A Prospective Observational Study to Evaluate the Safety of COVID-19 Vaccination in Pregnant Women
Conditions: Pregnancy
Sponsor: Duke University

Observational Maternal COVID-19 Vaccination Study  
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A Prospective Observational Study to Evaluate the Safety of COVID-19 Vaccination in 
Pregnant Women 
 
Short Title: Observational Maternal COVID-19 Vaccination Study  
 
 
Centers for Disease Control and Prevention  
Clinical Immunization Safety Assessment (CISA) Project  
 
 
Lead Site Principal Investigator: Geeta K. Swamy, MD 
Lead Site Sub-principal Investigator: Sarah Dotters-Katz, MD, MEd 
 
Contributing Site Principal Investigator: Elizabeth P. Schlaudecker, MD, MPH 
Contributing Site Sub-principal Investigator: Mary Allen Staat, MD, MPH 
 
Contributing Site Principal Investigator: Stephen I. Pelton, MD 
Contributing Site Sub-principal Investigator: Glenn Markenson, MD 
 
Centers for Disease Control and Prevention (CDC) Principal Investigator: Karen R. 
Broder, MD 
CDC Sub-principal Investigator: Naomi Tepper, MD 
 
 
NCT04826640 
Version Number: 3.0 
 
27 October 2021 
 
 
 
 
 
 
 

Observational Maternal COVID-19 Vaccination Study  
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STATEMENT OF COMPLIANCE 
• 
This trial will be conducted in compliance with the protocol, the International 
Conference on Harmonization (ICH) Guideline E6-Good Clinical Practice (GCP), 
and the applicable guidelines and regulatory requirements from the United States 
(US) Code of Federal Regulations (CFR), 45 CFR Part 46. 
• 
All study personnel with subject contact have completed Human Subjects 
Protection Training. 
 
 
 

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TABLE OF CONTENTS 
 
PROTOCOL SUMMARY .............................................................................................................................................. 5 
1. 
BACKGROUND .................................................................................................................................................. 8 
1.1 BACKGROUND ......................................................................................................................................................................... 8 
1.2 SUMMARY & RATIONALE...................................................................................................................................................... 9 
2. STUDY OBJECTIVES .............................................................................................................................................. 9 
2.1 STUDY OUTCOME MEASURES ............................................................................................................................................ 10 
2.1.1 Primary Outcome Measure (POM): ................................................................................................................. 10 
2.1.2 Secondary Outcome Measures (SOM): ........................................................................................................... 10 
2.1.3 Exploratory Outcome Measures (EOM): ....................................................................................................... 10 
3. STUDY DESIGN..................................................................................................................................................... 11 
3.1 MAIN STUDY DESIGN ........................................................................................................................................................... 11 
3.2 LABORATORY STUDIES ........................................................................................................................................................ 11 
3.2.1 Serologic studies ..................................................................................................................................................... 11 
4 
STUDY ENROLLMENT AND WITHDRAWALS ...................................................................................... 11 
4.1 
PARTICIPANT INCLUSION CRITERIA ............................................................................................................................. 11 
4.2 
PARTICIPANT EXCLUSION CRITERIA ............................................................................................................................ 12 
4.3 
RECRUITMENT ................................................................................................................................................................. 13 
4.4 
REASONS FOR AND HANDLING OF WITHDRAWALS ................................................................................................... 13 
4.5 
TERMINATION OF STUDY ............................................................................................................................................... 13 
5 
STUDY SCHEDULE, PROCEDURES, & EVALUATIONS ........................................................................ 14 
5.1 
SCHEDULE OF EVENTS .................................................................................................................................................... 14 
5.2 
REACTOGENICITY AND SAFETY ASSESSMENTS ........................................................................................................... 17 
5.3 
BIOSPECIMENS COLLECTION & HANDLING ................................................................................................................. 20 
5.3.1 
Serum ................................................................................................................................................................... 20 
6 
LABORATORY ANALYSES .......................................................................................................................... 20 
6.1 
COVID-19 LABORATORY ANALYSIS ........................................................................................................................... 20 
7 
STATISTICAL CONSIDERATIONS ............................................................................................................. 20 
7.1 
DEFINITIONS .................................................................................................................................................................... 21 
7.2 
SAMPLE SIZE AND POWER ESTIMATION ..................................................................................................................... 21 
7.3 
ANALYSIS PLAN ............................................................................................................................................................... 21 
7.3.1 
Study Populations ........................................................................................................................................... 21 
7.3.2 
Primary Objective ........................................................................................................................................... 21 
7.3.3 
Secondary Objective 1 ................................................................................................................................... 21 
7.3.4 
Secondary Objective 2 ................................................................................................................................... 21 
7.3.5 
Secondary Objective 3 ................................................................................................................................... 21 
7.3.6 
Secondary Objective 4 ................................................................................................................................... 22 
7.3.7 
Exploratory Objective 1 ................................................................................................................................ 22 
7.3.8 
Exploratory Objective 2 ................................................................................................................................ 22 
7.3.9 
Exploratory Objective 3. ............................................................................................................................... 22 
7.3.10 
Exploratory Objective 4 .......................................................................................................................... 22 
7.3.11 
Interim Safety Data Review .................................................................................................................. 23 
7.4 
DATA MANAGEMENT PLAN ........................................................................................................................................... 23 
7.4.1 Research Electronic Data Capture (REDCap) ............................................................................................. 23 
7.4.2 
Role of the CDC Investigators in the Project ......................................................................................... 24 

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HUMAN PARTICIPANTS ............................................................................................................................. 24 
8.1 
HUMAN PARTICIPANTS INVOLVEMENT, CHARACTERISTICS, AND DESIGN ............................................................ 24 
8.2 
SOURCES OF MATERIAL .................................................................................................................................................. 25 
8.3 
POTENTIAL RISKS AND BENEFITS ................................................................................................................................ 25 
8.4 
ADEQUACY OF PROTECTION AGAINST RISKS .............................................................................................................. 25 
8.4.1 
Protections against Risk ............................................................................................................................... 25 
8.4.2 
ClinicalTrials.gov Requirements ............................................................................................................... 26 
9.0 
HUMAN PARTICIPANTS .................................................................................................................................................. 26 
9.1.1 
Vulnerable Subjects Research .................................................................................................................... 26 
REFERENCES ............................................................................................................................................................. 27 
 
 

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PROTOCOL SUMMARY 
 
Title:  
A Prospective Observational Study to Evaluate the Safety of 
COVID-19 Vaccination in Pregnant Women 
Phase: 
N/A 
Population: 
350 adult pregnant women aged 18–45 years at <34 weeks 
gestation who are either receiving their booster dose of a 
COVID-19 vaccine or are receiving their first dose of the primary 
COVID-19 vaccine series during the current pregnancy in 
accordance with the Advisory Committee on Immunization 
Practices (ACIP) and American College of Obstetricians & 
Gynecologists (ACOG) national recommendations. 
Clinical Sites: 
Three: Duke University (Lead); Cincinnati Children’s Hospital 
Medical Center (Contributor); Boston Medical Center 
(Contributor) 
Study Duration: 
36 months (approximately 12 months to recruit/enroll, maximum 
of 9 months to follow, 15 months to perform analysis and 
laboratory assays) 
Participant Duration: 
Up to 12 months depending upon gestational age at enrollment 
and delivery.  Will be followed for 90 days postpartum. 
Description of Study 
Procedures: 
This is a prospective, observational study. During the study, 
pregnant women will be followed post COVID-19 vaccination.  
 
Injection-site (local) and systemic reaction data will be 
assessed on vaccination day and daily during the 7 days 
following vaccination (including both doses if the woman 
receives a 2-dose vaccine) using either identical web-based or 
paper diaries, depending on study participant preference. 
 
Maternal serum samples will be collected for antibody titers 
relevant to COVID-19 at time points that include prior to 
vaccination, ~28 days post vaccination completion, and at 
delivery or end of pregnancy.  At Duke University, maternal 
and infant cord blood will be collected at delivery and analyzed 
for the same antibody titers. At other clinical sites, these 
delivery samples will only be collected if feasible. 
 
Pregnant women will be followed through 90 days postpartum 
or 6 weeks postvaccination if pregnancy ends early, with 
comprehensive obstetric and neonatal outcomes obtained from 
medical record review. 

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Objectives: 
Primary Objective: 
• 
To assess adverse pregnancy outcomes in pregnant 
women vaccinated with COVID-19 vaccine 
 
Secondary Objectives: 
• 
To assess preterm births occurring in pregnant women 
vaccinated with COVID-19 vaccine 
• 
To assess combined fetal and neonatal deaths after 
COVID-19 vaccination 
• 
To assess spontaneous abortions after COVID-19 
vaccination 
• 
To assess solicited local and systemic reactogenicity 
events in pregnant women vaccinated with COVID-19 
vaccine 
 
Exploratory Objectives: 
• 
To assess serious adverse events (SAE) in pregnant 
women vaccinated with COVID-19 vaccine 
• 
To assess health outcomes through 3 months of age in 
infants born to women vaccinated with COVID-19 
vaccine 
• 
To assess safety profiles in pregnant women 
vaccinated with COVID-19 vaccine by baseline COVID-
19 serostatus (positive versus negative) 
• 
To assess safety profiles in pregnant women 
vaccinated with COVID-19 vaccine by history of 
infection (any positive COVID-19 tests, self-reported 
COVID-19 disease history) 
• 
To assess maternal immune responses to SARS-CoV-
2 antigens after COVID-19 vaccine* 
• 
To assess cord blood antibody levels to SARS-CoV-2 
antigens* 
Outcome Measures: 
Primary Outcome Measure:  
• 
Proportions of a composite of adverse pregnancy 
outcomes in pregnant women vaccinated with COVID-
19 vaccine 
 
Secondary Outcome Measures:  
• 
Proportions of preterm birth 
• 
Proportions of combined fetal and neonatal death 
• 
Proportions of spontaneous abortion 
• 
Proportions of pregnant women with moderate/severe 
solicited reactogenicity events (local and/or systemic) 
within 7 days after each dose of COVID-19 vaccine 

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• 
Proportion of women with ≥1 severe local and/or 
systemic reactogenicity event 
 
Exploratory Outcome Measures: 
• 
Proportion of women with SAEs 
• 
Proportion of infants with medically attended adverse 
events through 90 days of life after maternal COVID-19 
vaccination 
• 
Proportion of infants with SAEs through 90 days of life 
• 
Primary, secondary, exploratory outcome measure 
(EOM)1, and EOM2 by maternal baseline COVID-19 
serostatus (positive versus negative) 
• 
Primary, secondary, EOM1, and EOM2 by history of 
COVID-19 disease (positive COVID-19 tests or self-
reported history vs. negative tests/history) 
• 
*Exploratory outcome measures regarding maternal 
and cord blood antibody analyses will be included in a 
future protocol amendment 
Estimated Time to Complete 
Enrollment: 
Approximately 12 months for enrollment 

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1. BACKGROUND  
1.1 Background 
The novel coronavirus, SARS-CoV-2, also known as COVID-19, has emerged as a 
deadly global pandemic. Since its identification in December 2019 in China, almost 240 
million cases with almost 4.9 million deaths have been identified worldwide.[1] As of 
October 11, 2021, there were ~44 million cases and over 715,000 deaths associated 
with COVID-19 in the United States.[2] While many individuals have asymptomatic or 
mild to moderate respiratory illness that is self-limiting, significant morbidity and mortality 
are markedly increased in older individuals or those have underlying chronic illness such 
as cardiovascular and pulmonary diseases and diabetes. Treatment relies primarily on 
supportive therapy with the addition of remdesivir and monoclonal antibodies approved 
under emergency use authorization and dexamethasone in hospitalized patients.[3]  
 
Research on strategies to treat or prevent the disease have focused on nonpregnant 
adults, leaving pregnant women and their obstetric providers without the knowledge or 
tools needed to adequately care for them, their fetuses, and their soon-to-be born 
infants. Initial reports from China did not suggest an increase in maternal or infant 
mortality. However, several publications since suggest that pregnant women are at 
higher risk for severe disease including hospitalization, ICU admission, and mechanical 
ventilation.[4] Additionally, racial and ethnic disparities of COVID-19 cases in the United 
States are similar to the general population, with non-Hispanic black and Hispanic 
pregnant women having a higher risk of COVID-19 disease.[5] In addition, the high 
incidence of known risk factors for disease severity during pregnancy (hypertension, 
diabetes, and obesity) add to the risk of COVID-19 in pregnant women in the United 
States. Currently remdesivir and dexamethasone are used for hospitalized pregnant 
women with severe COVID-19 infection, though pregnant women remain systematically 
excluded from all other investigational treatment trials. 
 
The US Department of Health and Human Services announced the framework for 
Operation Warp Speed (OWS) on May 15, 2020, with the goal of delivering safe and 
efficacious vaccine to prevent COVID-19 by January 2021. Vaccines were developed 
and tested in clinical trials at a historic pace and in December 2020 and February 2021 
FDA authorized three COVID-19 vaccines under Emergency Use Authorizations 
(EUAs).[6]  Two are mRNA vaccines: Pfizer-BioNTech mRNA vaccine, for use in 
persons aged ≥16 years and Moderna for use in persons aged ≥18 years.[7, 8]  The 
third Janssen COVID-19 vaccine uses a replication-deficient adenovirus (Ad26) vector 
and is authorized for persons aged ≥18 years.[9] Following the EUAs, these vaccines 
were recommended by the Advisory Committee on Immunization Practices.[10] 
 
Pregnant women were excluded from the clinical trials supporting these EUAs. None of 
the currently authorized COVID-19 vaccines are live virus vaccines, and the EUAs do 
not contraindicate vaccination in pregnant women. CDC’s Interim Clinical Considerations 
state the following: “Any of the currently authorized COVID-19 vaccines can be 
administered to pregnant or lactating people; ACIP does not state a product preference. 
Pregnant people may choose to receive a COVID-19 vaccine.”[11] 
  
Limited data on the safety of COVID-19 vaccine in pregnant women has left experts in 
obstetrics, infectious disease, and infection control and prevention questioning the risk or 
appropriateness for pregnant women to continue to work in the healthcare setting.[12]  

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As of September 27, 2021, there have been over 161,000 pregnancies reported in 
CDC’s v-safe post-vaccination health checker. Data collected from v-safe through 
February 2021 has not indicated any safety concerns based on reactogenicity or 
adverse events observed in pregnant women.  Side effects in pregnant and nonpregnant 
populations were similar. Additionally, no differences in adverse pregnancy outcomes 
appear when comparing pregnant women participating in the v-safe pregnancy registry 
with the background rate.  Spontaneous abortion rate appears to be consistent between 
women receiving COVID-19 vaccination during pregnancy and background rate.[13] 
 
Overall, 65% of the US healthcare workforce are women, with nearly 80% of being 
between the ages of 16–54 years.[14] Additionally, 28.5% of women have at least one 
comorbid condition associated with COVID-19 hospitalization (obesity, hypertension, 
and diabetes).[15] Given all that we know about the disease course and treatments thus 
far, a preventive vaccine would be a far better public health intervention by reducing or 
eliminating COVID-19 related morbidity and mortality as well as significantly reduce 
healthcare resource utilization. 
1.2 Summary & Rationale 
In clinical practice, the FDA approved the Pfizer-BioNTech COVID-19 vaccine in August 
2021 and granted an Emergency Use Authorization for Moderna COVID-19 vaccine in 
December 2020 and Janssen COVID-19 vaccine in February 2021. As the COVID-19 
pandemic continues there is a need to comprehensively monitor the safety of COVID-19 
vaccines in pregnant women. Efforts currently underway include a study of the Pfizer-
BioNTech vaccine for women 24 0/7 to 34 0/7 weeks' gestation (NCT04754594).[16] 
Additionally, CDC is conducting several studies and activities to monitor the safety of 
COVID-19 in pregnant women.[17] This Clinical Immunization Safety Assessment 
(CISA) Project prospective observational study in pregnant women will provide detailed 
reactogenicity information and clinical outcomes data and will complement other 
research and surveillance efforts to better understand the safety of COVID-19 vaccine in 
pregnant women. CISA has experience in observational and randomized clinical trials of 
vaccines administered during pregnancy. 
 
2. STUDY OBJECTIVES 
Primary Objective (PO): 
• 
PO1: To assess adverse pregnancy outcomes in pregnant women vaccinated 
with COVID-19 vaccine. 
Adverse birth outcomes is a composite of occurrence of at least one of the 
following: preterm birth, spontaneous abortion, fetal death, or neonatal death. 
 
Secondary Objectives (SO): 
• 
SO1: To assess preterm births occurring in pregnant women vaccinated with 
COVID-19 vaccine 
• 
SO2: To assess combined fetal and neonatal deaths after COVID-19 vaccination 
• 
SO3: To assess spontaneous abortions after COVID-19 vaccination 
• 
SO4: To assess solicited local and systemic reactogenicity events in pregnant 
women vaccinated with COVID-19 vaccine 
 
Exploratory Objectives (EO): 

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• 
EO1: To assess serious adverse events (SAE) in pregnant women vaccinated 
with COVID-19 vaccine 
• 
EO2: To assess health outcomes through 3 months of age in infants born to 
women vaccinated with COVID-19 vaccine 
• 
EO3: To assess safety profiles in pregnant women vaccinated with COVID-19 
vaccine by baseline COVID-19 serostatus (positive versus negative) 
• 
EO4: To assess safety profiles in pregnant women vaccinated with COVID-19 
vaccine by history of infection (any positive COVID-19 tests, self-reported 
COVID-19 disease history) 
• 
EO5: To assess maternal immune responses to SARS-CoV-2 antigens after 
COVID-19 vaccine* 
• 
EO6: To assess cord blood antibody levels to SARS-CoV-2 antigens* 
2.1 Study Outcome Measures 
2.1.1 Primary Outcome Measure (POM):  
POM1: Proportions of adverse pregnancy outcomes in pregnant women 
vaccinated with COVID-19 vaccine   
Adverse birth outcome is a composite of occurrence of at least one of the 
following: preterm birth, spontaneous abortion, fetal death, or neonatal death. 
2.1.2 Secondary Outcome Measures (SOM): 
 
• 
SOM1: Proportions of preterm birth 
• 
SOM2: Proportions of combined fetal and neonatal death 
• 
SOM3: Proportions of spontaneous abortion 
• 
SOM4: Proportions of pregnant women with moderate/severe solicited 
reactogenicity events (local or systemic) within 7 days after each dose of COVID-
19 vaccine  
• 
SOM4.1: Proportion of women with ≥1 severe local or systemic reactogenicity 
event  
 
2.1.3 Exploratory Outcome Measures (EOM): 
 
• 
EOM1: Proportions of women with SAEs 
• 
EOM2.1: Proportion of infants with medically attended adverse events through 90 
days of life after maternal COVID-19 vaccination 
• 
EOM2.2: Proportion of infant with SAEs through 90 days of life 
• 
EOM3: Compare primary, secondary, EOM1, and EOM2 by maternal baseline 
COVID-19 serostatus (positive vs. negative) 
• 
EOM4:  Compare primary, secondary, EOM1, and EOM2 by history of COVID-19 
disease (positive COVID-19 tests or self-reported history vs. negative 
tests/history) 
• 
*EOM 5 and 6: Exploratory outcome measures regarding maternal and cord 
blood antibody analyses will be included in a future protocol amendment 
 

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3. STUDY DESIGN 
3.1 Main study design 
This study is a prospective, observational study to evaluate the safety of COVID-19 
vaccine(s) in 350 pregnant women who are either receiving their booster dose of a 
COVID-19 vaccine or are receiving the first dose of their primary COVID-19 vaccine 
series.. Duke will serve as the Lead Contractor in conjunction with Cincinnati Children’s 
Hospital Medical Center and Boston Medical Center. With Day 1 serving as the day of 
vaccination, participants will be followed through Day 7 (total 7 days) for symptoms of 
reactogenicity; if two doses are administered reactogenicity data will be collected after 
each dose.  For the PO, we will assess adverse birth outcomes as the primary study 
endpoint. SOs will individually assess adverse birth outcomes such as preterm birth, 
spontaneous abortion, fetal death and neonatal death as well as solicited reactogenicity 
events and overall maternal SAEs following vaccination. 
3.2 Laboratory studies 
3.2.1 Serologic studies – We will evaluate pre- and post-vaccination serologic 
responses in women vaccinated against COVID-19. Prevaccination blood samples will 
be analyzed qualitatively for COVID-19 (SARS-CoV-2) antibody status (positive or 
negative) at Cincinnati Children’s Hospital Medical Center in a CLIA-certified lab. 
Postvaccination geometric mean titers (GMTs) for each SARS-CoV-2 antigen will be 
calculated. Venous blood (approximately 12 mL of blood) will be collected from each 
participant in close proximity to the first vaccination (up to 3 days before or after 
vaccination) and approximately 28 days after the last dose of vaccine received. For 
participants receiving two doses of vaccine, an optional blood collection will occur at 
approximately 21 days after first vaccination and up to 2 days prior to second 
vaccination. Those receiving a booster dose of a COVID-19 vaccine will have blood 
draws on Day 1 (before vaccination) and Day 21.  At Duke, maternal and cord blood 
(approximately 12 mL of blood each) collection will be performed at delivery for 
serological analysis. At the other sites, these samples (maternal and cord blood) will be 
collected during delivery only if feasible for similar serological analysis. 
   
3.2.2 Future studies – In addition to the specified analyses described thus far, there 
might be other tests or assays that have yet to be identified that might be important for 
interpreting our study findings or of relevance to maternal-infant health outcomes.  
Therefore, participants will be offered, through an opt-in strategy, to allow for the storage 
of any remaining blood (serum/plasma) after all specified analyses have been 
completed. Additional laboratory assays may test for antibodies against other bacteria or 
viruses, markers of inflammation, or used in research on the health of mothers and 
infants. Specimens banked for use in other studies will be linked to information (including 
identifying information) that participants provided to the study. Because it is unknown if 
future testing will be of any utility, results of future testing will not be provided. In 
addition, participants will be offered, again through an opt-in strategy, to allow study staff 
to contact them in the future to take part in other research studies. 
 
4 STUDY ENROLLMENT AND WITHDRAWALS 
4.1 Participant Inclusion Criteria 
Participants who meet all of the following criteria will be eligible to participate in 
this interventional study: 
1. Pregnant women 18–45 years of age at the time of consent, inclusive 

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2. Intention of receiving or within 1 day following receipt of the first dose or only 
dose of COVID-19 vaccine or persons receiving a booster dose of a COVID-19 
vaccine based on ACIP and ACOG guidelines in response to the FDA EUA or 
approval and in conjunction with federal and local vaccination campaign 
distribution plans 
3. Willing to provide informed 
consent in a written or 
electronic format 
4. Gestational age at time of 
consent <34 weeks 0 days 
based on reconciliation of last 
menstrual period and 
ultrasound dating. Estimated 
due date (EDD) and 
gestational age (GA-EDD) will 
be based on reconciliation of 
“sure” first day of the last menstrual period (LMP) and earliest dating ultrasound.  
If the LMP is uncertain, then the earliest dating ultrasound will be used to 
determine EDD and GA. If the ultrasound derived-EDD is in agreement with sure-
LMP derived EDD (Table 1), then the LMP-derived EDD is used to determine 
GA. If the ultrasound derived EDD is not in agreement with the LMP-derived 
EDD, the ultrasound-derived EDD is used to determine GA. 
5. Intention of being available for entire study period and complete all relevant study 
procedures, including follow-up phone calls and collection of delivery information.   
6. English or Spanish literate. 
 
4.2 Participant Exclusion Criteria 
Participants who meet any of the following criteria will not be eligible to 
participate in this study: 
1. Has immunosuppression as a result of an underlying illness or medications, such 
as antirejection/transplant regiments or immunomodulatory agents. Stable HIV 
disease is permitted per the following parameters: 
a. Confirmed stable HIV disease defined as document viral load <50 
copies/mL and CD4 count >200 within 6 months before enrollment, and 
on stable antiretroviral therapy for at least 6 months 
2. Has known hepatitis B (HBV) or hepatitis C (HBC). Stable HBV or HBC are 
permitted per the following parameters: 
a. If known HBV: confirmed inactive chronic HBV infection:  HBsAg present 
for ≥6 months and HBeAg negative, anti-HBe positive; serum HBV DNA 
<2000 IU/mL; persistently normal ALT or AST levels; in those who had 
liver biopsy, findings that confirm absence of significant 
necroinflammation 
b. If known HCV: evidence of sustained virological response for ≥12 weeks 
after treatment or without evidence of HCV RNA viremia (undetectable 
HCV RNA) 
3. Use of oral, parenteral, or high-dose inhaled glucocorticoids 
4. Has an active neoplastic disease (excluding nonmelanoma skin cancer), 
including those who used anticancer chemotherapy or radiation therapy during 
the current pregnancy 
Table 1. Ultrasound Parameters for Using Sure LMP to Determine 
Gestational Age 
Gestational age at first 
ultrasound by LMP 
Ultrasound agreement with 
LMP 
8 6/7 wk or less 
± 5 days 
9 0/7 wk to 13 6/7 wk 
± 7 days 
14 0/7 wk to 15 6/7 wk 
± 7 days 
16 0/7 wk to 21 6/7 wk 
± 10 days 
22 0/7 wk to 27 6/7 wk 
± 14 days 
28 0/7 wk and beyond 
± 21 days 

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5. Signs or symptoms of active preterm labor, defined as regular uterine 
contractions with cervical change (dilation/effacement) 
6. Known fetal congenital anomaly, e.g., genetic abnormality or major congenital 
malformation based on antenatal ultrasound 
7. Anyone who is already enrolled or plans to enroll in another randomized clinical 
trial with any drug, vaccine or medical device. Coenrollment in behavioral or 
other observational intervention studies are allowed at any time. 
8. Any condition which, in the opinion of the investigators, might pose a health risk 
to the subject or interfere with the evaluation of the study objectives. 
9. Anyone who is a relative of any research study personnel or is an employee 
supervised by study staff. 
4.3 Recruitment 
This study will include pregnant women who have received or are planning to receive a 
COVID-19 vaccine. Pregnant women at <34 weeks, 18–45 years old, who are planning 
to receive or recently received (within previous 1 day) COVID-19 vaccine (either 
receiving their booster dose of a COVID-19 vaccine or are receiving the first dose of 
their primary COVID-19 vaccine series) will be recruited at Duke University Hospital 
(Duke), University of Cincinnati Medical Center (Cincinnati), or Boston Medical Center 
(Boston). Pregnant women will be recruited from prenatal clinics and COVID-19 
vaccination clinics affiliated with these sites. Medical records will be reviewed to identify, 
contact, and offer study enrollment to potentially eligible pregnant women. IRB-approved 
informational flyers/advertisements will be used to recruit pregnant women receiving 
vaccination through public COVID-19 vaccination sites or clinics (prenatal, primary care, 
or other clinic administering vaccine). Potential participants will be screened for eligibility 
and consented for study participation (if eligible) in-person (during routine prenatal care) 
or virtually (telephone or televisit). Medical and obstetric history, including vaccine 
history and COVID-19 disease history, will be obtained via participant self-report with 
verification by chart review whenever feasible (including medical records, employee 
health records, immunization registry records, and pharmacy records). 
4.4 Reasons for and Handling of Withdrawals 
The following may be reason for study withdrawal: 
• 
As deemed necessary by the principal investigator (PI) 
• 
Participant withdrawal of consent 
• 
Loss to follow-up 
• 
Termination of the study by the sponsor 
 
Participants who enroll in the study but do not receive any COVID-19 vaccine will be 
considered a screen-failure. Participants may withdraw their consent for study 
participation at any time and for any reason, without penalty. Participants who withdraw 
from the study after receiving at least one dose of vaccine will be considered lost to 
follow-up. Every attempt should be made to collect all data specified by the protocol, 
including collection of pregnancy outcome/safety data via medical record review for 
participants who request withdrawal from study interventions/procedures. 
4.5 Termination of Study  
This study may be terminated for safety concerns of the principal investigators from the 
Lead or Contributing sites, CDC, or participating IRBs. 
 

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5 STUDY SCHEDULE, PROCEDURES, & EVALUATIONS 
5.1 Schedule of events 
Pregnant women meeting the proposed eligibility criteria will be recruited. Informed 
consent (written or electronic) will be obtained from study participants prior to conducting 
any study procedures. Table 2 describes the proposed schedule of study visits with 
further details below.  
 
1 This blood collection may occur up to 3 days prior to or 3 days after first vaccination. If not done at Visit 1a, 
this should be collected at Visit 1b. 
2 Blood draw at Visit 3 is optional unless only one-dose vaccine or booster dose (given as standard of care) 
was received.   
3 Cord blood and maternal blood collection at Visit 6 will be collected when feasible by the site.  
4 Vaccination is not considered a study procedure but is included in this table as reference for when study 
visits should occur. 
5 This visit can occur up to one day before or one day after vaccination. 
6 Will only occur if vaccine received is a two-dose vaccine. 
 
Table 2. Study Visit Schedule 
Procedure 
Screening 
Visit 
Visit 1a 
Visit 
1b 
Visit 2 
Visit 3 
Visit 46 
Visit 
56 
SAE Visit 
Visit 6 
Visit 7 
Unscheduled 
Visit 
Type of contact 
Chart 
Abstraction/ 
Clinic/Phone 
Clinic/
Phone 
Clinic 
Phone/Text
/Email/Data 
Review 
Clinic 
Phone/Text/
Email/Data 
Review 
Clinic 
Phone/Text/
Email/Data 
Review 
Hospital/ 
Chart 
Abstraction 
Phone/Text/
Email/Chart 
Abstraction 
Clinic 
Informed consent & 
Medical Release of 
Information 
X 
 
 
 
 
 
 
 
 
 
 
Review Eligibility Criteria 
X 
 
 
 
 
 
 
 
 
 
 
Demographic, Medical, 
and obstetric history 
X 
 
 
 
 
 
 
 
 
 
 
Vaccination History 
X 
X 
 
 
 
 
 
 
 
 
 
Positive COVID-19 test 
history 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
Vital signs (temperature, 
blood pressure, and heart 
rate) 
 
X 
X 
 
X 
 
 
 
 
 
X 
Blood sample collection 
 
X 
X1 
 
X2 
 
X 
 
X3 
 
 
Vaccination4 
 
X5 
 
 
X6 
 
 
 
 
 
 
Obtain immediate adverse 
event information 
 
X 
 
 
X 
 
 
 
 
 
 
Dispense memory aid 
 
X 
 
 
 
 
 
 
 
 
 
Dispense study supplies 
 
X 
 
 
 
 
 
 
 
 
 
Complete memory aid 
form (REDCap or paper) 
 
X 
 
X 
X 
X 
 
 
 
 
 
Concomitant 
medications/vaccinations 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Obtain solicited and 
unsolicited adverse 
events 
 
 
 
X 
X 
 
 
 
 
 
X 
Obtain serious adverse 
event information 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Infant data collection 
 
 
 
 
 
 
 
 
 
X 
 

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Screening Visit, −30 to +1 day of vaccination (Chart Abstraction & Clinic Visit – 
may occur simultaneously with Visit 1) 
• Obtain informed consent (written or electronic) and release of medical record 
information 
• Review and confirm study eligibility 
• Obtain information on preferred method of contact for follow-up (telephone, email 
reminder or text reminder) 
• Obtain demographic data and vaccination history and COVID-19 disease history 
• Obtain medical history (e.g., chronic hypertension, diabetes, autoimmune disorder), 
obstetric history (e.g., parity, prior preterm birth, low birthweight, small for gestational 
age), and current pregnancy status (e.g., gestational diabetes, gestational 
hypertension, placenta previa, EDD) 
• Obtain concomitant medication/vaccination use 
 
Visit 1a, ±1 day within first dose or booster dose (Screening and Enrollment – 
Phone or Clinic Visit) 
• If Screening Visit occurred prior to Visit 1, review and confirm eligibility and all data 
collected during Screening Visit.  
• Confirm preferred method of contact for follow-up (telephone, email, or text 
reminder) 
• Confirm date of next scheduled study visit (attempt to coincide with regularly 
scheduled prenatal visit as feasible) 
 
Visit 1b, ±3 days within first dose or booster dose (Clinic Visit) 
• 
If not collected at Visit 1a, obtain 12 mL (~2 tubes) blood sample for serologic 
analysis 
• 
Obtain vital signs, including oral temperature, at this visit 
• 
Dispense oral thermometer, ruler (in order to standardize measurements) and 
memory aid. Review instructions for use of thermometer, ruler, and memory aid 
completion. Participants will be given the choice of completing the memory aid 
electronically or on paper. Participants who select the electronic method will enter 
their data into a REDCap web-based system. 
 
Visit 2, 7 + 3 days post first dose or booster dose (Phone/Text/Email/Online 
Memory Aid review) 
• 
Participants will complete their memory aid via paper or electronic entry from 
Day 1–7. 
• 
Participants using paper diary: 
o Study staff will contact participants using paper memory aid to collect 
and record memory aid data including AEs (solicited and unsolicited), 
SAEs, pregnancy status, and concomitant medications 
o Participants will be: 
 
Asked to notify the study staff if they are hospitalized or have a 
severe adverse event 
 
Follow up with their healthcare if they have symptoms they find 
concerning 
 
Reminded that their next visit will be within 2 days of their second dose 
for Visit 3 (unless received single dose vaccine) 
• 
Participants using REDCap web-based system: 

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o Study staff will review REDCap system to confirm data capture and 
assess for any AEs, SAEs, pregnancy status, and concomitant 
medications. 
o The study team will contact participants if they have any missing 
information. The study team may also contact participants if more 
information is needed to better describe AEs [including SAEs and severe 
(Grade 2) events] reported in the REDCap web-based system. 
o All participants using the REDCap web-based system will be:  
 
Asked to notify the study staff if they are hospitalized or have a 
severe adverse event 
 
Follow up with their healthcare provider if they have symptoms 
they find concerning 
• 
Study staff will also approach participants at follow-up prenatal appointments 
which should be within 2–4 weeks from vaccination visit based on routine 
prenatal care guidelines. In the instances where this is not possible, the study 
team will schedule a study visit for the participant to return to the research unit to 
complete the study visit. 
 
Visit 3, two-dose regimen, −2 days through day of second dose (Clinic Visit) 
• 
The timing of this visit will occur based on the schedule per EUA. 
• 
Obtain vital signs, including oral temperature, at this visit. 
• 
Record any AEs, SAEs, and concomitant medications. 
• 
Confirm preferred method of contact for follow-up (telephone, email, or text 
reminder).  
• 
Ensure participant has received the second dose of COVID-19 vaccine if the 
vaccine administered is a two dose vaccine. 
• 
Instruct participant to complete memory aid starting on the day of the second 
dose of vaccine for 7 days. 
• 
*Optional: Obtain 12 mL (~2 tubes) blood sample for serologic analysis. 
 
Visit 3, one dose received, one-dose regimen, or booster dose, 21 + 3 days 
post-vaccination (Clinic Visit) 
• 
Obtain vital signs, including oral temperature, at this visit. 
• 
Record any AEs, SAEs, and concomitant medications. 
• 
Confirm preferred method of contact for follow-up (telephone, email, or text 
reminder). 
• 
Obtain 12 mL (~2 tubes) blood sample for serologic analysis. 
 
Visit 4, 7 + 3 days post second dose (Phone/Text/Email) 
• 
Subjects will complete their memory aid via paper or electronic entry, study staff 
will review subject entered data within the database or by contacting them by 
phone. If any missing values or Grade 2 or greater events occurred (online 
memory aid), the study staff will contact them by phone to gather more 
information. 
• 
This visit will not occur for subjects that only receive one dose of the vaccine or a 
booster dose of the vaccine. 
 
Visit 5, window 28–35 days post second dose (Clinic Visit) 
• 
Obtain 12 mL (~2 tubes) blood sample for serologic analysis. 
• 
Record any AEs, SAEs, and concomitant medications. 

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• 
Confirm preferred method of contact for follow-up (telephone, email, or text 
reminder). 
• 
This visit will not occur for subjects that only receive one dose of the vaccine or a 
booster dose of the vaccine. 
 
SAE Visit, 6 weeks ± 7 days post last dose (Phone/Text/Email) 
• 
Record any SAEs the subject had since their last dose of any COVID-19 
vaccine, primary or booster. 
 
Visit 6, Birth Outcomes Visit, Medical Record Review/Phone Call/ Hospital  
Electronic medical records will be comprehensively reviewed for detailed information 
about maternal health events during pregnancy and maternal and infant outcomes as 
defined by the American College of Obstetrics & Gynecology’s reVITALize and Obstetric 
Data Definitions.[18] Concomitant medications during delivery hospitalization will be 
limited to those that are relevant to pregnancy outcomes of interest, e.g., antenatal 
corticosteroids, or tocolytics in the setting of preterm labor/preterm birth, magnesium in 
the setting of preeclampsia, antibiotics in the setting of Group B Streptococcus (GBS) 
prophylaxis or chorioamnionitis, etc. Maternal blood and infant cord blood will be 
collected at this visit, if feasible. 
 
In order to capture and follow all participants, as a separate plan of follow up, study 
participants who are not identified via medical record review at delivery will be contacted 
by phone approximately 2 weeks after their EDD to determine if delivery occurred 
elsewhere. If so, maternal and infant medical records will be requested from the delivery 
hospital for data collection. 
 
Visit 7, Postnatal Day 90 (window Postnatal Days 90–97) Phone Call/Text/Email 
Follow-Up/Chart Abstraction 
Study staff will contact study participants to record any maternal or infant SAEs, including 
neonatal/infant death and re-hospitalization, and concomitant medications. Information will 
also be collected on maternal or infant emergency room visits and unanticipated visits to 
the primary care pediatrician or a specialist. Data will be verified via review of medical 
records.  Sites will have subjects sign medical records release forms for both themselves 
and their infants at the time of informed consent. This is done so that in the event 
subjects and/or their infants are seen outside of the site’s medical coverages, that 
medical records regarding their emergency room or unanticipated visits can be 
requested. For neonatal deaths identified by the study team prior to Visit 7, study 
participants will contact participants only if more information is needed for data 
collection. 
 
*Unscheduled Visits 
• 
Obtain vital signs including oral temperature for the pregnant women. 
• 
Record any solicited and unsolicited AEs through Day 7, maternal and infant SAEs 
through 90 days after delivery, and concomitant medications. 
• 
Confirm preferred method of contact for follow-up (telephone, email, or text 
reminder). 
5.2 Reactogenicity and Safety Assessments 
Frequency and occurrence of local and systemic reactogenicity, unsolicited AEs, SAEs, 
concomitant medication use, and unscheduled medical care will be assessed through 7 
days post-vaccination (after each dose of vaccine) using a standard memory aid. At the 

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time of study enrollment, participants receiving their booster dose of a COVID-19 
vaccine or are receiving the first dose of their primary COVID-19 vaccine series will be 
given a thermometer and instructed on using the memory aid to document oral 
temperatures and postvaccination symptoms. Beginning on the evening of Study Visit 1 
(Day 1) following COVID-19 vaccination, these participants will record their oral 
temperature using the study-supplied thermometer for the next 7 days (Day 1–7) and, if 
applicable, again for 7 days following the second dose of the vaccine. Temperature will 
be recorded at roughly the same time each day or when a participant feels feverish. If a 
temperature ≥100.4°F (38°C) is recorded, a second measurement will be taken. If more 
than one temperature is taken on the same day, the highest temperature should be 
recorded. Fever will be defined as a measured temperature ≥ 100.4°F (38°C). 
Participants will classify local and other systemic reactogenicity events as mild, 
moderate, or severe as described in Tables 3 and 4. 
During Visits 2, 3, and 4 information reported by participants will be reviewed for 
accuracy and completion. Participants who report moderate or severe solicited AEs or 
express any concern about symptoms/unsolicited events will be encouraged to follow up 
with their obstetrician or primary care provider. Study staff will assist with coordination of 
referral appointments as necessary. Medical records will be obtained and reviewed for 
any unscheduled medical appointment through post-vaccination Day 43 following the 
last dose of the vaccine. 
 
 
 
Table 4: System Reactogenicity 
Systemic 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Fever **  
≥100.4 to ≤101.1° F  
≥101.2 to ≤102.0° F  
≥102.1° F 
Malaise (Fatigue) 
Noticeable but does not 
interfere with activity  
Interferes with activity but did not 
necessitate medical visit or absenteeism 
Prevents daily activity or resulted in 
medical visit or absenteeism  
Myalgia (Body 
aches/muscle 
pain) 
Noticeable but does not 
interfere with activity  
Interferes with activity but did not 
necessitate medical visit or absenteeism 
Prevents daily activity or resulted in 
medical visit or absenteeism  
Arthralgia (Joint 
pain) 
Noticeable but does not 
interfere with activity  
Interferes with activity but did not 
necessitate medical visit or absenteeism 
Prevents daily activity or resulted in 
medical visit or absenteeism  
Nausea 
Noticeable but does not 
interfere with activity  
Interferes with activity but did not 
necessitate medical visit or absenteeism 
Prevents daily activity or resulted in 
medical visit or absenteeism  
Vomiting 
Noticeable but does not 
interfere with activity  
Interferes with activity but did not 
necessitate medical visit or absenteeism 
Prevents daily activity or resulted in 
medical visit or absenteeism  
Table 3: Injection-site Reactogenicity  
Symptom 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Pain  
Noticeable but does not 
interfere with activity  
Interferes with activity but did not 
necessitate medical visit or absenteeism   
Prevents daily activity or resulted in 
medical visit or absenteeism 
Induration/  
Swelling 
25 to ≤50 mm  
51 to ≤100 mm   
>100 mm  
Erythema  
25 to ≤50 mm 
51 to ≤100 mm 
>100 mm 
Axillary 
swelling/Ten
derness  
Noticeable but does not 
interfere with activity  
Interferes with activity but did not 
necessitate medical visit or absenteeism    
Prevents daily activity or resulted in 
medical visit or absenteeism 

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Table 4: System Reactogenicity 
Systemic 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Diarrhea 
Noticeable but does not 
interfere with activity  
Interferes with activity but did not 
necessitate medical visit or absenteeism 
Prevents daily activity or resulted in 
medical visit or absenteeism  
Headache 
Noticeable but does not 
interfere with activity  
Interferes with activity but did not 
necessitate medical visit or absenteeism 
Prevents daily activity or resulted in 
medical visit or absenteeism  
Chills/shivering  
Noticeable but does not 
interfere with activity  
Interferes with activity but did not 
necessitate medical visit or absenteeism 
Prevents daily activity or resulted in 
medical visit or absenteeism  
** Oral temperature, no recent hot/cold beverages or smoking 
 
COVID-19 vaccine administration will follow site-specific vaccine campaign 
administration guidelines in accordance with current recommendations from the US Food 
and Drug Administration and the Advisory Committee on Immunization Practices (ACIP). 
There are no previously published randomized controlled COVID-19 vaccine trials that 
have been conducted in pregnant women; however, we do not foresee having a 
significant issue with SAEs given published observational studies and post-market 
surveillance data.[12, 19, 20] We will monitor study participants for SAEs during the 
protocol-defined surveillance period [i.e., from enrollment through 90 days postpartum]. 
 
An SAE is defined as an AE that meets one of the following conditions: 
• Results in death (including spontaneous abortion [SAB] and fetal death) during the 
period of protocol-defined surveillance 
• Is life-threatening (defined as immediate risk of death at the time of the event) 
• Requires inpatient hospitalization or prolonged hospitalization during the period of 
protocol-defined surveillance (other than routine hospital admission such as for labor 
and delivery) 
• Results in congenital anomaly or birth defect 
• Results in a persistent or significant maternal or infant disability/incapacity  
• Any other important medical event that may not result in death, be life threatening, or 
require hospitalization, may be considered an SAE when, based upon appropriate 
medical judgment, the event might jeopardize the participant and might require 
medical or surgical intervention to prevent one of the outcomes listed above. 
Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do 
not result in inpatient hospitalization, or the development of drug dependency or drug 
abuse. 
 
Reporting Adverse Events  
SAEs and unanticipated problems will be reported to the CDC and all participating IRBs 
according to institutional requirements. AEs that occur in a recipient following COVID-19 
vaccination should be reported to CDC’s Vaccine Adverse Event Reporting System 
(VAERS) by their vaccination site, primary care or obstetric provider, or by study staff. 
VAERS reporting will be shared with participants. Study site investigators will assess 
relatedness to vaccine or study procedures (related, possibly related, unlikely related, or 
not related) for SAEs. The study investigators will use their clinical judgement to make 
causality assessments and the final causality assessment decision is the responsibility 
of the site principal investigator where the subject was enrolled. 
 

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5.3 Biospecimens Collection & Handling 
5.3.1 Serum 
Maternal blood specimens and infant cord blood will be collected during study visits as 
described in Table 2. All blood samples (12 mL) will be collected into serum separator 
tubes and processed as follows: 
• 
Gently mix the tube by inverting 5 times. Allow blood to clot at room temperature 
for at least 30 minutes. 
• 
Centrifuge tube within 1-2 hours of collection at 2,000 relative centrifugal force 
(RCF) (g) for 10 minutes. 
• 
Gently remove the blood specimen tube stopper avoiding serum contamination 
with red blood cells. Using a single-use pipette, transfer 0.5 mL aliquots of serum 
(top layer) into 1.0mL or 1.8 mL cryovials. Up to 5 cryovials are expected. 
• 
Attach the study-specific barcode labels to the cryovial aliquots. Numbers should 
be placed lengthwise on the tube. 
• 
Freeze the cryovials at −80°C in the temperature-monitored research center 
freezer for future shipment. 
Serum aliquots will be stored until shipment to Cincinnati Children’s Hospital Medical 
Center for planned laboratory analyses. 
 
6 LABORATORY ANALYSES 
6.1 COVID-19 Laboratory Analysis 
Serum samples will be analyzed by the use of a qualitative enzyme-linked 
immunosorbent assay (ELISA) which measures IgG antibody to the SARS-CoV-2 Spike 
protein. Recombinant full length Spike protein is used to coat ELISA plates and serum 
samples that have an Optical Density (OD) value above the established cut off are 
considered positive for antibody. The assay was qualified for use in the Laboratory for 
Specialized Clinical Services at Cincinnati Children’s Hospital Medical Center (CCHMC), 
a laboratory that is certified by the Clinical Laboratory Improvement Amendments (CLIA) 
and College of American Pathologist (CAP) under US FDA Emergency Use 
Authorization. 
 
Qualitative serologic testing will be completed in periodic batches throughout the course 
of the study and will therefore not be available in real-time or for use in clinical decision-
making. CCHMC will share participant results with each study site as permitted by FDA 
and CDC. Study sites may share results with participants as permitted by FDA, CDC, 
and local site regulations. 
 
7 STATISTICAL CONSIDERATIONS 
In collaboration with Boston Medical Center, Cincinnati Children’s Hospital Medical 
Center, and CDC, the research team at Duke will oversee the statistical analysis. Data 
will reside on a secure Duke server maintained by Duke Health Technology Solutions 
(DHTS). For the study, a database will be developed and a dataset for the study without 
personal identifiers will be made available to the CDC upon request.  Duke statisticians 
will develop a comprehensive statistical analysis plan. The summary points of the 
analysis plan are presented below. 

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7.1 Definitions 
Pregnancy and birth outcomes in this study will be defined by the American College 
of Obstetrics and Gynecology’s REVITALIZE Obstetric Data Definitions[21], CDC 
national Vital Statistic System[22] or World Health Organization[23] if available.  
Definitions for the component of the primary outcome measures are as follows: 
• 
Preterm birth—born alive at less than 37 weeks and 0 days gestation 
• 
SAB—pregnancy loss prior to 20 weeks 0 days 
• 
Fetal death—intrauterine death of fetus at or after 20 weeks 0 days 
• 
Neonatal death—infant death within first 28 days of life 
7.2 Sample Size and Power Estimation 
Because this is an observational study with no randomization of subjects into 
treatment groups, there will be no formal statistical power or sample size calculation. 
7.3 Analysis Plan 
7.3.1 Study Populations – There will be one study population named the Study Cohort.  
The Study Cohort includes any participant that was enrolled and received at least 
one dose of a COVID-19 vaccine. 
 
7.3.2 Primary Objective – To assess adverse birth outcomes in pregnant women 
vaccinated with COVID-19 vaccine. Tables will be produced that summarize 
adverse birth outcomes (see definition above) with the number, percentage and 
95% confidence interval. These tables will be broken down by each site and 
across all sites. A listing of all adverse birth outcomes will also be presented. 
 
7.3.3 Secondary Objective 1 – To assess preterm births occurring in pregnant women 
vaccinated with COVID-19 vaccine. Tables will be produced that summarize 
preterm births with the number, percentage and 95% confidence interval. These 
tables will be broken down by each site and across all sites. 
 
7.3.4 Secondary Objective 2 – To assess combined fetal and neonatal deaths after 
COVID-19 vaccination. Tables will be produced that summarize combined fetal 
and neonatal deaths with the number, percentage and 95% confidence interval. 
These tables will be broken down by each site and across all sites. 
 
7.3.5 Secondary Objective 3 – To assess spontaneous abortions after COVID-19 
vaccination. Tables will be produced that summarize SABs with the number, 
percentage and 95% confidence interval. These tables will be broken down by 
each site and across all sites. This will be a subgroup analysis of only those 
participants vaccinated at <20 weeks gestational age. 
 

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7.3.6 Secondary Objective 4 – To assess solicited local and systemic reactogenicity 
events in pregnant women vaccinated with COVID-19 vaccine. Tables will be 
produced that summarize each solicited local and systemic reactogenicity event 
by classification (none, mild, moderate, and severe), as well as by moderate or 
severe. These tables will have the number and percentage for each classification 
and will be for each site and across all sites. The number and proportion of 
women with one or more severe local or systemic reaction will be presented 
along with a 95% confidence interval. These severe reactions will also be 
provided in a listing. 
 
7.3.7 Exploratory Objective 1 – To assess SAEs in pregnant women vaccinated with 
COVID-19 vaccine. Tables will be produced that summarize SAEs with the 
number, percentage and 95% confidence interval. These tables will be broken 
down by each site and across all sites. A listing of all SAEs will also be 
presented. 
 
7.3.8 Exploratory Objective 2 – To assess health outcomes through 3 months of age in 
infants born to women vaccinated with COVID-19 vaccine. Tables will be 
produced that summarize infants with medically attended adverse events through 
90 days of life after maternal COVID-19 vaccination with the number, percentage 
and 95% confidence interval. Similar tables will also be made for the proportion 
of SAEs in infants through 90 days of life. A listing of the medically attended 
adverse events and SAEs will also be presented.  The aforementioned tables for 
medically-attended adverse events and SAEs will also be presented by the 
trimester of vaccination. 
 
7.3.9 Exploratory Objective 3 – To assess safety profiles in pregnant women 
vaccinated with COVID-19 vaccine by baseline COVID-19 serostatus (positive 
versus negative). The tables described for the primary objective, secondary 
objectives, and exploratory objectives 1 and 2 will be presented by baseline 
COVID-19 serostatus grouping (positive or negative) instead of by site. The 
proportions by COVID-19 serostatus for the primary and secondary objectives 
will be descriptively assessed using an exact Mantel-Haenszel statistic 
(calculated in Proc Logistic in SAS) at the two-sided alpha=0.05 level. These 
descriptive analyses might be adjusted by site or other covariates depending on 
the number of outcomes at each site (need at least n=5 for each category 
breakdown) by COVID-19 serostatus. 
 
7.3.10 Exploratory Objective 4 – To assess safety profiles in pregnant women 
vaccinated with COVID-19 vaccine by history of infection (positive COVID-19 
tests, self-reported COVID-19 disease history). Analyses will follow same 
strategy as described above for Exploratory Objective 3. 
 
If multiple COVID-19 vaccines (e.g., Pfizer, Moderna,  Janssen, or others that may be 
approved in the future) or booster doses are administered to participants, then tables 
and comparisons as described for Exploratory Objective 3 will be presented stratified by 
vaccine and dose. 
 

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7.3.11  Interim Safety Data Review 
An interim safety data review of all SAEs will be performed with the goal of 
identifying unexpected safety concerns of clinical importance. The interim 
safety data review will be performed by a panel with relevant expertise who 
are not investigators on the study. The safety review panel will assess the 
clinical narratives of SAEs for all participants who were vaccinated. Additional 
data reviews will be generated if the CDC and study investigators determine 
they are needed. There are no statistical analyses planned for this safety 
data review. 
 Public Health Reporting  
The outcomes described above will be presented by demographic or other 
characteristics when deemed necessary by the CDC, in conjunction with study 
investigators. 
7.4 
Data Management Plan 
The amount of data that will be collected for the proposed project will be substantial and 
will require a sophisticated, practical and flexible system that can accommodate different 
modes of data collection and several separate linked surveys. The novel Vanderbilt-
designed resource developed specifically for online collection of research information, 
the Research Electronic Data Capture (REDCap) platform, will be used to design study 
forms, including the reaction forms and short customized questionnaires to collect 
information from study participants. This system will be used by Duke for data 
management. All electronic linkages will fulfill regulations for protection of human 
participants and requirements to minimize the risk of breach of confidentiality. After initial 
set-up, the work load required for electronic data collection will be substantially reduced 
(description of REDCap resources below). Duke investigators have previously used the 
REDCap system for collection and analysis of large quantities of data. Participants will 
be given the option to fill out their memory aid either directly in the REDCap system or 
on paper. All study-related documents containing protected health information, e.g., 
enrollment logs, case report forms, memory aids completed by study participants, will be 
maintained in secure research offices at Duke, which are accessible to research staff 
only. 
 
7.4.1 Research Electronic Data Capture (REDCap)  
Investigators within the NIH-funded Clinical and Translational Research Unit at 
Vanderbilt have developed REDCap (http://project-redcap.org/), to collect and manage 
data for diverse clinical and translational research studies. REDCap was designed 
around the concept of giving research teams an easy method to specify project needs 
and rapidly develop secure, web-based applications for collection, management and 
sharing of research data. REDCap accomplishes these key functions through use of a 
single study metadata table referenced by presentation-level operational modules. 
Based on this abstracted programming model, databases are developed in an efficient 
manner with little resource investment beyond the creation of a single data dictionary. 
The concept of metadata-driven application development is well established, and the 
critical factor for successful data collection lies in creating a simple workflow 
methodology allowing research teams to autonomously develop study-related metadata 
in an efficient manner. Of particular interest for this project, a subcomponent of REDCap, 
the REDCap Survey is designed for studies where data are collected directly from the 
research participant. This will be used with the web-based reaction forms that will be 

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24 
completed by the study participants. Both products include secure institutional data 
hosting and include full audit-trails in compliance with HIPAA security requirements. The 
REDCap Consortium is comprised of 647 active institutional, including CCHMC. The 
REDCap currently supports 68,000 projects with over 89,000 users spanning numerous 
research focus areas across the consortium. The current project will use this software 
application for the design of electronic forms to collect information from study 
participants, to link the baseline data, sample collection date, and laboratory results in an 
automated database family, to perform data cleaning and data quality assurance 
efficiently, and to design an analytical dataset for the analysis of the project data. 
 
Data will be entered directly into the REDCap database by members of the study team, 
from Duke, Cincinnati, and Boston. Study investigators will be responsible for assuring 
that all paper records are securely stored according to the requirements of their IRBs.  
The study investigators will be responsible for assuring the accuracy of the data entered 
from the paper forms into REDCap, as appropriate.  Only the assigned identifiers will be 
used in REDCap. Therefore, personal health identifiers will not appear in the REDCap 
database. 
 
In order to perform data cleaning and data quality assurance efficiently, numerous built-
in filters and checks for consistency of the data including range and limit checks, 
branching logic, and pull down menus to limit choices for categorical variables to a pre-
specified list will be implemented and performed automatically to minimize data entry 
error. The data will be randomly sampled and checked against source records on a 
regular basis. The data and related analytical datasets will also be stored at the lead and 
contributing sites with secured password-protected computers. Coded data without 
personal identifiers will be made available to the CDC and transferred using a secure 
transfer method as described above. 
 
7.4.2 Role of the CDC Investigators in the Project 
This study is funded by a CDC contract with Duke University, Cincinnati Children’s 
Hospital Medical Center and Boston University as Task Orders in the CISA Project 
Contract. CDC staff will collaborate with the sites to develop the protocol, conduct the 
study, ensure the study is aligned with US Department of Health and Human Services 
(CDC) public health priorities, and analyze the data and disseminate the results. CDC 
may receive access to coded data not containing any directly identifying information. 
 
8 
   HUMAN PARTICIPANTS  
8.1 Human Participants Involvement, Characteristics, and Design 
Duke, Cincinnati, and Boston investigators will be responsible for submitting the 
protocol, informed consent, memory aids, recruitment materials and any written or 
verbally conveyed materials specific to this project to their institutional review boards.  
The CDC, as the funding agency, supports an exception to the sIRB mandate for the 
participating sites under the provision at 114(b)(2)(ii). CDC staff will be responsible for 
submitting materials to the CDC IRB for review and for obtaining reliance on Duke IRB. 
 
To facilitate participant recruitment at the practices, we will request a waiver of consent 
and HIPAA authorization as per institutional requirements for ascertainment 
(identification, selection) or recruitment of potential participants while recording 

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identifiable private health information (PHI) prior to obtaining the participant’s consent.  
This information will be obtained from review of the electronic scheduling and medical 
record systems in the clinics in order to determine eligibility for study enrollment. We will 
review only the minimum amount of information necessary to determine eligibility, i.e., 
date of birth, current pregnancy status, pregnancy history, medical and surgical history, 
ultrasounds pertaining to current pregnancy, and recent laboratory test results. The PHI 
collected prior to consent will be used to recruit and screen only. Use of PHI in this 
manner involves no more than minimal risk to participants and no information will leave 
the study sites. Informed consent will be sought in accordance with 45 CFR 46.116, prior 
to enrollment. 
 
Continuing reviews will be submitted to the IRBs in accordance with the new Common 
Rule. Protocol deviations or concerns about study integrity will be reported promptly to 
the overseeing IRB in accordance with institutional requirements. 
8.2 Sources of Material 
Medical history and immunization history will be obtained from the medical record and 
from patient report. Demographic information will be obtained from the medical record 
and patient report. Participants will record solicited adverse reactogenicity events and 
any medical intervention sought on the day of and 7 days following both vaccinations on 
the memory aid. Memory aid information will be reported to the study team during a 
telephone call or in the web-based REDCap system. The research staff will assess one 
or more of the following: weight, height, temperature, blood pressure, and pulse. 
8.3 Potential Risks and Benefits 
Risks of blood drawing include pain, swelling, bleeding, or bruising at the site where the 
blood sample is collected. Subjects may also experience dizziness or fainting. There is a 
small risk of infection around the vein where the blood was collected.  Each maternal 
participant will be asked to have at least 3 blood samplings with the total volume not to 
exceed 50 mL. An optional blood sampling of an additional 12 mL may occur during Visit 
3. There is no risk to the participant or their newborn for collection of cord blood, as the 
cord blood is drawn from the umbilical cord/placenta after the baby is not attached to it. 
 
There is also the potential risk of loss of confidentiality about information obtained as 
part of this study. 
 
There is no direct benefit to the pregnant women participating in this study. However, 
there may be a benefit of learning more about the safety of COVID vaccines in pregnant 
women, which may inform vaccine recommendations for pregnant women. 
 
8.4 Adequacy of Protection Against Risks 
8.4.1 Protections against Risk 
Participants will be followed closely during the first 7 days after each vaccine dose for 
assessment of local and systemic reactogenicity, solicited and unsolicited AEs, SAEs, 
concomitant medication use, and unscheduled medical care. 
Every effort possible will be made to keep information about participants confidential. 
Computerized participant information will be kept in password-protected files on secured 
servers. Paper case report forms will be kept in locked files belonging to the study 
personnel. Any publications resulting from this work will not contain any identifiable 
participant information. 

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8.4.2 ClinicalTrials.gov Requirements 
As requested by CDC, the project is registered on ClinicalTrials.gov (NCT04826640). It 
is the responsibility of the lead site for creating, maintaining, and uploading pertinent 
information regarding the study to ClinicalTrials.gov. The lead site will post their IRB-
approved informed consent within the study’s record on ClinicalTrials.gov. Contributing 
sites will be responsible for providing the lead site with any changes to their site’s 
information as applicable. 
 
9.0 Human Participants 
In obtaining and documenting informed consent, the Investigator and study team will 
comply with the applicable regulatory requirements, Good Clinical Practices, and ethical 
principles. Informed consent form, either written or electronic, must be obtained per IRB-
approved processes at each site prior to initiation of any study activities. 
 
9.1.1 Vulnerable Subjects Research 
Vulnerable subjects 
This study proposes to include pregnant women and neonates. 
 
Pregnant women 
COVID-19 vaccines are provided under a FDA licensure or EUA and are recommended 
by CDC, ACIP and ACOG during pregnancy. 
 
The specific procedures to be performed as part of this study are limited to minimal 
blood draw (≤50 mL over a 4-week period), and other noninvasive procedures that are 
commonly performed during routine physical exams and are considered safe for 
pregnant women. These procedures do not pose greater than minimal risk to the fetus. 
 
This study will involve only those women who have given their free and informed 
consent in accordance with 45 CFR 46.116. The small amount of blood that will be 
drawn during the duration of pregnancy (up to 50 mL) are considered safe and are not 
expected to cause any harm to the baby. No inducement, monetary or otherwise, will be 
offered to terminate a pregnancy. Individuals engaged in the research will have no part 
in any decisions as to the timing, method, or procedures used to terminate a pregnancy, 
or in determining the viability of a neonate. 
 
Infants 
Identifiable private information will be collected about the infants at the time of delivery.  
Significant infant complications identified during the delivery visit will be followed up to 
90 days of life. 
 
Mothers will be informed about the infant data collection at the time they consent for the 
study, and thus, the consent form for pregnant women will also serve as the parental 
permission for including the infant as a participant after delivery. 
 

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