key: cord-1041485-74j67v73
authors: Nunes, Marta C.; Madhi, Shabir A.
title: COVID-19 vaccines in pregnancy
date: 2022-05-03
journal: Trends Mol Med
DOI: 10.1016/j.molmed.2022.04.012
sha: c5a30af1134839bde043a323134741d0eda81166
doc_id: 1041485
cord_uid: 74j67v73

Coronavirus disease 2019 (COVID-19) which is caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has been associated with severe illness in pregnant women. Furthermore, COVID-19 during pregnancy is associated with adverse foetal outcomes, including preterm labour. Pregnant women were largely excluded from initial clinical trials on the safety and efficacy of COVID-19 vaccines; however, they have since been included as part of the routine roll out of these vaccines. This narrative review, synthesis the evidence on the safety, immunogenicity, and effectiveness of mainly the messenger ribonucleic acid (mRNA) COVID-19 vaccines, which have been most widely used in pregnant women.

Obstetricians and Gynecologists, the USA Center of Disease Control (CDC), the World Health Organization (WHO) and other medical organizations and committees endorsed the routine use of COVID-19 vaccines for pregnant women based on a risk-benefit analysis [22] [23] [24] [25] [26] . Since these recommendations, pregnant women opting to be vaccinated were included in observational studies and vaccine safety monitoring registers, providing crucial information on the immunogenicity and safety of the available vaccines in this population [27] . Inadvertently, safety data on COVID-19 vaccines was also collected in some of the initial clinical trials when incidental pregnancies occurred during the studies [28] .

Vaccination of pregnant women against other pathogens such as influenza virus, Bordetella pertussis and tetanus is routine in many countries [29] . The use of COVID-19 vaccines developed with the newer non-replicating vector and mRNA technologies merits ongoing monitoring, including since future vaccination of pregnant women will involve increasing proportion of individuals with underlying immunity from past infection or receipt of vaccines before having fallen pregnant. In addition to vaccination of pregnant women protecting them against COVID-19, vaccination could also protect against adverse COVID-19 associated cohort study including 7809 pregnant women, 6815 lactating women, and 2901 participants who were neither pregnant nor lactating but planned on falling pregnant at the time of receipt of their first vaccine dose; iii) a prospective cohort of 84 pregnant and 16 non-pregnant vaccinated women; iv) and a cross-sectional study of 38 pregnant and 991 non-pregnant women who were vaccinated with BNT162b2 or mRNA-1273 [31, 36, 37, 48, 58, 59] .

The most common reported systemic adverse symptoms among pregnant women were tiredness (14%-72%), headache (5%-55%), myalgia (2%-54%), chills (1%-47%), nausea (5%-29%) and fever (2%-45%). In general, the rate of systemic adverse events was higher following the second vaccine dose for both mRNA vaccines [31, 36, 48] , as also evident in non-pregnant individuals [14, 16, 58] . Furthermore, higher frequency of adverse events was reported after the higher concentration mRNA-1273 vaccine (100g) than the BNT162b2 vaccine (30g) [48] . Among pregnant women, injection-site pain (57%-97%) was the most common local adverse event for both mRNA vaccines.

In general, the frequency of solicited local and systemic events and higher rate of reactogenicity after the second dose were similar among non-pregnant and pregnant women irrespective of the gestational age at time of vaccination. The exception was in Israel, where myalgia (24.1% vs.

49.2%), arthralgia (4.1% vs. 21.5%), headache (10.3% vs. 48.8%), injection-site pain (91.8% vs. 96.2%) and lymphadenopathy (2.1% vs. 9.6%) were less common among pregnant than non-pregnant BNT162b2 vaccinated women, respectively; while paresthesia (4.6% vs. 1.2%) was more frequent in pregnant women [31] . Similarly, the study from Romania also reported lower frequency of myalgia (6.6% vs. 12.7%), lymphadenopathy (4.8% vs. 10 .5%) and fever (10.1% vs. 16 .7%) in pregnant compared with non-pregnant women, although fatigue (82.8% vs. 67 .8%) was more frequently in the pregnant women. Furthermore, the study from Romania, also J o u r n a l P r e -p r o o f Journal Pre-proof reported that pregnant women who had a previous SARS-CoV-2 infection compared with those without past infection had a higher frequency of fever (25.9% vs. 10 .9%) and lymphadenopathy (14.8% vs. 4 .6%) after completing the full vaccination scheme [59] .

The first preliminary findings on pregnancy outcomes among women who received mRNA vaccines were reported using data from three USA vaccine safety monitoring systems: the "vsafe after vaccination health checker" surveillance system, the v-safe pregnancy registry, and the Vaccine Adverse Event Reporting System (VAERS) [60] [61] [62] . The pregnancy registry enrolled 3958 women, 2.3% reportedly vaccinated during the pre-conception period and 28.6%, 43.3% and 25.7% in the first, second and third trimester of pregnancy, respectively. At the time of the analysis, there were 712 livebirths including 9.4% preterm births, 3.2% newborns small for gestational age (SGA), 2.2% with congenital anomalies and the rate of stillbirths was 0.1%. The profile of pregnancy outcomes in the v-safe pregnancy registry were similar to the national rate of the respective pregnancy outcomes in the pre-COVID-19 pandemic era. None of the women whose children had congenital anomalies were vaccinated during the first trimester or preconception period. Also, no neonatal deaths were reported in babies born to the vaccinated women [48] .

Foetal death was the pregnancy outcome most often investigated in the studies conducted to date.

Two studies from the USA using the CDC vaccine safety databases and one case-control study from Norwegian registries investigated whether vaccination during pregnancy increased the risk of early foetal death [39, 41, 56] . In a large case-control surveillance of 105446 pregnancies, there was no association between receipt of a COVID-19 mRNA vaccine within 28-days prior to spontaneous abortions (8.6%) compared with ongoing pregnancies (8.0%; adjusted odds ratio:

(10064, 21.8%) and unvaccinated pregnant women, accounting for time-dependent vaccine exposures and propensity to be vaccinated [65] . Ninety-eight percent of the vaccinated women received their first dose during the second or third trimester ( Reassuring safety findings were also reported from two large population-based observational retrospective studies that addressed potential sources of bias in observational studies of vaccination during pregnancy, including healthy vaccinee bias and confounding by indication, immortal time bias, and cohort truncation [66, 67] . The report from Canada, linked the Ontario birth registry with the provincial vaccination system and identified 97590 pregnant women that were eligible for COVID-19 vaccination during the study period, of whom 23% had been vaccinated with at least one dose (<1% vaccinated in the first trimester and >99% received J o u r n a l P r e -p r o o f Journal Pre-proof mRNA vaccine). The women who received a COVID-19 vaccine compared with unvaccinated pregnant women had similar frequency of post-partum hemorrhage, chorioamnionitis, cesarean delivery; and no difference in low Apgar score or neonatal care admission in their newborn [66] .

Similarly, data from a Swedish Pregnancy Register and Norwegian Birth Registry were linked with the vaccine registries in the respective countries. Together the databases from Sweden and Norway included 157521 pregnant women, 18.1% who received a COVID-19 vaccine (3.9% vaccinated in the first trimester and >98% received an mRNA vaccine). There was no association between receipt of COVID-19 vaccine and risk for preterm birth, stillbirth, SGA, low newborn Apgar score or neonatal care admission [67] .

The impact of ChAdOx1 vaccination on fertility rates and birth outcomes was assessed among pregnancies that occurred during the conduct of phase 1 to 3 clinical trials in three countries (UK, Brazil, and South Africa) [28] . Although pregnancy was an exclusion criteria for all the trials, pregnancies transpired during the follow-up phase of the study after women had been vaccinated pre-conception. Overall, 121 (1%) pregnancies were reported among the 9755 women ≤49 years old who participated in the studies. Fertility rates were similar among women who received ChAdOx1 (1.02%) compared with those in the control groups (0.89%, p=0.53).

Although 52% of the pregnancies were still ongoing at the time of that analysis (July 2021), the rate of miscarriage was similar in pregnancies among the ChAdOx1 (14%) and the control groups (21%, p=0.51). An analysis restricted to the 15 livebirths identified three preterm births in the ChAdOx1 group. No stillbirths or neonatal deaths were reported in either group [28] . mRNA vaccines induce an immune response through toll-like receptor-3 activation. Activation of toll-like receptor-3 by other ways has been linked to adverse placental-associated pregnancy outcomes in rodent models including, growth restriction, preterm delivery, and foetal death [68- J o u r n a l P r e -p r o o f Journal Pre-proof 70] . Furthermore, SARS-CoV-2 infection during pregnancy has been associated with placental anomalies such as decidual arteriopathy, foetal vascular malperfusion, and chronic histiocytic intervillositis [71, 72] . Hence, it is important to evaluate the frequency of possible placental pathology in pregnant women vaccinated with mRNA vaccines. One report detected no difference in the frequency of placental histopathological lesions in 84 pregnant women vaccinated during pregnancy (vaccine brand not stated) compared with 116 unvaccinated women. Furthermore, high-grade chronic villitis was more common in unvaccinated (14%) than the vaccinated (5%, p=0.04) group [47].

The current data suggest that vaccination of pregnant women with COVID-19 vaccines is not associated with an increased risk of adverse pregnancy, maternal, and neonatal outcomes. Most of the vaccinations of the pregnant women, however involved mRNA vaccines administered during the second and third trimesters of pregnancy, which should be considered when interpreting the findings.

Despite 17 observational studies identified on the immunogenicity of COVID-19 vaccines in pregnant women up until end of February 2022, the majority have enrolled less than 100 participants; Table 1 Two studies from the USA described humoral responses to COVID-19 mRNA vaccines in pregnant compared with non-pregnant women, including serum IgG and used systems serology to investigated antibody effector functions [32, 74] . Both studies reported similar anti-S specific antibody-dependent neutrophil phagocytosis, antibody-dependent complement deposition, and antibody-dependent cellular phagocytosis in pregnant women compared with nonpregnant women. One study found, however, that antibody effector functions and Fc receptor (FcR) binding were lower in pregnant compared with the non-pregnant counterparts after the first vaccine dose; but similar after the second vaccine dose [74] . Also, despite overall lower IgG concentrations against multiple SARS-CoV-2 IgG epitopes in cord-blood compared with maternal blood, mRNA COVID-19 vaccination during third pregnancy trimester was associated J o u r n a l P r e -p r o o f with enrichment of functional RBD-specific FcR binding antibodies in cord-blood; as was also observed following SARS-CoV-2 infection in pregnant women [75] . The other study also assessed cellular immune responses to mRNA vaccination, by quantifying the S-specific CD4and CD8-T cells and central memory T-cells; and reported similar frequency of S-specific IFN-γ secreting cells in pregnant and non-pregnant women measured by enzyme-linked immunospot assay [32] .

It is established that binding and neutralizing antibodies induced by vaccines undergo maternal to foetus transplacental transfer [31, 32, 36, 40, 42, 43, 45, 46, 49, 51, 55, 57] . All studies, independent of which mRNA vaccine and when vaccination occurred during pregnancy, reported a positive correlation between maternal and cord-blood IgG concentrations. The cord-tomaternal blood IgG ratios were generally approximately 1, with the highest ratio of 2.6 for anti-RBD IgG among 114 term newborns whose mothers had received BNT162b2 in the second trimester of pregnancy; indicating active transplacental transfer of the anti-protein antibodies [40] . Lower ratio of cord-to-maternal blood anti-S (0.4-0.9) and anti-RBD (0.34-0.7) IgG were reported in term neonates whose mothers received two doses of BNT162b2 from late third trimester [45, 46] . These data suggest that earlier timing of COVID-19 vaccination is associated with higher cord-to-maternal ratio of IgG, however, this could be offset by waning of antibody concentrations in women who were vaccinated earlier in pregnancy relative to the time of delivery. This was corroborated on a study also reporting higher cord-to-maternal ratio (1. In a cohort study of 1359 pregnant women (2.4% received Ad.26.COV2.S and 97.6% an mRNA vaccine), although early third trimester vaccination was associated with the highest anti-S IgG concentration in maternal and cord-blood, newborns to fully vaccinated women (even if vaccinated early in the first trimester) had similar or higher IgG concentration than those born to women who were partially vaccinated before delivery [55] . Moreover, anti-S IgG concentrations after mRNA COVID-19 vaccination in pregnant women with SARS-CoV-2 infection prior to vaccination were comparable to IgG concentrations in women without history of SARS-CoV-2 infection vaccinated in the third trimester of pregnancy [55] . An inverse correlation was, however observed for both maternal and cord-blood anti-RBD IgG responses at delivery and the time interval between receipt of the second dose of BNT162b2 (≥7 days before delivery, at 21.9

weeks gestation) and delivery [40] . Besides the time from vaccination to delivery, birthweight was also found to be positively associated with transplacental anti-S IgG transfer [51], and J o u r n a l P r e -p r o o f maternal age was inversely correlated with maternal and neonatal IgG concentrations at delivery [40] . It will be important to understand what factors affect immune response to vaccines and transplacental transfer of antibodies to delineate the preferred time for vaccination of pregnant women to optimise protection against COVID-19 in the women and their newborns.

The potential direct protection of the infant against SARS-CoV-2 infections via transplacental acquisition of maternal IgG is dependent on the duration over which the antibody remains above the threshold associated with risk reduction of being infected or developing COVID-19. It is unclear whether putative thresholds of anti-S IgG or neutralizing antibody against wild type virus would also apply to young infants; and more so in the context of relatively antibody-evasive variants of concern for which no correlates are established even in adults. When the persistence of maternally-derived anti-S IgG sero-positivity was evaluated in young infants born to women vaccinated between 20 to 32 weeks of gestation sero-positivity was 98% (48 out of 49) at 2 months of age and 57% (16 out of 28) by 6 months of age, compared with 8% (1 of 12) in infants born to unvaccinated women who had SARS-CoV-2 infection during pregnancy at similar gestational ages as vaccination occurred in the vaccinated group [49] . These data, unsurprisingly indicate waning of anti-SARS-CoV-2 IgG over time. The effectiveness of mRNA vaccines during pregnancy against COVID-19 associated hospitalization in infants <6 months age was evaluated in 17 USA states from July 2021 to January 2022 (during which time the Delta and Omicron variants of concern circulated) using a test-negative, case-control study design [76, 77] . Included in the analysis were 379 hospitalized infants (176 cases and 203 controls); the maternal vaccination coverage was 16% among cases and 32% among controls, yielding a vaccine effectiveness of 61% (95%CI: 31% to 78%).

Vaccine effectiveness of 2 doses given early in pregnancy (first 20 weeks gestation) was 32% (95%CI: -43% to 68%), and 80% (95%CI: 55% to 91%) when administered from 21 weeks gestation through 14-days before delivery [76] .

In response, to the emergence of new SARS-CoV-2 variants of concern and to address potential waning of immunity over time, many countries now recommend at least a three dose schedule of mRNA vaccines, as well as a mRNA vaccine in those who previously received two doses of Two studies suggested differences in the humoral immune response to the two current mRNA vaccines, including higher antibody responses and more robust functional antibodies induced by mRNA-1273 compared with the BNT162b2 vaccine [36, 74] . Whether these differences between the two vaccines have any clinical implications on the mother-newborn dyads is unclear, but the robust immune responses to both mRNA vaccines suggests that they are likely to be as efficacious in pregnant women compared with non-pregnant adults.

For Tdap (tetanus-toxoid, reduced diphtheria-toxoid, pertussis) and influenza vaccines it has been shown that the timing of vaccine administration during pregnancy impacts the magnitude of transplacental IgG transfer to the foetus [82, 83]. Nonetheless, for infections that cause substantial morbidity in the pregnant women, such as influenza and now COVID-19, vaccine administration should be timed to optimize maternal immunity relative to viral circulation. Of note, immune responses to COVID-19 vaccines to date in high income settings have probably been mainly primary immune responses rather than anamnestic responses following infection induced immunity, which is now changing with the evolving pandemic.

The only vaccine effectiveness analysis assessing protection of maternal COVID-19 vaccination in young infants indicates protection against COVID-19 hospitalization during early infancy [76] , which requires further study. 

 Pregnant women are at risk for more severe disease following SARS-CoV-2 infection compared with non-pregnant individuals.

 COVID-19 in pregnant women is associated with greater risk of preterm labour. 

Despite initial reports of high vaccine efficacy against symptomatic COVID-19 due to the wildtype virus and Alpha variant of concern, there has been decline in vaccine effectiveness after 4-5 months following the second vaccine dose, albeit persistently high protection against severe COVID-19. Furthermore, emergence of other variants of concern such as Beta and Omicron, has In several observational studies a third dose of mRNA was associated with increased effectiveness against severe COVID-19 due to Omicron, with vaccine effectiveness nearing that observed with two doses against the wild-type virus and earlier variants of concern [88-90].

Regarding pregnant women, the CDC, American College of Obstetricians and Gynecologists, UK Health Security Agency, among others, recommend for pregnant women to stay up to date with their COVID-19 vaccines, including receiving a third mRNA dose [22] [23] [24] . In addition, pregnant women may receive any vaccine product available for their third dose, although mRNA vaccines are recommended.

Three studies published to date suggest that an mRNA vaccine administered as a third dose is in principle safe and induces a robust IgG response in the mother that is transfer to the newborn [55, 91, 92] . In Israel, 294 pregnant women who received three doses of mRNA vaccines had J o u r n a l P r e -p r o o f similar rates of preterm and SGA births compared with women who were unvaccinated (n=3368) or had only received two doses (n=2854). There was, however, a higher rate of post-partum hemorrhage in those who received three doses (9.5%) than in the unvaccinated (3.2%) or double vaccinated (3.5%) groups [91] . Although the underlying potential mechanism for this difference is unknown, safety of additional vaccine doses beyond the initial two-dose schedule warrant further study.

In Germany, three pregnant women who received ChAdOx1 as primary vaccination at gestational ages between 21 and 28 weeks and had a third dose 12 weeks thereafter with either 

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100% positive anti-S and anti-RBD IgG. 30% positive anti-RBD IgM. Anti-S IgG: 319 AU/mL

Association between maternal and cord-blood anti-S and anti-RBD IgG responses. -Cord-blood anti-S and anti

Israel 27-31 weeks GA): 49%, from 1 st dose to delivery 71

Neutralization responses. Reported as AU/mL. Overall: 100% positive anti-S and anti-RBD IgG. Early 3 rd trimester: anti-S IgG

anti-RBD IgM: 0%. Late 3 rd trimester: anti-S IgG

anti-RBD IgM: 18%. Overall: 100% positive anti-S and anti-RBD IgG. 0 positive anti-RBD IgM. Early 3 rd trimester: anti-RBD IgG: 9620 AU/mL

Late 3 rd trimester: anti-RBD IgG: 6697 AU/mL

Early 3 rd trimester: anti-S IgG: 1.3 (IQR: 1.1-1.6), anti-RBD IgG: 2.3 (IQR: 1.7-3.0), neutralization: 1.9 (IQR: 1.7-2.5). Late 3 rd trimester: anti-S IgG: 0.9

*Blood samples, collected at delivery if not stated otherwise

At delivery if not stated otherwise

AU/mL: arbitrary units per milliliter

U/mL: units per milliliter; S: spike-protein; RBD: receptor-binding domain