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Clinical Opinion ajog.org

The coronavirus disease 2019 vaccine in

pregnancy: risks, benefits, and recommendations
Irene A. Stafford, MD; Jacqueline G. Parchem, MD; Baha M. Sibai, MD

The Coronavirus Disease 2019

Vaccine During Pregnancy: Risks, The coronavirus disease 2019 has caused over 2 million deaths worldwide, with over
Benefits, and Recommendations 412,000 deaths reported in Unites States. To date, at least 57,786 pregnant women in
The current coronavirus disease 2019 the United States have been infected, and 71 pregnant women have died. Although
vaccines pregnant women are at higher risk of severe coronavirus disease 2019erelated illness,
As of January 23, 2021, over 98 million clinical trials for the available vaccines excluded pregnant and lactating women. The
cases of severe acute respiratory syn- safety and efficacy of the vaccines for pregnant women, the fetus, and the newborn
drome coronavirus 2 (SARS-CoV-2) remain unknown. A review of maternal and neonatal coronavirus disease 2019 morbidity
infection have been reported worldwide. and mortality data along with perinatal vaccine safety considerations are presented to
In the United States, over 24 million assist providers with shared decision-making regarding vaccine administration for this
people have been infected and at least group, including the healthcare worker who is pregnant, lactating, or considering
400,000 people have died because of pregnancy. The coronavirus disease 2019 vaccine should be offered to pregnant women
SARS-CoV-2 infection.1e4 The pressing after discussing the lack of safety data, with preferential administration for those at
need for therapeutics and vaccines to treat highest risk of severe infection, until safety and efficacy of these novel vaccines are
and prevent coronavirus disease 2019 validated.
(COVID-19)-related illness and its effect
on our global economic structure resulted Key words: coronavirus, lactation, coronavirus disease 2019, COVID-19 vaccine,
in multiple research studies seeking influenza A H1N1, maternal immunity, Middle East respiratory syndrome, mRNA vaccine,
effective tools to combat this disease.5e12 severe acute respiratory syndrome coronavirus 2, severe acute respiratory syndrome,
With the support of the US Department vaccine safety, Zika
of Health and Human Services (DHHS),
multiple researchers and pharmaceutical
companies are actively pursuing the efficacy data from their global trial.13e16 infection.22,23 Detailed summary data for
development and manufacture of effica- Vaccine efficacy was demonstrated to be the approved SARS-CoV-2 vaccines are
cious and timely vaccines against this 95% in preventing symptomatic and presented in Table 1. On December 13,
virus.5e12 On December 11, 2020, the laboratory-confirmed COVID-19 among 2020, and December, 20, 2020, the
Federal Drug Administration (FDA) is- persons without evidence of previous Advisory Committee on Immunization
sued the first Emergency Use Authoriza- infection for 7 days after the second dose Practices (ACIP) branch of the Centers
tion (EUA) for Pfizer-BioNTech’s mRNA was administered.13e16 Shortly after, on for Disease Control and Prevention
COVID-19 vaccine.13,14 This allowed the December 18, 2020, Moderna, Inc, was (CDC) issued an interim recommenda-
vaccine to be nationally distributed to issued an EUA after the safety and tion for use of the Pfizer-BioNTech and
adults aged
16 years using the safety and immunogenicity of their mRNA SARS- Moderna COVID-19 vaccines, respec-
CoV-2 vaccine data were published and tively, after the designated COVID-19
efficacy was demonstrated to be 94.1% working group reviewed the evidence
From the Department of Obstetrics, against symptomatic and laboratory- for vaccine efficacy and safety and
Gynecology, and Reproductive Sciences,
McGovern Medical School, The University of
confirmed infection in participants aged implementation considerations,
Texas Health Science Center at Houston,
18 years without evidence of previous including offering them to eligible preg-
Houston, TX. infection for 14 days after completion of nant and lactating women, despite their
Received Jan. 12, 2021; revised Jan. 24, 2021; the 2-dose series.17e21 Although not yet exclusion from these clinical trials.13e24
accepted Jan. 25, 2021. approved in the United States, the
The authors report no conflict of interest. Oxford-AstraZeneca vaccine was Coronavirus disease 2019 in pregnancy
This work has not been published previously and approved by the British Department of Mechanical and physiological alterations
is not under consideration for publication Health and Social Care in the United in pregnancy increase susceptibility to
elsewhere. Kingdom on December 30, 2020 after the certain infections.25e27 The immuno-
Corresponding author: Irene A. Stafford, MD. vaccine was shown to have a pooled effi- logic alterations that occur during
[email protected] cacy of 70.4% in preventing symptomatic pregnancy not only may be protective to
0002-9378/$36.00 and laboratory-confirmed COVID-19 14 the fetal allograft but also may create
ª 2021 Elsevier Inc. All rights reserved.
https://doi.org/10.1016/j.ajog.2021.01.022
days after completion of the 2-dose series vulnerability to certain viral
among adults without previous infections.25e27 More than 1600 reports

MONTH 2021 American Journal of Obstetrics & Gynecology 1

 Clinical Opinion
2 American Journal of Obstetrics & Gynecology MONTH 2021

TABLE 1
Summary of available SAR-CoV-2 vaccines
Name Vaccine type Experimental design Primary outcome Secondary Results
Pfizer-BioNTech mRNA BNT162b2 Double-blinded RCT 1:1 ratio of Efficacy against COVID-19 1) Severe COVID-19 d
1) Without previous COVID-19: 95.0%
vaccine to placebo >7 d after second dose efficacy (95% CI, 90.3e97.6)
defined by:
2 doses, 21 d apart a) Symptomatica 2) Safety or side effects 2) With or without previous COVID-19:
94.6% efficacy (95% CI, 89.9e97.3)

16 y old b) NAAT 3) Efficacy after first dose 3) Systemic complaints: first dose,
52%e59%; second dose, 39%
e51%
N¼43,448 within 4 days of symptom 4) In persons with or
onsetb without COVID-19
Multicenter, international In persons without previous
COVID-19c
Probability of vaccine efficacy
>30%
95.0% credible interval for
vaccine efficacy
Bayesian beta-binomial mode
Moderna mRNA-1273 Observer-blinded RCT 1:1 ratio Efficacy against COVID-19 1) Severe COVID-19d 1) Without previous COVID-19: 94.1%
of vaccine to placebo >14 d after second dose efficacy (95% CI, 89.3e96.8)
defined by:
2 doses, 28 d apart a) Symptomatice 2) Safety or side effects 2) In persons with previous COVID-19:
93.6% (95% CI, 88.6e96.5)

18 y old b) NAAT 3) Efficacy after first dose 3) Systemic complaints: first dose,
54.9%; second dose, 79.4%
N¼30,420 within 4 days of symptom 4) In persons with and
onsetf without previous COVID-
19
Multicenter, United States In persons without previous
COVID-19c
Probability of vaccine efficacy
>30%
1-sided O’Brien-Fleming
boundary for efficacy. Lan-
DeMets alpha-spending for
efficacy boundaries

ajog.org
Stafford. The coronavirus disease 2019 vaccine in pregnancy. Am J Obstet Gynecol 2021. (continued)
 ajog.org
TABLE 1
Summary of available SAR-CoV-2 vaccines (continued)
Name Vaccine type Experimental design Primary outcome Secondary Results
Oxford- Adenovirus-vectored Single-blind and double-blind (1 Efficacy against COVID-19 1) Efficacy after both doses, 1) Persons without previous COVID-19:
AstraZeneca vaccine site) RCT 1:1 ratio of vaccine to >14 d after second dose full dose vaccine efficacy: 90.0% (67.4
placebo 28 d apart defined by: e97.0) for 0.5 and full dose
Subset: 0.5 and full dose second a) Symptomaticg 2) Safety or side effects 2) Vaccine efficacy: 62.1% (95% CI,
dose 41.0e75.7) 2 full doses

18 y old b) NAATh 3) Efficacy in patients with 3) 1.6% severe side effects
previous COVID-19
N¼23,848 In persons without previous
COVID-19c
Multicenter, international Primary: efficacy after first
dose is 0.5 dose
Vaccine efficacy Poisson Excluded if NAAT is positive
regression model adjusted for within 14 d after second dose
age
CI, confidence interval; COVID-19, coronavirus disease 2019; FDA, Food and Drug Administration; NAAT, Nucleic acid amplification-based test; NP, nasopharyngeal; RCT, randomized controlled trial; RT-PCR, reverse transcription-polymerase chain reaction; SARS-
CoV-2, severe acute respiratory syndrome coronavirus 2.
a
Pfizer: fever, new or increased cough, new or increased shortness of breath, chills, new or increased muscle pain, new loss of taste or smell, sore throat, diarrhea, or vomiting; b Respiratory specimen obtained during the symptomatic period or within 4 days before or
after it that was positive for SARS-CoV-2 by nucleic acid amplification-based testing; c Participants were assessed for the presence of SARS-CoV-2ebinding antibodies specific to the SARS-CoV-2 nucleocapsid protein and had a nasopharyngeal swab for SARS-
CoV-2 RT-PCR testing using protocol-defined acceptable tests; d Severe COVID-19 as defined by the FDA includes severe systemic illness, respiratory failure, evidence of shock, significant acute renal, hepatic, or neurologic dysfunction; admission to the intensive
care unit; or death; e Moderna: 2 or more the following symptoms: fever (temperature of
38 C), chills, myalgia, headache, sore throat, or new olfactory or taste disorder or occurring in those who had at least 1 respiratory sign or symptom (including cough,
shortness of breath, or clinical or radiographic evidence of pneumonia); f One NP swab, nasal swab, or saliva sample (or respiratory sample, if hospitalized) positive for SARS-CoV-2 by RT-PCR; g AstraZeneca: temperature of >37.8 C, cough, shortness of breath,
and anosmia or ageusia. In some sites, the list of qualifying symptoms for swabbing was broader and included myalgia, chills, sore throat, headache, nasal congestion, diarrhea, runny nose, fatigue, nausea, vomiting, and loss of appetite; h One NP swab or nasal
swab positive for SARS-CoV-2 by RT-PCR by home kits using protocol-defined acceptable tests.
MONTH 2021 American Journal of Obstetrics & Gynecology

Stafford. The coronavirus disease 2019 vaccine in pregnancy. Am J Obstet Gynecol 2021.
and cesarean delivery for pregnant
hypertensive disorders, preterm birth,
higher risk of thromboembolic disease,
pregnancy outcomes, there remains a
that the infection increases other adverse
3.1e7.7]).46 Despite limited evidence
CI, 65e268] vs 5.0 [95% CI,
deaths per 100,000 women, 141 [95%
those without COVID-19 (number of
women with infection compared to
reporting an increased rate of death in
demonstrated
database of 20% of US hospitals
COVID-19 collected from an all-payer
admitted for delivery with and without
outcome of over 400,000 women
morbidity, mortality, and pregnancy
pants.45 A recent publication of
for approximately half of the partici-
and underlying conditions was missing
cases, and information on symptoms
ethnicity status was missing for 25% of
with known pregnancy status, race and
recorded.45 In addition, among those
women did not have pregnancy status
as over 64.5% of total cases involving
these surveillance data have limitations,
advanced maternal age.35e45 However,
derserved, have comorbidities, or are of
for subgroups of women who are un-
and comorbidities, with even higher risk
after adjusting for age, race, ethnicity,
compared with nonpregnant women
symptomatic COVID-19 infection
CI, 1.2e2.4) in pregnant patients with
(1.5 vs 1.2 per 1000 cases; aRR, 1.7; 95%
aRR, 2.9; 95% CI, 2.2e3.8), and death
ventilation (2.9 vs 1.1 per 1000 cases;
interval [CI], 2.6e3.4), mechanical
risk ratio [aRR], 3.0; 95% confidence
sion (10.5 vs 3.9 per 1000 cases; adjusted
risk of intensive care unit (ICU) admis-
other publications indicate an increased
nonpregnant adults,28e34 CDC data and
in pregnant women is similar to
suggested that the severity of COVID-19
435 pregnant women with infection have
recent meta-analysis with data from over
Although several studies, including a
tions among affected pregnancies.
transmission, and perinatal complica-
lenges, therapeutic options, intrauterine
analyses describing diagnostic chal-
cohort studies, case series, and meta-
have been published. Most reports are
evaluating COVID-19 and pregnancy

Clinical Opinion
similar outcomes,
3
Clinical Opinion ajog.org

women with infection, differentially occurred in 57% of pregnant women preliminary human studies have
represented across global regions.28e46 with infection.64e70 The Middle East demonstrated promising safety and
Although the absolute risk for severe respiratory syndrome, another corona- immunogenicity data using the mRNA
infection is low, the CDC has included virus, has demonstrated similar patho- vaccine model with other pathogens,
pregnancy as a risk factor for severe genicity, leading to adverse perinatal including the influenza virus, Zika virus,
COVID-19, and this has been echoed by events in over 90% of women with and rabies virus,81e88 but previous effi-
the Society for Maternal-Fetal Medicine infection in 2012.64e70 Currently, a safe cacy studies evaluating mRNA vaccines
(SMFM), the American College of Ob- and efficacious vaccine has not been during pregnancy are limited to animal
stetricians and Gynecologists (ACOG), developed for these pathogens. In 2009, studies involving the Zika virus, where
and other women’s health a novel strain of the influenza A virus, vaccination resulted in a significant
organizations.47e53 termed H1N1, resulted in a pandemic reduction of placental and fetal viral
Several reports of neonatal trans- with an estimated 40 million people burden.81e88 Details concerning trans-
mission and adverse outcomes for infected between April 2009 and April placental vaccine transfer have not been
newborns with infection have been 2010, resulting in more than 274,304 described.81e88 Although disclosed de-
reported; however, some of these data hospitalizations and 12,469 tails of the protocols are available for
are confounded by uncertainty sur- deaths.64e74 During the first 5 months review, the precise formulations of the
rounding testing and diagnostics for of the H1N1 pandemic, 788 cases were cationic nanoparticles used for mRNA
these neonates and other independent reported in pregnant women. Of those assembly of the COVID-19 vaccines
neonatal morbidities.54e60 Collec- cases, 30 pregnant women died, remain propriety to the manufacturing
tively, the current available data sug- comprising 5% of all reported 2009 pharmaceutical companies and pre-
gest an approximate 2% to 3% risk of influenza H1N1 deaths during this liminary safety data regarding the
vertical transmission with a minimal period.67e74 Furthermore, 4 case re- COVID-19 mRNA vaccines during
rate of persistent neonatal infection. ports of suspected H1N1 vertical gestation reference a perinatal or post-
Consistent with these observations are transmission in newborns have been natal reproductive toxicology study in
data showing that SARS-CoV-2 is not published, with 1 reported neonatal rats, which demonstrated no safety
routinely detected in amniotic fluid, death.75e77,78 In addition, observa- alert.13e23,47
cord blood, or neonatal nasopharyn- tional studies have demonstrated higher Ultimately, the advantage of past and
geal samples associated with affected frequencies of maternal infectious present influenza vaccine designs in
pregnancies.54e60 Several studies have morbidity, showing higher rates of comparison is the background benefit of
described the detection of viral RNA in maternal ICU admission and death known published protocols and historic
breast milk of mothers with infection; because of H1N1 influenza infection experience utilizing inactivated or atten-
however, there is no evidence to sug- compared with rates in nonpregnant uated virus since 1940, leading to a more
gest that the ingestion of breast milk populations, even more so than the expeditious design for safety and
from mothers with SAR-CoV-2 infec- rates of the current COVID-19 efficacy.89e95 These studies were accom-
tion increases the risk of transmission pandemic.79,80 plished with fewer challenges compared
to their newborns.61e63 Variable with the de novo human vaccine devel-
quantities of immunoglobulin A anti- Vaccines and reproductive toxicology opment for the novel SARS-CoV-
bodies were detected in 80% of 18 Although several vaccine efficacy and 2.13e23,81 Typically, vaccines intended for
breast milk samples collected from safety studies were conducted with pregnant or breastfeeding women rely on
women with infection in 1 study; pregnant and lactating women during critical review by the scientific commu-
however, the protective capacity of the H1N1 pandemic, the COVID-19 nity of all observational studies, case re-
these antibodies against infection for vaccine trials have excluded these ports and series, registries and
newborns and infants requires further groups, and therefore, critical perinatal experimental data regarding the type of
investigation.61e63 safety information remains largely vaccine, pathogen placental transfer
unknown.13e24,81 The mRNA (Pfizer- studies, toxicity and immunogenicity
Past pandemics and vaccine safety in BioNTech and Moderna) and viral vec- studies, and trimester-specific infection
pregnant women tor (AstraZeneca) COVID-19 vaccines risks. These reviews are conducted
Disproportionate rates of maternal are novel in design and, to date, are the through collaborative efforts by the Vac-
morbidity, adverse perinatal outcomes, first mRNA and viral vector vaccine trials cine Safety Datalink, a collaborative
and mortality because of infectious to have been comprehensively evaluated project between the CDC and others,
disease have been described in past for disease prevention in people.13e23,81 including the ACIP Workgroup, National
pandemics. During the 2002 severe Of note, the Ebola vaccine (rVSVDG- Institutes of Health, Task Force on
acute respiratory syndrome (SARS) ZEBOV-G, Merck) was developed using Research Specific to Pregnant Women
pandemic, which infected over 8000 similar viral vector technology and is and Lactating Women, World Health
people in 26 countries, maternal case currently approved for disease preven- Organization, and Global Advisory
fatality was 25%, and miscarriage tion in nonpregnant adults.81 Several Committee on Vaccine Safety.89e100

4 American Journal of Obstetrics & Gynecology MONTH 2021

ajog.org Clinical Opinion

Priority is granted to potential vaccines Coronavirus Disease 2019 Vaccine confirmed COVID-19 with clinical signs
that meet several key criteria when and Pregnancy that are indicative of severe systemic
considered for mass vaccination Maternal risks and benefits illness, including respiratory failure, evi-
campaigns.96e108 The vaccine should On December 19, 2020, the CDC and dence of shock, significant acute organ
demonstrate the potential to reduce ACIP released a statement supporting the dysfunction, admission to an ICU, or
morbidity in the pregnant woman and/or administration of both EUA-approved death.14e21 Although preliminary data
her fetus. In addition, there should exist a vaccines to prevent COVID-19 in per- report lower hospitalizations among
lack of evidence of adverse pregnancy sons aged
16 and 18 years, respectively, vaccine recipients, these valuable data are
outcomes or potential harm to the fetus starting with prioritization groups out- not yet available and therefore cannot be
or mother with vaccine exposure.96e108 lined by the ACIP.50,52,53 This strategy fully addressed when counseling the
Multiple randomized control trials includes beginning with healthcare pregnant patient concerned about these
and prospective studies have demon- personnel and long-term care facility more serious outcomes or the potential
strated vaccine efficacy against residents (Phase 1a), followed by persons reduction in the long-term sequelae of
influenza-related morbidity in the aged
75 years and nonhealthcare COVID-19 or risk of continued
pregnant patient and laboratory- frontline essential workers (Phase 1b), transmissibility.14e21 If validated, a
confirmed infection in their neonates, and in Phase 1c, the vaccines should be reduction in severe COVID-19 would
with an additional 6 months of efficacy offered to persons aged 65 to 74 years, benefit the fetus, given the negative effects
during early infancy.89e95 In addition, persons aged 16 to 64 years with high-risk maternal illness has on fetal status, which
these safety data included comprehen- medical conditions, and essential workers has driven medically indicated and
sive studies and monitoring programs not included in Phase 1b.50,52,53 In addi- spontaneous preterm birth and associ-
for the adjuvant- and nonadjuvant- tion, the CDC, ACOG, SMFM, and other ated neonatal sequelae.28e46 Counseling
containing inactivated trivalent sea- agencies support offering vaccination to to this point can include a discussion of
sonal influenza vaccine and the H1N1 pregnant and lactating women in these the continued pursuit and accumulation
monovalent vaccines.89e95 With sup- prioritized groups.47e53 Counseling of pregnancy-specific COVID-19 data
port from the CDC, American Academy should include discussion of the risks and worldwide, with current data suggesting
of Pediatrics, American Academy of benefits for those contemplating vaccina- that rates of severe morbidity (assisted
Family Medicine, ACIP, and ACOG, a tion before or during pregnancy or while ventilation, ICU admission, and death)
consensus statement was published, breastfeeding with their trusted provider are significantly higher among pregnant
recommending that all women receive and support network. Mild side effects women with symptomatic COVID-19
both the seasonal and 2009 H1N1 have been reported, ranging from a >80% compared with symptomatic nonpreg-
inactivated vaccines during pregnancy frequency of pain at injection site to a 40% nant cohorts, respectively, which equally
with FDA approval within 6 months rate of systemic complaints, including affect 5% of persons with infection.35e46
from the start of the H1N1 febrile morbidity, which on review has However, when examining critical care
pandemic.109e112 These vaccines, along been disproven to be teratogenic to the details and demographic variables of
with known toxoids, have been used to fetus during the first trimester of preg- pregnant women with infection in large
prevent infectious morbidity known to nancy.114,115 Bell palsy affected few re- national epidemiologic data, it remains
negatively impact maternal and cipients of both Pfizer-BioNTech and critical to acknowledge that in the largest
neonatal health.109e113 For example, Moderna vaccines but was not attributed studies to date, the rates of ICU admis-
the administration of the seasonal and to the vaccination.16,18,21 sion, invasive ventilation, and mortality
H1N1 influenza vaccine and tetanus Counseling regarding anticipated from COVID-19 are 2- to 3-fold higher
toxoid vaccine (combined with benefits is clear, as published data reveal among symptomatic pregnant women
diphtheria-pertussis, Tdap) has resul- between 94% and 95% efficacy in pre- over 35 years of age, with comorbidities
ted in a 92% reported reduction in venting laboratory-confirmed and mildly (obesity, diabetes, cardiovascular disease,
global pertussis morbidity and symptomatic COVID-19 among people 7 chronic lung disease), black or Asian race
mortality.113 to 14 days after completion of the vaccine or Hispanic ethnicity (Table 2).35e46 These
With the disclosure of full intent to series, with potential for similar efficacy findings are further supported by a recent
perform future research on COVID-19 for the pregnant patient based on similar publication analyzing data from a national
vaccine safety in this population, the efficacy observed between pregnant and database encompassing 20% of hospitali-
DHHS, companies, and researchers nonpregnant individuals in other vaccine zations in the United States, including
prioritized the emergent delivery of a trials, regardless of pregnancy women hospitalized for childbirth be-
safe and effective vaccine to the public, specifics.13e21,81,96e109 tween April 1, 2020, and November 23,
responding to an emergent call to action, Major secondary endpoints of the 2020.46 Women with laboratory-
unfortunately with limited time and BioNTech and Moderna COVID-19 vac- confirmed COVID-19 along with obesity
lower thresholds for evidence before cine studies include the efficacy of the (body mass index of >35, kg/m2) or dia-
implementation for the pregnant and vaccine against severe infection-related betes or hypertensive disorders were
lactating patient.13e24,81 morbidity, defined by the FDA as significantly more likely to require

MONTH 2021 American Journal of Obstetrics & Gynecology 5

Clinical Opinion ajog.org

TABLE 2
ICU admissions, invasive ventilation, and deaths among symptomatic women of reproductive age with
laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (N[409,462)

Outcome or characteristica Pregnant (n[23,434) Nonpregnant (n[386,028) Risk ratio (95% CI)
b
ICU admission
All 245 (10.5) 1492 (3.9) 3.0 (2.6e3.4)
Age group (y)
25e34 118 (9.1) 467 (3.5) 2.4 (2.0e3.0)
35e44 78 (19.4) 781 (6.4) 3.2 (2.5e4.0)
Race and ethnicity
Hispanic or Latina 89 (12.8) 429 (5.0) 2.8 (2.2e3.5)
Asian, non-Hispanic 20 (35.7) 52 (6.0) 6.6 (4.0e11.0)
Black, non-Hispanic 46 (13.6) 334 (6.2) 2.8 (2.0e3.8)
White, non-Hispanic 31 (5.6) 348 (2.8) 2.3 (1.6e3.3)
Underlying health conditions
Diabetes 25 (58.5) 274 (44.8) 1.5 (1.0e2.2)
c
CVD 13 (42.8) 247 (32.1) 1.5 (0.9e2.6)
d
Invasive ventilation
All 67 (2.9) 412 (1.1) 2.9 (2.2e3.8)
Age group (y)
25e34 30 (2.3) 123 (0.9) 2.5 (1.6e3.7)e
35e44 26 (6.5) 221 (1.8) 3.6 (2.4e5.4)
Race and ethnicity
Hispanic or Latina 33 (4.7) 143 (1.7) 3.0 (2.1e4.5)
Asian, non-Hispanic 4 (7.1) 19 (2.2) NA
Black, non-Hispanic 10 (3) 86 (1.6) 2.5 (1.3e4.9)
White, non-Hispanic 12 (2.2) 102 (0.8) 3.0 (1.7e5.6)
Underlying health conditions
Diabetes 10 (23.4) 98 (16.0) 1.7 (0.9e3.3)
c
CVD 6 (19.7) 82 (10.6) 1.9 (0.8e4.5)f
Deathg
All 34 (1.5) 447 (1.2) 1.7 (1.2e2.4)
Age group (y)
25e34 15 (1.2) 125 (0.9) 1.2 (0.7e2.1)
35e44 17 (4.2) 282 (2.3) 2.0 (1.2e3.2)
Race and ethnicity
Hispanic or Latina 14 (2.0) 87 (1.0) 2.4 (1.3e4.3)
Asian, non-Hispanic 1 (1.8) 11 (1.3) NA
Black, non-Hispanic 9 (2.7) 167 (3.1) 1.4 (0.7e2.7)
White, non-Hispanic 3 (0.5) 83 (0.7) NA
Stafford. The coronavirus disease 2019 vaccine in pregnancy. Am J Obstet Gynecol 2021. (continued)

6 American Journal of Obstetrics & Gynecology MONTH 2021

ajog.org Clinical Opinion

TABLE 2
ICU admissions, invasive ventilation, and deaths among symptomatic women of reproductive age with laboratory-
confirmed severe acute respiratory syndrome coronavirus 2 (N[409,462) (continued)

Outcome or characteristica Pregnant (n[23,434) Nonpregnant (n[386,028) Risk ratio (95% CI)
Underlying health conditions
Diabetes 6 (14.1) 78 (12.7) 1.5 (0.6e3.5)h
CVDc 7 (23.0) 89 (11.6) 2.2 (1.0e4.8)i
Data are presented by pregnancy status, age, race, ethnicity, and comorbidities. Data for extracorporeal membrane oxygenation, multiple or other race, non-Hispanic, and unknown are included. Only
adjusted risk ratio is included.
CI, confidence interval; CVD, cardiovascular disease; ICU, intensive care unit; NA, not available.
Adapted from Zambrano et al.45
a
Percentages are based on the total number of pregnancies per status group: adjusted for age, categorical race and ethnicity variable, and dichotomous indicators for diabetes, CVD, and chronic lung
disease; b A total of 17,007 (72.6%) symptomatic pregnant women and 291,539 (75.5%) symptomatic nonpregnant women were missing information on ICU admission status; c CVD accounts for
the presence of hypertension; d A total of 17,903 (76.4%) pregnant women and 299,413 (77.6%) nonpregnant women were missing information regarding receipt of invasive ventilation and were
assumed to have not received it; e Adjusted for presence of diabetes, CVD, and chronic lung disease only; data on race and ethnicity were from the adjustment set because of model convergence
issues; f Adjusted for presence of diabetes and chronic lung disease and age as a continuous covariate only; data on race and ethnicity were removed from the adjustment set because of model
convergence issues; g A total of 5152 (22.0%) pregnant women and 66,346 (17.2%) nonpregnant women were missing information on death and were assumed to have survived; h Adjusted for
presence of CVD and chronic lung disease and age as a continuous variable; i Adjusted for presence of diabetes and chronic lung disease and age as a continuous variable.
Stafford. The coronavirus disease 2019 vaccine in pregnancy. Am J Obstet Gynecol 2021.

mechanical ventilation or die compared vaccine arms.14e21 All pregnancy vari- safety is neither helpful nor logical given
with women without those morbidities ables and outcomes, including any that these phases of reproductive life are
(odds ratio, 3.85 [95% CI, 2.05e7.21]; adverse safety events, will be recorded but physiologically and biologically distinct.
4.51 [95% CI, 2.10e9.70]; 116.1 [95% CI, are currently not available given the Experts (Academy of Breastfeeding Med-
22.91e588.50], respectively). Current data temporal relationship of these pregnan- icine, ACOG, etc.) agree that vaccination
report that more than 21% of pregnant cies and trial participation.14e21 poses minimal to no potential risk to the
women with COVID-19 in the United Limited unpublished data are currently newborn, given that vaccine-related
States have been admitted to the hospital, available from animal developmental and mRNA has not been detected in early
but only 1.6% of women hospitalized for reproductive toxicity studies, which have breast milk studies and no plausible
delivery between April 1, 2020, and revealed no safety concerns in over 1000 mechanism of neonatal harm has been
November 23, 2020, were positive for rats that received the Moderna COVID-19 identified.47e53,81 Based on the biology of
COVID-19.1e4,35e46 Overall, rates of se- vaccine before or during gestation with other vaccines, there is the potential for
vere morbidity among pregnant women regard to female reproduction, fetal or neonatal benefit if vaccine-stimulated
remain low, with ICU admission approx- embryonal, or postnatal develop- immunoglobulin A passes through breast
imating 3% and necessity for invasive ment17,18,47 Although human data sur- milk and provides additional protection
ventilator support and death at 1.0 and rounding detailed transplacental vaccine against SARS-CoV-2 infection.47e53
0.2%, respectively.35e46 Even when transfer, fetal teratogenicity, and immu- Overall, safety for lactating women seems
symptomatic of COVID-19, these rates are nogenicity are lacking, the administration reassuring with no reason to suspect that
substantially reduced to 0.9, 0.2, and 0.1%, of the vaccine does not seem to affect receipt of the vaccine would lead to any
respectively, in women less than 35 years fertility or miscarriage rate in animal adverse neonatal effects or harmful
of age without complicating health con- studies.14e21,47,54,81 Because of the pro- changes to lactation.47e53
ditions.45 In fact, according to current tection of passive immunoglobulins in
CDC surveillance data, mortality rates in preventing infectious morbidity for the Summary
persons less than 40 years of age is neonate, certain vaccines are recom- In alignment with the current consensus
0.0063%.1e4 mended by the ACOG, CDC, and ACIP statements and practice bulletin publi-
for administration during pregnancy and cations from the CDC, ACOG, SMFM,
Fetal risks and benefits in the third trimester of pregnancy and other women’s health organizations,
When balancing risks and benefits, it is (influenza, Tdap), a benefit that may we recognize that pregnant women meet
important to clarify that there is no hu- or may not be revealed with longi- the criteria as a prioritized group for
man trial demonstrating fetal and tudinal immunogenicity studies for administrating Pfizer-BioNTech and
neonatal safety with the COVID-19 the Pfizer-BioNTech and Moderna Moderna COVID-19 vaccines, especially
vaccines.14e21 Furthermore, 36 pregnan- vaccines.11,14e21,47e112 for those with high-exposure
cies were reported among participants in Regarding lactation, it is worth noting occupations.47e53 Importantly, for
the Pfizer-BioNTech and Moderna clin- that grouping pregnant and lactating pregnant frontline workers currently
ical trials combined, including 18 in the women together in discussion of vaccine eligible for the vaccination, efficacy and

MONTH 2021 American Journal of Obstetrics & Gynecology 7

Clinical Opinion ajog.org

TABLE 3
Recommended criteria for the administration of the currently available EUA-approved COVID-19 vaccines
(BioNTech and Moderna COVID-19 vaccines) during pregnancy if one or more of the listed conditions is met using
the Interim Clinical Considerations for use of the mRNA COVID-19 vaccines currently utilized in the United States
 Healthcare providers
 Women aged
35 y
 Multiple gestation
 Cancer
 Chronic hypertension
 Chronic kidney disease
 Chronic obstructive pulmonary disease
 Heart conditions, such as heart failure, coronary artery disease, or cardiomyopathies
 Immunocompromised state (weakened immune system) from solid organ transplant
 Autoimmune diseases (systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, graves’ disease,
psoriasis or psoriatic arthritis, Addison’s disease
 Obesity (body mass index of 30 kg/m2 or higher)
 Sickle cell disease
 Smoking (current or history)
 Type 1 or 2 diabetes mellitus
Contraindications: severe allergic reaction (eg, anaphylaxis) after a previous dose of an mRNA COVID-19 vaccine or any of its components.
Immediate allergic reaction of any severity to a previous dose of an mRNA COVID-19 vaccine or any of its components (including PEG).
Immediate allergic reaction of any severity to polysorbate (because of potential cross-reactive hypersensitivity with the vaccine ingredient (PEG).
COVID-19, coronavirus disease 2019; EUA, Emergency Use Administration; PEG, polyethylene glycol.
Adapted from the Centers for Disease Control and Prevention.116
Stafford. The coronavirus disease 2019 vaccine in pregnancy. Am J Obstet Gynecol 2021.

safety data will not be available in time to highest risk of more severe infection- 5. Pascarella G, Strumia A, Piliego C, et al.
inform their decision-making. Pregnant related diseases until safety and efficacy COVID-19 diagnosis and management: a
comprehensive review. J Intern Med 2020;288:
women who choose to wait for more of these novel COVID-19 vaccines are 192–206.
data should be supported and updated ensured (Table 3).116 - 6. Williamson EJ, Walker AJ, Bhaskaran K, et al.
with evidence by their trusted healthcare Factors associated with COVID-19-related
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GLOSSARY OF TERMS
Advisory Committee on Immunization Practices ACIP
Developmental and Reproductive Toxicology DART
Emergency Use Authorization EUA
Global Advisory Committee on Vaccine Safety GACVS
National Institutes of Health NIH
US Department of Health and Human Services DHHS
Vaccine Safety Datalink VSD
World Health Organization WHO

12 American Journal of Obstetrics & Gynecology MONTH 2021