An Observational, Retrospective Cohort Database Study to Assess the Safety of Boostrix (U.S. Formulation), a Reduced Tetanus, Diphtheria, Acellular Pertussis Vaccine (Tdap), Following Routine Immunization of Pregnant Women in the United States
Conditions: Whooping Cough
Sponsor: GlaxoSmithKline

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The safety of Boostrix
following routine immunization 
of pregnant women
EPI-PERTUSSIS-047 VS US DB (207221)
Final Version of December 15, 2017
Amendment 1 – November 13, 2018
Amendment 2 – November 12, 2019
Sponsor: GlaxoSmithKline Biologicals SA
Rue de l’Institut 89
1330 Rixensart, Belgium
 
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Protocol Amendment 2 Sponsor Signatory Approval
eTrack study number and 
Abbreviated Title
207221 (EPI-PERTUSSIS-047 VS US DB)
Date of protocol
Final: 15 December 2017
Date of protocol amendment 1
Final: 13 November 2018
Date of protocol amendment 2
Final: 12 November 2019
Detailed Title 
An observational, retrospective cohort database 
study to assess the safety of Boostrix (U.S. 
formulation), a reduced tetanus, diphtheria, 
acellular pertussis vaccine (Tdap), following 
routine immunization of pregnant women in the 
United States. 
Sponsor signatory
Nadia Meyer, MD
Clinical and Epidemiology R&D Project Leader 
(CEPL), DTP, Polio, Hib containing vaccines
GSK Biologicals’ R&D Center Belgium
Signature
Date
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Protocol Amendment 1 Rationale
Amendment number:
Amendment 1
Rationale/background for changes:
The protocol has been amended following the comments received from the Center for 
Biologics Evaluation and Research. The following changes were implemented:

Objectives: The protocol has been modified to include pregnancies irrespective of
low or high-risk status (to reflect the current use of the vaccine). A primary
objective has been added to rule out a two-fold increase in the incidence of four
pre-specified maternal and infant adverse events. A secondary objective has been
added to explore differences in eight other pre-specified maternal and infant
adverse events.

Endpoints:

The list of endpoints has been reviewed in view of their medical and scientific
significance. Prioritization of endpoints was also based on the 2014
collaboration between the Brighton Collaboration Foundation and the World
Health Organization (WHO) to address gaps in the safety assessment of
vaccines during pregnancy (1). The following endpoints were removed:
Gestational diabetes, premature uterine contractions, macrosomia, fetal
distress, placenta previa, and delivery methods. The following endpoints were
added: Small for gestational age (SGA), preterm delivery, neonatal death,
maternal death, and preterm pre-labor rupture of membranes (PPROM).

Spontaneous abortion with or without congenital anomaly (CA) and
therapeutic abortion with or without CA occur, by definition, before 20 weeks
of gestation (2). Therefore, these events will not be part of the main analysis
on the safety of Boostrix administered after the 27th week of gestation.
However, the incidence of these events will be collected for subjects who
received Boostrix prior to the 27th week of gestation and described in the
study report.

Endpoints have been classified as either primary or secondary.

Risk factors: additional factors defining a pregnancy as “high-risk” have been
added.

Case definitions: Pre-specified maternal and infant adverse events reflect the data
captured by ICD-9 and ICD-10 coding according to the clinical practice of
obstetrics.

Further details on the statistical methods have been added for each endpoint.
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Protocol Amendment 2 Rationale
Amendment number:  Amendment 2
Rationale/background for changes:
The protocol has been amended to modify the secondary endpoint of “post-
partum hemorrhage (PPH)” to “transfusion during delivery hospitalization” as 
a proxy for severe PPH. We originally planned to identify PPH from automated 
diagnosis codes (ICD-9 and ICD-10) and then perform chart review to confirm 
the event. However, in October 2017 (ACOG Practice Bulletin PPH 2017), the 
threshold for estimated blood loss (EBL) for PPH diagnosis changed, affecting 
the comparison between the historical (~2012-2013) and the Boostrix exposed 
(2018-2019) cohorts. The potential for using EBL as an objective measure is 
limited by differential missingness of EBL data between these two cohorts as well 
as inconsistency in EBL measurements. We propose to use transfusion during 
delivery hospitalization as an indicator of severe blood loss and as a proxy for 
severe PPH. Transfusion can be captured by procedure codes, and transfusion 
data are stable across the study period. Transfusion is a relevant endpoint 
because hemorrhage that leads to blood transfusion is the leading cause of severe 
maternal morbidity in the United States (ACOG Practice Bulletin PPH 2017).
The following changes have been implemented.

Secondary objectives; Data collection Figure 1; Statistical methods Tables 6 and
7 - "Post-partum hemorrhage" was changed to "Transfusion during delivery
hospitalization."

Case definitions; Data collection and management - Transfusion during delivery
hospitalization is captured by procedure codes and will not be chart reviewed.

Data collection Figure 1; Statistical methods Table 7 - Transfusion will be
identified among pregnant women with delivery hospitalizations.

Analysis of primary and secondary objectives; Statistical methods Table 7 - The
statistical method for analyzing transfusion will be an adjusted Poisson
regression model. Robust variance estimation is not planned since the incidence
is expected to be <2%.
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Protocol Amendment 2 Investigator Agreement
I agree:

To conduct the study in compliance with this protocol, any mutually agreed future
protocol amendments or protocol administrative changes, with the terms of the study
agreement and with any other mutually agreed upon study conduct procedures and/or
study conduct documents provided by GlaxoSmithKline Biologicals (GSK
Biologicals).

To assume responsibility for the proper conduct of the study.

That I am aware of, and will comply with applicable guidelines and all applicable
regulatory requirements, such as the Declaration of Helsinki, International Ethical
Guidelines for Epidemiological Studies (Council for International Organizations of
Medical Sciences [CIOMS]), United States Food and Drug Administration (FDA)
Best Practices for Conducting and Reporting Pharmacoepidemiologic Safety Studies
using Electronic Healthcare Data, and International Society for
Pharmacoepidemiology (ISPE) guidelines for Good Pharmacovigilance Practice
(GPP).

To ensure that all persons assisting me with the study are adequately informed about
study-related duties and functions as described in the protocol.

That I have been informed that certain regulatory authorities require the sponsor to
obtain and supply, as necessary, details about the investigator’s ownership interest in
the sponsor, and more generally about his/her financial ties with the sponsor. GSK
Biologicals will use and disclose the information solely for the purpose of complying
with regulatory requirements.
Hence I:

Agree to supply GSK Biologicals with any necessary information regarding
ownership interest and financial ties (including those of my spouse and dependent
children).

Agree to promptly update this information if any relevant changes occur during the
course of the study and for one year following completion of the study.

Agree that GSK Biologicals may disclose any information it has about such
ownership interests and financial ties to regulatory authorities.

Agree to provide GSK Biologicals with an updated Curriculum Vitae and other
documents required by regulatory agencies for this study, within reason.
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eTrack study number and
Abbreviated Title
207221 (EPI-PERTUSSIS-047 VS US DB)
Date of protocol
Final: 15 December 2017
Date of protocol amendment 1
Final: 13 November 2018
Date of protocol amendment 2
Final: 12 November 2019
Detailed Title 
An observational, retrospective cohort database 
study to assess the safety of Boostrix (U.S.
formulation), a reduced tetanus, diphtheria, 
acellular pertussis vaccine (Tdap), following routine 
immunization of pregnant women in the United 
States. 
Principal Investigator name
Hung Fu Tseng, PhD, MPH
Research Scientist III
Kaiser Permanente Southern California
Department of Research and Evaluation
Tel: 
Fax: 
Email:
Signature
Date
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SYNOPSIS
Detailed Title
An observational, retrospective cohort database study to 
assess the safety of Boostrix (U.S. formulation), a reduced 
tetanus, diphtheria, acellular pertussis vaccine (Tdap),
following routine immunization of pregnant women in the 
United States.
Rationale for the 
study
To describe the safety of Boostrix administered during 
pregnancy by conducting a post-marketing study that will 
provide safety information to the public and healthcare 
providers. This will be one of the largest cohorts of pregnant 
women vaccinated with Boostrix in the U.S. Through 
partnership between Kaiser Permanente Southern California 
(KPSC) and the sponsor, GlaxoSmithKline (GSK), we will 
provide information about the safety of maternal vaccination 
with Boostrix and maternal and infant adverse events in a 
community setting.
Primary endpoints were differentiated from secondary 
endpoints to allow evaluating the safety of maternal 
vaccination with sufficient statistical power on the primary 
endpoints and to allow for hypothesis generation/signal 
detection on secondary endpoints.
Primary endpoints were selected based on their medical 
relevance, also considering the background incidence or 
prevalence of these endpoints.
Description of the 
database
Vaccination and medical event data will be extracted directly 
from the electronic health record (EHR, Health Connect), 
which is the legal record of all medical care received within 
the KPSC health care system. Records of vaccinations and 
medical events can only be entered by medical staff.
Primary Objective
To rule out a two-fold increase (non-inferiority testing) in the 
incidence of each of the following maternal and infant adverse 
events:

Preeclampsia and/or eclampsia

Intra-uterine infections such as chorioamnionitis and
endometritis

Small for gestational age (SGA)

Preterm delivery
among women who were vaccinated with Boostrix on or after 
the 1st day of the 27th week of gestation as compared to the 
 
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incidence in a historical cohort of pregnant women 
(approximately January 1, 2012 to December 31, 2013) who 
were unvaccinated with any Tdap vaccine throughout their 
pregnancy.
Secondary 
Objectives
(amended 12
November 2019)
1.
To explore the difference (superiority testing) in the 
incidence rate of other maternal and infant adverse 
events, namely:

Transfusion during delivery hospitalization (as a proxy 
for severe post-partum hemorrhage)

Poor fetal growth

Stillbirth/fetal death with or without congenital anomalies

Neonatal death (within 28 days of birth)

Maternal death (while pregnant or within 42 days of end 
of pregnancy) 

Placental abruption

Preterm pre-labor rupture of membranes (PPROM)

Congenital anomalies (CA) at birth and through 6 months 
of age
between women who were vaccinated with Boostrix on or 
after the 1st day of the 27th week of gestation and a 
historical cohort of pregnant women (approximately 
January 1, 2012 to December 31, 2013) who were 
unvaccinated with any Tdap vaccine throughout their 
pregnancy.
2.
To describe the incidence of maternal and infant adverse 
events described above, as well as the incidence of 
spontaneous and therapeutic abortions with or without 
congenital anomalies, among pregnant women vaccinated 
with Boostrix before the 27th week of gestation. 
Study design

Type of study: Observational retrospective database study

Type of design: Matched cohort study

End of study: The date the database analysis is 
completed.

Primary completion date: The date of final collection of
data for all outcomes

Study population: pregnant women with prenatal care and 
continuous membership (allowing up to a 31-day gap) at 
KPSC between the 1st day of the 27th week of pregnancy 
and the index (vaccination) date
 
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
Exposed (from the 27th week of gestation): Women 
who received the Tdap vaccine (Boostrix) on or after 
the 1st day of the 27th week of pregnancy; and who 
were not vaccinated with any other Tdap vaccine at 
any other time during the pregnancy in scope of this 
study.

Unexposed: Women matched to the exposed cohort, 
pregnant sometime during the approximate estimated 
period between 1/1/2012-12/31/2013 who did not 
receive any Tdap vaccine during the pregnancy in 
scope of this study.
Of note, women vaccinated with Boostrix before the 27th
week of gestation, with membership at the date of vaccination, 
and who were not vaccinated with any other Tdap vaccine at 
any other time during the pregnancy in scope of this study will 
be part of a descriptive analysis (secondary objective).

General study aspects: Subject-level data will be 
collected for pregnant women and their infants through 
the EHR. For each individual pregnant woman, follow up 
will begin on the date they received the Boostrix vaccine, 
or the index date for the unvaccinated cohort, and will 
end on the date of disenrollment or the end of pregnancy, 
whichever came first. Infants born in KPSC hospitals 
from unvaccinated and vaccinated mothers will be 
followed for 6 months.
Number of subjects
Approximately 15,000 pregnant women vaccinated with 
Boostrix over a period of approximately one year. 
Unexposed pregnant women will be matched 1:1 to the 
exposed group and will be identified from a historical cohort. 
We aim to have a total sample size of approximately 30,000 
pregnant women. 
Endpoint(s)
(amended 12
November 2019)
Primary
Maternal and infant adverse events identified from KPSC’s 
EHR system using the pregnancy episode flowsheet and
diagnosis codes:

Preeclampsia and eclampsia 

Intra-uterine infections such as chorioamnionitis and
endometritis 

Small for gestational age (SGA)

Preterm delivery
 
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Secondary
Maternal and infant adverse events identified from KPSC’s 
EHR system using the pregnancy episode flowsheet, diagnosis 
codes, procedure codes, or death records:

Transfusion during delivery hospitalization

Poor fetal growth

Stillbirth/fetal death with or without congenital anomalies

Neonatal death (within 28 days of birth)

Maternal death (while pregnant or within 42 days of end 
of pregnancy) 

Placental abruption

Preterm pre-labor rupture of membranes (PPROM)

Congenital anomalies (CA) at birth and through 6 months 
of age overall and by system organ class

Spontaneous abortion (only for women exposed to 
Boostrix before the 27th week of gestation)

Therapeutic abortion (only for women exposed to 
Boostrix before the 27th week of gestation)
To avoid capture of preexisting conditions, diagnostic codes 
representing each condition should not appear prior to the 
index date within the pregnancy under study. With the 
exception of SGA, preterm delivery, and transfusion, medical 
records of the potential events will then be reviewed by 
trained research associates to confirm the diagnosis and to 
ascertain that it is an incident event. Analyses will be done on 
chart confirmed incident events.
 
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TABLE OF CONTENTS
PAGE
SYNOPSIS......................................................................................................................7
LIST OF ABBREVIATIONS...........................................................................................14
GLOSSARY OF TERMS ...............................................................................................16
1.
INTRODUCTION....................................................................................................18
1.1.
Background ................................................................................................18
1.2.
Rationale for the study................................................................................19
2.
OBJECTIVE ...........................................................................................................20
2.1.
Primary objective ........................................................................................20
2.2.
Secondary objectives (amended 12 November 2019).................................20
3.
STUDY DESIGN ....................................................................................................21
3.1.
Study setting...............................................................................................21
3.2.
Feasibility assessment................................................................................22
3.3.
Study design overview................................................................................24
4.
STUDY POPULATION/CASE DEFINITION(S).......................................................25
4.1.
Study population.........................................................................................25
4.2.
Case definitions (amended 12 November 2019) .........................................26
4.3.
Number of subjects.....................................................................................26
4.4.
Inclusion criteria..........................................................................................26
5.
DATA COLLECTION AND MANAGEMENT (amended 12 November 2019) ..........27
6.
STATISTICAL METHODS......................................................................................29
6.1.
Primary and secondary pre-specified events of interest (amended 
12 November 2019)....................................................................................29
6.2.
Statistical methods......................................................................................29
Covariates ...................................................................................29
Analysis of primary and secondary objectives (amended 
12 November 2019).....................................................................31
Analyses interpretation ................................................................33
6.3.
Sample size considerations ........................................................................33
7.
STUDY CONSIDERATIONS..................................................................................34
8.
CONDUCT OF THE STUDY ..................................................................................34
8.1.
Regulatory and ethical considerations ........................................................35
8.2.
Informed consent and data privacy .............................................................35
8.3.
Additional data............................................................................................35
9.
REFERENCES.......................................................................................................36
 
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LIST OF TABLES
PAGE
Table 1
Race/ethnicity of women receiving the Tdap vaccine during 
pregnancy at seven selected medical centers at Kaiser 
Permanente Southern California, 2016 ..................................................22
Table 2
Age of women at Tdap vaccination during pregnancy at seven 
selected medical centers at Kaiser Permanente Southern 
California, 2016......................................................................................23
Table 3
Membership among women receiving the Tdap vaccine during 
pregnancy at seven selected medical centers at Kaiser 
Permanente Southern California, 2016 ..................................................23
Table 4
Gestational age of women at Tdap vaccination during pregnancy 
at seven selected medical centers at Kaiser Permanente 
Southern California, 2016.......................................................................24
Table 5
Tdap vaccine receipt during pregnancy at Kaiser Permanente 
Southern California, 2011-2016..............................................................24
Table 6
List of primary and secondary endpoints (amended 12 November 
2019)......................................................................................................29
Table 7
Analytic population and statistical methods by endpoint
(amended 12 November 2019)...............................................................32
Table 8
Power to rule out a two-fold increase with 15,000 pregnant 
women in each cohort ............................................................................33
 
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LIST OF FIGURES
PAGE
Figure 1. Illustration of data flow (amended 12 November 2019)...................................28
 
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LIST OF ABBREVIATIONS
ACIP
Advisory Committee on Immunization Practices
ACOG
American College of Obstetrics and Gynecology
ADaM
Analysis Data Model
CA
Congenital anomaly / congenital anomalies
CDC
Centers for Disease Control and Prevention
CDISC
Clinical Data Interchange Standards Consortium
CI
Confidence interval
CIOMS
Council for International Organization of Medical 
Sciences
EDD
Estimated date of delivery
EHR
Electronic health records
FDA
United States Food and Drug Administration
GPP
Good Pharmacovigilance Practice
GSK
GlaxoSmithKline
HIPAA
Health Insurance Portability and Accountability Act of 
1996 (U.S.)
HIV
Human immunodeficiency virus
ICD-9
International Classification of Diseases, 9th Revision
ICD-10
International Classification of Diseases, 10th Revision
IRB
Institutional Review Board
ISPE
International Society for Pharmacoepidemiology
KPSC
Kaiser Permanente Southern California
MRN
Medical record number
OB-GYN
Obstetrics and Gynecology
PHI
Protected health information
 
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PPROM
Preterm pre-labor rupture of membranes
REDCap
Research Electronic Data Capture
RIPC
Regional Immunization Practices Committee
SAS
Statistical Analysis Software
SDTM
Study Data Tabulation Module
SGA 
Small for gestational age
Tdap
Tetanus, diphtheria, acellular pertussis 
U.S.
United States
VAERS
Vaccine Adverse Event Reporting System
VSD
Vaccine Safety Datalink
WHO
World Health Organization
 
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GLOSSARY OF TERMS
Adverse Events:
Pre-specified, pregnancy-related diagnoses or pregnancy 
outcomes or infant diagnosis to be compared between the 
exposed and unexposed cohorts. 
Cohort study:
Epidemiology study where subjects in a study population 
are classified according to their exposure status and 
followed over time to ascertain the outcome(s). 
Database study:
A study involving the use of pre-existing data maintained 
in an electronic format.
End of study:
For database studies, end of study is the date the database 
analysis is complete. For this study, that is the date the 
analysis of congenital anomaly (among KPSC-born 
infants through 6 months of age) is complete. 
Exposed cohort (from 
the 27th week of 
gestation):
Subjects classified as exposed to Tdap (Boostrix) on the 
1st day of the 27th week of gestation or later. 
eTrack:
GSK’s tracking tool for clinical/epidemiology studies.
Health Connect: 
Electronic health record system which is the legal record 
of all received medical care within the KPSC health care 
system.
Index date of the 
matched pair of exposed 
and unexposed pregnant 
women:
The unexposed cohort of pregnant women will be 
matched 1:1 to the exposed group of pregnant women for 
comparisons of maternal and infant adverse events 
between the two cohorts. The matched pair will have an 
index date, which is determined by the number of days 
from pregnancy start to Boostrix vaccination of the 
exposed woman. Every unexposed woman will be 
assigned an index date that is determined by the number 
of days from pregnancy start to the Boostrix vaccination 
date of her matched exposed woman. The same number 
of days calculated in the exposed woman will be added to 
the pregnancy start of the unexposed woman to identify 
her index date. Both groups will be followed from the 
index date to the events of interest and pregnancy 
outcomes.
Pregnancy start:
Corresponds to a gestational age of 0 weeks based on the 
most reliable estimated date of delivery. 
Completion date:
The date of final collection of data for all outcomes.
 
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Retrospective study:
A study that looks backward in time (e.g. at events that 
occurred in the past; outcomes and exposure can no 
longer be influenced), usually using medical records, 
databases or interviews in order to address one or more 
study endpoints. 
Subject:
Term used throughout the protocol to denote a person 
about whom some medical information has been recorded 
in a database.
Unexposed cohort: 
Subjects classified as not exposed to any Tdap vaccine 
during the pregnancy under study
 
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1.
INTRODUCTION
1.1.
Background
Whooping cough, also referred to as pertussis, is a highly contagious respiratory disease 
primarily caused by the bacterium Bordetella pertussis. The disease is most severe in 
unvaccinated or incompletely vaccinated infants, who may develop apnea, seizures
secondary to hypoxia, pulmonary hypertension, pneumonia, otitis media, and death (3).
Cyclical increases in pertussis incidence continue to be described every 3 to 5 years in 
most developed countries despite high vaccination coverage. This is explained largely by 
waning immunity both after vaccination and after natural infection (4-6). 
Two tetanus-diphtheria-acellular pertussis (Tdap) vaccines (Adacel and Boostrix) were 
licensed for use in the United States (U.S.) in 2005 (7). These vaccines were 
recommended for routine use in non-pregnant adolescents and adults when introduced. In 
2010, the California Department of Health began recommending Tdap vaccine to women 
at any stage of pregnancy in response to a pertussis outbreak and several infant deaths
(8). One year later, the Advisory Committee on Immunization Practices (ACIP) advised 
Tdap to be administered during pregnancy, at 20 weeks gestation or later, to women who 
had not been previously vaccinated (9). In October 2012, ACIP expanded its 
recommendation of administering Tdap during pregnancy (10); in order to increase the 
protection of newborns, all pregnant women should be offered Tdap, regardless of 
whether they have received Tdap previously. While the ACIP recommends that optimal 
timing for Tdap administration is between 27 and 36 weeks gestation to optimize transfer 
of anti-pertussis antibodies, Tdap may be given at any time during pregnancy. Both 
Adacel and Boostrix can be used interchangeably.
Prelicensure clinical study data showed that the incidence of unsolicited adverse events 
reported in the 31 days after vaccination was comparable between recipients of Boostrix 
and Adacel (17.8% and 22.2% for Boostrix and Adacel, respectively). Serious adverse 
events during 0-6 months following vaccine were reported by 1.4% and 1.7% of subjects, 
respectively. During the 6-month extended safety evaluation period, no serious adverse 
events of a neuroinflammatory nature or with information suggesting an autoimmune 
etiology were reported in subjects who received Boostrix (11).
Safety events following Tdap immunization during pregnancy have been increasingly 
examined in recent years. A placebo-controlled clinical trial of Adacel administered to 
pregnant women (2008-2012) found no Tdap-associated serious adverse events (12).
During a time when Tdap was not routinely recommended for pregnant women, 
spontaneous abortions were the most frequent pregnancy-specific adverse events (16.7%) 
identified through the Vaccine Adverse Event Reporting System (VAERS), a national 
database used for monitoring the safety of vaccines in the population (13). However, the 
number of pregnant women who received the vaccine was small (n=132) and likely a 
selective group since the vaccine was not in routine use. A small study observing a 
limited number of maternal and infant outcomes (chorioamnionitis, postpartum 
endometritis, premature rupture of membranes, 5-minute Apgar score, birth defects) also 
found no Tdap-associated adverse events (14). However, the authors found that Tdap was 
associated with women having decreased odds of cesarean delivery. In a study of 2010-
 
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2012 live births in two California health care systems participating in the Vaccine Safety 
Datalink (VSD) project, no associations between Tdap and maternal hypertensive 
disorders were found, although a small but statistically significant increased risk of 
chorioamnionitis was observed (6.1% in vaccinated, 5.5% in unvaccinated) (15), a 
finding consistent with a larger subsequent study at seven U.S. health care system VSD 
sites (16). An increased risk of chorioamnionitis was also found in a different U.S.-based 
study of over one-million pregnant women (2010-2014), which also found an increased 
risk of postpartum hemorrhage, one case of post-immunization anaphylaxis, and 12 cases 
of post-delivery encephalopathy (17). However, this study did not find a significant 
association with preeclampsia/eclampsia or premature rupture of membranes. An 
evaluation of acute events post vaccination found no associations between Tdap 
immunization and a composite outcome of acute events, incident neurologic events or
thrombotic events, or proteinuria in a large VSD cohort (18). Additionally, a study of 
infant outcomes found that Tdap was not significantly associated with increased risk for 
structural birth defects or microcephaly for vaccinations given during any week of 
pregnancy (19). Except for the aforementioned VSD studies in which Adacel comprised 
the majority of Tdap vaccines administered (15), the Tdap product in the other studies 
was not explicitly mentioned. 
Considering that Boostrix is recommended to be used interchangeably with Adacel, and
there are limited observational safety data on Boostrix during pregnancy, a post-
marketing study describing the safety of Boostrix vaccine in pregnant women is 
particularly necessary and can provide timely safety information to the public and 
healthcare providers.
1.2.
Rationale for the study
The rationale for the current study is to assess the safety of Boostrix administered on or 
after the 1st day of the 27th week of pregnancy by conducting a post-marketing study that 
will provide safety information to the public and healthcare providers. This will be one of 
the largest cohorts of pregnant women vaccinated with Boostrix in the U.S. Through 
partnership between Kaiser Permanente Southern California (KPSC) and the sponsor, 
GlaxoSmithKline (GSK), we will provide information about the safety of maternal 
vaccination with Boostrix and maternal and infant adverse events in a community setting. 
The observational study design takes advantage of KPSC’s electronic health record 
(EHR) system, Health Connect. We will capture adverse events following Boostrix 
vaccination in pregnant women and adverse events in an unexposed historical 
comparison cohort of pregnant women. Retrospective ascertainment of pregnant women 
through Health Connect is an efficient strategy in comparison to a recruitment study, 
which would be practically and financially infeasible because pregnant women are not 
likely to enroll in safety studies.
Primary endpoints were differentiated from secondary endpoints to allow evaluating the 
safety of maternal vaccination with sufficient power on the primary endpoints and to 
allow for hypothesis generation/signal detection on secondary endpoints.
Primary endpoints were selected based on their medical relevance, considering also the 
background incidence or prevalence of these endpoints.
 
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2.
OBJECTIVE
2.1.
Primary objective
To rule out a two-fold increase (non-inferiority testing) in the incidence of each of the 
following maternal and infant adverse events:

Preeclampsia and/or eclampsia

Intra-uterine infections such as chorioamnionitis and endometritis

Small for gestational age (SGA)

Preterm delivery
among women who were vaccinated with Boostrix on or after the 1st day of the 27th week 
of gestation as compared to the incidence in a historical cohort of pregnant women 
(approximately January 1, 2012 to December 31, 2013) who were unvaccinated with any 
Tdap vaccine throughout their pregnancy.
2.2.
Secondary objectives (amended 12 November 2019)
1.
To explore differences (superiority testing) in the incidence rate of other maternal 
and infant adverse events, namely:

Transfusion during delivery hospitalization (as a proxy for severe post-partum 
hemorrhage)

Poor fetal growth

Stillbirth/fetal death with or without congenital anomalies

Neonatal death (within 28 days of birth)

Maternal death (while pregnant or within 42 days of end of pregnancy) 

Placental abruption

Preterm pre-labor rupture of membranes (PPROM)

Congenital anomalies (CA) at birth and through 6 months of age
between women who were vaccinated with Boostrix on or after the 1st day of the 27th
week of gestation and a historical cohort of pregnant women (approximately January 
1, 2012 to December 31, 2013) who were unvaccinated with any Tdap vaccine 
throughout their pregnancy.
2.
To describe the incidence of maternal and infant adverse events described above, as 
well as the incidence of spontaneous and therapeutic abortion with or without 
congenital anomalies, in pregnant women who were vaccinated with Boostrix before 
the 27th week of gestation.
 
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3.
STUDY DESIGN
3.1.
Study setting
KPSC is an integrated healthcare system that provides comprehensive prepaid health 
services for its 4.4 million members. There are 15 medical centers that include a total of 
225 medical office buildings throughout Southern California. Members are racially 
diverse and include the entire socio-demographic spectrum, and over 99% are 
community-dwelling. The demographic makeup of the KPSC membership closely 
mirrors the Southern California population and the California census population (20).
Compared to the racial/ethnic distribution of the U.S. population, the KPSC membership 
has twice as many individuals of Asian descent and three times as many Hispanics. Data 
regarding demographics, services, diagnoses, and procedures are tracked in the KPSC 
EHR (Health Connect) from the outpatient, emergency department, and hospital settings. 
Health Connect is the legal record of all medical care received within the KPSC system. 
Records of vaccinations and medical events can only be entered by medical staff. 
Pharmacy records and vaccinations are linked through patients’ unique medical record 
numbers (MRNs). Vaccinations received outside of the health plan are recorded with 
appropriate documentation.
KPSC is a pre-paid health care system. Vaccines are typically provided to KPSC 
members at no charge, which is an incentive for members to receive immunizations 
within the system. Also, there is a very strong motivation for members to use services 
internally. For outside providers to be reimbursed by the health plan for covered 
emergent or contract care, claims must be submitted with documentation of the episode 
of care. Thus, the capture of care delivered to members by electronic administrative data 
is reasonably assumed to be very comprehensive. The KPSC Regional Immunization 
Practice Committee (RIPC) makes recommendations to ensure appropriate use of 
vaccination and implementation of new ACIP immunization recommendations within 
KPSC.
Standard of care regarding use of Tdap in pregnant women
On October 24, 2012, ACIP voted to recommend Tdap for pregnant women with every 
pregnancy irrespective of previous Tdap history. In December 2012, the KPSC RIPC 
followed ACIP guidance and recommended that providers of prenatal care implement a 
Tdap immunization program for all pregnant women. The guidance indicated that all 
health-care personnel should administer a dose of Tdap during each pregnancy 
irrespective of the patient’s prior history of receiving Tdap. In order to maximize the 
maternal antibody response and passive antibody transfer to the infant, optimal timing for 
Tdap administration was specified between 27 and 36 weeks gestation.
Prior to the conduct of this observational study of Boostrix in pregnancy, Adacel had 
been the only Tdap vaccine on the KPSC formulary. 
 
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Process for identifying pregnancy information
If a woman receives prenatal care at KPSC, her pregnancy is recorded in a pregnancy 
episode flowsheet. The flowsheet is contained in the woman’s medical record and is 
created at the beginning of the pregnancy. It is appended with all pregnancy encounters 
including prenatal visits, the hospital admission for birth, as well as any post-partum 
visits. Pregnancy and birth information at KPSC including maternal age, pre-pregnancy 
height and weight, perinatal risk factors, prenatal visit information, complications of 
pregnancy and delivery, and procedures used during labor and delivery are available from 
the EHR and can be viewed in Health Connect. 
Process for linking mothers and infants
As standard of care at KPSC, all infants born in KPSC hospitals are automatically 
assigned a MRN regardless of whether the mother is a current plan member.  If the 
mother is a current member, the baby’s MRN is automatically linked to her medical 
record in her pregnancy episode flowsheet. 
3.2.
Feasibility assessment
The following tables display data to describe Tdap vaccination among pregnant women at 
seven selected KPSC medical centers that will administer the Boostrix vaccine. 
Approximately 15,000 women vaccinated with Boostrix will be included in this study,
over approximately a one-year period.
Pregnant women receiving the Tdap vaccine
The following table provides demographic information on pregnant women receiving the 
Tdap vaccine at seven selected medical centers at KPSC (Table 1). There were 19,804 
pregnant women receiving the vaccine within these medical centers in 2016. Over half of 
them were of Hispanic race/ethnicity (57%). The age distribution shows that pregnant 
women aged 27-35 years old made up more than half (55%) of the Tdap-exposed 
pregnant women (Table 2). 
Table 1
Race/ethnicity of women receiving the Tdap vaccine during 
pregnancy at seven selected medical centers at Kaiser Permanente 
Southern California, 2016
Mother’s race/ethnicity
Frequency
Percent
Asian
2,494
12.6%
Black
1,643
8.3%
Hispanic
11,354
57.3%
Multiple
512
2.6%
Native American/ Alaskan
11
0.1%
Others
24
0.1%
Pacific Islander
23
0.1%
Unknown
33
0.2%
White (Non-Hispanic white)
3,710
18.7%
TOTAL
19,804
100%
 
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Table 2
Age of women at Tdap vaccination during pregnancy at seven 
selected medical centers at Kaiser Permanente Southern California, 
2016
Mother’s age at vaccination (years)
Frequency
Percent
15-26
5,785
29.2%
27-35
10,858
54.8%
36-45
3,132
15.8%
>45
29
0.2%
TOTAL
19,804
100%
Membership among Tdap vaccinated pregnant women
At seven selected medical centers within KPSC, 18,875 (95.3%) pregnant women had 
continuous membership (allowing up to a 31-day gap) at least from the start of the 27th
week of pregnancy (Table 3). There were 16,147 (82%) women who were members since 
the beginning of pregnancy.
Table 3
Membership among women receiving the Tdap vaccine during 
pregnancy at seven selected medical centers at Kaiser Permanente 
Southern California, 2016
Membership during pregnancy*
Frequency
Percent
Gestation: 0 to 26 weeks only
260
1.3%
Gestation: 27 weeks to delivery only
2,728
13.8%
Gestation: 0 weeks to delivery
16,147
81.5%
Partial membership**
669
3.4%
TOTAL
19,804
100%
* Represents women with membership (allowing up to a 31-day gap) during the entire indicated period.
** 447 had membership during the post-vaccine pregnancy period
Gestational age at Tdap vaccination
There were 19,554 (98.7%) pregnant women who received Tdap vaccination at or after 
27 weeks of pregnancy (Table 4). There were 18,611 (94.0%) women who were 
vaccinated between 27 and 36 weeks gestation.
 
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Table 4
Gestational age of women at Tdap vaccination during pregnancy at 
seven selected medical centers at Kaiser Permanente Southern 
California, 2016
Gestational age at vaccination
Frequency
Percent
<27 weeks
250
1.3%
27 weeks to 32 weeks
15,111
76.3%
33 weeks to 36 weeks
3,500
17.7%
>36 weeks
943
4.8%
TOTAL
19,804
100%
Note: Only those women meeting eligibility criteria, including membership, will be included in the analysis.
Rationale for historical comparison cohort 
The estimated period of 1/1/2012-12/31/2013 was chosen for the unvaccinated 
comparison group because Tdap uptake ranged between 27% and 38% during this time 
(Table 5). The aim is to restrict the unvaccinated population to approximately 2012-2013
to minimize the concerns of confounding by indication. Given that Tdap uptake exceeded 
65% starting in 2014, a concurrent unvaccinated cohort will yield a small and selective 
sample, and is not representative of an unvaccinated group.
Table 5
Tdap vaccine receipt during pregnancy at Kaiser Permanente 
Southern California, 2011-2016
Tdap during pregnancy
No Tdap during pregnancy
Year
Frequency
Percent
Frequency
Percent
2011
18325
40.0%
27471
60.0%
2012
13128
27.6%
34486
72.4%
2013
18309
38.3%
29519
61.7%
2014
32660
65.3%
17366
34.7%
2015
35754
68.4%
16513
31.6%
2016
38475
69.3%
17058
30.7%
3.3.
Study design overview
The study design is an observational retrospective matched cohort study. This proposed 
research will be conducted among pregnant women who are members of KPSC. 
The exposed cohort will consist of pregnant women irrespective of their risk profile (low 
or high-risk) who received the Tdap vaccine (Boostrix) on or after the 1st day of the 27th
week of pregnancy during the vaccination period at ob-gyn clinics of seven selected 
medical centers. 
Approximately 15,000 women vaccinated with Boostrix will be included in this study 
over approximately a one-year period. The unexposed cohort will consist of pregnant 
women during the approximate estimated period from 1/1/2012 to 12/31/2013 who never 
received Tdap vaccine during pregnancy. 
 
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Of note, women vaccinated with Boostrix before the 27th week of gestation, with 
membership at the date of vaccination, and who were not vaccinated with any other Tdap 
vaccine at any other time during the pregnancy in scope of this study will be part of a 
descriptive analysis (secondary objective).
Subject-level data will be collected for pregnant women and their infants through the 
EHR. For each individual pregnant woman, analytical follow up will begin on the date 
they receive the Boostrix vaccine, or the index date for the unvaccinated cohort, and will
end on the date of disenrollment or the end of pregnancy, whichever came first. For the 
maternal death endpoint, pregnant women will be followed for 42 days after the end of 
pregnancy. Infants born in KPSC hospitals will be followed for 6 months.
4.
STUDY POPULATION/CASE DEFINITION(S)
4.1.
Study population
The exposed and unexposed cohorts will consist of pregnant women with evidence of
prenatal care and continuous membership (allowing up to a 31-day gap) at KPSC 
between the 1st day of the 27th week of gestation and the index (vaccination) date.
Women will be considered exposed if they received Boostrix on or after the 1st day of the 
27th week of gestation at selected ob-gyn clinics at seven medical centers throughout 
KPSC (vaccination period planned to begin in January 2018). Unexposed pregnant 
women comprise women pregnant sometime during the approximate estimated period 
between 1/1/2012 and 12/31/2013 who did not receive any Tdap vaccine during 
pregnancy. If needed, we will consider adding additional years to increase the eligible 
number of unexposed pregnant women. Gestational age will be estimated from the most 
reliable estimated date of delivery (EDD) which is based on the last menstrual period, the 
first accurate ultrasound examination, or both. Obstetric providers are recommended to
reference guidelines from the American College of Obstetrics and Gynecology (ACOG) 
to calculate EDD (21). Pregnancy start date will correspond to a gestational age of 0 
weeks. 
Matching process for pregnant women who were vaccinated with Boostrix after the 27th
week of gestation
The unexposed cohort will be matched 1:1 to the exposed group for comparisons of 
maternal and infant adverse events between the two cohorts. Every unexposed woman 
will be assigned an index date that is determined by the number of days from pregnancy 
start to the Boostrix vaccination date of her matched exposed woman. The same number 
of days calculated in the exposed woman will be added to the pregnancy start of the 
unexposed woman to identify her index date. 
Existing health conditions, age, lifestyle factors, and conditions of pregnancy can place a 
pregnancy at risk (22). Therefore, matching variables include maternal age at pregnancy 
start (± 1 year), race/ethnicity (White, Black, Hispanic, Asian, and Other) and multiple 
gestation. Other pregnancy high-risk conditions will be considered as potential covariates 
in the analysis (see Section 6.2.1 Covariates). 
 
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For example, suppose there is a 28-year-old (at pregnancy start) Hispanic pregnant 
woman expecting twins with a pregnancy start date of 2/18/2018 receiving Boostrix on 
8/30/2018 on the 194th day of her pregnancy (from pregnancy start date to vaccination). 
We will match her with a Hispanic woman pregnant sometime between 1/1/2012 and 
12/31/2013, who was 27-29 years of age at pregnancy start and had a multiple gestation 
pregnancy, with an index date assigned to be the 194th day of pregnancy, and who never 
received Tdap vaccine during pregnancy. If a match is not feasible within the proposed 
two-year period, the pool of unexposed women can be expanded to include unexposed 
pregnant women from additional years. Both groups will be followed for events of 
interest from the index date. In this example, both women will be followed from the 
194th day of their pregnancy.
4.2.
Case definitions (amended 12 November 2019)
Endpoints of interest will be extracted from the EHR using the pregnancy episode 
flowsheet, diagnosis codes (ICD-9 and ICD-10 codes), procedure codes, or death records. 
While these events are recorded as part of routine care, in general, ACOG recommended 
guidelines are used by KPSC providers to diagnose and manage these conditions (23-31).
With the exception of SGA, preterm delivery, and transfusion, chart review will be 
performed for the pre-specified maternal and infant adverse events to confirm the events
and that the events are incident after the index date.
4.3.
Number of subjects
Approximately 15,000 pregnant women vaccinated with Boostrix over a period of 
approximately one year. Unexposed pregnant women, matched 1:1 to the exposed group, 
will be identified from a historical cohort. Therefore, we aim to have a total sample size 
of approximately 30,000 pregnant women. 
4.4.
Inclusion criteria

Pregnant women with prenatal care and continuous membership (allowing up to a 
31-day gap) at KPSC between the 1st day of the 27th week of gestation and the 
index (vaccination) date.

Exposed cohort (from the 27th week of gestation): Pregnant women vaccinated with 
Boostrix on or after the 1st day of the 27th week of gestation; who were not 
vaccinated with any other Tdap vaccine at any other time during the pregnancy in 
scope of this study. 

Unexposed cohort: Women matched to the exposed cohort and pregnant sometime
during the approximate estimated period between 1/1/2012-12/31/2013 and did not 
receive any Tdap vaccine during the pregnancy in scope of this study.
 
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For the analysis of congenital anomalies among live births, at birth and through six 
months of age, the following additional inclusion criteria for infants will be applied:

Live born

Born in KPSC hospitals 
Note: Pregnant women vaccinated with Boostrix during pregnancy before the 27th week 
of gestation, with membership at the date of vaccination, and who were not vaccinated 
with any other Tdap vaccine at any other time during the pregnancy in scope of this study 
will be part of a descriptive analysis (secondary objective). 
5.
DATA COLLECTION AND MANAGEMENT (amended 12
November 2019)
Vaccination and medical event data will be extracted directly from the EHR (Health 
Connect), which is the legal record of all medical care received within the KPSC system.
Figure 1 provides an overview of the data flow for this study. All details of a patient 
encounter, including diagnoses, procedures, and physician’s notes, are entered into the 
EHR at the point of care. All vaccinations are entered into the EHR when they are given, 
with vaccine, dose, manufacturer, and lot number entered at the time of vaccination. 
Vaccinations received outside of the health plan are recorded with appropriate 
documentation. Records of vaccinations and medical events can only be entered by 
medical staff. Endpoints of interest will be extracted from the EHR using the pregnancy 
episode flowsheet, diagnosis codes (ICD-9 and ICD-10 codes), procedure codes, or death 
records. 
We will rely on automated data from the EHR to ascertain SGA, preterm delivery, and 
transfusion. For other endpoints, chart abstraction will be performed for the pre-specified 
maternal and infant adverse events to confirm the event and that they are incident after 
the index date when applicable (i.e., events diagnosed during pregnancy that may have 
onset prior to index date). Events will be reviewed in the chart in which the incident 
diagnosis code is identified (i.e., mother’s chart or infant’s chart). Unknown pregnancy 
outcomes and KPSC live born singleton infants with unknown birthweight will also be 
chart reviewed. Chart abstractors will not be masked to the exposure status as they will 
have access to the entire medical record within Health Connect, including vaccination 
status. Data will be abstracted directly from Health Connect. For the chart abstracted 
data, the study team will develop a chart abstraction form in the Research Electronic Data 
Capture system (REDCap) and a chart abstraction manual (32). The chart abstraction 
manual will be developed for the purposes of ensuring standardization and uniformity of 
data collection among the chart abstractors. The chart abstraction manual may include
guidance on how to navigate through the EHR to search for pertinent information 
(including screenshots of the EHR for reference), directives for how to address questions
in the abstraction form, and explanations of clinical terms and other variable definitions. 
A sample of abstraction forms will be quality checked by a second person. Logic and data 
range checks will be performed on the abstracted data collected electronically in 
REDCap.
 
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Electronic data and chart reviewed data will be combined into a Statistical Analysis 
Software (SAS) dataset for analysis. Double programming will be performed to check the 
total number of eligible subjects included in the analysis. All other programming will be 
reviewed by a second person. The results of the original and validation programming will 
be compared, any discrepancies will be investigated, and action will be taken to resolve 
discrepancies. 
The study datasets will be formatted according to Clinical Data Interchange Standards 
Consortium (CDISC). We will develop specifications to include information about the 
number of domains, mapping rules, and will output the dataset according to the SAS 
study dataset, required analysis report and CDISC implementation guide; map the 
original SAS data to the domains according to the specification to create Study Data 
Tabulation Module (SDTM) and Analysis Data Model (ADaM) datasets; validate the 
SDTM and ADaM datasets using an open source CDISC validation program (e.g., 
Pinnacle 21); and produce submission documentation including DEFINE.XML and Study 
Data Reviewers Guide for SDTM and ADaM.
Figure 1. Illustration of data flow (amended 12 November 2019)
 
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6.
STATISTICAL METHODS
This study will involve both descriptive and multivariable analyses, and all analyses will 
be conducted using the SAS statistical software package (version 9.3 or later). 
6.1.
Primary and secondary pre-specified events of interest
(amended 12 November 2019)
The pre-specified events of interest are maternal and infant outcomes identified from 
KPSC’s EHR system using the pregnancy episode flowsheet, diagnosis codes, procedure 
codes, or death records for the exposed and unexposed groups. While these events are 
recorded as part of routine care, in general, ACOG recommended guidelines are used by 
KPSC providers to diagnose and manage these conditions (23-31). In addition, we will 
use a commonly accepted definition to identify congenital anomalies, such as that used 
by the National Birth Defects Prevention Network (33). Additional birth outcomes will 
be captured for descriptive purposes, but not considered adverse events: birth length, 
head circumference, and Apgar scores. To avoid capture of preexisting conditions, 
diagnostic codes representing each condition should not appear prior to the index date 
within the pregnancy under study. All pre-specified events of interest will be collected 
through the completion date. Analyses will be done on chart confirmed incident events
when applicable.
Table 6
List of primary and secondary endpoints (amended 12 November 
2019)
Primary endpoints
Preeclampsia and/or eclampsia
Intra-uterine infections such as chorioamnionitis and endometritis
Small for gestational age (SGA)
Preterm delivery
Secondary 
endpoints
Transfusion during delivery hospitalization 
Poor fetal growth
Stillbirth/fetal death with or without congenital anomalies
Neonatal death (within 28 days of birth)
Maternal death (while pregnant or within 42 days of end of pregnancy)
Placental abruption
Preterm pre-labor rupture of membranes (PPROM)
Congenital anomalies at birth and through 6 months of age
Spontaneous abortion with or without congenital anomalies (only for women exposed to 
Boostrix before the 27th week of gestation)
Therapeutic abortion with or without congenital anomalies (only for women exposed to 
Boostrix before the 27th week of gestation)
6.2.
Statistical methods
Covariates
Baseline characteristics of pregnant women and information on other relevant covariates 
will be extracted through automated data. Data will be in the form of International 
Classification of Diseases, 9th or 10th Revision (ICD-9 or ICD-10) codes or structured 
data fields. While data on these characteristics will be collected, only the potential
 
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confounders associated with the exposure or outcome will be considered in adjusted 
analyses and will be a subset of the covariates of interest. Identification of the potential
confounders will be determined through bivariate analyses and by prior knowledge based 
on the literature (22).
Medical conditions indicative of a high-risk pregnancy to be considered as covariates 
include:

thyroiditis,

diabetes, 

other autoimmune diseases (mixed connective tissue disease such as systemic lupus 
erythematosus), 

renal and cardiac chronic diseases, 

obesity (pre-pregnancy BMI>40), 

pre-existing hypertension, 

Rhesus sensitization, 

HIV infection, 

syphilis infection,

cervical incompetence.
Some additional covariates of interest to be collected and explored (if data are available)
include: 

smoking status

alcohol use

length of membership prior to 27 weeks gestation (but after pregnancy start) 

health care utilization (receipt of medical care) prior to the index date (but after 
pregnancy start)

number of previous pregnancies 

history of pregnancy loss

receipt of other vaccines during pregnancy, e.g., influenza vaccine

receipt of vaccines containing diphtheria, tetanus toxoid or pertussis containing 
antigens within one year before pregnancy 

season of pregnancy start

Medicaid insurance (public health insurance: Indication of low income status)
 
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Analysis of primary and secondary objectives (amended 12
November 2019)
Demographics and pregnancy information will be compared between the exposed and 
unexposed cohorts. Bivariate analyses will be conducted for all covariates of interest. 
Continuous variables will be summarized by means, medians, ranges, and standard 
deviations and compared using t-tests; categorical variables will be summarized by 
frequency distributions and compared using chi-square tests for the exposed and 
unexposed groups. Potential confounders will be determined based on bivariate analyses 
and scientific relevance.
For events identified at delivery such as SGA, preterm delivery, and transfusion during
delivery hospitalization, we will calculate crude incidence and 95% confidence intervals 
(CI) for each adverse event for the exposed and unexposed groups. The incidence of each 
maternal adverse event during pregnancy will be calculated separately and will consist of 
the total number of women with the condition in the numerator and the number of women 
for whom the condition can be assessed in the denominator. The adjusted relative risk 
with CI will be estimated by a Poisson regression model with adjustment for potential 
confounders. If the outcome is common (i.e., incidence>2%), a Poisson regression model 
with robust variance estimation will be used to estimate the relative risk (34). For primary 
endpoints, a two-sided 98.75% CI will be used for the relative risk with multiple 
comparison adjustment, while for secondary endpoints a two-sided 95% CI will be used. 
For events identified any time after the index date such as intra-uterine infection, we will 
calculate crude incidence and 95% CI for each adverse event for the exposed and 
unexposed groups. The incidence of each maternal adverse event during pregnancy will 
be calculated separately and will consist of the total number of women with the condition 
in the numerator and the total person time in the denominator. The person-year for a 
pregnant woman will be the time from the index date to the date of each adverse event,
end of the pregnancy, or disenrollment, whichever comes first. The adjusted relative risk 
with CI will be estimated by a Poisson regression model accounting for the follow-up 
time with adjustment for potential confounders. If the outcome is common (i.e., 
incidence>2%), a Poisson regression model with robust variance estimation will be used 
to estimate the relative risk. For primary endpoints, a two-sided 98.75% CI will be used
for the relative risk with multiple comparison adjustment, while for secondary endpoints 
a two-sided 95% CI will be used.
Congenital anomalies will be identified at birth and through 6 months of age among 
infants born in KPSC hospitals. Most congenital anomalies are diagnosed by 6 months of 
age (35). The prevalence of congenital anomalies (overall, by type, at birth, and through 6 
months of age) will be calculated as the number of infants with a congenital anomaly in 
the numerator and the total number of infants born in KPSC hospitals in the denominator. 
The proportion of live births without congenital anomalies will be calculated as 1 minus 
the proportion of live births with congenital anomalies among all KPSC live born infants.
The adjusted relative risk with 95% CI will be estimated by a Poisson regression model 
with adjustment for potential confounders. If the outcome is common (i.e., incidence
>2%), a Poisson regression model with robust variance estimation will be used to 
estimate the relative risk.
The following table outlines the planned method of analysis by endpoint.
 
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Table 7
Analytic population and statistical methods by endpoint (amended 12 November 2019)
Primary endpoints
Analytic population
Statistical Methods
Preeclampsia and eclampsia
All pregnant women eligible for inclusion/exclusion criteria
Adjusted Poisson regression model accounting for follow up time, 
with robust variance estimate
Intra-uterine infections such as chorioamnionitis
and endometritis
All pregnant women eligible for inclusion/exclusion criteria
Adjusted Poisson regression model accounting for follow up time, 
with robust variance estimate
Small for gestational age (SGA)
KPSC live born infant, singleton only**
Adjusted Poisson regression model, with robust variance 
estimate
Preterm delivery
Pregnant women with live birth, with index (vaccination) date 
prior to 37 weeks gestation
Adjusted Poisson regression model, with robust variance 
estimate 
Secondary endpoints
Analytic population
Statistical Methods
Transfusion during delivery hospitalization
Pregnant women with delivery hospitalization
Adjusted Poisson regression model
Poor fetal growth 
All pregnant women eligible for inclusion/exclusion criteria
Adjusted Poisson regression model accounting for follow up time, 
with robust variance estimate
Stillbirth/fetal death*
Pregnant women with pregnancy outcome
Adjusted Poisson regression model 
Neonatal death (within 28 days of birth)
KPSC live born infants
Adjusted Poisson regression model 
Maternal death (while pregnant or within 42 
days of end of pregnancy)
All pregnant women eligible for inclusion/exclusion criteria
Adjusted Poisson regression model accounting for follow up time
Placental abruption
All pregnant women eligible for inclusion/exclusion criteria
Adjusted Poisson regression model accounting for follow up time
Preterm pre-labor rupture of membranes 
(PPROM)
All pregnant women, with index (vaccination) date prior to 37 
weeks gestation
Adjusted Poisson regression model accounting for follow up time
Congenital anomalies (CA) at birth and through 
6 months of age
KPSC live born infants
Adjusted Poisson regression model, with robust variance 
estimate if outcome is common
Spontaneous abortion 
Pregnant women exposed to Boostrix before the 27th week 
of gestation 
Descriptive analysis (proportion)
Therapeutic abortion
Pregnant women exposed to Boostrix before the 27th week 
of gestation 
Descriptive analysis (proportion)
* Stillbirth/fetal death will be described with or without congenital anomalies separately, but will be analyzed as one outcome.
** There are no well accepted SGA metrics for infants born to pregnant women with multiple gestation.
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Analyses interpretation
Analysis of primary endpoints will be used to evaluate the safety of maternal vaccination 
and concluded to be non-inferior if the upper limit of the 98.75% CI for the adjusted 
relative risk is below 2.
While the analysis of primary endpoints will be used to evaluate the safety of maternal 
vaccination with sufficient statistical power, the analysis of secondary endpoints will be 
used for hypothesis generation/signal detection.
6.3.
Sample size considerations
The power computation for the primary objective was performed using PASS non-
inferiority of two independent proportions using Miettinen and Nurminen method. 
Although the power is not based on the Poisson regression model, it is expected to reflect 
the power on the planned analysis since inference on proportion and incidence rate 
provide similar results when incidence rates are low.
The following table (Table 8) shows the power to rule out a two-fold increase considering 
an assumed possible design bias leading to a 1.25 relative risk increase. 
To be able to make independent conclusions for each of the four primary endpoints while 
controlling the type I error below 2.5%, a Bonferroni adjustment will be used, i.e., each 
primary endpoint will be evaluated using a one-sided 0.625% (2.5% type I error / 4
primary endpoints) nominal type I error. More specifically, the upper limit of the two-
sided 98.75% CI will be used to make conclusions.
Considering that the four primary endpoints are expected to have an incidence rate above 
1%, the power to conclude that maternal immunization is non-inferior for any primary 
endpoint is at least 95% and the power to conclude that maternal immunization is non-
inferior for all 4 primary endpoints is at least 80% (100% - 4*beta).
Table 8
Power to rule out a two-fold increase with 15,000 pregnant women in 
each cohort
Incidence rate in 
unvaccinated 
cohort
One-sided type I nominal 
error
True relative 
risk
Power
Beta
1%
0.625%
1.25
95.7%
4.3%
 
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7.
STUDY CONSIDERATIONS
Most of the Boostrix exposures during pregnancy will occur at 27 weeks gestation or 
later. As such, we expect pregnancy outcomes that occur earlier in pregnancy such as 
spontaneous abortion and therapeutic abortion to be rare in our study. Furthermore, while 
we will describe the frequency of congenital anomalies among the exposed and 
unexposed cohorts, we note that the most plausible time period for development of 
congenital anomalies is during early pregnancy (35). Cautious interpretation of maternal 
Boostrix immunization and congenital anomalies is warranted.
One potential limitation is that the exposed (Boostrix vaccinated) cohort and the 
unexposed cohort come from different time periods. With the exposed cohort from the 
ICD-10 era and the unexposed cohort from the ICD-9 era there is a potential risk of bias 
if the prevalence of adverse events is higher or lower in either exposed or unexposed 
cohorts due to coding variation or secular trends. This issue is not specific to KPSC but 
rather affects all health care organizations and similar research conducted in the U.S. 
However, this is not a major concern at KPSC as there is specific mapping (crosswalk) 
between ICD-9 and ICD-10 for all of the outcomes (36, 37). Most importantly, no matter 
which system is used, a comprehensive list of codes will be used to identify all potential 
events of interest. In addition, a review of medical records will be conducted to determine 
whether the events are truly incident events with onset after the index date (vaccination 
date for the exposed). Similarly, by using a historical cohort to identify the unexposed 
group to compare to a current exposed cohort, there is a concern that the baseline 
incidence of the selected safety endpoints will vary significantly between the Tdap 
(Boostrix) vaccination period and the historical comparison period. However, the 
advantage of comparing to a historical population of pregnant women during 
approximately 2012-2013 is that we are identifying an unvaccinated group during a 
period when prenatal Tdap vaccine uptake was low, making these pregnant women more 
representative of an unvaccinated cohort. A current unvaccinated cohort would yield a 
small and selective sample (given over 70% Tdap uptake) that is not representative of an 
unvaccinated group and would be affected by confounding by indication. 
If a safety signal is identified, further exploration of the data will be completed to 
investigate alternative potential sources for the Boostrix-outcome association, including
but not limited to changing secular trends or coding practices. 
8.
CONDUCT OF THE STUDY
GlaxoSmithKline (GSK) will engage KPSC to provide activities including conducting the 
study on behalf of GSK. The study will be conducted by the Investigator at KPSC’s 
premises under the oversight of the sponsor, GSK. Through this partnership, we will 
provide critical information about the safety of maternal vaccination with Boostrix in a 
community setting.
 
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8.1.
Regulatory and ethical considerations
The study will be conducted in accordance with all applicable regulatory requirements, 
including all applicable subject privacy requirements and the guiding principles of the 
Declaration of Helsinki, International Ethical Guidelines for Epidemiological Studies 
(CIOMS), FDA Best Practices for Conducting and Reporting Pharmacoepidemiologic 
Safety Studies using Electronic Healthcare Data, and ISPE guidelines for Good 
Pharmacovigilance Practice (GPP).
The KPSC team will obtain approval of the final protocol from the Institutional Review 
Board (IRB) at KPSC prior to study start.
8.2.
Informed consent and data privacy
Subjects included in this study will be identified among KPSC health plan members. 
Informed consent is not required because Boostrix is a licensed vaccine given to eligible 
KPSC members as part of routine clinical care. KPSC will obtain IRB approval for the 
use of patient data and to ensure protection of data privacy. Individual written Health 
Insurance Portability and Accountability Act (HIPAA) authorizations prior to initiating 
data collection will not be required.
8.3.
Additional data
Additional summary level data will be provided from KPSC to GSK throughout the 
course of the study. This will include aggregated data from automated data sources, and 
will include the following:

Monthly vaccine uptake report including uptake among pregnant women and non-
pregnant individuals. Uptake among pregnant women will be broken down by 
women vaccinated at 27 weeks and above versus women vaccinated before 27 
weeks. 

Quarterly cohort identification report, i.e., exposure data: This report will provide the 
uptake among pregnant women vaccinated on or after the 1st day of the 27th week of 
gestation, with additional inclusion/exclusion criteria applied as indicated in the 
study protocol.

Quarterly identification of pre-specified adverse events and pregnancy outcomes.

Quarterly report demonstrating the progress of chart review for the pre-specified 
adverse events (e.g. number of events identified, number in progress of being 
reviewed, number completed).
 
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9.
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September, 22, 2017.
 
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12.
Munoz FM, Bond NH, Maccato M, Pinell P, Hammill HA, Swamy GK, et al. 
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Kharbanda EO, Vazquez-Benitez G, Lipkind HS, Klein NP, Cheetham TC, 
Naleway A, et al. Evaluation of the association of maternal pertussis vaccination 
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TC, et al. Maternal Tdap vaccination and risk of infant morbidity. Vaccine. 
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Layton JB, Butler AM, Li D, Boggess KA, Weber DJ, McGrath LJ, et al. Prenatal 
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Structural Birth Defects in Offspring. Jama. 2016;316(17):1823-5.
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21.
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23.
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membranes. Practice Bulletin No. 172. Obstet Gynecol. 2016;128(4):e165-77.
 
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24.
American College of Obstetricians and Gynecologists. Executive summary: 
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labor. Practice Bulletin No. 171. Obstet Gynecol. 2016;128:e155-64.
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Practice Bulletin No. 134. Obstet Gynecol. 2013;121:1122-33.
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Obstetricians and Gynecologists Practice Bulletin no. 150. Early pregnancy loss. 
Obstet Gynecol. 2015;125(5):1258-67.
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34.
Zou G. A modified poisson regression approach to prospective studies with binary 
data. Am J Epidemiol. 2004;159(7):702-6.
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37.
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GEMs.html on October 30, 2017.
 
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APPENDIX A
AMENDMENTS AND ADMINISTRATIVE 
CHANGES TO THE PROTOCOL
GlaxoSmithKline Biologicals SA
Vaccines R & D
Protocol Amendment 2
eTrack study number 
and Abbreviated Title
207221 (EPI-PERTUSSIS-047 VS US DB)
Amendment number:
Amendment 2
Amendment date:
Final: 12 November 2019
Rationale/background for changes: 
The protocol has been amended to modify the secondary endpoint of “post-
partum hemorrhage (PPH)” to “transfusion during delivery hospitalization” as 
a proxy for severe PPH. We originally planned to identify PPH from automated 
diagnosis codes (ICD-9 and ICD-10) and then perform chart review to confirm 
the event. However, in October 2017 (ACOG Practice Bulletin PPH 2017), the 
threshold for estimated blood loss (EBL) for PPH diagnosis changed, affecting 
the comparison between the historical (~2012-2013) and the Boostrix exposed 
(2018-2019) cohorts. The potential for using EBL as an objective measure is 
limited by differential missingness of EBL data between these two cohorts as well 
as inconsistency in EBL measurements. We propose to use transfusion during 
delivery hospitalization as an indicator of severe blood loss and as a proxy for 
severe PPH. Transfusion can be captured by procedure codes, and transfusion 
data are stable across the study period. Transfusion is a relevant endpoint 
because hemorrhage that leads to blood transfusion is the leading cause of severe 
maternal morbidity in the United States (ACOG Practice Bulletin PPH 2017).
The following changes have been implemented.
Secondary objectives; Data collection Figure 1; Statistical methods Tables 6 
and 7 - "Post-partum hemorrhage" was changed to "Transfusion during 
delivery hospitalization."
Case definitions; Data collection and management - Transfusion during 
delivery hospitalization is captured by procedure codes and will not be chart 
reviewed. 
Data collection Figure 1; Statistical methods Table 7 - Transfusion will be 
identified among pregnant women with delivery hospitalizations.
Analysis of primary and secondary objectives; Statistical methods Table 7 -
The statistical method for analyzing transfusion will be an adjusted Poisson 
 
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regression model. Robust variance estimation is not planned since the 
incidence is expected to be <2%.
Amended text has been included in bold italics and deleted text in strikethrough in the 
following sections:
Synopsis:
Secondary Objectives

Post-partum hemorrhage Transfusion during delivery 
hospitalization (as a proxy for severe post-partum 
hemorrhage)
Endpoint(s)
Secondary

Post-partum hemorrhage Transfusion during delivery 
hospitalization
With the exception of SGA, and preterm delivery, and 
transfusion, medical records of the potential events will then 
be reviewed by trained research associates to confirm the 
diagnosis and to ascertain that it is an incident event.
Section 2.2 Secondary objectives

Post-partum hemorrhage Transfusion during delivery hospitalization (as a proxy for 
severe post-partum hemorrhage)
Section 4.2 Case definitions
With the exception of SGA, and preterm delivery, and transfusion, chart review will be 
performed for the pre-specified maternal and infant adverse events to confirm the events 
and that the events are incident after the index date.
Section 5 Data collection and management
We will rely on automated data from the EHR to ascertain SGA, and preterm delivery, 
and transfusion.
Figure 1. Illustration of data flow was updated and changes include:

Post-partum hemorrhage secondary endpoint was changed to “Transfusion during 
delivery hospitalization”

Modified sentence “All secondary endpoints but transfusion will be confirmed by 
medical record review”

Secondary endpoints, footnote a, modified to say “Identified among pregnant women 
with KPSC delivery delivery hospitalization”
 
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Section 6.1 Primary and secondary pre-specified events of interest 
Table 6
List of primary and secondary endpoints
Secondary 
endpoints
Post-partum hemorrhage Transfusion during delivery hospitalization 
Poor fetal growth
Stillbirth/fetal death with or without congenital anomalies
Neonatal death (within 28 days of birth)
Maternal death (while pregnant or within 42 days of end of pregnancy)
Placental abruption
Preterm pre-labor rupture of membranes (PPROM)
Congenital anomalies at birth and through 6 months of age
Spontaneous abortion with or without congenital anomalies (only for women exposed to 
Boostrix before the 27th week of gestation)
Therapeutic abortion with or without congenital anomalies (only for women exposed to 
Boostrix before the 27th week of gestation)
Section 6.2.2 Analysis of primary and secondary objectives
For events identified at delivery such as SGA, and preterm delivery, and transfusion 
during delivery hospitalization, we will calculate crude incidence and 95% confidence 
intervals (CI) for each adverse event for the exposed and unexposed groups.
Table 7
Analytic population and statistical methods by endpoint
Secondary endpoints
Analytic population
Statistical Methods
Post-partum hemorrhage Transfusion 
during delivery hospitalization
Pregnant women with KPSC
delivery delivery hospitalization
Adjusted Poisson regression model, 
with robust variance estimate
 
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Protocol Amendment 2 Final
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