did a subgroup analysis among newborns exposed to first trimester vaccination (n=2021) versus unexposed newborns (n=3580) and found no difference in congenital anomalies (risk ratio 0.69, 95% confidence interval 0.44 to 1.04).61 Additionally, the risk for major heart malformations was lower among the exposed group (risk ratio 0.46, 0.24 to 0.82). Given the importance of timing in pregnancy and risk of fetal anomalies, a large cohort study evaluating the association of covid-19 vaccination during early pregnancy with risk of congenital fetal anomalies identified an anomaly in 27 (5.1%) of 534 unvaccinated people versus 109 (4.2%) of 2622 people who received at least one dose of vaccine (P=0.35).77 Importantly, after control for potential confounders such as hemoglobin A1c level in the first trimester and age at delivery, vaccination within the highest risk period for teratogenicity was not associated with presence of congenital anomalies identified by ultrasonography (adjusted odds ratio 1.05, 0.72 to 1.54).
We identified nine studies evaluating the risk of stillbirth after covid-19 vaccination.384962647071727475 None found an increased risk; however, given the rarity of stillbirth as an event, large studies will be needed to evaluate this risk adequately. In the largest study (n=28 506), no difference was seen in risk of stillbirth after vaccination (2.1 v 1.4 per 100 000 pregnancy days at risk in vaccinated compared with unvaccinated; adjusted hazard ratio 0.86, 0.63 to 1.17).74 The small number of stillbirths meant that the study could not explore the risk of stillbirth according to vaccination by pregnancy trimester, number of doses, or vaccine type. A recent systematic review and meta-analysis including five of these studies found that the risk of stillbirth was significantly lower in those vaccinated in pregnancy by 15% (pooled odds ratio 0.85, 0.73 to 0.99).80
Twelve studies evaluated the risk of preterm birth after maternal covid-19 vaccination, and the data are reassuring.363839425061647071727374 One retrospective study of the Pfizer vaccine in Israel found the overall rate of preterm birth to be 5.5% in the vaccinated group compared with 6.2% in the unvaccinated group (P=0.31); however, people vaccinated in the second trimester of pregnancy (n=964) were more likely to have a preterm birth than those vaccinated in the third trimester (n=1329) (8.1% v 6.2%; P<0.001).72 This association persisted after adjustment for potential confounders (adjusted odds ratio 1.49, 1.11 to 2.01). The authors note that no preterm births were seen within two weeks after second trimester vaccination and that most of the preterm births were late preterm, suggesting that unmeasured confounding might have contributed to the results. A larger retrospective study in the US did not find an increased risk of preterm birth with maternal vaccination (4.9% v 7.0%; adjusted hazard ratio 0.91, 0.82 to 1.01).73 Additionally, no increased risk of preterm birth was seen in the very large cohort study in Norway and Sweden, including no difference between second and third trimester vaccination.74
Nine studies evaluated NICU admission rates after maternal vaccination, and none identified an increased risk.363842505764707478 The largest study found that overall rates of adverse newborn outcomes were lower among those born to people vaccinated during pregnancy versus those vaccinated afterwards, including lower NICU admission (11.0% v 13.3%; adjusted risk ratio 0.85, 0.80 to 0.90).78 Additionally, compared with the 30 115 mothers who were never vaccinated, no significantly increased risks of any outcomes were seen in those vaccinated during pregnancy, and NICU admission (11.0% v 12.8%; adjusted risk ratio 0.92, 0.87 to 0.97) was significantly lower among those who were vaccinated during pregnancy.
On the basis of review of available data, no increased risk of adverse pregnancy outcomes was observed among people vaccinated against SARS-CoV-2 during pregnancy, supporting recommendations for vaccination of pregnant patients against SARS-CoV-2. Vaccine safety concerns have been a significant barrier to vaccine acceptance in pregnancy; thus, highlighting the amount of accumulated data is important.
Covid-19 vaccine side effects in pregnancy
We identified 12 studies evaluating adverse effects after maternal covid-19 vaccination.373839404244555871818283 In general, symptoms after covid-19 vaccination are usually mild to moderate and occur within the first three days after vaccination. Most occur the day after vaccination and resolve within one to two days. The second dose is associated with more frequent and severe symptoms. The vaccine side effect profile in pregnancy seems to be similar to that in non-pregnant people, with pain at the injection site, fatigue, headache, and myalgia being the most frequent symptoms.3738425571 Although routine prophylaxis with acetaminophen is not recommended in some countries, pregnant patients should take acetaminophen if they experience fever after vaccination. Severe allergic reactions are rare following covid-19 vaccination in non-pregnant patients (4.7 per million for Pfizer-BioNTech and 2.5 per million for Moderna). Anaphylaxis following vaccination in pregnancy should be managed the same as in non-pregnant patients.21
A large prospective cohort study including 7809 pregnant people found that covid-19 vaccines were well tolerated among people who were pregnant, lactating, or planning pregnancy. Odds of several reactions were decreased among people who were pregnant, such as fever after Pfizer dose 2 (odds ratio 0.44, 0.38 to 0.52; P<.001) and after Moderna dose 2 (0.48, 0.40 to 0.57; P<0.001) compared with those who were neither pregnant nor lactating.55 The frequency of complaints after vaccination was similar to that observed in non-pregnant patients, and reports of adverse outcomes were infrequent. Additionally, a prospective study of 83 vaccinated pregnant women who were age matched with 166 vaccinated female non-pregnant controls found the frequency of complaints following vaccine administration did not differ between pregnant and non-pregnant patients (18.1% v 16.9%; P=0.20).82 However, pregnant patients were more likely to report fever (4.8% v 0.6%; P=0.04) and gastrointestinal symptoms (4.8% v 0%; P=0.01). This could reflect differences in the physiologic responses to the vaccines in pregnancy. One study used data from the “v-safe after vaccination health checker” surveillance system, the v-safe pregnancy registry, and the Vaccine Adverse Event Reporting System (VAERS) to characterize the initial safety of mRNA covid-19 vaccines in pregnancy.71 Local and systemic reactogenicity was compared between people who identified as pregnant and non-pregnant women. The study found small differences in reporting frequency between pregnant people and non-pregnant women observed for specific reactions (injection site pain was reported more frequently in pregnancy, and other systemic reactions were reported more frequently among non-pregnant women), but the overall reactogenicity profile was similar. None of the available data indicate obvious increased adverse effects or safety concerns with use of covid-19 vaccines in pregnancy.
Covid-19 vaccine hesitancy in pregnancy
The search identified 42 articles evaluating vaccine hesitancy in pregnancy in the English language from around the world. Table 4 outlines the studies with either positive or negative associations with willingness or decision for vaccination in pregnancy; three additional studies did not fit these criteria but discussed factors associated with vaccine uptake.115116117 Factors positively associated with vaccine willingness/uptake in pregnancy tended to be the same around the globe, including older maternal age, higher education, previous influenza vaccine uptake, higher level of trust in the healthcare system, increased perceived risk of covid-19, fertility treatments, urban living, and higher socioeconomic status (table 4). Factors associated with a lower likelihood of vaccination during pregnancy included younger age, lower education/socioeconomic status, and lack of adherence to influenza vaccination recommendations. Pregnancy itself was found to be negatively associated with vaccine acceptance in several studies when a non-pregnant cohort was used for comparison.
Covid-19 vaccine hesitancy in pregnancy
Data from Vaccine Safety Datalink, a collaboration between the Centers for Disease Control and Prevention (CDC) and multiple integrated health systems, analyzed receipt of at least one dose of any covid-19 vaccine in 135 968 pregnant women between 14 December 2020 and 8 May 2021.91 Vaccination increased with age, with highest rates of at least one dose observed among women aged 35-49 years (22.7%) and lowest rates among those aged 18-24 years (5.5%). Receipt of at least one dose was highest among Asian women (24.7%), followed by white (19.7%) women, and lowest among Black (6.0%) and Hispanic (11.9%) women. One study found that the impact of education and influenza vaccination history on vaccine acceptance varied depending on race, suggesting that different public health messaging might be appropriate for Black or African-American women because of their lived experiences with systemic racism and mistrust in the healthcare system.90
Another emerging theme from the data was the importance of counseling from healthcare providers. Previous data show that the recommendation and offer of the influenza vaccine by a healthcare provider are critical for uptake in pregnancy.118 Several studies found that a provider’s recommendation was positively associated with covid-19 vaccination.878998110 A large nationwide prospective study in the US was used to characterize vaccination rates and acceptance during pregnancy in the first six months of vaccine rollout.89 Among 2506 pregnant respondents, 57.4% had received one dose of covid-19 vaccination in pregnancy. In an adjusted model, the predictors of lower odds of vaccination included Black race (21.8%) compared with white race (58.2%) (P<0.001); being counseled about vaccination by a provider was a strong predictor of getting vaccinated (69.4%) compared with no counseling (38.5%) (P<0.001). The best methods to provide educational resources to providers and to ensure that covid-19 vaccination recommendations are routinely discussed with obstetric patients should be a research priority. Ensuring that providers have up to date information on the maternal and neonatal safety of covid-19 vaccines in pregnancy is critical, as this is needed to help guide their counseling.
In a large multi-country study of 17 871 women, including 5282 who were pregnant, conducted before vaccines were available, 2747 (52.0%) pregnant women and 9214 (73.4%) non-pregnant women indicated an intention to receive a covid-19 vaccine.102 The top three reasons why pregnant women would decline vaccination even if the vaccine were safe and free were that they did not want to expose their developing baby to any possible harmful side effects (65.9%), they were concerned that approval of the vaccine would be rushed for political reasons (44.9%), and they would like to see more safety and effectiveness data during pregnancy (48.8%). Vaccine acceptance was lowest in Russia, the US, and Australia. The strongest predictors of vaccine acceptance included confidence in vaccine safety or effectiveness, worrying about covid-19, belief in the importance of vaccines to their own country, compliance with mask guidelines, trust of public health agencies/health science, and attitudes toward routine vaccines.
Over the past year, substantial data have been generated on covid-19 vaccines in pregnancy. Concerns for fetal/neonatal safety due to lack of data on safety of the vaccines in pregnancy are often cited as justification for declining the vaccine during pregnancy. The inclusion of pregnant people in vaccine research is of crucial importance to help to increase knowledge for this population.
Guidelines
WHO states that pregnant women can receive covid-19 vaccines and, if not already vaccinated, should have access to WHO Emergency Use Listing approved vaccines, as the benefits of vaccination during pregnancy outweigh potential risks.119 WHO recommends the Johnson & Johnson-Janssen, Moderna, Novavax, Oxford-AstraZeneca, and Pfizer-BioNTech vaccines and permits Sinopharm, BIBP-CorV, Sinovac CoronaVac, and Bharat Biotech Covaxin. In the UK, the Royal College of Obstetricians and Gynaecologists (RCOG) and Joint Committee on Vaccination and Immunisation (JCVI) state that: “COVID-19 vaccines are strongly recommended in pregnancy.”120 The RCOG prefers that pregnant women be offered the Pfizer-BioNTech or Moderna mRNA vaccines, where available, given the greater amount of data on this vaccine type and that current data have not raised any safety concerns. However, women who have already had one dose of the Oxford-AstraZeneca vaccine are advised to complete vaccination with a second dose of the same vaccine.
In the US, the CDC, the ACOG, and the SMFM all recommend that people who are pregnant get vaccinated and stay up to date with their covid-19 vaccines, including getting a booster shot.2021121 Overall, the CDC states a preference for mRNA covid-19 vaccines over the Johnson & Johnson-Janssen vaccine for primary and booster vaccination; however, the latter vaccine may be considered in certain situations such as an allergic reaction, limited access to mRNA vaccines, or patient preference; this includes during pregnancy.
As of 12 March 2022, China’s position is that covid-19 vaccination during pregnancy is not recommended, and vaccination while lactating is recommended for some or all.19 In India, with approximately 25 million births annually, the currently available covid-19 vaccines are Covishield and Covaxin.19 At present, the recommendations from the Ministry of Health and Family Welfare, Government of India, state that pregnancy and lactation are contraindications to covid-19 vaccinations.122 However, the Federation of Obstetric and Gynaecological Societies of India’s position statement on covid-19 vaccination for pregnant and breastfeeding women states that protection from covid-19 vaccination should extend to pregnant and lactating women, given that the benefits seem to far outweigh any theoretical and remote risks of vaccination.123 The International Society of Infectious Diseases in Obstetrics and Gynaecology advises policy makers and societies to prioritize pregnant women to receive vaccination against SARS-CoV-2 and favors the mRNA vaccines until further safety information becomes available.124
Conclusions
Covid-19 vaccination is the safest and most effective way for people who are pregnant to protect themselves and their babies against severe covid-19 disease. Available data do not support an increased risk of adverse outcomes following covid-19 vaccination in pregnancy, so vaccination should be recommended as the benefits of vaccination during pregnancy seem to outweigh any potential risks. The immunogenicity of vaccinations in pregnancy seems to be similar to that in the non-pregnant population; however, the optimal timing of vaccination in pregnancy for neonatal/infant benefit remains uncertain. Additional information on non-mRNA vaccines, vaccination early in pregnancy, and longer term infant outcomes are also needed. Given that pregnant people are at increased risks for severe complications from covid-19, increasing the data and knowledge surrounding vaccination in this population is important to help to reduce vaccine hesitancy. Along with more data, directed personal vaccine counseling by obstetric providers to pregnant patients may also improve vaccination rates. To meet all these goals, pregnant people around the world must be prioritized in covid-19 vaccine research.
Research questions
Should the covid-19 vaccine schedule in pregnancy be different from that in non-pregnant people? Does an optimal gestational timing of covid-19 vaccination in pregnancy exist?
What are the degree and extent of neonatal/infant protection with maternal covid-19 vaccination in pregnancy?
What are the most effective strategies to reduce vaccine hesitancy in pregnancy?
Do perinatal outcomes differ among the various covid-19 vaccines?
Patient involvement
We provided an initial draft of the manuscript and outline of the key points of the paper to a patient who chose to be vaccinated in pregnancy and one who opted to wait until post partum. They both expressed concern about unknown fetal risks with receiving a novel vaccine in pregnancy. The patient who declined vaccination stated that she did not want to be responsible for choosing anything that might increase the risk for adverse perinatal outcomes for her baby and she would proceed with vaccination only once pregnancy specific data were available. The patient who got vaccinated and also boosted in pregnancy reported that a key factor in her decision was previous history with always receiving recommended vaccinations before covid-19 and trusting medicine at baseline. Both patients emphasized the importance of receiving direct vaccine counseling about their specific pregnancy from their obstetric healthcare provider. On the basis of these observations, we modified the manuscript to ensure a focus on perinatal outcomes and vaccine hesitancy and also to acknowledge the importance of counseling by the obstetric provider on covid-19 vaccination in pregnancy.
Acknowledgments
We thank Sharon L Leslie, nursing informationist, Woodruff Health Sciences Center Library, Emory University, Atlanta, GA, USA, for developing and conducting the literature search strategy.
Footnotes
Series explanation: State of the Art Reviews are commissioned on the basis of their relevance to academics and specialists in the US and internationally. For this reason they are written predominantly by US authors
Contributors: All authors defined the intellectual content, conducted the literature research, acquired data, and participated in preparing, editing, and critically reviewing the manuscript. DJJ is the guarantor.
Competing interests: We have read and understood the BMJ policy on declaration of interests and declare: MLB and CMD receive NIH grant funding for DMID 21-0004, an observational, prospective cohort study of the immunogenicity and safety of SARS-CoV-2 vaccines administered during pregnancy or post partum and evaluation of antibody transfer and durability in infants.
Provenance and peer review: Commissioned; externally peer reviewed.