Boostrix Pregnancy Registry: a Prospective, Exploratory, Cohort Study to Detect and Describe Any Abnormal Pregnancy Outcomes in Women Intentionally or Unintentionally Vaccinated With Boostrix® During Pregnancy or Within 28 Days Preceding Conception
Conditions: Pertussis
Sponsor: GlaxoSmithKline

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Study Protocol
Sponsor:
GlaxoSmithKline Biologicals
Rue de l’Institut 89
1330 Rixensart, Belgium
1.
PASS INFORMATION
Title
Boostrix Pregnancy Registry: a prospective, 
exploratory, cohort study to detect and describe 
any abnormal pregnancy outcomes in women 
intentionally or unintentionally vaccinated with 
Boostrix during pregnancy or within 28 days 
preceding conception.
Protocol version identifier
201327 (EPI-PERTUSSIS-028 VS US PR)
Date of last version of the 
protocol 
Amendment 1 Final: 05 October 2017
EU PAS Register No
Not applicable
Active substance
J07AJ52, bacterial vaccine, pertussis vaccines
Medicinal product
Boostrix, Tetanus Toxoid, Reduced Diphtheria 
Toxoid and Acellular Pertussis Vaccine, 
Adsorbed
Product reference
Not applicable
Procedure number
Not applicable
Marketing Authorization Holder
GlaxoSmithKline (GSK) Biologicals
Rue de l’Institut 89
1330 Rixensart, Belgium
Joint PASS
No
Research question and objectives
Co-primary objectives

To describe the characteristics of 
registered pregnancies (women vaccinated 
with Boostrix during pregnancy or within 28 
days preceding conception) with any 
abnormal pregnancy outcomes.
 
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!
To assess the proportion of registered 
pregnancies (women vaccinated with 
Boostrix during pregnancy or within 28 
days preceding conception) with any 
abnormal pregnancy outcomes.
Country of study
United States
Authors (Amended on 05 
October 2017)
Coordinating author:
!
, Scientific Writer, Keyrus 
Biopharma, contractor for GSK Biologicals
GSK contributors:
!
, Senior Manager, 
Safety Evaluation & Risk Management, 
Vaccine Clinical Safety and 
Pharmacovigilance
!
, Director, Safety Evaluation 
& Risk Management, Vaccine Clinical 
Safety and Pharmacovigilance
!
, Director, Director, 
Head of Safety Evaluation & Risk 
Management, Vaccine Clinical Safety and 
Pharmacovigilance (Therapeutic)
!
, Director, Safety Evaluation 
& Risk Management, Vaccine Clinical 
Safety and Pharmacovigilance
!
, Director, Head of 
Safety Evaluation & Risk Management, 
Vaccine Clinical Safety and 
Pharmacovigilance (Prophylactic)
!
, Director, Safety Evaluation & 
Risk Management, Vaccine Clinical Safety 
and Pharmacovigilance
!
, Senior Manager, Vaccine 
Value & Health Science Epidemiology
!
, Director, Global Regulatory 
Affairs
!
, Safety Scientist, Safety
Evaluation & Risk Management, Vaccine 
Clinical Safety and Pharmacovigilance
!
, Safety Physician, Safety 
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Evaluation & Risk Management, Vaccine 
Clinical Safety and Pharmacovigilance
!
, Safety Evaluation & Risk 
Management Team Leader, Vaccine 
Clinical Safety and Pharmacovigilance
!
, Head, Safety 
Evaluation & Risk Management, Vaccine 
Clinical Safety and Pharmacovigilance
!
, Clinical and 
Epidemiology Project Lead, DTP Polio Hib 
– containing vaccines
!
, Regulatory Affairs
!
, Study Delivery Lead
!
, Manager, CMG US
!
, Director, CMG US
!
, Clincial Safety Associate, 
CMG
!
, Senior Manager, 
Pharmacovigilance
2.
MARKETING AUTHORIZATION HOLDER 
Marketing authorization holder
GlaxoSmithKline Biologicals
Rue de l’Institut 89, 1330 Rixensart, Belgium
© [2014-2017] GSK group of companies or its licensor
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TABLE OF CONTENTS
PAGE
1. PASS INFORMATION ...............................................................................................1
2. MARKETING AUTHORIZATION HOLDER................................................................3
LIST OF ABBREVIATIONS.............................................................................................7
3. RESPONSIBLE PARTIES .........................................................................................8
4. ABSTRACT ...............................................................................................................9
5. AMENDMENTS AND UPDATES.............................................................................14
6. MILESTONES (AMENDED ON 05 OCTOBER 2017) ..............................................14
7. RATIONALE AND BACKGROUND..........................................................................14
7.1.
Background ................................................................................................14
7.1.1.
Boostrix vaccine...........................................................................14
7.1.2.
Animal studies/human exposure ..................................................14
7.1.3.
Medical conditions for use ...........................................................17
7.1.4.
Characteristics of exposure..........................................................19
7.1.5.
Potential benefits of product.........................................................19
7.2.
Rationale (Amended on 05 October 2017) ...............................................19
8. RESEARCH QUESTION AND OBJECTIVES..........................................................20
8.1.
Co-primary objectives .................................................................................20
9. RESEARCH METHODS..........................................................................................20
9.1.
Study design...............................................................................................20
9.1.1.
Overview (Amended on 05 October 2017)...................................20
9.1.2.
Rationale for study design ...........................................................21
9.2.
Setting ........................................................................................................21
9.2.1.
Study population..........................................................................21
9.2.1.1.
Patient population .....................................................21
9.2.1.2.
Potential annual exposure ........................................22
9.2.2.
Patient recruitment (Amended on 05 October 2017)....................22
9.2.3.
Selection of a comparison group ...............................................22
9.2.4.
Study period (Amended on 05 October 2017)..............................23
9.2.5.
Inclusion criteria...........................................................................23
9.2.6.
Exclusion criterion........................................................................23
9.3.
Variables.....................................................................................................24
9.3.1.
Primary endpoint..........................................................................24
9.3.2.
Data to be collected (Amended 05 October 2017) .......................24
9.4.
Data sources (Amended on 05 October 2017)............................................25
9.5.
Study size...................................................................................................25
9.6.
Data management ......................................................................................25
9.6.1.
Data collection (Amended on 05 October 2017)........................25
9.6.2.
Processing of reports (Amended on 05 October 2017)..............26
 
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9.6.2.1.
Solicitation of outcome (Amended on 05 
October 2017) ...........................................................26
9.6.2.2.
Classification of outcomes (Amended 05 
October 2017) ............................................................26
9.7.
Data analysis (Amended on 05 October 2017).........................................27
9.8.
Quality control.............................................................................................29
9.9.
Limitations of the research methods ...........................................................29
10. PROTECTION OF HUMAN SUBJECTS..................................................................30
10.1.
Regulatory and ethical considerations, including the informed 
consent process..........................................................................................30
11. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS............................................................................................................30
12. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS 
(AMENDED ON 05 OCTOBER 2017)......................................................................30
13. REFERENCES (AMENDED ON 05 OCTOBER 2017).............................................31
 
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LIST OF ANNEXES
PAGE
Annex 1
List of stand-alone documents................................................................36
Annex 2
ENCePP Checklist for study protocols ...................................................37
Annex 3
Glossary of terms...................................................................................46
Annex 4
Amendments and administrative changes to the protocol.......................48
Annex 5
Trademarks............................................................................................61
Annex 6
Protocol Amendment 1 sponsor signatory approval ...............................62
 
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LIST OF ABBREVIATIONS
ACIP
Advisory Committee on Immunization Practices
AE
Adverse Event
CBER
Center for Biologics Evaluation and Research
CDC
Centers for Disease Control and Prevention
DLP
Data Lock Point
DTaP
Diphtheria and tetanus toxoids and acellular pertussis vaccine
DTP
Diphtheria and tetanus toxoids and whole cell pertussis vaccine
EDD
Estimated Date of Delivery
FDA
Food and Drug Administration
FHA
Filamentous Hemagglutinin
GCP
Good Clinical Practice
GSK
GlaxoSmithKline
HCP
Healthcare Professional
ICD-9 CM
International Classification of Diseases, Ninth Revision, 
Clinical Modification
ICH
International Conference on Harmonization
LMP
Last Menstrual Period
MACDP
Metropolitan Atlanta Congenital Defects Program
MedDRA
Medical Dictionary for Regulatory Activities
PASS
Post-Authorization Safety Study
PT
Pertussis Toxin
Td
Tetanus and diphtheria toxoid vaccine
Tdap
Combined reduced antigen content tetanus toxoid, diphtheria 
toxoid, and acellular pertussis vaccine
UK
United Kingdom
US
United States
 
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3.
RESPONSIBLE PARTIES 
GlaxoSmithKline (GSK) Biologicals has the overall responsibility for the conduct of the 
study.
 
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4.
ABSTRACT
Title
Boostrix Pregnancy Registry: a prospective, exploratory, cohort 
study to detect and describe any abnormal pregnancy outcomes 
in women intentionally or unintentionally vaccinated with 
Boostrix during pregnancy or within 28 days preceding 
conception.
201327 (EPI-PERTUSSIS-028 VS US PR), Amendment 1 
Final: 05 October 2017
Main author
, Senior Manager, Safety Evaluation & 
Risk Management, Vaccine Clinical Safety and 
Pharmacovigilance, GSK Biologicals
Rationale and 
background
(Amended on 05 
October 2017)
In the US, Boostrix is indicated for active booster 
immunization against tetanus, diphtheria, and pertussis as a 
single dose in individuals 10 years of age and older. 
The purpose of this Registry is to detect and describe any 
abnormal pregnancy outcomes, including teratogenicity, in
females intentionally or unintentionally exposed to Boostrix
during their pregnancies in the US. The combination of the 
large number of women who are of reproductive capacity and 
may be exposed to tetanus, diphtheria, and pertussis; and the 
lack of data concerning exposure to Boostrix during pregnancy 
makes such a Registry an important component of the ongoing 
effort to assess the safety of Boostrix. The Registry was 
originally initiated on 03 May 2005, as part of a program of 
enhanced Pharmacovigilance. Following new European Union 
pharmacovigilance legislation, pregnancy registries are to be 
considered as post-authorization safety studies (PASS). The 
ongoing Registry is therefore converted into a PASS in Q1 
2014.
The intent of the Registry is to prospectively collect data 
describing exposure to Boostrix immediately before or during 
pregnancy, potential confounding factors (such as exposure to 
other medications), and information related to the outcome of 
the pregnancy. Retrospective reports will be captured by the 
Registry but will not be included in the analyses of prospective 
reports.
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Research question 
and objectives
Co-primary objectives

To describe the characteristics of registered pregnancies 
(women vaccinated with Boostrix during pregnancy or 
within 28 days preceding conception) with any abnormal 
pregnancy outcomes.

To assess the proportion of registered pregnancies 
(women vaccinated with Boostrix during pregnancy or 
within 28 days preceding conception) with any abnormal 
pregnancy outcomes.
Study design
(Amended on 05 
October 2017)

This study is a transition of an US ongoing pregnancy 
registry (starting on 03 May 2005) into a PASS. 

This is a prospective*, observational, exploratory, 
cohort study. The Boostrix pregnancy registry study 
requires voluntary, prospective reporting of eligible 
pregnancies by patients and healthcare professionals 
(HCPs). Data such as vaccination with Boostrix during 
pregnancy or within 28 days preceding conception, 
potential confounding factors (such as exposure to other 
medications) and information related to the outcome of the 
pregnancy will be collected prospectively**.
* Exposed pregnancies reported to the Registry before the 
transition into a PASS (between 03 May 2005 and Q1
2014), from which data were collected and analyzed
prospectively, will also be included in the analyses.
** Some pregnancy exposures may be reported after 
pregnancy outcome has been identified (retrospective 
reports). The Registry will capture retrospective reports, 
but these reports will not be included in the analyses of 
prospective reports.

Study population: pregnant women, residing in the United 
States (US), vaccinated with Boostrix during pregnancy or 
within 28 days preceding conception volunteering to take 
part in the study.

Type of study: self-contained.

Data collection: initial and follow-up data will be 
collected using questionnaires. Follow-up of cases is 
performed within 2 months of the estimated date of 
delivery (EDD) to ascertain outcome and approximately 
6 months and 12 months after the EDD (for all live births
for whom the contact details of their HCP will be 
available) to ascertain the presence of birth defects not 
diagnosed before.
 
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
After transition of the ongoing pregnancy registry into a 
PASS, data will be collected for a minimum of 5 years, 
starting Q1 2014.
Population, 
including the 
setting and study 
population
In the US, Boostrix is indicated for active booster 
immunization against tetanus, diphtheria, and pertussis. 
Originally licensed for persons aged 10 through 18 years, the 
vaccine was approved by the Food and Drug Administration 
(FDA) for use in persons aged 19 through 64 years in 2008, and 
in persons aged 65 years and older in 2011. The study 
population includes women vaccinated with Boostrix during 
pregnancy or within 28 days preceding conception.
Size of the potential “at-risk” population
The US Census Bureau estimates that, as of 1 July 2012, the 
resident US female population was 62,744,930 between the 
ages of 15 and 44 years old [US Census Bureau, 2013]. The 
provisional fertility rate in the US in 2012 was 63.2 births 
per 1000 women aged 15-44 years and the provisional count 
of births was 3.96 millions [CDC, 2012].
Number of pregnant vaccinees
Boostrix is classified as FDA Pregnancy Category B since
September 2012. Since February 2013, Boostrix vaccination is 
recommended by the Advisory Committee on Immunization 
Practices (ACIP) in each pregnancy. 
More than 20 million doses of Boostrix were distributed in the 
US between May 2005 and July 2011. Experiences with the 
ongoing Boostrix pregnancy registry (391 exposed pregnancies 
reported prospectively and 5 exposed pregnancies reported 
retrospectively between 03 May 2005 and 02 August 2013) and 
other vaccine pregnancy registries indicate that it is likely that 
fewer than 100 pregnancies per year will be registered.
Variables
Primary endpoint
Occurrence of any abnormal pregnancy outcomes in women 
intentionally or unintentionally vaccinated with Boostrix during 
pregnancy or within 28 days preceding conception.
Data sources
(Amended on 05 
October 2017)
Reporting of vaccine-exposed pregnancies to the Registry is 
voluntary. Registration can be initiated from a HCP or from 
a consumer, in which case permission is requested to obtain 
confirmation and follow-up from their HCP. Follow-up 
from the HCP of the infant post birth 6 and 12 months will 
be performed when the contact details are available and 
 
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with consumer’s permission. A toll-free telephone number 
for reporting adverse events (AEs) and vaccine-exposed 
pregnancies to the Registry will be listed in the product 
information leaflet and on the GSK Registry website. 
Retrospective post-marketing reports and relevant scientific 
publications are potential sources of supplementary
information.
Study size
No minimum sample size is required for this descriptive study.
Refer to Abstract Section “Study population” above for the 
size of the potential “at-risk” population and the number of 
pregnant vaccinees.
Data analysis
(Amended on 05 
October 2017)
Pregnancy outcomes include spontaneous abortion (pregnancy 
loss before 22 weeks gestation), fetal deaths/stillbirths (loss 
at or after 22 weeks gestation), elective/induced abortions 
and live births. The presence or absence of birth defects or 
other abnormalities is evaluated within each of the preceding 
outcome categories.
Pregnancy outcomes are stratified by the trimester of 
exposure, with an additional stratum for preconception 
exposure with no subsequent administration of vaccine during 
pregnancy. Reports of multiple exposures during a pregnancy 
are classified by the earliest trimester of exposure. The 
calculations of risk for birth defects are made by dividing the 
number of infants with birth defects by the total number of 
infants with and without birth defects. The outcomes of the 
study will be assessed against known rates from an external 
reference group for the likelihood of a safety signal warranting 
further investigation.
Spontaneous abortions without birth defects are excluded from 
the risk calculations. 
All defects regardless of trimester of vaccine exposure will be 
included in the periodic summary reports of this Registry and 
stratified by trimester of exposure.
A section of each periodic summary report, separate from the 
analysis of prospective reports, will describe all abnormal 
outcomes of retrospectively reported cases.
Milestones
(Amended on 05 
October 2017)
The Registry was originally initiated on 03 May 2005, as part 
of a program of enhanced pharmacovigilance, and is converted 
into a PASS in Q1 2014. GSK plans to continue the Registry 
for a minimum of 5 years, starting Q1 2014. Summary reports 
with cumulative analysis will be written annually. A final 
 
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cumulative report will be written and submitted within one 
year of completion of the five-year period. After submission 
of the final report, GSK will continue the Registry pending 
Center for Biologics Evaluation and Research (CBER) 
review of the report and determination whether the Registry 
can be discontinued.
References
Centers for Disease Control and Prevention (CDC). Recent 
Trends in Births and Fertility Rates Through December 2012. 
http://www.cdc.gov/nchs/data/hestat/births_fertility_decemb
er_2012/births_fertility_december_2012.htm. Accessed: 27 
November 2013.
United States Census Bureau (US Census Bureau), Population 
Division. Annual Estimates of the Resident Population for 
Selected Age Groups by Sex: April 1, 2010 to July 1, 2012. 
Release date June 2013. 
http://www.census.gov/popest/data/national/asrh/2012/index.ht
ml. Accessed: 27 November 2013.
 
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5.
AMENDMENTS AND UPDATES 
The summary of the amendment is provided in Annex 4.
6.
MILESTONES (AMENDED ON 05 OCTOBER 2017)
Milestone
(Including Data Lock Point (DLP) of each report)
Planned Submission date
Start of data collection
Q1 2014a
End of data collection
2 August 2019b
Annual report 1 (DLP: 2 August 2015)
Q2 2016
Annual report 2 (DLP: 2 August 2016)
Q2 2017
Annual report 3 (DLP: 2 August 2017)
Q2 2018
Annual report 4 (DLP: 2 August 2018)
Q2 2019
Annual report 5/Final report (DLP: 2 August 2019)
Q2 2020C
Registration in the EU PAS register
Q1 2014
a The Registry was originally initiated on 03 May 2005, as part of a program of enhanced pharmacovigilance. 
Following new European Union Pharmacovigilance legislation, pregnancy registries are to be considered as 
post-authorization safety studies (PASS). The ongoing Registry will therefore be converted into a PASS. GSK 
plans to continue the Registry for a minimum of 5 years, starting Q1 2014. Summary reports will be written 
annually and will be submitted with the Periodic Benefit-Risk Evaluation Report (PBRER) and the 
Development Safety Update Report (DSUR) for Boostrix.
b After submission of the final report, GSK will continue the Registry pending Center for Biologics Evaluation and 
Research (CBER) review of the report and determination whether the Registry can be discontinued.
C Since the annual reports also contain cumulative data, the last annual report (with DLP: 2 August 2019) 
will serve the purpose of the Final report.
7.
RATIONALE AND BACKGROUND 
7.1.
Background
7.1.1.
Boostrix vaccine
Boostrix is a vaccine indicated for active booster immunization against tetanus, 
diphtheria, and pertussis. It contains tetanus toxoid, diphtheria toxoid, and pertussis 
antigens (inactivated pertussis toxin [PT] and formaldehyde-treated filamentous 
hemagglutinin [FHA] and pertactin). Each 0.5-mL dose is formulated to contain 5 Lf of 
tetanus toxoid, 2.5 Lf of diphtheria toxoid, 8 g of inactivated PT, 8 g of FHA, and 2.5 
g of pertactin (69 kD outer membrane protein). Each antigen is individually adsorbed 
onto aluminium hydroxide.
7.1.2.
Animal studies/human exposure
No published or unpublished clinical data on immunogenicity, efficacy, or effectiveness 
in pregnant women are available since pregnant women have been routinely excluded 
from clinical trials. However, there are no specific safety concerns or expectations of 
harm, and use in pregnancy is not contraindicated. 
There are two non-clinical studies performed recently:
 
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1.
HLS HEY0017: A study of effects on fertility, embryo-fetal and prenatal and post-
natal development in rats by intramuscular administration (including pre-mating 
immunization phase) with Boostrix, Boostrix (United States [US] formulation), and 
Boostrix IPV (study report dated 2012, [GlaxoSmithKline Biologicals Clinical Study 
Report HLS HEY0017]).
2.
HLS HEY0018: A study of effects on female fertility and embryo-fetal development 
in rabbits by intramuscular administration (including pre-mating immunization 
phase) with Boostrix and Boostrix IPV (study report dated 2013, [GlaxoSmithKline 
Biologicals Clinical Study Report HLS HEY0018]).
These studies have shown that there are no key safety findings after the use of Boostrix in 
rats and rabbits. The first study was mainly focused on the reproductive profile in rats and 
the other study explored the developmental toxicity in rabbits. In the reproductive 
toxicity study with rats, it was concluded that female rats did not develop important pre-
and post-natal adverse effects and that Boostrix did not affect the growth or development 
of the offspring studied. In the developmental toxicity study with rabbits, it was 
concluded that female rabbits adequately tolerate Boostrix and that the vaccine did not 
adversely affect embryo-fetal development or survival. 
In order to generate data on pregnancy outcomes, GSK closely monitored outcomes of 
unplanned pregnancies in clinical trials, and established a pregnancy exposure registry in 
the US on 03 May 2005. 
Up to 02 August 2013, 10 pregnancy reports were received from clinical trials. Three 
pregnancies were exposed within 28 days prior to conception; these three pregnancies 
resulted in three infants without birth defects. Four pregnancies were exposed during the 
first trimester. Of these, three were lost to follow-up and one resulted in spontaneous 
abortion in a vaccinee with epilepsy, who was taking lamotrigine prior to and during the 
pregnancy. Two pregnancies were exposed during an unspecified trimester; both of 
which were lost to follow-up. The remaining one pregnancy involved exposure to 
Boostrix during an unspecified time prior to conception and no follow-up information has 
been received until now.
The Boostrix pregnancy registry was originally initiated as part of a program of enhanced 
pharmacovigilance. As of 02 August 2013, 391 pregnancies involving exposure to 
Boostrix in the US had been prospectively reported since the initiation of the pregnancy 
registry. Among these, 153 (39%) were lost to follow-up and 200 (51%) were ongoing at 
the time of last contact, including one report from a physician of an unspecified 
‘congenital anomaly’ and one report from a healthcare provider regarding a defect noted 
from an abnormal prenatal screening test (left ventricular echogenic intracardiac focus) in 
a 22-year-old woman who was exposed to Boostrix during the third trimester. Outcomes 
were reported for 38 (10%) pregnancies, and consisted of 35 live infants born without 
birth defects, one spontaneous abortion at seven weeks gestation with exposure to 
Boostrix vaccine during the first trimester, and two live infants with birth defects exposed 
during the second trimester (plagiocephaly in a female diagnosed at two months of age, 
family history of occipital deformational plagiocephaly) and third trimester (mild left foot 
ligament laxity in a male diagnosed at birth). Five retrospective pregnancy reports were 
received up to 02 August 2013. Two pregnancies resulted in a live infant. The outcome of 
 
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one pregnancy was unknown. The remaining two reports pertained to one spontaneous 
abortion at eight weeks of gestation with exposure during the first trimester and one 
infant who was delivered at an unspecified gestational age and who was diagnosed at 
birth with pulmonary hypertension and arterial venous malformation (exposure during an 
unspecified trimester to both Boostrix and Adacel, on the same day). The infant died 
while hospitalized; the cause of death was not provided and it was unknown whether an 
autopsy was performed.
Since 2005, 60 prospective spontaneous reports and two retrospective spontaneous 
reports were received from outside the US. Among the pregnancies reported 
prospectively, 12 were reported to be ongoing, 28 were lost to follow-up and 19 had an 
outcome reported as normal delivery. One subject delivered a live infant with a 
congenital anomaly (trigonocephaly) approximately 5 days after vaccination. One out of 
the two pregnancies reported retrospectively resulted in the birth of a live infant without
congenital anomaly, the other pregnancy with exposure during the third trimester resulted 
in the birth of a live infant with fetal pleural effusion and cardiomegaly. These events 
were considered as unlikely related to vaccination by the reporting physician.
In 2011, the Advisory Committee on Immunization Practices (ACIP) reviewed published 
and unpublished data from the Vaccine Adverse Event Reporting System, Sanofi Pasteur 
(Adacel) and GSK (Boostrix) pregnancy registries, and small studies [Talbot, 2010; Gall, 
2011] investigating the administration of combined reduced antigen content tetanus 
toxoid, diphtheria toxoid, and acellular pertussis vaccine (Tdap) in pregnancy [Centers for 
Disease Control and Prevention (CDC), 2011a]. ACIP concluded that available data from 
these studies did not suggest any elevated frequency or unusual patterns of adverse events
(AEs) in pregnant women who received Tdap and that the few serious AEs reported were 
unlikely to have been caused by the vaccine. Both tetanus- and diphtheria-toxoid
vaccines (Td) and tetanus toxoid vaccines have been used extensively in pregnant women 
worldwide to prevent neonatal tetanus. Tetanus- and diphtheria toxoid containing 
vaccines administered during pregnancy have not been shown to be teratogenic [Silveria, 
1995; Czeizel, 1999]. From a safety perspective, ACIP concluded that administration of 
Tdap after 20 weeks gestation is preferred to minimize the risk for any low-frequency 
AEs and the possibility that any spurious association might appear causative [CDC, 
2013a; Terranella, 2013].
Pregnancy and birth outcomes in infants born to women who did or did not receive Tdap 
vaccine during pregnancy were assessed in a retrospective cohort study [Shakib, 2013].
The study, ending in 2009, was performed before Tdap administration during pregnancy 
was recommended. From May 2005 through August 2009, 138 women 12-45 years of 
age with documented Tdap administration during pregnancy (cases) were identified at 
Intermountain Healthcare facilities; 552 pregnant women without documentation of Tdap 
immunization were randomly selected as controls. The mean age of pregnant women was 
27 years for both cases (range: 14-40) and controls (range: 14-43) (p = 0.735). Of the
immunized women, 63% received Tdap in the first trimester and 37% in the second or 
third trimester. The incidence of spontaneous or elective abortion was not higher in cases 
than in controls. There were no significant differences in pre-term delivery, gestational 
age, or birth weight between both groups. At least one congenital anomaly was identified 
in 3.7% infants in the exposed group and 4.4% infants in the control group (p = 0.749). In 
 
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infants of exposed women, 3.6% had International Classification of Diseases, Ninth 
Revision, Clinical Modification (ICD-9 CM) diagnoses consistent with complex chronic 
conditions within 12 months compared with 10.4% of infants in the control group (p = 
0.054). The authors concluded that there was no increase in adverse outcomes in infants 
born to women receiving Tdap compared to infants of women in the control group.
7.1.3.
Medical conditions for use
Though the incidences of diphtheria, tetanus and pertussis during childhood have 
decreased with immunization programs, immunity to each of these diseases gradually 
decreases in the absence of administration of booster vaccine doses.
Pertussis is highly contagious (greater than 90% risks of infection have been reported 
among unvaccinated household contacts) and can cause severe disease, particularly 
among very young children. During the pre-vaccination era, pertussis was one of the 
most common childhood diseases and a major cause of infant mortality. Following the 
introduction of vaccines, the number of cases fell dramatically. In the US, the annual 
number of reported cases of pertussis decreased from an average of 175,000 per year 
between 1940 and 1945, to 2900 per year between 1980 and 1990 [CDC, 2012a]. Since 
the 1990s, the number of cases has been gradually increasing [WHO, 2012]. Despite high 
vaccination coverage, outbreaks have been reported in numerous countries including the 
US since 2004. In 2012, 48,277 cases of pertussis were reported in the US, but many 
more go undiagnosed and unreported. In recent years, adolescents and adults have 
accounted for a large proportion of cases of pertussis. In Europe, between 1998 and 2002, 
disease incidence remained steady among infants < 1 year of age; whereas the rate 
doubled in adolescents and adults, from 16% to 35% [Celentano, 2005]. Between 2008 
and 2010, adolescents and adults accounted for more than 50% of all cases in Europe 
[EUVAC.NET, 2008; EUVAC.NET, 2009; EUVAC.NET, 2010]. A similar shift has 
been reported in the US [Murphy, 2008].
Pertussis can be severe in infants and children, but in adults the symptoms tend to be mild 
and indistinguishable from those of other respiratory infections [CDC, 2012a]. However, 
infected adults can still transmit the disease to susceptible individuals, including infants 
who have not completed the full vaccination course. It has been established that siblings 
and adolescent or adult family members with unrecognized pertussis represent the 
primary source of infection to infants [Bisgard, 2004; Jardine, 2009]. The majority of 
patients with pertussis will gradually recover; however, some develop potentially life-
threatening complications, including pneumonia, neurological complications, otitis 
media, anorexia and dehydration. Young infants are most at risk of complications; CDC 
data from 1997 to 2000 found that pneumonia occurred in 5.2% of pertussis cases, but in 
infants younger than 6 months of age it occurred in 11.8% of cases [CDC, 2012a]. 
The occurrence of diphtheria is currently rare in the US primarily because of the high 
level of appropriate vaccination among children and because of an apparent reduction in 
the circulation of toxigenic strains of Corynebacterium diphtheriae. Between 2000 and 
2012, 5 cases of diphtheria were reported in the US. The overall case fatality risk for 
diphtheria is 5-10% with higher risk in persons less than 5 years and older than 40 years 
of age (up to 20%), and has changed very little in the last 50 years [CDC, 2012b]. 
 
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Tetanus is the only vaccine-preventable disease that is infectious, though not contagious.
The incidence of tetanus increases with age due to inadequate booster vaccination in 
countries where immunization programs are implemented [CDC, 2011b]. In the US, 
tetanus has become a disease primarily affecting older adults. Vaccinated mothers confer 
protection to their infants through transplacental transfer of maternal antibody. Neonatal 
tetanus, which is fatal in 25% of affected neonates, occurs among infants born under 
unhygienic conditions to inadequately vaccinated mothers [Hackley, 1999]. In the US, 
233 tetanus cases were reported between 2001 and 2008; among the 197 cases with 
known outcomes, the case-fatality rate was 13.2%. Among all persons with reported 
tetanus, the risk for fatal disease was greater among those aged ≥ 65 years than those 
aged < 65 years [CDC, 2011b].
Originally, Boostrix was licensed in 2005 for persons aged 10 through 18 years. In 2008, 
the US Food and Drug Administration (FDA) approved an expanded age indication for
Boostrix to include persons aged 19 through 64 years. In 2011, the indicated age range 
was further expanded to include persons aged 65 years and older. Boostrix is now 
licensed in the US for use in persons aged 10 years and older as a single-dose booster 
vaccination. For prevention of tetanus, diphtheria, and pertussis, ACIP recommends that 
adolescents and adults receive a one-time booster dose of Tdap. Adolescents aged 11 
through 18 years who have completed the recommended childhood diphtheria and tetanus 
toxoids and whole cell pertussis/ diphtheria and tetanus toxoids and acellular pertussis 
(DTP/ DTaP) vaccination series should receive a single dose of Tdap instead of Td
vaccine, preferably at a preventive-care visit at the age of 11 or 12 years. For adults aged 
19 through 64 years who previously have not received a dose of Tdap, a single dose of 
Tdap should replace a single decennial Td booster dose [CDC, 2011c]. Vaccination with 
Tdap is recommended for all adults aged 65 years and older [CDC, 2012c]. Tdap can be 
administered regardless of interval since the last tetanus- or diphtheria-toxoid containing 
vaccine. After receipt of Tdap, persons should continue to receive Td for routine booster 
vaccination against tetanus and diphtheria, in accordance with previously published 
guidelines [CDC, 2012c]. 
In response to pertussis epidemics, several Health Authorities from different countries 
(US, United Kingdom [UK], New Zealand, Argentina, etc.) recommended Tdap 
vaccination in pregnancy in order to indirectly protect newborns that are more at risk of 
acquiring pertussis, before they begin the primary vaccination series. In the US, ACIP 
voted on 24 October 2012 to recommend Tdap vaccination in each pregnancy. Maternal 
vaccination programs with Tdap vaccines have also been recommended by Public Health 
Authorities in a number of other countries (Switzerland, Mexico, Brazil, Argentina, 
Ireland, UK, and Pan American Health Organization) [CDC, 2013a; HPA, 2013a]. The 
UK Health Protection Agency is currently evaluating the effectiveness of maternal 
immunization. A pertussis vaccination program for pregnant women was introduced on 
01 October 2012 and pregnant women were offered a 5-component acellular pertussis 
containing vaccine (diphtheria-tetanus-acellular pertussis-inactivated polio) between 28 
and 38 weeks of gestation. Between October 2012 and June 2013, the uptake of pertussis 
vaccine in pregnant women in the UK was approximately 50%; there has been a slight 
decline in uptake during 2013 [HPA, 2013b]. Surveillance data captured until end of July 
2013, 9 months after initiation of the vaccination program, were presented recently. 
These data show that the target population of women is strongly supportive of 
 
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immunization against pertussis in pregnancy. Since October 2012 pertussis activity has 
fallen, especially in infants aged less than 3 months of age. Early calculations of 
programme effectiveness are high and safety data are reassuring [Campbell, 2013].
7.1.4.
Characteristics of exposure
Women can be intentionally or unintentionally exposed to vaccines during pregnancy. In 
general, the women are closely monitored throughout the remainder of the pregnancy.
Refer to Section 9.2.1.2 for potential annual exposure in pregnant women.
7.1.5.
Potential benefits of product
No clinical data on the safety or immunogenicity of the use of Boostrix during pregnancy 
or lactation have been generated. It is generally accepted that inactivated vaccines pose 
no risk to the pregnant or lactating woman [CDC, 2011d]. In the absence of supporting 
data, Boostrix should only be administered to pregnant women when clearly needed, and 
when the possible benefit outweighs the possible risks to the fetus. In the US, Tdap 
vaccination is recommended by ACIP in each pregnancy ([CDC, 2013a], see Section 
7.1.3).
7.2.
Rationale (Amended on 05 October 2017)
The purpose of this Registry is to detect and describe any abnormal pregnancy outcomes, 
including teratogenicity, in females intentionally or unintentionally exposed to Boostrix 
during their pregnancies or within 28 days preceding conception. The combination of the 
large number of women who are of reproductive capacity and may be exposed to tetanus, 
diphtheria, and pertussis; and the lack of data concerning exposure to Boostrix during 
pregnancy makes such a Registry an important component of the ongoing effort to assess 
the safety of Boostrix. The Registry was originally initiated on 03 May 2005, as part of a 
program of enhanced pharmacovigilance. Following new European Union 
Pharmacovigilance legislation, pregnancy registries are to be considered as PASS. The 
ongoing Registry is therefore converted into a PASS in Q1 2014. 
The Registry requires voluntary, prospective reporting of eligible pregnancies by patients 
and HCPs. Patient confidentiality is strictly maintained. The intent of the Registry is to 
prospectively collect data describing exposure to Boostrix immediately before or during 
pregnancy, potential confounding factors (such as exposure to other medications), and 
information related to the outcome of the pregnancy.
 
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8.
RESEARCH QUESTION AND OBJECTIVES 
8.1.
Co-primary objectives

To describe the characteristics of registered pregnancies (women vaccinated with 
Boostrix during pregnancy or within 28 days preceding conception) with any 
abnormal pregnancy outcomes.

To assess the proportion of registered pregnancies (women vaccinated with 
Boostrix during pregnancy or within 28 days preceding conception) with any 
abnormal pregnancy outcomes.
Refer to Section 9.3.1 for the definition of the primary endpoint.
9.
RESEARCH METHODS
9.1.
Study design
9.1.1.
Overview (Amended on 05 October 2017)

This study is a transition of an ongoing pregnancy registry (starting on 03 May 
2005) into a PASS. 

This is a prospective*, observational, exploratory, cohort study. The Boostrix
pregnancy registry study requires voluntary, prospective reporting of eligible 
pregnancies by patients and HCPs. Data such as vaccination with Boostrix during 
pregnancy or within 28 days preceding conception, potential confounding factors 
(such as exposure to other medications) and information related to the outcome of the 
pregnancy will be collected prospectively**.
* Exposed pregnancies reported to the Registry before the transition into a PASS 
(between 03 May 2005 and Q1 2014), from which data were collected and analyzed 
prospectively, will also be included in the analyses.

** Some pregnancy exposures may be reported after pregnancy outcome has been 
identified (retrospective reports). The Registry will capture retrospective reports, but 
these reports will not be included in the analyses of prospective reports.

Study population: pregnant women, vaccinated with Boostrix during pregnancy or 
within 28 days preceding conception, volunteering to take part in the study.

Type of study: self-contained.

Data collection: initial and follow-up data will be collected using questionnaires.
Data for enrollment will be collected using the Initial Notification Form.
Follow-up of cases is performed within 2 months of the estimated date of 
delivery (EDD) to ascertain pregnancy outcome (through the Pregnancy 
Outcome Form) and approximately 6 months and 12 months after the EDD (for all 
live births for whom the contact details of their HCP will be available) to ascertain 
 
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the presence of birth defects not diagnosed before (through the 6- and 12-month 
post-delivery Follow-Up Form).

After transition of the ongoing pregnancy registry into a PASS, data will be collected 
for a minimum of 5 years, starting Q1 2014.
9.1.2.
Rationale for study design 
This prospective cohort study is designed as a Registry. After market authorization, AEs
that occur after administration of the vaccine can and should always be reported. In that 
case, however, there is no clear group in which the events occur and so a proper rate of 
occurrence cannot be estimated. In this pregnancy registry, participants are recruited 
between administration of the vaccine and the potential occurrence of an AE (i.e., a 
teratogenic effect in the offspring). This allows for a more proper estimation of the rate of 
occurrence of these events. Nevertheless, the results of this study still need to be regarded 
with caution as the exact number of women exposed during pregnancy is unknown. 
Incidences of events can therefore not be calculated from the study data. 
Furthermore, it is likely that pregnant women who accept vaccination may differ from 
those who refuse vaccination in underlying health status, propensity to seek medical care, 
propensity to report AEs and differences in access to medical care in general. The 
differential response/participation by vaccinated versus unvaccinated pregnant women in 
a pregnancy registry could significantly bias risk estimates and possibly in unpredictable 
ways, because of the inability to collect adequate data to characterize the non-responders. 
Therefore, the risks of any identified birth defects will be compared to those in the 
general population, such as that defined by the Metropolitan Atlanta Congenital Defects 
Program (MACDP).
9.2.
Setting
9.2.1.
Study population
9.2.1.1.
Patient population
In the US, Boostrix is indicated for active booster immunization against tetanus, 
diphtheria, and pertussis. Originally licensed for persons aged 10 through 18 years, the 
vaccine was approved by the FDA for use in persons aged 19 through 64 years in 2008, 
and in persons aged 65 years and older in 2011. 
The study population includes women vaccinated with Boostrix during pregnancy or 
within 28 days preceding conception.
 
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9.2.1.2.
Potential annual exposure
Size of the potential “at-risk” population
The US Census Bureau estimates that, as of 1 July 2012, the resident US female 
population was 62,744,930 between the ages of 15 and 44 years old [US Census Bureau, 
2013]. The provisional fertility rate in the US in 2012 was 63.2 births per 1000 
women aged 15-44 years and the provisional count of births was 3.96 millions [CDC, 
2012d].
Number of pregnant vaccinees
Boostrix was originally classified as FDA Pregnancy Category C, which was changed to 
Category B in September 2012, as a study of developmental toxicity in female rats
showed no key safety concerns. Pregnancy Category B means that animal reproduction 
studies have failed to demonstrate a risk to the fetus and there are no adequate and well-
controlled studies in pregnant women. Since February 2013, Boostrix vaccination is 
recommended by the ACIP in each pregnancy.
More than 20 million doses of Boostrix were distributed in the US between May 2005 
and July 2011. Experiences with the ongoing Boostrix pregnancy registry (391 exposed 
pregnancies reported prospectively and five exposed pregnancies reported retrospectively 
between 03 May 2005 and 02 August 2013) and other vaccine pregnancy registries (e.g., 
smallpox vaccine [CDC, 2003], varicella vaccine [Shields, 2001], and Twinrix) indicate 
that it is likely that fewer than 100 pregnancies per year will be registered.
9.2.2.
Patient recruitment (Amended on 05 October 2017)
Reporting of vaccine-exposed pregnancies to the Registry is voluntary. Since the 
initiation of the Registry in 2005, GSK has taken several measures to increase the rate of 
pregnancy registration (accrual). A GSK Registry web page has been created with 
instructions for enrolling patients in the Registry and GSK has requested that the FDA 
post a link to this web page on their Pregnancy Registry Website. The forms for 
enrolling and reporting outcomes are also accessible to healthcare providers through 
the GSK Registry web page. In response to a 2008 request from the FDA to facilitate 
enrollment, GSK initiated a dedicated toll-free telephone number (
), at 
which US-based callers can receive assistance in the registration of pregnancies. Notice 
of this new toll-free number was posted on the GSK web page in January 2009; the new 
toll-free number was added to the US Prescribing Information in early 2009. The 
Prescribing Information and GSK Registry website each give a brief summary of the 
purpose and intent of the Registry, along with telephone contact information. Fax contact 
information is available on the GSK Registry web page.
9.2.3.
Selection of a comparison group
This registry study is a prospective cohort study. Active enrollment of a valid internal 
comparison group is not feasible. The outcomes of the study will be assessed against 
known rates from an external reference group for the likelihood of a safety signal 
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warranting further investigation. Background risks from existing, external systems (e.g., 
the National Birth Defects Prevention Network and the National Center for Health 
Statistics) will be used.
9.2.4.
Study period (Amended on 05 October 2017)
The Registry was originally initiated on 03 May 2005, as part of a program of enhanced 
pharmacovigilance, and converted into a PASS in Q1 2014. GSK plans to continue the 
Registry for a minimum of 5 years, starting Q1 2014. After submission of the final 
report, GSK will continue the Registry pending CBER review of the report and 
determination whether the Registry can be discontinued.
9.2.5.
Inclusion criteria
A subject will be included in the Registry if all of the following criteria are met:

Exposure to vaccine occurs during pregnancy or within 28 days preceding 
conception.

Subject is a US resident.

A HCP is identified (name, address and phone number).

Subject can be identified (by GSK or HCP).
Data from registered subjects will be included in the analyses if the following criterion is 
met:

Pregnancy is ongoing and the outcome is unknown.
9.2.6.
Exclusion criterion
Data from registered subjects will not be included in the analyses if the following 
criterion is met:

Outcome of pregnancy is known at the time of initial report. Types of known 
outcomes include prenatal testing reports in which the results are abnormal or 
outside the reference range, indicating possible abnormality in the fetus. Typically,
pregnancies > 16 weeks gestation will have undergone prenatal testing that can 
identify whether a child has congenital abnormalities.
 
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9.3.
Variables
9.3.1.
Primary endpoint

Occurrence of any abnormal pregnancy outcomes in women intentionally or 
unintentionally vaccinated with Boostrix during pregnancy or within 28 days 
preceding conception.
9.3.2.
Data to be collected (Amended 05 October 2017)
Initial and follow-up data will be collected using questionnaires. Data for enrollment 
will be collected using the Initial Notification Form. Follow-up of cases is 
performed within 2 months of the estimated date of delivery (EDD) to ascertain 
pregnancy outcome (through the Pregnancy Outcome Form) and approximately 6 
months and 12 months after the EDD (for all live births for whom the contact details of 
their HCP will be available) to ascertain the presence of birth defects not diagnosed 
before (through the 6- and 12-month post-delivery Follow-Up Form). The following 
data will be collected:

Patient identifier.

Maternal data, including date of birth, date of last menstrual period (LMP), 
EDD.

Maternal relevant medical/family history.

Paternal relevant medical/family history.

Type of conception.

Prenatal testing.

Maternal prenatal drug/vaccine exposure, including drug/vaccine name, date of 
administration, route of administration, dose, lot number, indication.

Pregnancy outcome.

Method of delivery.

Infant/fetal information, including gestational weeks at birth/miscarriage/ 
termination, gender, length, weight, Apgar score.

Description of birth defects, if applicable.

AEs experienced by the fetus/infant or the mother.

Reporter information.

Any additional data that seems relevant for this study.
 
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9.4.
Data sources (Amended on 05 October 2017)
Reporting of vaccine-exposed pregnancies to the Registry is voluntary. Registration 
can be initiated from a HCP or from a consumer, in which case permission is 
requested to obtain confirmation and follow-up from their HCP. Follow-up from the 
HCP of the infant post birth 6 and 12 months will be performed when the contact 
details are available and with consumer’s permission. A toll-free telephone number 
for reporting AEs and vaccine-exposed pregnancies to the Registry is listed in the 
product information leaflet and on the GSK Registry website. Retrospective post-
marketing reports and relevant scientific publications are potential sources of 
supplementary information.
9.5.
Study size
No minimum sample size is required for this descriptive study.
Refer to Section 9.2.1.2 for the size of the potential “at-risk” population and the 
number of pregnant vaccinees.
9.6.
Data management
9.6.1.
Data collection (Amended on 05 October 2017)
Initial and follow-up data will be collected using questionnaires. Initial data will be 
collected before the outcome is known. Follow-up of cases will be performed at the 
following timepoints:

For consumer reports:

At initial notification of pregnancy exposure: 2 attempts at 4-6 week 
intervals will be made to obtain more information about the pregnancy 
(e.g. estimated time of delivery (EDD) and/or last menstrual period (LMP) 
and to obtain permission to contact the patient’s HCP

Within 2 months after EDD, 1 additional attempt is made if permission to 
contact the patient’s HCP has not already been granted to obtain more 
information about the pregnancy and obtain the permission to contact the 
patient’s HCP.

Within 2 months after EDD (and if the patient has not previously provided 
the contact information for the infant’s HCP): 2 attempts at 4-6 week 
intervals will be made for the prospective cases reporting a live birth to 
obtain the contact information of the HCP supervising the health of the 
infant.
 
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
For the HCP reports:

At initial notification of pregnancy exposure or once permission has been 
granted for reports initially received from a consumer, two attempts at 4-6 
week intervals will be made to obtain more information via pregnancy 
follow-up form.

Within 2 months of the EDD, to ascertain outcome. Two follow-up attempts 
to obtain outcome information will be made before any case is considered lost 
to follow-up.

An additional follow-up attempt will be done for the live births approximately 6 
months and 12 months after the EDD to ascertain the presence of birth defects 
not diagnosed at the time of the initial pregnancy outcome. This follow-up will 
be done for the prospective reports if the consumer has granted the permission
and when the contact details of the HCP attending the infant are available.
9.6.2.
Processing of reports (Amended on 05 October 2017)
Reports are entered into the GSK safety database by GSK Case Management Group
(CMG) using existing mechanisms and practices. Medical Dictionary for Regulatory 
Activities (MedDRA) is used in the database to code AEs.
Follow-up is conducted by CMG. The HCP is contacted if she/he requests or if initial 
information is insufficient or needs clarification. The follow-up of cases is performed 
as described in section 9.6.1.
9.6.2.1.
Solicitation of outcome (Amended on 05 October 2017)
As explained in section 9.6.1, within two months after the EDD and if the HCP has not 
already provided the pregnancy outcome, she/he is sent an outcome form 
(questionnaire). The mode of communication is generally via standard letter.
Two attempts are made to secure the outcome information from the HCP via standard 
letter. For the live births and with the mother’s permission, attempts are made to solicit 
information from the pediatrician and/or other specialists who have provided 
healthcare/consultation to the child until 12 months of age.
9.6.2.2.
Classification of outcomes (Amended 05 October 2017)
This Registry uses the term ‘birth defects’ for outcomes sometimes referred to as 
‘congenital anomalies’. For purposes of analysis, pregnancy outcomes are 
dichotomized according to the presence or absence of birth defects. Pregnancy 
outcomes are further categorized as: 1) live births, 2) spontaneous abortions (i.e., 
pregnancy losses), 3) Elective/induced abortions and 4) Fetal deaths/Stillbirths. 
This Registry adopts a definition of a child with a birth defect as any live or stillborn 
neonate with a structural or chromosomal abnormality diagnosed before 6 years of age. 
The Registry employs a conservative approach of including all morphologic 
anomalies, including minor ones, as birth defects. 
 
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To provide consistency in the definitions of major defects in this Registry, CDC 
MACDP criteria are used for the classification of defects [CDC, 2008; Correa-Villasenor, 
2003]. Some of the conditions excluded from the MACDP criteria for major structural 
defects may actually have major clinical, functional, or genetic significance. Therefore, 
minor malformations not appearing in the CDC inclusion list may be classified as birth 
defects in this Registry. In addition, CDC guidelines disqualify as defects those findings 
that are present in infants delivered at less than 36 weeks of gestation and are attributable 
to prematurity itself, such as a patent ductus arteriosus or inguinal hernias. Infants with 
infectious conditions (e.g., neonatal sepsis) or isolated biochemical abnormalities (e.g., 
hyperbilirubinemia) are classified as being without birth defects unless there is a 
possibility that the condition reflects an unrecognized congenital abnormality. All other 
congenital abnormalities are included in the ‘birth defects’ category, regardless of 
whether the neonate is delivered alive, including structural defects in neonates delivered 
prior to 20 weeks of gestation or weighing less than 500 g.
9.7.
Data analysis (Amended on 05 October 2017)
Pregnancy outcomes include spontaneous abortion (pregnancy loss before 22 weeks 
gestation), fetal deaths/stillbirths (loss at or after 22 weeks gestation), 
elective/induced abortions and live births. Gestational weeks are counted from the 
date of the LMP. The second trimester is considered to begin at week 14 and the third 
trimester begins at week 28. The presence or absence of birth defects or other 
abnormalities is evaluated within each of the preceding outcome categories.
Pregnancy outcomes are stratified by the trimester of exposure, with an additional 
stratum for preconception exposure with no subsequent administration of vaccine during 
pregnancy. Reports of multiple exposures during a pregnancy (i.e., multiple 
administrations of Boostrix) are classified by the earliest trimester of exposure. When 
exposure occurs before and after conception, the exposure is classified by the dose 
administered after conception. The calculations of risk for birth defects are made by 
dividing the number of infants with birth defects by the total number of infants with and 
without birth defects. Given the descriptive nature of this study, confidence intervals
will not be calculated. The outcomes of the study will be assessed against known rates 
from an external reference group for the likelihood of a safety signal warranting further 
investigation.
The majority of spontaneous abortions occur early in pregnancy [Wilcox, 1981;
Wilcox, 1983; Ellish, 1996]. If spontaneous abortions were to be evaluated as an 
outcome of interest, it would be essential to enroll pregnancies as soon as possible after 
vaccination with Boostrix. Because enrollment and recognition of pregnancy would 
occur at various times, it would be virtually impossible to meaningfully evaluate the 
effects of Boostrix on pregnancy loss [Kennedy, 2004]. Therefore, spontaneous 
abortions without birth defects are excluded from the risk calculations. 
The risk in the general population of all birth defects meeting CDC criteria is 
approximately 3% (1 of 33) of live births [CDC, 2013b]. The estimated risk cited in the 
medical literature varies because of differences in case definitions, populations sampled 
and ascertainment methods. The Collaborative Perinatal Project, using a broader case 
 
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definition and prospective ascertainment, reports a frequency of 5% to 7% [Chung, 
1975]. Most major structural defects originate during the first trimester of pregnancy, 
which is the critical time for organogenesis [CDC, 2013b]. For such defects, exposures 
occurring in the second or third trimester are not likely to be causally associated. 
However, for the sake of completeness and to enable the assessment of possible increases 
in the frequency of birth defects, all defects will be included in the periodic summary 
reports of this Registry.
Criteria for review of a specific individual report include:

Is the timing of the vaccination with Boostrix commensurate with the 
ontogenetic development of the organ(s) affected by the abnormalities?

Is there another known or likely cause (e.g., pre-existing genetic or chromosomal 
defect or exposure to a known teratogen)?

Is the congenital abnormality not previously described (i.e., is it new to medical 
science)? 

Is there a unique constellation of defects (i.e., is there a new syndrome)?
Criteria for review of aggregate data include:

Is there a deviation from the expected frequency of all defects indicating an 
increase in the overall risk of defects?

Is there a deviation from the expected frequencies of individual defects?

Is there uniqueness (e.g., a pattern) of the abnormalities that is suggestive of a common 
etiology?
Studies have shown that the risk of spontaneous abortion is high early in pregnancy and 
decreases substantially from week 8 to week 28, yielding a cumulative estimated risk of 
10% to 22% [Wilcox, 1981; Wilcox, 1983; Wilcox, 1988; Fenster, 1997; Windham, 
1997; Khattak, 1999; Anderson, 2000; Osborn, 2000].
While the Registry is to be limited to prospective reports, some pregnancy exposures are 
reported after pregnancy outcome has been identified (retrospective reports). The 
Registry will capture retrospective reports, but these reports will not be included in the 
analyses of prospective reports. In general, retrospective notification of outcomes 
following exposure to drugs or vaccines is biased toward reporting the severe and 
unusual cases and is not reflective of the general experience with the drug. Information 
about the total number of exposed pregnancies, i.e., the pool of exposures from which the 
retrospective reports arise, is unknown; therefore, incidences of outcomes cannot be 
calculated from these data. A series of reported birth defects, however, can be analyzed to 
detect patterns of specific congenital abnormalities and can identify early signals of new 
vaccine-associated risks. A section of each periodic summary report, separate from the 
analysis of prospective reports, will describe all abnormal outcomes of retrospectively 
reported cases.
 
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Exposed pregnancies reported to the Registry before the transition into a PASS (between 
03 May 2005 and Q1 2014), from which data were collected and analyzed prospectively, 
will also be included in the analyses.
9.8.
Quality control
Data will be recorded using questionnaires. Subject data necessary for analysis, follow-up 
and reporting will be entered/transmitted into a validated database or data system. Data 
management will be performed in accordance with applicable GSK standards.
To ensure compliance with Good Clinical Practice (GCP) and all other applicable 
guidelines and regulatory requirements, GSK may conduct a quality assurance audit. 
Regulatory agencies may also conduct a regulatory inspection of this study. Such 
audits/inspections can occur at any time during or after completion of the study.
9.9.
Limitations of the research methods
This Registry is a prospective cohort study. Active enrollment of a valid internal 
comparison group is not feasible. Therefore, background risks from existing, external 
systems (e.g., the National Birth Defects Prevention Network and the National Center for 
Health Statistics) are used. The potential limitations of comparisons between Registry 
and background data depend upon the event(s) being compared and will be discussed on 
an ad hoc basis in the relevant periodic Registry reports.
Potential sources of biases are described below:

As reporting of pregnancies is voluntary, it is possible that even among prospectively 
reported pregnancies there could be bias in type of pregnancies which are reported. 
For example, high-risk pregnancies may be more likely to be reported.

The calculation of risk, which does not include spontaneous abortions or voluntary 
terminations for which no defects have been reported, may introduce bias. It is 
unknown what proportions of these pregnancies consist of potentially normal 
outcomes versus congenital abnormalities. GSK attempts to obtain information on 
anomalies detected at the time of the outcome, but this may not be known to the 
reporting physician.

Those pregnancies that have reached EDD but for which outcome information was 
unobtainable are considered lost to follow-up. It is possible that outcomes among 
pregnancies lost to follow-up could differ from those with documented outcomes. 
All attempts are made to minimize this potential source of bias.
Refer to Section 9.1.2 for other potential limitations of the study.
 
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10.
PROTECTION OF HUMAN SUBJECTS
10.1.
Regulatory and ethical considerations, including the 
informed consent process
The study will be conducted in accordance with the International Conference on 
Harmonization (ICH) Guideline for GCP or other applicable guidelines, all applicable 
subject privacy requirements and the guiding principles of the Declaration of Helsinki.
The study has been designed and will be conducted in accordance with the ICH 
Harmonized Tripartite Guideline for clinical investigation of medicinal products in the 
pediatric population (ICH E11) and all other applicable ethical guidelines.
GSK will obtain favorable opinion/approval to conduct the study prior to study start or 
will document that neither a favorable opinion nor an approval to conduct the study is 
needed.
Conduct of the study includes, but is not limited to, the following:

Institutional Review Board review and favorable opinion/approval of study protocol 
and any subsequent amendments;

Institutional Review Board review and favorable opinion/approval of waiver for 
documentation of informed consent.
11.
MANAGEMENT AND REPORTING OF ADVERSE 
EVENTS/ADVERSE REACTIONS 
Reporting of vaccine-exposed pregnancies to the Registry is voluntary. All reports 
received by the Registry will be entered into the GSK safety database and reported to 
regulatory authorities according to applicable regulations.
12.
PLANS FOR DISSEMINATING AND COMMUNICATING 
STUDY RESULTS (AMENDED ON 05 OCTOBER 2017)
Study information from this protocol will be posted on publicly available clinical trial 
registers following finalization of the protocol and, whenever possible, before initiation 
of the study.
GSK plans to continue the Registry for 5 years. Summary reports will be written annually
and will be submitted with the Periodic Benefit-Risk Evaluation Report and the DSUR
for Boostrix. A final report will be written and submitted within one year of completion 
of the five-year period as described in Section 6. After submission of the final report, 
GSK will continue the Registry pending CBER review of the report and determination 
whether the Registry can be discontinued.
 
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Summary results of observational studies that are designed to inform the safety or 
effectiveness, including cost-effectiveness, of GSK vaccines/products as used in ordinary 
clinical practice are publicly registered within 12 months of completion of the analysis. 
GSK also aims to publish the results of these studies in the indexed, peer reviewed 
scientific literature; manuscripts are submitted within 18 months of the completion of the 
analysis.
13.
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in Adults Aged 65 Years and Older - Advisory Committee on Immunization Practices 
(ACIP), 2012. MMWR. 2012(c); 61(25): 468-470.
Centers for Disease Control and Prevention (CDC). Recent Trends in Births and Fertility 
Rates Through December 2012(d). 
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december_2012.htm. Accessed: 27 November 2013.
Centers for Disease Control and Prevention (CDC). Updated recommendations for use of 
tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine (Tdap) in 
pregnant women--Advisory Committee on Immunization Practices (ACIP), 2012. 
MMWR. 2013(a); 62(7): 131-135. 
Centers for Disease Control and Prevention (CDC). Birth defects. 
http://www.cdc.gov/ncbddd/birthdefects/facts.html. Accessed: 27 November 2013(b).
Chung CS, Myrianthopoulos NC. Factors affecting risks of congenital malformations: 
Reports from the Collaborative Perinatal Project. Birth Defects Original Article Series. 
1975; 11 (10).
Correa-Villasenor A, Cragan J, Kucik J, O'Leary L, Siffel C, Williams L. The 
Metropolitan Atlanta Congenital Defects Program: 35 years of birth defects surveillance 
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67: 617-24. 
Czeizel AE, Rockenbauer M. Tetanus toxoid and congenital abnormalities. Int J Gynecol 
Obstet. 1999; 64: 253-258.
Ellish NJ, Saboda K, O'Connor J, et al. A prospective study of early pregnancy loss. Hum 
Reprod. 1996; 11: 406-12. 
EMA 2006. 
http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural
_guideline/2009/11/WC500011303.pdf. Accessed on 05 October 2017.
 
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European surveillance network for vaccine-preventable diseases (EUVAC.NET). 
Pertussis surveillance report 2008. 
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European surveillance network for vaccine-preventable diseases (EUVAC.NET). 
Pertussis surveillance annual report 2009. 
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European surveillance network for vaccine-preventable diseases (EUVAC.NET). 
Pertussis surveillance report 2010. 
http://www.euvac.net/graphics/euvac/pdf/pertussis_2010.pdf. 
Fenster L, Hubbard AE, Windham GC, Waller KO, Swan SH. A prospective study of 
work-related physical exertion and abortion. Epidemiology. 1997; 8: 66-74. 
Gall SA, Myers J, Pichichero M. Maternal immunization with tetanus-diphtheria-
pertussis vaccine: effect on maternal and neonatal serum antibody levels. Am J Obstet 
Gynecol. 2011; 204: 334.e-5.
GlaxoSmithKline Biologicals Clinical Study Report HLS HEY0017. Boostrix, Boostrix-
IPV and Boostrix US Vaccines: Study for Effects on Fertility, Embryo-fetal and Pre- and 
Postnatal Development in the CD Rat by Intramuscular Administration (including Pre-
mating Immunisation phase). 
GlaxoSmithKline Biologicals Clinical Study Report HLS HEY0018. Boostrix Vaccines: 
Study for Effects on Female Fertility and Embryo-Fetal Development in the New Zealand 
White Rabbit by Intramuscular Administration (Including Pre-Mating Immunisation 
Phase). 
Hackley BK. Immunizations in Pregnancy: A Public Health Perspective. Journal of 
Nurse-Midwifery. 1999; 44(2): 106-117. 
Health Protection Agency (HPA). Questions and answers - Pertussis vaccination 
programme for pregnant women. Updated 11 February 2013(a). 
http://www.hpa.org.uk/Topics/InfectiousDiseases/InfectionsAZ/WhoopingCough/Immun
isationForPregnantWomen/whooqandaPertussisVaccinationProgrammeforPregnantWom/
Accessed: 27 November 2013.
Health Protection Agency (HPA). Pertussis Vaccination Programme for Pregnant 
Women: vaccine coverage estimates in England, October 2012 to June 2013. Health 
Protection Report. 2013(b); 7(40). http://www.hpa.org.uk/hpr/archives/2013/hpr4013.pdf. 
Jardine A, Conaty SJ, Lowbridge C, et al. Who gives pertussis to infants? Source of 
infection for laboratory confirmed cases less than 12 months of age during an epidemic, 
Sydney, 2009. Commun Dis Intell. 2010; 34(2): 116-121.
http://www.health.gov.au/internet/main/publishing.nsf/Content/cdi3402-1. Accessed: 09 
December 2013.
 
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Kennedy DL, Uhl K, Kweder SJ. Pregnancy exposure registries. Drug Safety. 2004; 27:
215-228. 
Khattak S, K-Moghtader G, McMartin K, Barrera M, Kennedy D, Koren G. Pregnancy 
outcome following gestational exposure to organic solvents. JAMA. 1999; 281: 1106-
1109. 
Murphy TV, Slade BA, Broder KR, et al. Prevention of pertussis, tetanus, and diphtheria 
among pregnant and postpartum women and their infants. Recommendations of the 
Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2008; 
57(RR-4): 1-51.
Osborn JF, Cattaruzza MS, Spinelli A. Risk of spontaneous abortion in Italy, 1978-1995, 
and the effect of maternal age, gravity, marital status and education. Am J Epidemiol. 
2000; 151: 98-105. 
Shakib JH, Korgenski K, Sheng X, Varner MW, Pavia AT, Byington CL. Tetanus, 
diphtheria, acellular pertussis vaccine during pregnancy: Pregnancy and infant health 
outcomes. J Pediatrics. 2013; 163: 5 (1422-1426.e4).
Shields KE, Galil K, Seward J, Sharrar RG, Cordero JF, Slater E. Varicella vaccine 
exposure during pregnancy: Data from the first 5 years of the Pregnancy Registry. Obstet 
Gynecol. 2001; 98: 14-19. 
Silveria CM, Caceres VM, Dutra MG, Lopes-Camelo J, Castilla EE. Safety of tetanus 
toxoid in pregnant women: a hospital-based case-control study of congenital anomalies. 
Bull World Health Organ. 1995; 73: 605-608.
Talbot EA, Brown KH, Kirkland, KB, Baughman AL, Halperin SA, Broder KP. The 
safety of immunizing with tetanus-diphtheria-acellular pertussis vaccine (Tdap) less than 
2 years following previous tetanus vaccination: experience during a mass vaccination 
campaign of healthcare personnel during a respiratory illness outbreak. Vaccine. 2010; 
28: 8001-8007.
Terranella A, Asay GR, Messonnier ML, Clark TA, Liang JL. Pregnancy dose Tdap and 
postpartum cocooning to prevent infant pertussis: a decision analysis. Pediatrics. 2013;
131(6): e1748-1756.
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Estimates of the Resident Population for Selected Age Groups by Sex: April 1, 2010 to 
July 1, 2012. Release date June 2013. 
http://www.census.gov/popest/data/national/asrh/2012/index.html. Accessed: 27 
November 2013.
Wilcox AJ, Treloar AE, Sandler DP. Spontaneous abortion over time: comparing 
occurrence in two cohorts of women a generation apart. Am J Epidemiol. 1981; 114: 548-
553. 
 
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Wilcox AJ. Surveillance of pregnancy loss in human populations. Amer J Industr Med. 
1983; 4: 285-291. 
Wilcox AJ, Weinberg CR, O'Connor JF, et al. Incidence of early loss of pregnancy. New 
Engl J Med. 1988; 319: 189-194.
Windham GC, Von Behren J, Fenster L, Schaefer C, Swan SH. Moderate maternal 
alcohol consumption and risk of spontaneous abortion. Epidemiology. 1997; 8: 509-514. 
World Health Organization (WHO). WHO vaccine-preventable diseases: monitoring 
system - 2012 global summary. Disease incidence. 2012. 
http://apps.who.int/immunization_monitoring/en/globalsummary/timeseries/tsincidencep
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Annex 1
List of stand-alone documents
No.
Document Reference No
Date
Title
1
201327 (EPI-PERTUSSIS-028 VS US PR)
06-MAR-2014
List of stand-alone documents
2
201327 (EPI-PERTUSSIS-028 VS US PR)
06-MAR-2014
ENCePP Checklist for study protocols
3
201327 (EPI-PERTUSSIS-028 VS US PR)
06-MAR-2014
Glossary of terms
4
201327 (EPI-PERTUSSIS-028 VS US PR)
05-OCT-2017
Amendments and administrative changes to 
the protocol
5
201327 (EPI-PERTUSSIS-028 VS US PR)
06-MAR-2014
Trademarks
6
201327 (EPI-PERTUSSIS-028 VS US PR)
06-MAR-2014
Protocol Sponsor Signatory Approval
 
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Annex 2
ENCePP Checklist for study protocols
 
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ENCePP Checklist for study protocols
Section 1: Milestones
Yes
No
N/A
Page 
Number(s)
1.1
Does the protocol specify timelines for 
1.1.1 Start of data collection1
13
1.1.2 End of data collection2
13
1.1.3 Study progress report(s) 
See comments
1.1.4 Interim progress report(s)
13, see 
comments
1.1.5 Registration in the EU PAS register
13, see 
comments
1.1.6 Final report of study results.
13
Comments:
For 1.1.3: no progress reports are planned for this study
For 1.1.4: five annual reports are planned for this study
For 1.1.6: the EU PAS register number will be generated at the time of the final version of the 
protocol.
Section 2: Research question
Yes
No
N/A
Page 
Number(s)
2.1
Does the formulation of the research question 
and objectives clearly explain: 
2.1.1 Why the study is conducted? (e.g. to address an 
important public health concern, a risk identified in the 
risk management plan, an emerging safety issue)
13-18
2.1.2 The objective(s) of the study?
19
                                                
1 Date from which information on the first study is first recorded in the study dataset or, in the case of 
secondary use of data, the date from which data extraction starts.
2 Date from which the analytical dataset is completely available.
 
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Section 2: Research question
Yes
No
N/A
Page 
Number(s)
2.1.3 The target population? (i.e. population or 
subgroup to whom the study results are intended to be 
generalized)
20-21
2.1.4 Which formal hypothesis(-es) is (are) to be 
tested? 
2.1.5 If applicable, that there is no a priori hypothesis?
Comments:
Section 3: Study design
Yes
No
N/A
Page 
Number(s)
3.1
Is the study design described? (e.g. cohort, 
case-control, randomized controlled trial, new or 
alternative design) 
19
3.2
Does the protocol specify the primary and 
secondary (if applicable) endpoint(s) to be investigated?
22
3.3
Does the protocol describe the measure(s) of 
effect? (e.g. relative risk, odds ratio, deaths per 1000 
person-years, absolute risk, excess risk, incidence rate 
ratio, hazard ratio, number needed to harm (NNH) per 
year)
25-27
Comments:
Section 4: Source and study populations
Yes
No
N/A
Page 
Number(s)
4.1
Is the source population described?
23
4.2
Is the planned study population defined in 
terms of:
4.2.1 Study time period?
21
 
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Section 4: Source and study populations
Yes
No
N/A
Page 
Number(s)
4.2.2 Age and sex?
20, 22
4.2.3 Country of origin?
20, 22
4.2.4 Disease/indication? 
16-18
4.2.5 Co-morbidity?
4.2.6 Seasonality?
4.3
Does the protocol define how the study 
population will be sampled from the source population? 
(e.g. event or inclusion/exclusion criteria)  
22
Comments:
Section 5: Exposure definition and 
measurement
Yes
No
N/A
Page 
Number(s)
5.1
Does the protocol describe how exposure is 
defined and measured? (e.g. operational details for 
defining and categorising exposure) 
23-24
5.2
Does the protocol discuss the validity of 
exposure measurement? (e.g. precision, accuracy, 
prospective ascertainment, exposure information 
recorded before the outcome occurred, use of validation 
sub-study)
19, 26
5.3
Is exposure classified according to time 
windows? (e.g. current user, former user, non-use)
25-26
5.4
Is exposure classified based on biological 
mechanism of action and taking into account the 
pharmacokinetics and pharmacodynamics of the drug?
5.5
Does the protocol specify whether a dose-
dependent or duration-dependent response is 
measured?
 
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Comments:
Section 6: Endpoint definition and 
measurement
Yes
No
N/A
Page 
Number(s)
6.1
Does the protocol describe how the endpoints 
are defined and measured? 
19, 22
6.2
Does the protocol discuss the validity of 
endpoint measurement? (e.g. precision, accuracy, 
sensitivity, specificity, positive predictive value, 
prospective or retrospective ascertainment, use of 
validation sub-study)
19, 20, 27
Comments:
Section 7: Confounders and effect modifiers
Yes
No
N/A
Page 
Number(s)
7.1
Does the protocol address known confounders? 
(e.g. collection of data on known confounders, methods 
of controlling for known confounders)
22, 23
7.2
Does the protocol address known effect 
modifiers? (e.g. collection of data on known effect 
modifiers, anticipated direction of effect)
19, 25, 26
Comments:
 
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Yes
No
N/A
Page 
Number(s)
8.1
Does the protocol describe the data source(s) 
used in the study for the ascertainment of:
8.1.1 Exposure? (e.g. pharmacy dispensing, general 
practice prescribing, claims data, self-report, face-to-face 
interview, etc.) 
23, 24
8.1.2 Endpoints? (e.g. clinical records, laboratory 
markers or values, claims data, self-report, patient 
interview including scales and questionnaires, vital 
statistics, etc.)
23, 24
8.1.3 Covariates?
23, 24
8.2
Does the protocol describe the information 
available from the data source(s) on:
8.2.1 Exposure? (e.g. date of dispensing, drug quantity, 
dose,  number of days of supply prescription, daily 
dosage,  prescriber) 
23, 24
8.2.2 Endpoints? (e.g. date of occurrence, multiple 
event, severity measures related to event) 
23, 24
8.2.3 Covariates? (e.g. age, sex, clinical and drug use 
history, co-morbidity, co-medications, life style, etc.)
23, 24
8.3
Is a coding system described for:
8.3.1 Diseases? (e.g. International Classification of 
Diseases (ICD)-10)
8.3.2 Endpoints? (e.g. Medical Dictionary for Regulatory 
Activities (MedDRA) for adverse events)
24
8.3.3 Exposure? (e.g. WHO Drug Dictionary, Anatomical 
Therapeutic Chemical (ATC)Classification System)
8.4
Is the linkage method between data sources 
described? (e.g. based on a unique identifier or other) 
Comments:
 
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Yes
No
N/A
Page 
Number(s)
9.1
Is sample size and/or statistical power 
calculated? 
See 
comments
Comments:
For 9.1: This is an exploratory/descriptive study. No minimum sample size is required. Reference 
pages 20 and 24 of the protocol.
Section 10: Analysis plan
Yes
No
N/A
Page 
Number(s)
10.1
Does the plan include measurement of excess 
risks?
10.2
Is the choice of statistical techniques 
described? 
25-26
10.3
Are descriptive analyses included?
25-26
10.4
Are stratified analyses included?
25-26
10.5
Does the plan describe methods for adjusting 
for confounding?
25-26
10.6
Does the plan describe methods addressing 
effect modification?
Comments:
Section 11: Data management and quality 
control
Yes
No
N/A
Page 
Number(s)
11.1
Is information provided on the management of 
missing data?
11.2
Does the protocol provide information on data 
storage? (e.g. software and IT environment, database 
maintenance and anti-fraud protection, archiving)
24, 27, 28
11.3
Are methods of quality assurance described?
27
 
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control
Yes
No
N/A
Page 
Number(s)
11.4 
Does the protocol describe possible quality 
issues related to the data source(s)?
11.5
Is there a system in place for independent review 
of study results? 
Comments:
Section 12: Limitations
Yes
No
N/A
Page 
Number(s)
12.1
Does the protocol discuss:
12.1.1 Selection biases?
20, 27
12.1.2 Information biases?
(e.g. anticipated direction and magnitude of such 
biases, validation sub-study, use of validation and 
external data, analytical methods)
20, 27
12.2
Does the protocol discuss study feasibility? 
(e.g. sample size, anticipated exposure, duration of 
follow-up in a cohort study, patient recruitment)
20, 21, 23
12.3 Does the protocol address other limitations? 
20, 27
Comments:
Section 13: Ethical issues
Yes
No
N/A
Page 
Number(s)
13.1
Have requirements of Ethics 
Committee/Institutional Review Board approval been 
described?
27, 28
13.2
Has any outcome of an ethical review 
procedure been addressed?
 
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Yes
No
N/A
Page 
Number(s)
13.3
Have data protection requirements been 
described?
27, 28
Comments:
Section 14: Amendments and deviations
Yes
No
N/A
Page 
Number(s)
14.1
Does the protocol include a section to 
document future amendments and deviations? 
13
Comments:
Section 15: Plans for communication of study 
results
Yes
No
N/A
Page 
Number(s)
15.1
Are plans described for communicating study 
results (e.g. to regulatory authorities)? 
28
15.2
Are plans described for disseminating study 
results externally, including publication?
28
Comments:
Name of the main author of the protocol: 
Date: 
/
/
Signature: ___________________________
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Annex 3
Glossary of terms
Adverse event:
Any untoward medical occurrence in a subject, 
temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal 
product, or temporally associated with a study procedure.
An AE can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding), 
symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal product. For 
marketed medicinal products, this also includes failure to 
produce expected benefits (i.e., lack of efficacy), abuse or 
misuse.
Cohort study:
A form of epidemiological study where subjects in a 
study population are classified according to their 
exposure status/disease and followed over time 
(prospective/ retrospective) to ascertain the outcome(s). 
Eligible:
Qualified for enrollment into the study based upon strict 
adherence to inclusion/exclusion criteria.
eTrack:
GSK Biologicals’ tracking tool for clinical/ 
epidemiological trials.
Non-interventional 
(observational) Human 
Subject Research:
Studies where medicinal products, should they be 
administered, are prescribed in normal (routine) medical 
practice. No medical care or medical/scientific procedures 
as required in a research protocol are administered to 
participants except as part of routine medical care.
Post-Authorization 
Safety Study (PASS):
A pharmaco-epidemiological study or a clinical trial 
carried out in accordance with the terms of the marketing 
authorization, conducted with the aim of identifying or 
quantifying a safety hazard relating to an authorized 
medicinal product. This includes all GSK sponsored non-
interventional studies and clinical trials conducted 
anywhere in the world that are in accordance with the 
terms of the European marketing authorization and where 
the investigation of safety is the specific stated objective.
Note: The phrase ‘In accordance with the terms of the 
European marketing authorization’ means that the 
product is used according to the European label (e.g., 
within the recommended dose range, the approved 
formulation, indication etc.).
 
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Prospective study:
A study in which the subjects/cases are identified and 
then followed forward in time in order to address one or 
more study objectives.
Protocol amendment:
The International Conference on Harmonization (ICH) 
defines a protocol amendment as: ‘A written description 
of a change(s) to or formal clarification of a protocol.’ 
GSK Biologicals further details this to include a change 
to an approved protocol that affects the safety of subjects, 
scope of the investigation, study design, or scientific 
integrity of the study.
Research protocol:
A document that describes the objective(s), design, 
methodology, statistical considerations and organization 
of a study. The protocol usually also gives the 
background and rationale for the study, but these could be 
provided in other protocol referenced documents.
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 objectives. 
Self-contained study:
Study with objectives not linked to the data of another 
study.
Study population:
Sample of population of interest.
Subject:
Term used throughout the protocol to denote an 
individual who has been contacted in order to participate 
or participates in the epidemiological study or a person 
about whom some medical information has been recorded 
in a database.
 
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Annex 4
Amendments and administrative changes to the 
protocol
GlaxoSmithKline Biologicals SA
Vaccines R & D 
Protocol Amendment 1
eTrack study number 
and Abbreviated Title:
201327 (EPI-PERTUSSIS-028 VS US PR)
Amendment number:
Amendment 1
Amendment date:
05 October 2017
Co-ordinating author:
, Scientific Writer
Rationale/background for changes: 
The current protocol is being amended to correct the protocol deviations identified,
and describe the data collection and management process to be followed. A summary 
of the amendments done to the protocol is provided below:
Number of Follow -up attempts:
According to the initial version of the protocol, outcomes will be solicited within 3 
months after the expected delivery date (EDD) and “at least 3 attempts to obtain 
outcome information will be made before any case is considered lost to follow-up”.
For this study, two attempts had been made before any case was considered lost to 
follow-up instead of the 3 attempts described in the protocol. The two-attempt follow-
up process is consistent with the GSK standard operating procedures for spontaneous 
pregnancy reports received worldwide. This is considered an acceptable standard 
practice in attempting to obtain follow-up information.
Considering the above rationale, this amendment will reduce the requirement of 3 
follow-up attempts to 2 follow-up attempts to obtain pregnancy outcome data in order 
to reflect current practices. Also, follow-up retrospectively on subjects who have 
already been lost to follow-up after two consecutive attempts to obtain outcome data
is also not recommended in this amendment. By not pursuing a third follow-up 
attempt among lost to follow-up patients, the data collected before and after the 
deviation was consistent and comparable to one-another. Furthermore, the risk of 
recall bias via retrospective data collection is also avoided.
Additionally, data collection section has been updated to describe in more detail the 
initial and follow-up process of data collection for the reports received from 
consumers and HCPs.
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Additional Follow up at 6 and 12 months after EDD:
According to the initial version of the protocol, additional follow-up questionnaires 
should be sent for all live births approximately 6 months and 12 months after EDD to
ascertain the presence of birth defects not diagnosed at the time of the initial follow 
up. However neither of these follow-up questionnaires were implemented as of this 
protocol amendment.
GSK Biologicals acknowledges the importance of this information and intends to 
implement both 6- and 12-month follow-up attempts prospectively. The data 
collection form for 6- and 12-month follow-ups will be developed in parallel to this 
protocol amendment. For the subjects already enrolled, there will be no attempt to 
collect the 6 and 12-month data as the likelihood of having appropriate contact details 
and/or receiving reliable data is low and such practice is likely to introduce recall bias, 
hence compromising the validity of the results. 
Hence, the above proposed changes will only be applicable for patients to be enrolled 
after the approval of this protocol amendment (and the related documents/forms)
when the pregnancy outcome is a live birth, the contact details of the HCP attending 
the infant are available and with the consumer’s permission.
Originally, a signed consent form from pregnant subjects was only requested when 
these registered themselves into the registry, and to allow GSK to contact their HCPs. 
GSK will now also encourage HCPs who register their patients to provide these with 
the consent form. This consent will also allow to contact the HCP supervising the 
health of the infant up until 12 months after delivery (the updated consent form will 
now request contact information from HCP supervising the health of infant). This new 
consent form will be implemented for all prospective reports after the protocol 
amendment approval.
Gestational age cut-off for spontaneous abortions and stillbirths:
The 20 weeks’ cut-off in gestational age has been replaced by 22 weeks based on 
WHO-ICD 10 noted in the EMA Guideline on pregnancy exposure [EMA, 2006], as 
per the standard definition used by GSK Biologicals. It is recognized that national 
regulations might be different.
Exclusion Criteria section:
The following sentence have been deleted from the exclusion criteria section 
“Pregnancies in which prenatal testing indicates a normal pregnancy would also be 
excluded because inclusion of such pregnancies could potentially bias results toward 
a lower overall estimate of risk for defects” 
 
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It is important to notice that besides the presence of that wording in the initial version 
of the protocol, normal pregnancies have not been excluded from the registry since 
the beginning. The prenatal routine testing is non-invasive and is performed during 
prenatal visits (usually at least one by pregnancy trimester). The routine screening 
includes, blood serum assessment, ultrasound undertaken in first and second trimester, 
nuchal translucency measurement and serum screening for alpha-fetoprotein. Neither 
of the prenatal testing (regardless if it is routine or specific targeted) do not diagnose 
100% of the cases. Thus, by excluding the pregnancies with normal prenatal 
screening, part of the anomalies will be excluded as well. Additionally, considering 
that most pregnancies in the US go through foetal ultrasounds by the first trimester of 
gestation, this exclusion criterion will limit the number of subjects who enrol into the 
registry and enrich for subjects with low prenatal care coverage.
Hence, the exclusion criterion is being amended not to exclude the pregnancies with 
normal prenatal screening, in line with the process followed on this pregnancy 
registry, where the reported pregnancies with normal prenatal testing were always 
included.
Pregnancy registry reports Milestones:
The table summarizing the dates for submission of the annual reports has been 
updated to reflect the data lock point and the updated submission dates of each report.
Amended text has been included in bold italics and deleted text in strikethrough in 
the following sections:
Cover page: 
Authors
!
, Safety Scientist, Safety 
Evaluation & Risk Management, Vaccine 
Clinical Safety and Pharmacovigilance
!
, Safety Physician, Safety 
Evaluation & Risk Management, Vaccine 
Clinical Safety and Pharmacovigilance
!
, Safety Evaluation & Risk 
Management Team Leader, Vaccine 
Clinical Safety and Pharmacovigilance
!
, Head, Safety 
Evaluation & Risk Management, Vaccine 
Clinical Safety and Pharmacovigilance
!
, Clinical and 
Epidemiology Project Lead, DTP Polio Hib
– containing vaccines
!
, Regulatory Affairs
!
, Study Delivery Lead
!
, Manager, CMG US

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!
, Director, CMG US
!
, Clincial Safety Associate, 
CMG
!
, Director CMG
Copyright 2014 of the GlaxoSmithKline group of companies. All rights reserved. Unauthorized copying 
or use of this information is prohibited
© [2014-2017] GSK group of companies or its licensor.
List of abbreviations:
DLP
Data Lock Point
Abstract:
Rationale and 
background
In the US, Boostrix is indicated for active booster 
immunization against tetanus, diphtheria, and pertussis as a 
single dose in individuals 10 years of age and older. 
The purpose of this Registry is to detect and describe any 
abnormal pregnancy outcomes, including teratogenicity, in 
females intentionally or unintentionally exposed to Boostrix 
during their pregnancies in the US. The combination of the 
large number of women who are of reproductive capacity and 
may be exposed to tetanus, diphtheria, and pertussis; and the 
lack of data concerning exposure to Boostrix during pregnancy 
makes such a Registry an important component of the ongoing 
effort to assess the safety of Boostrix. The Registry was 
originally initiated on 03 May 2005, as part of a program of 
enhanced Pharmacovigilance. Following new European Union 
pharmacovigilance legislation, pregnancy registries are to be 
considered as post-authorization safety studies (PASS). The 
ongoing Registry will is therefore be converted into a PASS in 
Q1 2014. Timelines for collection of follow-up data will be 
adapted in order to correspond to the follow-up timelines of 
other GSK pregnancy registries.
The intent of the Registry is to prospectively collect data 
describing exposure to Boostrix immediately before or during 
pregnancy, potential confounding factors (such as exposure to 
other medications), and information related to the outcome of 
the pregnancy. Retrospective reports will be captured by the 
Registry but will not be included in the analyses of prospective 
reports.
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Study design

This study is a transition of an US ongoing pregnancy 
registry (starting on 03 May 2005) into a PASS. 

This is a prospective*, observational, exploratory, cohort 
study. The Boostrix pregnancy registry study requires 
voluntary, prospective reporting of eligible pregnancies by 
patients and healthcare professionals (HCPs). Data such as 
vaccination with Boostrix during pregnancy or within 28 
days preceding conception, potential confounding factors 
(such as exposure to other medications) and information 
related to the outcome of the pregnancy will be collected 
prospectively**.
* Exposed pregnancies reported to the Registry before the 
transition into a PASS (between 03 May 2005 and Q1 2014), 
from which data were collected and analyzed prospectively, 
will also be included in the analyses.
** Some pregnancy exposures may be reported after pregnancy 
outcome has been identified (retrospective reports). The 
Registry will capture retrospective reports, but these reports 
will not be included in the analyses of prospective reports.

Study population: pregnant women, residing in the United 
States (US), vaccinated with Boostrix during pregnancy or 
within 28 days preceding conception volunteering to take 
part in the study. 

Type of study: self-contained.

Data collection: initial and follow-up data will be collected 
using questionnaires. Follow-up of cases is performed 
within 2 3 months of the estimated date of delivery (EDD) 
to ascertain outcome and approximately 6 months and 12 
months after the EDD (for all live births for whom the 
contact details of their HCP will be available) to ascertain 
the presence of birth defects not diagnosed before.

After transition of the ongoing pregnancy registry into a 
PASS, data will be collected for a minimum of 5 years, 
starting Q1 2014.
 
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Data sources

Reporting of vaccine-exposed pregnancies to the Registry 
is voluntary. Registration can be initiated from a HCP or 
from a consumer, in which case permission is requested to 
obtain confirmation and follow-up from their HCP, follow-
up from the HCP of the infant post birth 6 and 12 months 
will be performed when the contact details are available
and with consumer’s permission. A toll-free telephone 
number for reporting adverse events (AEs) and vaccine-
exposed pregnancies to the Registry will be listed in the 
product information leaflet and on the GSK Registry 
website. Retrospective post-marketing reports and relevant 
scientific publications are potential sources of 
supplementary information.
Data analysis

Pregnancy outcomes include spontaneous abortion 
(pregnancy loss before 22 20 weeks gestation), fetal 
deaths/stillbirths (loss at or after 22 20 weeks gestation), 
elective/therapeutic induced abortions and live births. The 
presence or absence of birth defects or other abnormalities 
is evaluated within each of the preceding outcome 
categories.

Pregnancy outcomes are stratified by the trimester of 
exposure, with an additional stratum for preconception 
exposure with no subsequent administration of vaccine 
during pregnancy. Reports of multiple exposures during a 
pregnancy are classified by the earliest trimester of 
exposure. The calculations of risk for birth defects are 
made by dividing the number of infants with birth defects 
by the total number of infants with and without birth 
defects. The outcomes of the study will be assessed against 
known rates from an external reference group for the 
likelihood of a safety signal warranting further 
investigation.

Spontaneous abortions without birth defects are excluded 
from the risk calculations. 

All defects regardless of trimester of vaccine exposure will 
be included in the periodic summary reports of this 
Registry and stratified by trimester of exposure.

A section of each periodic summary report, separate from 
the analysis of prospective reports, will describe all 
abnormal outcomes of retrospectively reported cases.
Milestones

The Registry was originally initiated on 03 May 2005, as 
part of a program of enhanced pharmacovigilance, and will
now be is converted into a PASS in Q1 2014. GSK plans 
to continue the Registry for a minimum of 5 years, starting 
Q1 2014. Summary reports with cumulative analysis will 
 
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be written annually. A final cumulative report will be 
written and submitted 18 months after the last annual 
report within one year of completion of the five year 
period. After submission of the final report, GSK will 
continue the Registry pending Center for Biologics 
Evaluation and Research (CBER) review of the report and 
determination whether the Registry can be discontinued.
Section 6
Milestones
Milestone
(Including Data Lock Point (DLP) of each report)
Planned Submission date
Start of data collection
Q1 2014a
End of data collection
2 August 2019bQ4 2018b
Annual report 1 (DLP: 2 August 2015)
Q2 2016
Annual report 2 (DLP: 2 August 2016)
Q2 2017 Q1 2016
Annual report 3 (DLP: 2 August 2017)
Q2 2018 Q1 2017
Annual report 4 (DLP: 2 August 2018)
Q2 2019 Q1 2018
Annual report 5/Final report (DLP: 2 August 2019)
Q2 2020C Q1 2019
Registration in the EU PAS register
Q1 2014
Final report 
Q2 2020 (18 months after the last annual report)
a The Registry was originally initiated on 03 May 2005, as part of a program of enhanced pharmacovigilance. 
Following new European Union Pharmacovigilance legislation, pregnancy registries are to be considered as 
post-authorization safety studies (PASS). The ongoing Registry will therefore be converted into a PASS. GSK 
plans to continue the Registry for a minimum of 5 years, starting Q1 2014.Summary reports will be written 
annually and will be submitted with the Periodic Benefit-Risk Evaluation Report (PBRER) and the 
Development Safety Update Report DSUR) for Boostrix.
b After submission of the final report, GSK will continue the Registry pending Center for Biologics Evaluation and 
Research (CBER) review of the report and determination whether the Registry can be discontinued.
C Since the annual reports also contain cumulative data, the last annual report (with DLP: 2 August 2019) 
will serve the purpose of the Final report.
Section 7.2
Rationale
The purpose of this Registry is to detect and describe any abnormal pregnancy outcomes, 
including teratogenicity, in females intentionally or unintentionally exposed to Boostrix 
during their pregnancies or within 28 days preceding conception. The combination of the 
large number of women who are of reproductive capacity and may be exposed to tetanus, 
diphtheria, and pertussis; and the lack of data concerning exposure to Boostrix during 
pregnancy makes such a Registry an important component of the ongoing effort to assess 
the safety of Boostrix. The Registry was originally initiated on 03 May 2005, as part of a 
program of enhanced pharmacovigilance. Following new European Union 
Pharmacovigilance legislation, pregnancy registries are to be considered as PASS. The 
ongoing Registry will now be is therefore be converted into a PASS in Q1 2014. 
Timelines for collection of follow-up data will be adapted in order to correspond to the 
follow-up timelines of other GSK pregnancy registries. The Boostrix pregnancy registry 
was and will be maintained by Vaccine Clinical Safety and Pharmacovigilance.
 
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The Registry requires voluntary, prospective reporting of eligible pregnancies by patients 
and HCPs. Patient confidentiality is strictly maintained. The intent of the Registry is to 
prospectively collect data describing exposure to Boostrix immediately before or during 
pregnancy, potential confounding factors (such as exposure to other medications), and 
information related to the outcome of the pregnancy.
Section 9.1.1 Study design overview
!
Data collection: initial and follow-up data will be collected using questionnaires.
Data for enrollment will be collected using the Initial Notification Form.
Follow-up of cases is performed within 2 3 months of the estimated date of 
delivery (EDD) to ascertain pregnancy outcome (through the Pregnancy 
Outcome Form) and approximately 6 months and 12 months after the EDD (for all 
live births for whom the contact details of their HCP will be available) to ascertain 
the presence of birth defects not diagnosed before (through the 6- and 12-month 
post-delivery Follow-Up Form).
Section 9.2.2 Patient recruitment
Reporting of vaccine-exposed pregnancies to the Registry is voluntary. Since the 
initiation of the Registry in 2005, GSK has taken several measures to increase the rate of 
pregnancy registration (accrual). A GSK Registry web page has been created with 
instructions for enrolling patients in the Registry and GSK has requested that the FDA 
post a link to this web page on their Pregnancy Registry Website. The forms for 
enrolling and reporting outcomes are also accessible to healthcare providers through 
the GSK Registry web page. In response to a 2008 request from the FDA to facilitate 
enrollment, GSK initiated a dedicated toll-free telephone number (
), at 
which US-based callers can receive assistance in the registration of pregnancies. Notice 
of this new toll-free number was posted on the GSK web page in January 2009; the new 
toll-free number was added to the US Prescribing Information in early 2009. The 
Prescribing Information and GSK Registry website each give a brief summary of the 
purpose and intent of the Registry, along with telephone and fax contact information. Fax 
contact information is available on the GSK Registry web page.
Section 9.2.4 Study period
The Registry was originally initiated on 03 May 2005, as part of a program of enhanced 
pharmacovigilance, and will now be converted into a PASS in Q1 2014. GSK plans to 
continue the Registry for a minimum of 5 years, starting Q1 2014. After submission of 
the final report, GSK will continue the Registry pending CBER review of the report and 
determination whether the Registry can be discontinued.
Section 9.2.6 Exclusion criteria
Data from registered subjects will not be included in the analyses if the following 
criterion is met:

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
Outcome of pregnancy is known at the time of initial report. Types of known 
outcomes include prenatal testing reports in which the results are abnormal or 
outside the reference range, indicating possible abnormality in the fetus. Pregnancies 
in which prenatal testing indicates a normal pregnancy would also be excluded 
because inclusion of such pregnancies could potentially bias results toward a lower 
overall estimate of risk for defects [Honein, 1999]. Typically pregnancies > 16 
weeks gestation will have undergone prenatal testing that can identify whether a 
child has congenital abnormalities.
Section 9.3.2 Data to be collected
Initial and follow-up data will be collected using questionnaires. Data for enrollment 
will be collected using the Initial Notification Form. Follow-up of cases is 
performed within 2 months of the estimated date of delivery (EDD) to ascertain 
pregnancy outcome (through the Pregnancy Outcome Form) and approximately 6 
months and 12 months after the EDD (for all live births for whom the contact details of 
their HCP will be available) to ascertain the presence of birth defects not diagnosed 
before (through the 6- and 12-month post-delivery Follow-Up Form). The following 
data will be collected:

Patient identifier.

Maternal data, including date of birth, date of last menstrual period (LMP), 
EDD.

Maternal relevant medical/family history.

Paternal relevant medical/family history.

Type of conception.

Prenatal testing.

Maternal prenatal drug/vaccine exposure, including drug/vaccine name, date of
administration, route of administration, dose, lot number, indication.

Pregnancy outcome.

Method of delivery.

Infant/fetal information, including gestational weeks at birth/miscarriage/ 
termination, gender, length, weight, Apgar score.

Description of birth defects, if applicable.

AEs experienced by the fetus/infant or the mother.

Reporter information.

Any additional data that seems relevant for this study.
Section 9.4
Data sources
Reporting of vaccine-exposed pregnancies to the Registry is voluntary. Registration 
can be initiated from a HCP or from a consumer, in which case permission is 
requested to obtain confirmation and follow-up from their HCP. Follow-up from the 
 
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HCP of the infant post birth 6 and 12 months will be performed when the contact 
details are available and with consumer’s permission. A toll-free telephone number 
for reporting AEs and vaccine-exposed pregnancies to the Registry is listed in the 
product information leaflet and on the GSK Registry website. Retrospective post-
marketing reports and relevant scientific publications are potential sources of 
supplementary information.
Section 9.6.1 Data collection
Initial and follow-up data will be collected using questionnaires. Initial data will be 
collected before the outcome is known. Follow-up of cases will be performed at the 
following timepoints:

For consumer reports:

At initial notification of pregnancy exposure: 2 attempts at 4-6 week 
intervals will be made to obtain more information about the pregnancy 
(e.g. estimated time of delivery (EDD) and/or last menstrual period (LMP) 
and to obtain permission to contact the patient’s HCP

Within 2 months after EDD, 1 additional attempt is made if permission to 
contact the patient’s HCP has not already been granted to obtain more 
information about the pregnancy and obtain the permission to contact the 
patient’s HCP.

Within 2 months after EDD (and if the patient has not previously provided 
the contact information for the infant’s HCP): 2 attempts at 4-6 week 
intervals will be made for the prospective cases reporting a live birth to 
obtain the contact information of the HCP supervising the health of the 
infant.

For the HCP reports:

At initial notification of pregnancy exposure or once permission has been 
granted for reports initially received from a consumer, two attempts at 4-6 
week intervals will be made to obtain more information via pregnancy 
follow-up form.

Within 2 3 months of the EDD, to ascertain outcome. At least three Two 
follow-up attempts to obtain outcome information will be made before any 
case is considered lost to follow-up.

An additional follow-up attempt will be done for all the live births 
approximately 6 months and 12 months after the EDD to ascertain the presence 
of birth defects not diagnosed at the time of the initial follow-up. This follow-up 
will be done for the prospective reports if the consumer has granted the
permission and when the contact details of the HCP attending the infant are 
available.
 
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Section 9.6.2 Processing of reports
Initial Reports are entered into the GSK safety database by GSK Call Center Case 
Management Group (CMG) using existing mechanisms and practices. Medical 
Dictionary for Regulatory Activities (MedDRA) is used in the database to code AEs.
Follow-up is conducted by the CMG. The HCP is contacted if she/he requests or if 
initial information is insufficient or needs clarification. The HCP is encouraged to keep 
a copy of the initial completed form in the patient’s chart. The follow-up of cases is 
performed as described in section 9.6.1.
Section 9.6.2.1
Solicitation of outcome
As explained in section 9.6.1, within three two months after the EDD and if the HCP has 
not already provided the pregnancy outcome, she/he is sent an outcome form 
(questionnaire), along with a copy of the initial completed pregnancy form. The 
mode of communication is the one through which the initial information was 
received (telephone, fax, or postal mail) generally via standard letter.
Two At least 3, attempts are made to secure the outcome information from the HCP via 
standard letter. The second and third attempts utilize all modes of contact available (mail, 
fax, telephone). If outcome is not received from the HCP and contact information is 
available for the patient, she is then contacted by mail or fax.
In the event of an abnormal outcome For the live births and with the mother’s 
permission, attempts are made to solicit information from the pediatrician and/or other 
specialists who have provided healthcare/consultation to the child until 12 months of 
age.
Section 9.6.2.2
Classification of outcome
This Registry uses the term ‘birth defects’ for outcomes sometimes referred to as 
‘congenital anomalies’. For purposes of analysis, pregnancy outcomes are 
dichotomized according to the presence or absence of birth defects. The latter group is
Pregnancy outcomes are further categorized as: 1) live births, 2) spontaneous abortions 
(i.e., pregnancy losses), 3) Elective/induced abortions 4) and Fetal deaths/Stillbirths.
This Registry adopts a definition of a child with a birth defect as any live or stillborn 
neonate with a structural or chromosomal abnormality diagnosed before 6 years of age. 
The Registry employs a conservative approach of including all morphologic 
anomalies, including minor ones, as birth defects. 
To provide consistency in the definitions of major defects in this Registry, CDC 
MACDP criteria are used for the classification of defects [CDC, 2008; Correa-Villasenor, 
2003]. Some of the conditions excluded from the MACDP criteria for major structural 
defects may actually have major clinical, functional, or genetic significance. Therefore, 
minor malformations not appearing in the CDC inclusion list may be classified as birth 
defects in this Registry. In addition, CDC guidelines disqualify as defects those findings 
that are present in infants delivered at less than 36 weeks of gestation and are attributable 
 
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to prematurity itself, such as a patent ductus arteriosus or inguinal hernias. Infants with 
infectious conditions (e.g., neonatal sepsis) or isolated biochemical abnormalities (e.g., 
hyperbilirubinemia) are classified as being without birth defects unless there is a 
possibility that the condition reflects an unrecognized congenital abnormality. All other 
congenital abnormalities are included in the ‘birth defects’ category, regardless of 
whether the neonate is delivered alive, including structural defects in neonates delivered 
prior to 20 weeks of gestation or weighing less than 500 g.
Section 9.7
Data analysis
Pregnancy outcomes include spontaneous abortion (pregnancy loss before 22 20 weeks 
gestation), fetal deaths/stillbirths (loss at or after 22 20 weeks gestation), 
elective/therapeutic induced abortions and live births. Gestational weeks are counted 
from the date of the LMP. The second trimester is considered to begin at week 14 and 
the third trimester begins at week 28. The presence or absence of birth defects or other 
abnormalities is evaluated within each of the preceding outcome categories.
Pregnancy outcomes are stratified by the trimester of exposure, with an additional 
stratum for preconception exposure with no subsequent administration of vaccine during 
pregnancy. Reports of multiple exposures during a pregnancy (i.e., multiple 
administrations of Boostrix) are classified by the earliest trimester of exposure. When 
exposure occurs before and after conception, the exposure is classified by the dose 
administered after conception. The calculations of risk for birth defects are made by 
dividing the number of infants with birth defects by the total number of infants with and 
without birth defects. An exact 95% confidence interval is calculated using standard 
statistical software. Given the descriptive nature of this study, confidence intervals will 
not be calculated. The outcomes of the study will be assessed against known rates from 
an external reference group for the likelihood of a safety signal warranting further 
investigation.
Section 12
Plans for disseminating and communicating study results
Study information from this protocol will be posted on publicly available clinical trial 
registers following finalization of the protocol and, whenever possible, before initiation 
of the study.
GSK plans to continue the Registry for 5 years. Summary reports will be written annually
and will be submitted with the Periodic Benefit-Risk Evaluation Report and the DSUR
for Boostrix. A final report will be written and submitted after 5 years within one year of 
completion of the five-year period as described in Section 6. After submission of the 
final report, GSK will continue the Registry pending CBER review of the report and 
determination whether the Registry can be discontinued.
Summary results of observational studies that are designed to inform the safety or 
effectiveness, including cost-effectiveness, of GSK vaccines/products as used in ordinary 
clinical practice are publicly registered within 8 12 months of completion of the analysis. 
GSK also aims to publish the results of these studies in the searchable indexed, peer 
reviewed scientific literature; manuscripts are submitted within 18 months of the 
completion of the analysis.
 
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Section 13
References
Honein MA, Paulozzi LJ, Cragan JD, Correa A. Evaluation of selected characteristics of 
pregnancy drug registries. Teratology. 1999; 60(6): 356-364. 
EMA 2006. 
http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural
_guideline/2009/11/WC500011303.pdf. Accessed on 05 October 2017.
 
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Annex 5
Trademarks
The following trademarks are used in the present study outline. Note: In the remainder of 
the document, the names of the vaccines will be written without the superscript symbol 
™ or ®.
Trademarks of the GSK group of 
companies
Generic description
Boostrix 
tetanus toxoid, reduced diphtheria toxoid 
and acellular pertussis vaccine, adsorbed
Boostrix IPV
combined diphtheria, tetanus, acellular 
pertussis (adsorbed) and inactivated
poliomyelitis vaccine
Twinrix 
hepatitis A inactivated & hepatitis B 
(recombinant) vaccine
Trademarks not owned by the GSK
group of companies
Generic description
Adacel (Sanofi Pasteur)
tetanus toxoid, reduced diphtheria toxoid 
and acellular pertussis vaccine, adsorbed
 
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Annex 6
Protocol Amendment 1 sponsor signatory approval
eTrack study number and 
Abbreviated Title
201327 (EPI-PERTUSSIS-028 VS US PR)
Date of protocol amendment
Amendment 1 Final: 05 October 2017
Detailed Title
Boostrix Pregnancy Registry: a prospective, 
exploratory, cohort study to detect and describe any 
abnormal pregnancy outcomes in women intentionally 
or unintentionally vaccinated with Boostrix during 
pregnancy or within 28 days preceding conception.
Sponsor signatory
Narcisa Mesaros, MD
Clinical and Epidemiology Project Lead, 
DTP Polio Hib – containing vaccines,
GlaxoSmithKline Biologicals, SA
Signature
Date
 
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