A Post-marketing, Observational, Retrospective, Cohort Study to Assess the Safety of RefortrixTM (Tdap) When Administered During Pregnancy in a Maternal Immunization Program in Brazil.
Conditions: Diphtheria
Sponsor: GlaxoSmithKline

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P A S S I N F O R M A T I O N
Title :
A p ost -mar keti n g , o bser vati o nal, retr os pecti ve,
c o h ort st u d y t o assess t he safety of Ref ortri x T M
( T da p) w he n a d mi nistere d d uri n g pre g na nc y i n a 
mater nal i m m u nizati o n pr o gra m i n Brazil.
Pr ot oc ol versi o n i de ntifier:
2 0 3 1 5 3 ( E PI -P E R T U S SI S -0 3 7 V S B R)
D ate of l ast versi o n of t he 
pr ot oc ol:
Fi nal Versi o n 1 : 1 1 Se pte m ber 2 0 1 5
E U P A S Re gister N o:
T o be deter mi ne d.
Acti ve s u bst a nce :
Di p ht heria t o x oi d, Teta n us t o x oi d, B or detell a 
pert ussis a nti ge ns ( Pert ussis t o x oi d, Fila me nt o us 
Hae ma g gl uti ni n a n d Pertacti n)
Me dici n al pr o d uct :
Gla x o S mit h Kli ne ( G S K) Bi ol o gicals’ c o m bi ne d 
re d uce d-a nti ge n-c o nte nt di p ht heria, teta n us a n d 
acell ular pert ussis ( T da p ) vacci ne (Ref ortri x ™) 
( 2 6 3 8 5 5)
Pr o d uct refere nce:
D E/ H/ 0 2 1 0/ 0 0 1 - 0 0 2
Pr oce d ure n u m ber:
T o be all ocate d.
M ar keti n g A ut h oris ati o n H ol der
( M A H):
Gla x o S mit h Kli ne Bi ol o gicals
R ue de l’I nstit ut, 8 9
1 3 3 0 Ri xe nsart, Bel gi u m
J oi nt P A S S :
N o
Rese arc h q uesti o n a n d 
o bjecti ves :
T o assess t he ris k of a series of pre -defi ne d safet y 
o utc o mes f oll o wi n g r o uti ne vacci nati o n wit h 
Ref ortrix i n a c o h ort of pre g na nt w o me n 
c o m pare d t o a hist orical c o h ort of u n vacci nate d 
pre g na nt w o me n i n Brazil 
C o u ntr y of st u d y:
Brazil
A ut h or s:
C o ntri b uti n g a ut h ors:

, Direct or, E pi de mi ol o g y

, Direct or, E pi de mi ol o g y

, E pi de mi ol o gist

, E pi de mi ol o g y Scie ntist

, E pi de mi ol o g y  A nal yst

, Re gi o nal 
E pi de mi ol o g y  Direct or, L A T A M

, Se ni or E pi de mi ol o gist, 
L A T A M

 Pr oject Statisticia n , Ni n g ya n g 
Gr o u p C o., f or G S K Bi ol o gicals

, Lea d Statisticia n

, St u d y  Deli ver y Lea d

, L o cal Deli ver y Lea d, 
Q ui ntiles, f or G S K Bi ol o gicals

, Cli nical Safet y  
 
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R e prese ntati ve

, Safet y Scie ntist

, St u d y  Data Ma na ger, 
Tata C o ns ulta nc y  Ser vices, f or G S K 
Bi ol o gicals

, Gl o bal Pate nt 
re prese ntati ve

, Ma na ger , Gl o bal 
Re g ulat or y  Affairs
C o or di n ati n g a ut h or:

, Scie ntific Writer
M A R K E TI N G A U T H O RI S A T I O N H O L D E R 
M A H :
Gla x o S mit h Kli ne Bi ol o gicals
R ue de l’I nstit ut, 8 9
1 3 3 0 Ri xe nsart, Bel gi u m
M A H c o nt act
pers o n :
, Direct or, E pi de mi ol o g y, 
Gla x o S mit h Kli ne Bi ol o gicals
R ue de l’I nstit ut, 8 9
1 3 3 0 Ri xe nsart, Bel gi u m
G S K Bi ol o gi c al s’ pr ot o c ol f or p o st -a ut h ori s a ti o n s af et y st u di e s I N S- BI O-P A S S -1 0 0 0 v 1 4. 1. 1
C o p yri g ht 2 0 1 5 of t he Gl a x o S mit h Kli ne gr o u p of c o m p a nies. All ri g hts reser ve d. U n a ut h orise d 
c o p yi n g or use of t his i nf or m ati o n is pr o hi bite d.
 
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1.
TABLE OF CONTENTS
PAGE
1.
TABLE OF CONTENTS ...........................................................................................3
1.1.
LIST OF TABLES .........................................................................................6
2.
LIST OF ABBREVIATIONS ......................................................................................7
3.
RESPONSIBLE PARTIES........................................................................................9
4.
ABSTRACT............................................................................................................10
5.
AMENDMENTS AND UPDATES............................................................................15
6.
MILESTONES........................................................................................................15
7.
RATIONALE AND BACKGROUND ........................................................................15
7.1.
Background ................................................................................................15
7.2.
Rationale ....................................................................................................16
8.
RESEARCH QUESTION AND OBJECTIVES ........................................................16
8.1.
Co-primary objectives .................................................................................16
8.2.
Secondary objectives..................................................................................17
9.
RESEARCH METHODS.........................................................................................17
9.1.
Study design...............................................................................................17
9.1.1.
Discussion of study design...........................................................18
9.1.2.
Feasibility assessment.................................................................18
9.2.
Setting ........................................................................................................19
9.2.1.
Number of subjects/centres .........................................................19
9.2.2.
Inclusion criteria...........................................................................19
9.2.3.
Exclusion criteria..........................................................................20
9.2.4.
Outline of the study procedures ...................................................20
9.2.5.
Detailed description of study procedures .....................................21
9.2.5.1.
Screening ...................................................................21
9.2.5.2.
Check inclusion and exclusion criteria ........................21
9.2.5.3.
Allocate subject number .............................................21
9.2.5.4.
Obtain demographic data, medical and 
gynaecological antecedents .......................................21
9.2.5.5.
Obtain concomitant vaccination history 
(Exposed cohort) ........................................................22
9.2.5.6.
Record risk factors......................................................22
9.2.5.7.
Record clinical data of pregnancy...............................22
9.2.5.8.
Record data from physical examination of 
neonate ......................................................................22
9.2.5.9.
Record adverse pregnancy outcome ..........................22
9.2.5.10.
Record intercurrent medical 
conditions/medications ...............................................22
9.2.5.11.
Study conclusion ........................................................22
9.3.
Variables.....................................................................................................23
 
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9.3.1.
Study cohort definitions................................................................23
9.3.2.
Endpoints.....................................................................................23
9.3.2.1.
Co-primary endpoints .................................................23
9.3.2.2.
Secondary endpoints..................................................23
9.3.3.
Potential confounding factors.......................................................24
9.4.
Data sources ..............................................................................................24
9.5.
Study size...................................................................................................25
9.6.
Data management ......................................................................................26
9.7.
Data analysis ..............................................................................................27
9.7.1.
Cohorts for analyses....................................................................27
9.7.1.1.
Total Cohort (TC)........................................................27
9.7.1.2.
According-To-Protocol (ATP) Cohort ..........................27
9.7.2.
Analysis of demographics and baseline characteristics................27
9.7.3.
Analysis of co-primary endpoints .................................................27
9.7.4.
Analysis of secondary endpoints..................................................28
9.7.5.
Handling of missing data..............................................................28
9.7.6.
Conduct of analysis .....................................................................29
9.7.6.1.
Sequence of analyses ................................................29
9.7.6.2.
Statistical considerations for interim analyses.............29
9.8.
Quality control.............................................................................................29
9.9.
Limitations of the research methods ...........................................................29
9.10.
Other aspects .............................................................................................31
10. PROTECTION OF HUMAN SUBJECTS ................................................................31
10.1.
Data Privacy ...............................................................................................31
11. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS ..........................................................................................................31
12. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY 
RESULTS...............................................................................................................32
12.1.
Posting of information on publicly available registers and publication 
policy ..........................................................................................................32
12.2.
Provision of study results to investigators ...................................................32
13. REFERENCES.......................................................................................................33
Annex 1
List of stand-alone documents................................................................36
Annex 2
Glossary of terms...................................................................................37
Annex 3
Trademarks............................................................................................45
Annex 4
List of principal and coordinating investigators .......................................46
Annex 5
Sponsor Information...............................................................................47
Annex 6
Feasibility assessment ...........................................................................48
Annex 7
Definitions and evaluations of selected terms and adverse events 
of interest in pregnant women participating in clinical trials 
(adapted from Munoz, 2013) ..................................................................49
 
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Annex 8
Planned variables to be collected in electronic Case Report Form 
(eCRF) ...................................................................................................64
Annex 9
Recommendations for Refortrix vaccine in Brazil ...................................67
Annex 10
Protocol Sponsor Signatory Approval.....................................................68
Annex 11
Protocol Investigator Agreement ............................................................69
Annex 12
ENCePP Checklist for study protocols ...................................................71
 
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1.1.
LIST OF TABLES
PAGE
Table 1
Study cohorts and epoch foreseen in the study......................................18
Table 2
List of study procedures .........................................................................20
Table 3
Events of interest to be collected from the medical files .........................21
Table 4
Background proportions of different safety outcomes.............................25
Table 5
Power estimation of each safety outcome with background 
proportions from the feasibility assessment without multiple 
adjustment and sample size of 1200 subjects in each cohort .................26
Table 6
Sample size and power estimation without and with multiple 
adjustment for background proportions of 3% and 5% and 
relative risk of 2......................................................................................26
 
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2.
LIST OF ABBREVIATIONS
ACIP
Advisory Committee on Immunization Practices
AE
Adverse Event
ATP Cohort
According-To-Protocol Cohort
CARS
Computer Aided Regulatory Submission
CDC
Centers for Disease Control and Prevention
CI
Confidence Interval
CONEP
Comissão Nacional de Ética em Pesquisa
D-Rh
Rhesus factor
eCRF
electronic Case Report Form
EMA
European Medicines Agency
GCP
Good Clinical Practice
GSK
GlaxoSmithKline
GVP
Good Pharmacovigilance Practices
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IRB
Institutional Review Board
LMP
Last Menstrual Period
MACDP
Metropolitan Atlanta Congenital Defects Program
MAH
Marketing Authorisation Holder
MoH
Ministry of Health
OR
Odds Ratio
PAHO
Pan American Health Organization
PASS
Post-Authorisation Safety Study
PII
Personally Identifiable Information
 
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PNI
National Immunization Program (Brazil)
QC
Quality Control
SAE
Serious Adverse Event
SDD
Statistical Analysis System Drug Development
TC
Total Cohort
Tdap
Combined reduced-antigen-content diphtheria, tetanus 
and acellular pertussis (Tdap) vaccine
TSS
Targeted Safety Study
UK
United Kingdom
USA
United States of America
VAERS
Vaccine Adverse Event Reporting System
WHO
World Health Organization
 
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3.
R E S P O N SI B L E P A R TI E S
G S K Bi ol o gicals has t he o verall res p o nsi bilit y  f or t he c o n d uct of t he st u d y.
(Direct or, E pi de mi ol o g y ) is t he G S K Bi ol o gicals desi g nate d c o ntact 
pers o n f or t hi s st u d y.
Refer t o A n ne x 4 f or t he list of pri nci pal a n d c o or di nati n g i n vesti gat ors.
 
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4.
A B S T R A C T
Title
A p ost -mar keti n g , o bser vati o nal, retr os pecti ve, c o h ort st u d y t o 
assess t he safet y of Ref ortri x T M ( T da p) w he n a d mi nistere d 
d uri n g pre g na nc y i n a mater nal i m m u nizati o n pr o gra m i n 
Brazil.
Versi o n a n d d ate of 
t he pr ot oc ol
Fi nal Versi o n 1 : 1 1 Se pte m ber 2 0 1 5
M ai n a ut h or
, Gla x o S mit h Kli ne Bi ol o gicals
R ati o n ale a n d 
b ac k gr o u n d
Pert ussis ca n ca use seri o us a n d s o meti mes life- t hreate ni n g 
c o m plicati o ns i n i nfa nts, es peciall y wit hi n t he first 6 m o nt hs 
of life w he n it is t o o earl y t o recei ve a n d c o m plete t heir 
pri mar y  vacci nati o n sc he d ule a gai nst pertussis. I n Brazil, 
bet wee n 2 0 0 8 a n d 2 0 1 2 , 1 8 5 pert ussis-relate d deat hs occ urre d 
i n c hil dre n less t ha n 4 ye ars of a ge a n d t he maj orit y of cases 
occ urre d i n i nfa nts . T he i ncrease d fatalit y rate i n t his gr o u p 
le d t he c o u ntr y t o i ntr o d uce t he acell ular pert ussis vacci nati o n 
pr o gra m i n pre g na nt w o me n. B y  t he e n d of 2 0 1 4, t he Nati o nal 
I m m u nizati o n Pr o gra m i n Brazil ( P NI) starte d i m ple me ntati o n 
of t he mater nal i m m u nizati o n pr o gra m, a d mi nisteri n g o ne 
d ose of c o m bi ne d re d uce d a nti ge n c o nte nt di p ht heria -teta n us-
acell ular pert ussis ( T da p) vacci ne (Ref ortrix ) d uri n g t he last 
tri mester of pre g na nc y ( 2 7 t o 3 6 c o m plete d wee ks of 
pre g na nc y or u ntil 2 0 da y s bef ore t he deli ver y d ue date).
T he effects of Ref ortrix vacci nati o n i n pre g na nt w o me n w ere
n ot e val uate d i n pre-lice ns ure st u dies a n d m ost of t he safety 
e val uati o ns ha ve bee n c o n d ucte d usi n g s p o nta ne o us re p orti n g 
s yste ms w hic h ha ve t heir o w n li mitati o ns li ke u n der / o ver 
re p orti n g, re p orti n g bias a n d q ualit y  iss ues. T heref ore, st u dies 
usi n g a p pr o priat e desi g ns t hat f oc us o n re gi o ns w here t he 
mater nal i m m u nizati o n pr o gra m is starti n g ca n pr o vi de
val ua ble i nf or mati o n.
Rese arc h q uesti o n 
a n d o bjecti ves
T he ai m of t his retr os pecti ve st u d y is t o i n vesti gate t he 
ass ociati o n bet wee n r o uti ne Ref ortrix vacci nati o n d uri n g 
pre g na nc y a n d s pecific pre g na nc y-relate d a d verse e ve nts 
( A Es) a n d A Es i n ne o nates f oll o wi n g t he r o uti ne mater nal
Ref ortrix vacci nati o n d uri n g pre g na nc y . T he A Es i de ntifie d 
f or t his st u d y are t h ose c o nsi dere d i m p orta nt i n t he c o nte xt of 
m ater nal i m m u nizati o n [Z hete y e va, 2 0 1 2; K har ba n da , 2 0 1 4] 
a n d f or w hic h it w o ul d be feasi ble t o o btai n t he re q uire d data 
(refer t o secti o n 1 0. 1. 2).
T he d ia g n osis of pre g na nc y-relate d A Es will f oll o w t he 
i nter nati o nal case defi niti o ns (refer t o A n ne x 7 ) a n d will be 
 
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obtained directly from the medical records. Since the vaccine 
is routinely administered in the third trimester of pregnancy, 
the events that are more commonly reported during this period
have been chosen as primary endpoints.
Co-primary objectives:

To compare the risk of gestational diabetes, pregnancy-
related hypertension and pregnancy haemorrhage (ante-
partum (after 24 weeks of gestation), intra-partum or 
post-partum) in a cohort of women following vaccination 
with Refortrix as part of the maternal immunization 
program in Brazil (Exposed cohort) with a historical 
cohort of unvaccinated pregnant women before the 
implementation of this immunization program 
(Unexposed cohort).

To compare the risk of preterm birth and small for 
gestational age in neonates born to subjects in the 
Exposed cohort and to subjects in the Unexposed cohort.
Secondary objectives:

To describe the risk of pregnancy-related AEs/neonate-
related events of interest (premature rupture of 
membranes, preterm premature rupture of membranes, 
premature uterine contraction, neonatal death, maternal 
death, still birth and neonatal hypoxic ischaemic 
encephalopathy) in the Exposed and Unexposed cohorts.

To describe the risk of congenital anomalies in neonates 
in the Exposed and Unexposed cohorts.

To describe the risk of pregnancy-related AEs and birth 
outcomes per calendar year in the Unexposed cohort.
 
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Study design

Type of design: An observational, retrospective, cohort, 
single-centre study.

This is a Targeted Safety Study (TSS) and a Post-
Authorisation Safety Study (PASS).

Study population: The study population will consist of 
two cohorts:

Exposed Cohort (cohort of pregnant women who 
received Refortrix as part of the maternal 
immunization program in Brazil)

Unexposed Cohort (historical cohort of unvaccinated 
pregnant women before the implementation of the 
immunization program)

Data collection: electronic Case Report Form (eCRF)
based on medical chart data.

Period of data collection: The minimum period of the 
data collection is expected to be 6 months assuming the 
availability of the subject medical files adequate to attain
the sample size required for the analysis. The data of 
Unexposed subjects who delivered during the period from 
September 2012 to August 2014 will be included. The 
maternal immunization program in Brazil was scheduled 
to start in September 2014. Therefore, the data of 
Exposed subjects will be collected once the maternal 
immunization program is well implemented in Brazil and 
the inclusion of data will start from May 2015 till the 
Exposed cohort is enrolled completely.

Epoch 001: Retrospective data collection.
Population
The study population will consist of pregnant women aged 
between 18 and 45 years, who are residing in the study area 
(city of São Bernardo do Campo) and delivered in the 2 years 
before or during the period following the implementation of 
the PNI. The subjects who delivered in the study centre from
May 2015 will be considered as potentially exposed subjects 
who had opportunity to receive vaccine and those who 
delivered before implementation of the PNI (September 2014)
will be considered as potentially unexposed subjects. Subjects 
meeting all the inclusion/exclusion criteria will be eligible for 
enrolment in the study.
Variables
Co-primary endpoints:

Occurrence of any of the following pregnancy-related 
AEs in Exposed and Unexposed subjects.

Gestational diabetes.
 
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
Pregnancy-related hypertension (including pre-
eclampsia, eclampsia and HELLP syndrome).

Pregnancy haemorrhage (ante-partum (after 24 
weeks of gestation), intra-partum or post-partum).

Occurrence of any of the following outcomes in neonates 
from Exposed and Unexposed subjects.

Preterm birth

Small for gestational age
Secondary endpoints:

Occurrence of pregnancy-related AEs of interest/ 
neonate-related events up to delivery in Exposed and 
Unexposed subjects.

Premature rupture of membranes.

Preterm premature rupture of membranes.

Premature uterine contraction.

Neonatal death.

Maternal death.

Still birth.

Neonatal hypoxic ischaemic encephalopathy.

Occurrence of congenital anomalies in the neonates of 
Exposed and Unexposed subjects.

Occurrence of pregnancy-related AEs and birth outcomes 
per calendar year in the Unexposed cohort.
Data sources
This retrospective study will use the medical files and other 
hospital documents (admission list, images and other test 
results, etc.) for collecting demographic data, 
medical/gynaecological history, pregnancy-related AEs of 
interest and AEs in neonates. No intervention or additional 
evaluation will be done on the diagnosis or evaluation of these 
events and only the final diagnosis as described in the source 
document will be included in the study.
To evaluate the vaccination exposure, the information in the 
anamnesis and pregnancy card archived in the medical files 
will be used as the only source.
Study size
The planned sample size of this study is 2400 subjects. Using 
a two-sided (alpha = 0.01) test assuming the ratio of subjects 
in the Exposed cohort to the Unexposed cohort is 1:1 and 
assuming a background proportion of events in the Unexposed 
cohort to be 3%, a total of 2400 subjects [1200 subjects in 
each cohort], will be needed to have more than 80% power to 
 
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detect a relative risk of 2 or higher.
Data analysis
The main analysis for co-primary objectives will contain only 
the subjects with vaccination date in the Exposed cohort and 
subjects from the Unexposed cohort. If more than 10% of 
subjects have missing vaccination date in the Exposed cohort, 
a sensitivity analysis will be performed with the imputed 
vaccination date to 27 completed weeks of gestational age.
The risk for each primary endpoint (gestational diabetes, 
pregnancy-related hypertension, pregnancy haemorrhage, 
preterm birth and small for gestational age) will be calculated.
For each specific endpoint, the number of subjects where the 
event occurred (between the index date and the date of the 
delivery) will be divided by the total number of subjects at 
risk for both the Exposed and Unexposed cohorts respectively, 
together with its exact 95% confidence interval (CI).
The co-primary endpoints of pregnancy (gestational diabetes, 
pregnancy-related hypertension and pregnancy haemorrhage) 
will be pooled together as well as the birth outcomes (preterm 
birth and small for gestational age). The analysis of the risk 
for the pooled endpoints will be performed using the same 
method as for the separate co-primary endpoints.
The comparison of the risk with its two sided 95% CI of each 
primary endpoint between the Exposed cohort and the 
Unexposed cohort will be obtained by means of logistic 
regression. Univariate analysis will describe the association 
between Tdap vaccination status, maternal age, parity and 
gestational age.
A multiple logistic regression model will be fitted with a 
backward selection to identify the possible confounding 
factors for each of the primary outcomes using an alpha level 
of 0.1. Potential confounders will be parity, age of the mother 
at the start of the pregnancy and congenital anomalies (in 
parents or first degree relatives). Adjusted odds ratio (OR) and 
its 95% CI will be derived from the final model.
Milestones
Data collection is planned to start in Quarter 2-2016 and end
in Quarter 4-2016. The final report of study results is planned 
in Quarter 2-2017.
 
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5.
AMENDMENTS AND UPDATES
None.
6.
MILESTONES
Milestone
Planned date
Start of data collection
Quarter 2 2016
End of data collection
Quarter 4 2016
Final report of study results
Quarter 2 2017
7.
RATIONALE AND BACKGROUND
7.1.
Background
Pertussis can cause serious and sometimes life-threatening complications in infants, 
especially within the first 6 months of life when it is too early to receive and complete 
their primary vaccination schedule against pertussis. In Brazil, between 2008 and 2012,
185 pertussis-related deaths occurred in children less than 4 years of age and the majority 
of cases occurred in infants [WHO, 2014]. The increased fatality rate in this group led the 
country to introduce the acellular pertussis vaccination program in pregnant women. By 
the end of 2014, the National Immunization Program in Brazil (PNI) started 
implementation of the maternal immunization program [MoH, 2014], administering one 
dose of combined reduced antigen content diphtheria-tetanus-acellular pertussis (Tdap) 
vaccine (Refortrix) during the last trimester of pregnancy (27 to 36 completed weeks of 
pregnancy or until 20 days before the delivery due date).
Although the Tdap maternal immunization strategy has been implemented in the United 
Kingdom (UK), the United States of America (USA) and other countries, only limited 
data on the safety of Refortrix in pregnant women is available. The data from the Vaccine 
Adverse Event Reporting System (VAERS), pregnancy registries and case series have 
concluded that there is no indication of any safety concern about maternal, foetal and 
infant outcomes following vaccination during pregnancy with Tdap [Healy, 2006; 
Murphy, 2008; Gall, 2011; Zheteyeva, 2012; ACIP, 2013; CDC, 2015].
Immunization with inactivated vaccines during the last trimester of pregnancy can be 
beneficial because maternal antibodies can be transferred efficiently to the foetus across 
placenta, thus providing indirect protection to infants for the first months of life [Keller-
Stanislawski, 2014]. Additionally, the risk of abnormal organogenesis is minimal at that 
gestational age.
 
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7.2.
Rationale
The effects of Refortrix vaccination in pregnant women were not evaluated in pre-
licensure studies and most of the safety evaluations have been conducted using 
spontaneous reporting systems which have their own limitations like under/over 
reporting, reporting bias and quality issues. Therefore, observational studies using 
appropriate designs that focus on regions where the maternal immunization program is 
starting can provide valuable information.
A retrospective cohort study in this country will present a unique opportunity to continue 
monitoring the safety of this vaccine in a large population of vaccinated pregnant women, 
especially in the immediate period after introduction at the end of 2014 of this maternal 
immunization program. This study will generate safety data that could be used to
complement other data generated by the Ministry of Health (MoH) in Brazil. Together, 
these should provide a comprehensive evaluation of routine maternal Tdap vaccination in 
Brazilian women.
8.
RESEARCH QUESTION AND OBJECTIVES
The aim of this retrospective study is to investigate the association between routine 
Refortrix vaccination during pregnancy and specific pregnancy-related adverse events 
(AEs) and AEs in neonates. The AEs identified for this study are those considered 
important in the context of maternal immunization [Zheteyeva, 2012; Kharbanda, 2014] 
and for which it would be feasible to obtain the required data (refer to section 9.1.2).
The diagnosis of pregnancy-related AEs will follow the international case definitions
(refer to Annex 7) and will be obtained directly from the medical records. The list of
outcomes as potential pregnancy-related AEs of interest is derived from literature. Since 
the vaccine is routinely administered in the third trimester of pregnancy, the events that 
are more commonly reported during this period have been chosen as primary endpoints. 
Refer to Annex 2 for the definition of each of these events.
8.1.
Co-primary objectives

To compare the risk of gestational diabetes, pregnancy-related hypertension and 
pregnancy haemorrhage (ante-partum (after 24 weeks of gestation), intra-partum or 
post-partum) in a cohort of women following vaccination with Refortrix as part of 
the maternal immunization program in Brazil (Exposed cohort) with a historical 
cohort of unvaccinated pregnant women before the implementation of this 
immunization program (Unexposed cohort).

To compare the risk of preterm birth and small for gestational age in neonates born 
to subjects in the Exposed cohort and to subjects in the Unexposed cohort.
 
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8.2.
Secondary objectives

To describe the risk of pregnancy-related AEs/neonate-related events of interest 
(premature rupture of membranes, preterm premature rupture of membranes, 
premature uterine contraction, neonatal death, maternal death, still birth and neonatal 
hypoxic ischaemic encephalopathy) in the Exposed and Unexposed cohorts.

To describe the risk of congenital anomalies in neonates in the Exposed and 
Unexposed cohorts.

To describe the risk of pregnancy-related AEs and birth outcomes per calendar year 
in the Unexposed cohort.
9.
RESEARCH METHODS
9.1.
Study design

Type of design: An observational, retrospective, cohort, single-centre study.

This is a Targeted Safety Study (TSS) and a Post-Authorisation Safety Study 
(PASS).

Study population: The study population will consist of two cohorts:

Exposed Cohort (cohort of pregnant women who received Refortrix as part of the 
maternal immunization program in Brazil)

Unexposed Cohort historical cohort of unvaccinated pregnant women before the 
implementation of the immunization program)
Refer to Section 9.3.1 for definition of the study cohorts.

Data collection: electronic Case Report Form (eCRF) based on medical chart review.

Period of data collection: The minimum period of data collection is expected to be 6 
months assuming the availability of the subject medical files adequate to attain the 
sample size required for the analysis. The data of Unexposed subjects who delivered 
during the period from September 2012 to August 2014 will be included. The 
maternal immunization program in Brazil was scheduled to start in September 2014. 
Therefore, the data of Exposed subjects will be collected once the maternal 
immunization program is well implemented in Brazil and the inclusion of data will 
start from May 2015 till the Exposed cohort is enrolled completely.

Epoch 001: Retrospective data collection.
The study cohorts and epoch foreseen in the study are presented in Table 1.
 
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Table 1
Study cohorts and epoch foreseen in the study
Study Cohorts
Approximate number of 
subjects
Age (Min/Max)
Epochs
Epoch 001
Exposed cohort 
1200
18 years-45 years 
x
Unexposed cohort
1200
18 years-45 years 
x
Refer to Section 9.3.2 for definition of the endpoints.
9.1.1.
Discussion of study design
Considering that Refortrix is now routinely recommended for all pregnant women in 
Brazil through the maternal immunization program, randomised controlled trials are not 
considered ethical. Therefore, an observational cohort study provides the opportunity to 
evaluate the safety of this routinely used vaccine.
The feasibility assessment (refer to section 9.1.2 for details) indicated that adequate and 
appropriate data exist and are available to allow a retrospective cohort design to be used, 
with the further advantage of being time efficient.
As maternal immunization with Refortrix is recommended by the Ministry of Health 
(MoH) and vaccine uptake is expected to be high with limited possibility to recruit 
contemporary unvaccinated pregnant women, the comparative cohort (Unexposed) will 
comprise a historical cohort of pregnant women who delivered in the same hospital 
(study centre) in the two years before implementation of the maternal immunization 
program with Refortrix (started in end of 2014) in Brazil.
Considering that more than 20% of the pregnant population in this area in Brazil are 
classified as high risk pregnancies (refer to Annex 6), excluding this group from the study 
would represent an important selection bias and it would decrease the representativeness 
of the study population. In addition, high risk pregnancy is not an exclusion criterion to 
receive the Tdap vaccination according to the maternal immunization guidelines in Brazil
[ESC, 2014]. Therefore the study will include both low and high risk pregnancy women 
as determined and defined by local guidelines [MoH, 2010; MoH, 2012].
9.1.2.
Feasibility assessment
A feasibility assessment was conducted in seven potential study centres from south-east 
Brazil during September 2014-November 2014.The objective was to assess the research 
capabilities and availability of data for the collection of pregnancy-related AEs and 
vaccination data, as well as to identify the most adequate study design for this setting. 
These sites were pre-selected based on their capacity to perform clinical research and 
with an available population of pregnant women that could be enrolled in the study. The 
results of this exercise demonstrated that at least three out of the seven centres evaluated 
have the potential to perform the study and have appropriate data available. The final 
decision to opt for a single centre was due to its recruitment capacity, completeness of 
records of the pregnancy-related AEs/birth outcomes and transcript information from 
antenatal care visits on vaccination exposure for the Exposed cohort. Refer to Annex 6
for details on the feasibility assessment.
 
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9.2.
Setting
9.2.1.
Number of subjects/centres
The study will be conducted in a single centre in south-east Brazil. The subjects who 
delivered in the study centre from May 2015 will be considered as potentially exposed 
and those who delivered before September 2014 will be considered as potentially 
unexposed (the data of Unexposed subjects will be included for the period of September 
2012 – August 2014). The estimated number of subjects to be included in each cohort
(Exposed and Unexposed) is 1200 (total 2400 subjects). Refer to Section 9.5 for a 
detailed description of the criteria used in the estimation of sample size.
The study centre was selected based on the accuracy and completeness observed in the 
medical records. The selected study centre receives approximately 300 pregnant women 
per month for delivery. Refer to Section 9.2.5.1 for details on screening of the subjects.
9.2.2.
Inclusion criteria
Deviations from inclusion criteria are not allowed because they can potentially jeopardise 
the scientific integrity of the study or regulatory acceptability. Therefore, adherence to 
the criteria as specified in the protocol is essential.
All subjects must satisfy ALL the following criteria at study entry:

Subjects between 18 and 45 years of age at the time of pregnancy under 
consideration for the study, who deliver in the study centre.
Note: Only the latest pregnancy in the specified period will be included (to avoid 
multiple pregnancies from the same mother).

Residents of the study area (city of São Bernardo do Campo).

Subjects who were compliant with the routine antenatal care [Gestacao de Alto 
Risco, 2010; Cadernos de Attencao Basica, 2012], including at least one ultrasound 
assessment report early in the pregnancy.

Subjects with the complete and relevant medical records available.
Inclusion criteria for the Exposed cohort:

Subjects who received one dose of Refortrix vaccine in the recommended time 
period between 27 and 36 completed weeks of pregnancy (or as late as 20 days 
before delivery due date) as part of the maternal immunization program in Brazil, 
and according to the program recommendations from May 2015 onwards.

Subjects with appropriate vaccination records.
Inclusion criteria for the Unexposed cohort:

Subjects who had delivered in the same hospital (study centre) before 
01 September 2014 (September 2012-August 2014) and who did not receive Tdap 
vaccination during pregnancy to the best knowledge of the investigator.
 
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9.2.3.
Exclusion criteria
The following criterion should be checked at the time of study entry. If the exclusion 
criterion applies, the subject must not be included in the study:

Subjects who have been transferred to other specialised centres, where their medical 
records would be inaccessible for the study (private clinics, psychiatric or prison 
hospitals, other state hospitals, etc).
9.2.4.
Outline of the study procedures
The study procedures consist only of the collection of retrospective data from the source 
documents (refer to section 9.4 for data sources) available at the study centre.
Table 2 represents the list of procedures in the study.
Table 2
List of study procedures
Epoch 001: Retrospective data collection from medical files
Screening 
O
Check inclusion/exclusion criteria 
●
Allocate subject number 
●
Obtain demographic data 
●
Obtain medical history and gynaecological history
●
Obtain data on vaccination during the pregnancy (Exposed cohort)
●
Record any risk factor of interest *
●
Record clinical data on pregnancy relevant to the specified study 
period** 
●
Record data from physical examination of the neonate
●
Record adverse pregnancy outcome and follow-up 
●
Record intercurrent medical conditions and/or medications***
●
Study conclusion 
●
● is used to indicate a study procedure that requires documentation in the individual eCRF. Details of the data to be 
collected in eCRF are presented in Annex 8.
○ is used to indicate a study procedure that does not require documentation in the individual eCRF.
*Risk factors of interest: Refer to Section 9.3.3 for details.
**In case of multiple pregnancies, details of the latest pregnancy in the specified period will be included.
***The intercurrent medical conditions and/or medications reported at the time of delivery will be recorded.
 
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The events of interest to be collected from the medical files are presented in Table 3.
Table 3
Events of interest to be collected from the medical files
Events*
Time point
Gestational diabetes, pregnancy-related hypertension 
and pregnancy haemorrhage (ante-partum (after 24 
weeks of gestation), intra-partum or post-partum)
After week 27
Preterm birth
After week 27 up to week 37
Small for gestational age
After week 27
Premature rupture of membranes, preterm premature 
rupture of membranes, premature uterine contraction, 
neonatal death, maternal death, still birth, neonatal 
hypoxic ischaemic encephalopathy
After week 27
Congenital anomalies
After week 27 up to birth.
*For definitions, refer to Annex 2.
9.2.5.
Detailed description of study procedures
9.2.5.1.
Screening
Potential subjects in the age range for the study will be identified using the electronic 
admission listings at the centre. This will provide a list of total candidate subjects eligible
for the study. For the Unexposed cohort, to reach an equal number of subjects who 
delivered in each of the two years, a random sample of subjects will be selected each 
month (using Microsoft Excel or equivalent application). This will enable identification 
of 50 eligible subjects per month to reach the required number of 600 subjects per year. 
In contrast, for the Exposed cohort, all subjects who delivered from May 2015 onwards 
will be considered sequentially for enrolment until the total number of 1200 is reached. 
This will facilitate investigating any trends over time in AE reporting.
Only the medical files from those candidate subjects will be evaluated to determine if 
they qualify for the study.
9.2.5.2.
Check inclusion and exclusion criteria
Check all applicable inclusion and exclusion criteria as described in Sections 9.2.2 and 
9.2.3 before enrolment.
9.2.5.3.
Allocate subject number
Subject numbers will be allocated sequentially to the medical file of each subject who has 
been included in the study.
9.2.5.4.
Obtain demographic data, medical and gynaecological antecedents
Age of the subject in years and area of residence will be obtained from the medical file. 
Medical history including diabetes, hypertension and haemorrhage in previous 
pregnancies will be obtained. The gynaecological history including parity, type of 
 
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delivery, pre-vaccination ultrasound report and delivery month/year will be obtained if 
applicable.
9.2.5.5.
Obtain concomitant vaccination history (Exposed cohort)
The information on Refortrix vaccination during pregnancy including gestational age 
when the vaccination was administered and date of administration will be obtained from 
the vaccination section in the medical file. Also, the information on any concomitant 
vaccination administered during the pregnancy will be obtained.
9.2.5.6.
Record risk factors
All the available data on risk factors will be obtained from medical file (refer to Annex 
8).
9.2.5.7.
Record clinical data of pregnancy
All the events of interest (refer to Table 3) diagnosed and recorded in the medical file in 
the period after 27 completed weeks of the pregnancy will be included. Other pregnancy 
events will not be evaluated.
9.2.5.8.
Record data from physical examination of neonate
Height, weight, head circumference, Apgar scores and birth complications will be 
obtained from medical file of the mother.
9.2.5.9.
Record adverse pregnancy outcome
Adverse pregnancy outcomes and pregnancy-related or neonate-related events of interest
will be recorded.
9.2.5.10.
Record intercurrent medical conditions/medications
Intercurrent medical conditions and medications reported at the time of delivery, if any,
will be recorded.
9.2.5.11.
Study conclusion
The investigator will:

review all the data collected to ensure accuracy and completeness

complete the Study Conclusion screen in the eCRF.
The information on pregnancy-related AEs/outcomes and birth outcomes will be obtained 
from medical file according to the details on final visit available in the medical file.
 
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9.3.
Variables
9.3.1.
Study cohort definitions

Exposed cohort: Women, 18-45 years of age at the time of pregnancy, who delivered
in the hospital (study centre) from May 2015 and who received one dose of Refortrix
during 27 to 36 weeks of pregnancy (or as late as 20 days before delivery due date) 
as part of the maternal immunization program in Brazil. The index date will be 
considered as the date of Refortrix administration or where not specified, as 27 
completed weeks of gestation.

Unexposed cohort: Women, 18-45 years of age at the time of pregnancy, who 
delivered in the hospital (study centre) before implementation of the maternal 
immunization program in Brazil in September 2014 and who did not receive Tdap 
vaccination during pregnancy as per information of the investigator. The Unexposed
cohort will include those subjects who had delivered in the period during September 
2012-August 2014. This period was chosen because Tdap vaccine was not 
administered to pregnant women before the maternal immunization program was 
implemented in the country.
9.3.2.
Endpoints
9.3.2.1.
Co-primary endpoints

Occurrence of any of the following pregnancy-related AEs in Exposed and 
Unexposed subjects.

Gestational diabetes.

Pregnancy-related hypertension (including pre-eclampsia, eclampsia and 
HELLP syndrome).

Pregnancy haemorrhage (ante-partum (after 24 weeks of gestation), intra-partum
or post-partum).

Occurrence of any of the following outcomes in neonates from Exposed and 
Unexposed subjects.

Preterm birth.

Small for gestational age.
9.3.2.2.
Secondary endpoints

Occurrence of pregnancy-related AEs of interest/neonate-related events up to 
delivery in Exposed and Unexposed subjects.

Premature rupture of membranes.

Preterm premature rupture of membranes.

Premature uterine contraction.
 
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
Neonatal death.

Maternal death.

Still birth.

Neonatal hypoxic ischaemic encephalopathy.

Occurrence of congenital anomalies in the neonates of Exposed and Unexposed 
subjects.

Occurrence of pregnancy-related AEs and birth outcomes per calendar year in the 
Unexposed cohort.
9.3.3.
Potential confounding factors
Age of the mother and high risk pregnancy are considered as important confounding 
factors for the occurrence of pregnancy-related AEs of interest, so they will be controlled 
in the analysis.
Other potential important confounding factors associated with onset of the outcomes of 
interest will also be collected: smoking, multiparity, multiple births, assisted fertilisation, 
congenital anomalies (in parents or first degree relatives), alcohol consumption and 
recreational drug use. Antecedents of previous pregnancies would be predictive factors 
for the development of a pregnancy-related AE and where available, they will be 
described. These are: history of spontaneous abortion/ miscarriage, preterm delivery, 
preterm premature rupture of membranes (P-PROM), red blood cell isoimmunisation 
[e.g., D-Rh (Rhesus factor) sensitised], pre-eclampsia, eclampsia and major congenital 
anomalies during previous pregnancies. Other conditions of interest to record are 
hypertension, diabetes and anaemia.
Further, confounders may include multi-foetal gestation, diagnosis of a foetus with 
aneuploidy or a major congenital anomaly, cervical insufficiency or incompetent cervix, 
premature contractions, bleeding throughout the gestation, gestational hypertension, 
maternal immunization with diphtheria, hepatitis B or other vaccines [Exposed cohort
(refer to section 9.2.5.5)] and an active infection (treated or untreated).
The study will start monitoring for pregnancy outcomes on the day of vaccine 
administration for the Exposed cohort and at 27 completed weeks of gestation for the 
Unexposed cohort, and end at the date of delivery. Only the outcomes of interest 
diagnosed and described in the medical files during the risk period will be included in the 
study. For details, refer to Table 3. The study outcomes would be accounted in the same 
risk period for both the Exposed and Unexposed cohorts.
9.4.
Data sources
This retrospective study will use the medical files and other hospital documents 
(admission list, images and other test results, etc.) for collecting demographic data, 
medical/gynaecological history, pregnancy-related AEs of interest and AEs in neonates. 
No intervention or additional evaluation will be done on the diagnosis or evaluation of 
 
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these events and only the final diagnosis as described in the source document will be 
included in the study. 
To evaluate the vaccination, the information in the anamnesis and pregnancy card
archived in the medical files will be used as the only source.
9.5.
Study size
The background proportions of different safety outcomes from publications [Munoz, 
2005; Zheteyeva, 2012; Goldfarb, 2014; Passini, 2014] and as reported in the feasibility 
assessment from Brazil are summarised in Table 4 below.
Table 4
Background proportions of different safety outcomes
Safety Outcome
MUNOZ 2005 
(Influenza Vaccination) 
- Proportion
GOLDFARB
2014*-Proportion
Feasibility assessment-
Proportion
(Brazil local data)
Exposure
VAC
UNVAC
VAC
UNVAC
UNVAC
Co-Primary endpoints
Gestational Diabetes
2.2%
1.7%
2.95%
(2.53-3.64)
Pre-eclampsia
4.8%
3.9%
1.6%
Vaginal or Intrauterine 
haemorrhage
16.4%
Preterm Delivery
7.8%
21.2%
Around 10%
Secondary endpoints
Congenital Anomalies
0.79%
Transient Hypertension
6.7%
2.9%
14.3%
Eclampsia
1.6%
Premature Rupture of 
Membranes
2.6%
2.4%
3.53%
Still Birth
0.31%
VAC: Vaccinated group
UNVAC: Unvaccinated group
* Tdap vaccine coverage of 81.6%
Sample size:
The background proportions from the feasibility reports and literature for some of the co-
primary endpoints ranged from 1.6% - 16.4%, from 0.79% - 10% for some of the 
secondary endpoints and unknown for the rest of the endpoints (refer to Table 4), besides
the power estimation for each endpoint were assessed in Table 5. Therefore, a 
conservative proportion of 3% was chosen for the sample size calculation.
Using a two-sided (alpha = 0.01) test, assuming the ratio of subjects in the Exposed 
cohort to the Unexposed cohort is 1:1 and assuming a background proportion of events in 
the Unexposed cohort to be 3%, a total of 2400 subjects [(1200 subjects in each cohort]
will be needed to have more than 80% power to detect a relative risk of 2 or higher.
The power estimation of each safety outcome with background proportions is presented 
in Table 5.
 
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Table 5
Power estimation of each safety outcome with background 
proportions from the feasibility assessment without multiple 
adjustment and sample size of 1200 subjects in each cohort
Safety outcome
Assumed 
background 
proportion
Alpha level
Two-sided
Ratio between 
vaccinated and 
control
Power for 
RR=2(%)*
Co-primary endpoints
Gestational Diabetes
0.0295
0.05
1:1
94.0
Pre-eclampsia
0.016
0.05
1:1
72.6
Vaginal or intrauterine 
haemorrhage
0.164
0.05
1:1
>99.9
Preterm Delivery
0.1
0.05
1:1
>99.9
Secondary endpoints
Congenital anomalies
0.0079
0.05
1:1
43.2
Transient Hypertension
0.143
0.05
1:1
>99.9
Premature Rupture of 
Membranes
0.0353
0.05
1:1
>99.9
Still birth
0.0031
0.05
1:1
20.0
Two independent proportions were used for the sample size calculation in PASS.
*RR: Relative risk
The sample size and power estimation is presented in Table 6.
Table 6
Sample size and power estimation without and with multiple 
adjustment for background proportions of 3% and 5% and relative 
risk of 2
Assumed 
background 
proportion
Multiple 
comparisons
Alpha 
level
Two-
sided
Number of 
vaccinated 
subjects
Ratio between 
vaccinated and 
control
Total Number 
of subjects 
needed
Power (%)
0.03
1
0.05
749
1:1
1498
80
0.05
1
0.05
435
1:1
870
80
0.03
5
0.01
1114
1:1
2228
80
0.05
5
0.01
647
1:1
1294
80
Two independent proportions were used for the sample size calculation in PASS.
Bonferroni adjustment was used for adjustment of alpha level.
9.6.
Data management
A validated GSK defined electronic data collection tool will be used as the method for 
data collection.
In all cases, Personally Identifiable Information (PII) will not be collected nor transmitted 
to GSK (refer to Annex 2 for definition). Subject data necessary for analysis and 
reporting will be entered into a validated database or data system. Clinical data 
management will be performed in accordance with applicable GSK standards and data 
cleaning procedures.
While completed eCRFs are reviewed by a GSK Biologicals’ Site Monitor at the study 
site, omissions or inconsistencies detected by subsequent eCRF review may necessitate 
 
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clarification or correction of omissions or inconsistencies with documentation and 
approval by the investigator or appropriately qualified designee. In all cases, the 
investigator remains accountable for the study data. Refer to Annex 8 for details.
Once the database is archived and the study report is complete and approved by all 
parties, the participating investigator will be provided with a CD-ROM of the final 
version of the data generated from the investigational site.
9.7.
Data analysis
All the statistical calculations will be done in SAS 9.2 or higher.
In case of multiple pregnancies, only the latest pregnancy in the specified period will be 
included in the study to avoid correlation of the safety endpoints from different 
pregnancies for one subject. The latest pregnancy will be considered in the study and the 
analysis.
9.7.1.
Cohorts for analyses
9.7.1.1.
Total Cohort (TC)
The TC will include all subjects enrolled in the study. All the information for these 
subjects will be entered in the eCRF.
9.7.1.2.
According-To-Protocol (ATP) Cohort
The ATP cohort will include all the evaluable subjects (i.e. those meeting all eligibility 
criteria, complying with the procedures defined in the protocol).
9.7.2.
Analysis of demographics and baseline characteristics
The baseline and demographic characteristics of the Exposed and Unexposed cohorts will 
be tabulated in a summary of statistics (mean, median, standard deviation and range) 
including age and gestational age.
9.7.3.
Analysis of co-primary endpoints
The main analysis for co-primary objectives will contain only the subjects with 
vaccination date in the Exposed cohort and subjects from the Unexposed cohort. If more 
than 10% of subjects have missing vaccination date in the Exposed cohort, a sensitivity 
analysis will be performed using the imputed vaccination date to 27 completed weeks of 
gestational age to evaluate if this has any potential impact on the results.
The risk for each primary endpoint (gestational diabetes, pregnancy-related hypertension, 
pregnancy haemorrhage, preterm birth and small for gestational age) will be calculated.
For each specific endpoint, the number of subjects where the event occurred [between the 
index date (refer to Annex 2 for definition of index date) and the date of the delivery] will 
be divided by the total number of subjects at risk for both the Exposed and Unexposed 
 
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cohorts respectively, together with its exact 95% confidence interval (CI).The co-primary 
endpoints of pregnancy (gestational diabetes, pregnancy-related hypertension and 
pregnancy haemorrhage) will be pooled together and of birth outcome (preterm birth and 
small for gestational age) will be pooled together in addition. The analysis of the risk for 
the pooled endpoints will be performed using the same method as for the separate co-
primary endpoints.
The comparison of the risk with its two sided 95% CI of each primary endpoint between 
the Exposed cohort and the Unexposed cohort will be obtained by means of logistic
regression model, using the exposure status as a binary independent variable in the 
model. Absence of increased risk will be concluded if this CI contains 1.
Univariate analysis will describe the association between Tdap vaccination status,
maternal age, parity and gestational age.
A multiple logistic regression model will be fitted with a backward selection to identify 
the possible confounding factors for each of the primary safety event using an alpha level 
of 0.1. Potential confounders will be parity, age of the mother at the start of the 
pregnancy and congenital anomalies (in parents or first degree relatives). Adjusted odds 
ratio (OR) and its 95% CI will be derived from the final model.
9.7.4.
Analysis of secondary endpoints
The risk for each secondary endpoint (pregnancy-related AEs and birth outcomes) will be 
calculated by the number of subjects with at least one of the each event occurring 
between the index date (refer to Annex 2 for definition of index date) and the date of the 
delivery, corresponding to that endpoint divided by the total number of subjects at risk for 
both the Exposed and Unexposed cohort, together with its exact 95% CI. If more than 
10% of subjects have missing vaccination date in the exposed cohort, a sensitivity 
analysis will be performed as for the co-primary endpoints.
In addition, the risk of all the co-primary and secondary endpoints will be calculated by 
calendar year as well to evaluate the comparability among the Exposed and Unexposed 
cohorts.
9.7.5.
Handling of missing data
Missing or non-evaluable primary and secondary outcome measurements will not be 
replaced. Therefore, the main analysis will exclude subjects with missing or non-
evaluable data.
A sensitivity analysis will also be performed if more than 10% of the measurements are 
missing for each endpoint. In the first instance, missing outcomes will be imputed with a 
value of ‘0’. In the second instance, all missing outcomes will be imputed with a value of 
‘1’. The risk for each endpoint will then be analysed using similar methods as mentioned 
in sections 9.7.3 and 9.7.4 for all the co-primary and secondary endpoints.
For subjects in the Exposed cohort whose date of the vaccination is not available, it will 
be imputed to the completed 27th gestational week as the recommended start time for the 
vaccination for the sensitivity analysis.
 
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9.7.6.
Conduct of analysis
9.7.6.1.
Sequence of analyses
The statistical analyses will be performed when all data are available. All analyses will be 
performed on final and clean data.
9.7.6.2.
Statistical considerations for interim analyses
No interim analyses are planned for this study.
9.8.
Quality control
GSK will monitor the study to verify that the data are authentic, accurate, and complete. 
Direct access to all study-site related and indirect access to source data is mandatory for 
the purpose of monitoring review. 
While completed eCRFs are reviewed by a GSK Biologicals’ Site Monitor at the study
site, omissions or inconsistencies detected by subsequent eCRF review may necessitate
clarification or correction of omissions or inconsistencies with documentation and
approval by the investigator or appropriately qualified designee. In all cases, the
investigator remains accountable for the study data.
To ensure compliance with Good Clinical Practice (GCP) and all applicable 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. If an audit or inspection occurs, the 
investigator and institution agree to allow the auditor/inspector direct access to all 
relevant documents and to allocate his/her time and the time of his/her staff to the 
auditor/inspector to discuss findings and any relevant issues.
The final study dataset will be archived and stored on a secured, access limited, computer 
platform SAS Drug Development (SDD) according to GSK Biological Standard 
Procedures. Specific statistical programs will be written in SAS 9.2 (or higher) and 
validated according to the GSK standard procedures. The validation of the quality control 
(QC) of the statistical analysis will be documented. All statistical programs, output files 
and QC documentation will be saved as read-only files on SDD.
The final study protocol and possible amendments, the final statistical report and the QC 
document, and the final study report(s) will be archived on a Document management 
system based on the Documentum platform: Computer Aided Regulatory Submission 
(CARS).
9.9.
Limitations of the research methods
There is a possibility that timing of events with respect to the exposure may not always 
be captured with appropriate accuracy, particularly with retrospective studies which make 
use of the existing data (which may be limited). However, considering that the antenatal 
 
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care visits at regular intervals are standard of care in Brazil [MoH, 2010; MoH, 2012], the 
e appropriate documentation of vaccination and pregnancy events for the Exposed cohort,
and pregnancy events for the Unexposed cohort is expected. This will allow the 
determination of the timing of the events as compared to the moment of the exposure. 
The availability of these data was checked during the feasibility assessment (refer to
Annex 6).
Incomplete and imprecise medical records could lead to bias and misclassification of the 
events. To minimise this, the feasibility assessment was performed in the study centre 
selected to determine the quality and completeness of the medical records for both 
vaccination exposure and pregnancy outcomes. The pregnancy outcomes diagnosed at the 
study centre during the pregnancy are recorded. However, for some of the outcomes this 
may be the earliest date of diagnosis at the site rather than the actual date of onset. 
Therefore, date of diagnosis will be used based on the assumption that it is the date of 
onset, although this may not be the case in some instances and is recognised as being a 
limitation of the study.
The information on concomitant vaccinations administered during pregnancy will not be 
available for the Unexposed cohort, but this information can be retrieved for the Exposed 
cohort. This will prevent formal quantitative comparison with the Unexposed cohort and
is a limitation of the study. However, the availability of information on other vaccines 
given to pregnant women who received Tdap will enable some insight and comment on 
whether any increased safety signal observed may be solely attributed to Refortrix.
Congenital anomalies diagnosed at birth will be used as there will be no post-delivery 
follow-up visit. Therefore, anomalies which may manifest at a later stage will not be 
captured.
For vaccinated subjects, whilst the date of Refortrix vaccination is being systematically 
collected, there is a possibility that it may not always be available with the appropriate 
level of accuracy needed. For example, index date (refer to Annex 2 for definition) may 
not always be available from the medical files with no feasible means of subsequently 
obtaining this information. The potential lack of the date of Refortrix vaccination for 
every subject in the Exposed cohort is therefore considered as a study limitation. Since 
the subjects will not be contacted during the study, the assumption will therefore be made 
that the index date is 27 completed weeks of gestation, which is the earliest time point to 
receive the vaccination from the maternal immunization program in Brazil. The number 
of women without the date of Refortrix administration will therefore be assessed 
following the data collection, if more than 10% of them are without the date of Refortrix
administration, a sensitivity analysis will be performed on top of the primary analysis 
(refer to section 9.7.3 for details) (as this could create a potential selection bias in the 
Exposed cohort compared to the Unexposed cohort).
Another potential limitation is the possibility that the maternal Tdap vaccination program 
itself may have influenced the attitude of pregnant women towards attending antenatal 
care or medical consultation. This could potentially lead to an increased frequency of 
reporting of pregnancy-related AEs. However, the evaluation done during the feasibility 
assessment that was confirmed by other studies performed at the study centre indicated a 
high acceptance of vaccination in the study population with no changes in the reporting 
or ascertainment of the expected pregnancy-related AEs. Therefore, the Exposed and 
Unexposed cohorts are assumed to be comparable.
 
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When using a historical cohort as the unexposed comparison group, caution is required
due to potential bias from changes over time and confounding factors including
differences in standard of care and pregnancy management practices (from the 
perspective of both the pregnant woman and the health care professional). Using a 
comparative cohort collected over two calendar years will provide some capacity to 
identify any such potential differences in relation to the Exposed cohort.
9.10.
Other aspects
Not Applicable.
10.
PROTECTION OF HUMAN SUBJECTS
The study will be conducted in accordance with the International Conference on 
Harmonisation (ICH) Guideline for Good Clinical Practice (GCP), applicable local 
guidelines in Brazil, all applicable subject privacy requirements and the guiding 
principles of the Declaration of Helsinki.
GSK will obtain favourable opinion/approval to conduct the study prior to a site initiating 
the study in that country or will document that neither a favourable opinion nor an 
approval to conduct the study is needed.
Conduct of the study includes, but is not limited to, the following:

Independent Ethics Committee (IEC)/ Comissão Nacional de Ética em Pesquisa 
(CONEP) review and favourable opinion/approval of study protocol and any 
subsequent amendments.
As this study will be based on a retrospective analysis from medical records, informed 
consent will not be requested from the subjects in this study [PAHO, 2005] and a waiver 
from this process will be requested by the investigator from the IEC and CONEP.
No contact will be established with the subjects to obtain, clarify or record information
and anonymisation of source data will be guaranteed.
10.1.
Data Privacy
Data privacy will be protected by using anonymised individual data (refer to Annex 2 for 
definition of anonymised data). No Personally Identifiable Information (PII) will be 
collected in the study, including date of birth. No GSK Biologicals personnel or delegates 
will have the ability to link data to an identifiable individual.
11.
MANAGEMENT AND REPORTING OF ADVERSE 
EVENTS/ADVERSE REACTIONS 
According to the 06 June 2013 European Medicines Agency (EMA) - EMA/873138/2011 
Guideline on Good Pharmacovigilance Practices (GVP) [EMA, 2013], the sponsors of 
 
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non-interventional studies based on secondary data sources are not required to report 
suspected adverse events or adverse reactions as Individual Case Safety Reports 
(VI.C.1.2.1).
Only the pregnancy and birth outcomes related to primary and secondary objectives (refer 
to section 8) will be recorded and collected retrospectively from the subjects participating 
in the study. Other post-vaccination AEs or Serious Adverse Events (SAEs) have been 
collected and reported to the national pharmacovigilance system Notivisa, [Notivisa, 
2015] as per the country regulations.
12.
PLANS FOR DISSEMINATING AND COMMUNICATING 
STUDY RESULTS
12.1.
Posting of information on publicly available registers and 
publication policy
Study information from this protocol will be posted on publicly available clinical trial 
registers following finalisation of the protocol and, whenever possible, before initiation of 
the data extraction/ analysis.
Summary results of observational studies that are designed to inform the safety, 
effectiveness, including cost-effectiveness, of GSK vaccines/products (and other 
informative studies) are publicly registered within 8 months of completion of the 
analysis. GSK also aims to publish the results of these studies in the searchable, peer 
reviewed scientific literature; manuscripts are submitted within 18 months of the 
completion of the analysis. At the time of publication, this protocol will be fully 
disclosed.
12.2.
Provision of study results to investigators
Where required by applicable regulatory requirements, the investigator signatory will be 
requested for the approval of the study report. The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually-agreed 
location.
 
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13.
REFERENCES
Advisory Committee on Immunization Practices (ACIP) Updated Recommendations for 
Use of Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine 
(Tdap) in Pregnant Women, 2012. Morb Mortal Wkly Rep 2013; 62(07):131–5.
Brazilian National Pharmacovigilance Centre: An Overview of Case Safety Reports 
Assessment (Notivisa). 
http://portal.anvisa.gov.br/wps/wcm/connect/db01ad004a07fdeda2a4abaa19e2217c/Poste
r.pdf?MOD=AJPERES. Accessed: 11 September 2015.
Cadernos de Attencao Basica, 2012. 
http://bvsms.saude.gov.br/bvs/publicacoes/cadernos_atencao_basica_32_prenatal.pdf. 
Accessed on 11 September 2015.
Centers for Disease Control and Prevention (CDC). Pregnancy and Whooping Cough: 
Vaccine safety. http://www.cdc.gov/pertussis/pregnant/hcp/vaccine-safety.html. 
Accessed: 11 September 2015.
Centers for Disease Control and Prevention (CDC). Birth Defects and Genetic Diseases 
Branch 6-digit Code for Reportable Congenital Anomalies 1996. 
http://www.cdc.gov/ncbddd/birthdefects/documents/MACDPcode0807.pdf. Accessed:
11 September 2015.
Epidemiological surveillance center (ESC) Informe Técnico – Vacina difteria, tétano e 
coqueluche (dtpa) - outubro de 2014, Governo do estado secretaria de estado da saúde 
coordenadoria de controle de doenças centro de vigilância epidemiológica. 
http://www.cve.saude.sp.gov.br/htm/imuni/pdf/IF14_VAC_DTpa.pdf. Accessed: 
11 September 2015.
European Medicines Agency (EMA) - EMA/873138/2011 Guideline on Good 
Pharmacovigilance Practices. 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2013/06/
WC500144009.pdf. Accessed: 11 September 2015.
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(4), 334.e1–334.e5.
Gestacao de Alto Risco,2010. 
http://bvsms.saude.gov.br/bvs/publicacoes/gestacao_alto_risco.pdf. Accessed on 11
Spetember 2015.
Goldfarb IT, Little S, Brown J, Riley LE. Use of the combined tetanus-diphtheria and 
pertussis vaccine during pregnancy. Am J Obstet Gynecol 2014; 211:299.e1-5
Healy CM, Baker CJ. Prospects for prevention of childhood infections by maternal 
immunization. Curr. Opin. Infect. Dis 2006; 19(3), 271–6.
 
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Keller-Stanislawski B, Janet AE, et al. Safety of immunization during pregnancy: A 
review of the evidence of selected inactivated and live attenuated vaccines. Vaccine 2014, 
(32) 7057–7064.
Kharbanda EO, et al. Evaluation of the Association of Maternal Pertussis Vaccination 
With Obstetric Events and Birth Outcomes. JAMA 2014, 312(18):1897-1904.
Ministry of Health (MoH) Manual técnico Gestacao de Alto Risco 2010. 
http://bvsms.saude.gov.br/bvs/publicacoes/gestacao_alto_risco.pdf. Accessed: 
11 September 2015.
Ministry of Health (MoH) Cadernos de Atencao Basica 2012. 
http://bvsms.saude.gov.br/bvs/publicacoes/cadernos_atencao_basica_32_prenatal.pdf. 
Accessed: 11 September 2015.
Ministry of Health (MoH) Informe Técnico para Implantação da Vacina Adsorvida 
Difteria, Tétano e Coqueluche (Pertussis Acelular) Tipo adulto – dTpa, Ministério da 
Saúde Secretaria de Vigilância em Saúde Departamento de Vigilância Epidemiológica 
Coordenação Geral do Programa Nacional de Imunizações, Brasília, Setembro 2014. 
http://www.cve.saude.sp.gov.br/htm/imuni/pdf/IF14_VAC_DTpa.pdf. Accessed: 
11 September 2015
Munoz FM, Greisinger AJ, Wehmanen OA, Mouzoon ME, Hoyle JC, Smith FA, et al., 
Safety of influenza vaccination during pregnancy. Am J Obstet Gynecol 2005; 192: 1098-
1106.
Munoz FM, Sheffield JS, Beigi RH et al. Research on vaccines during pregnancy: 
Protocol design and assessment of safety. Vaccine. 2013; 31(40): 4274-4279. 
http://dx.doi.org/10.1016/j.vaccine.2013.07.042
Murphy TV, Slade BA, Broder KR, Kretsinger K, Tiwari T, Joyce MP, et al., Prevention 
of Pertussis, Tetanus, and Diphtheria Among Pregnant and Postpartum Women and Their 
Infants. Recommendations of the Advisory Committee on Immunization Practice (ACIP)
2008. MMWR. http://www.cdc.gov/MMWR/preview/mmwrhtml/rr5704a1.htm.
Accessed: 11 September 2015.
Passini R Jr, Cecatti JG, Lajos GJ, Tedesco RP, Nomura ML, et al. Brazilian Multicentre 
Study on Preterm Birth (EMIP): Prevalence and Factors Associated with Spontaneous 
Preterm Birth. PLoS One 2014, 9(10): e109069.
Pan American Health Organization (PAHO) BUENAS PRÁCTICAS CLÍNICAS: 
Documento de las Américas. IV Conferencia Panamericana Para la Armonización de la 
Reglamentación Farmacéutica, República Dominicana 2-4 Marzo 2005. 
http://www.anvisa.gov.br/medicamentos/pesquisa/buenaspracticas_espanol.pdf. 
Accessed: 11 September 2015.
 
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World Health Organization (WHO) SAGE pertussis working group background paper 
2014.
http://www.who.int/immunization/sage/meetings/2014/april/1_Pertussis_background_FI
NAL4_web.pdf. Accessed: 11 September 2015.
Zheteyeva YA, Moro PL, Tepper NK, Rasmussen SA, Barash FE, Revzina NV,et al. 
Adverse event reports after tetanus toxoid, reduced diphtheria toxoid, and acellular 
pertussis vaccines in pregnant women. Am J Obstet Gynecol 2012; 207(1):59.e1–7.
 
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Annex 1
List of stand-alone documents
No.
Document Reference No
Date
Title
1
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2
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Glossary of terms
3
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Trademarks
4
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List of principal and coordinating investigators
5
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Sponsor Information
6
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Feasibility assessment
7
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Definitions and evaluations of selected terms and 
adverse events of interest in pregnant women 
participating in clinical trials (adapted from [Munoz, 
2013])
8
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Planned variables to be collected in electronic 
Case Report Form (eCRF)
9
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Recommendations for Refortrix vaccine in Brazil
10
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Protocol Sponsor Signatory Approval 
11
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Protocol Investigator Agreement 
12
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ENCePP checklist for study protocols
 
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Annex 2
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 unfavourable 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.
Anonymised data:
Information about an individual that GSK or a third party 
cannot reasonably attribute to the individual, or could 
only attribute to the individual by expending a 
disproportionate amount of time, effort or expense (e.g. 
de-identified or aggregated information). For the purpose 
of this policy, Key-Coded personally identifiable 
information shall not be considered Anonymised 
Information
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). 
Congenital anomalies:
The collection of congenital anomalies is based on the 
Centers for Disease Control and Prevention (CDC) 
Metropolitan Atlanta Congenital Defects Program 
(MACDP) guidelines [CDC, 2015] and include 
morphological, functional, chromosomal or genetic 
anomalies, regardless of whether detected at birth or not, 
the foetus is delivered dead or alive, or defects are 
identified by prenatal ultrasound, amniocentesis or 
examination of the products of conception.
Live-born neonates with transient (postural) defects, 
infectious conditions or biochemical disorders are 
classified as being without congenital anomalies unless 
there is a reasonable possibility that the condition reflects 
an unrecognised congenital birth defect.
 
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Eclampsia:
Features of pre-eclampsia are accompanied by new onset 
generalized seizures. See more at Pregnancy-related 
hypertension.
Eligible:
Qualified for enrolment into the study based upon strict 
adherence to inclusion/exclusion criteria.
Epidemiological study:
An observational or interventional study without 
administration of medicinal product(s) as described in a 
research protocol.
Epoch:
An epoch is a self-contained set of consecutive time 
points or a single time point from a single protocol. Self-
contained means that data collected for all subjects at all 
time points within that epoch allows to draw a complete 
conclusion. Typical examples of epochs are retrospective 
data collection and prospective data collection, etc.
eTrack:
GSK Biologicals’ tracking tool for clinical/ 
epidemiological trials.
Evaluable:
Meeting all eligibility criteria, complying with the 
procedures defined in the protocol, and, therefore, 
included in the according-to-protocol (ATP) analysis (see 
Section 9.7.1.2 for details on criteria for evaluability).
Gestational Age:
Gestational age is based on first day of the last menstrual 
period (LMP) OR the first trimester ultrasound, if no 
known date of LMP OR known date of fertilisation; with 
the second trimester beginning at week 14 0/7, and the 
third trimester beginning at week 28 0/7.
Gestational diabetes:
Onset or first recognition of abnormal glucose tolerance 
during pregnancy (the diagnosis is based on 
administration of glucose challenge test at 24-28 weeks of 
gestation). Includes Class A1: Euglycaemia achieved with 
diet and/or exercise and Class A2: Euglycaemia achieved 
with medication. Refer to Annex 7 for details on 
diagnosis.
HELLP syndrome:
Form of severe pre-eclampsia with associated laboratory 
abnormalities including haemolysis (H), elevated liver 
(EL) function tests and low platelets (LP) with or without 
proteinuria. Refer Pregnancy-related or gestational 
hypertension for more details. Patients are classified as
having partial HELLP syndrome when one or two 
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High-risk pregnancy:
Pregnancy that threatens the health or life of the mother 
or her fetus. Risk factors for a high-risk pregnancy can 
include existing health conditions such as high blood 
pressure, diabetes, being Human Immunodeficiency Virus 
(HIV)-positive, overweight, obesity, multiple births and 
young or old maternal age.
Index date:
For the Exposed cohort, the index date will be the date of 
Refortrix vaccination given as part of the maternal 
immunization program in Brazil. For the Unexposed 
cohort, the gestational age of 27 completed weeks will be 
considered as the index date. Only the events for each 
endpoint occurring after the index date for both groups
will be considered.
Key coded information:
Refers to encoded or otherwise pseudo-anonymised 
Personally Identifiable Information (PII) from which 
direct identifiers have been removed and replaced by a 
unique identifier or random code. Key coded PII shall not 
be considered anonymised information.
Last Menstrual period 
(LMP):
Considered as the first day of the LMP before conception 
(fertilisation) onset. The first day of LMP is equal to first 
day of gestation. The estimated day of conception 
(fertilisation) is calculated as the first day of LMP plus 14 
days.
Live birth:
Delivery of a live infant, regardless of maturity or birth 
weight, as determined by the presence of spontaneous 
respirations, a heartbeat, and spontaneous movement.
Maternal death:
Death of a woman while pregnant or within 42 days of 
termination of pregnancy, irrespective of the duration and 
site of the pregnancy, from any cause related to or 
aggravated by the pregnancy or its management, but not 
from accidental or incidental causes.
Neonatal death:
Death of neonate at any time from birth to 28 days of life, 
regardless of gestational age.
Neonatal hypoxic 
ischaemic 
encephalopathy:
A disturbance of neurological function in the earliest days 
of life in the term infant manifested by difficulty in 
initiation and maintaining respiration, depression of tone 
and reflexes, abnormal level of consciousness and often 
seizures, which may follow an intrapartum hypoxic insult 
or due to another cause.
 
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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.
Personally Identifiable 
Information (PII):
Information which directly (e.g. by name) or indirectly 
(e.g. by one or more identifiers such as height, weight, 
date of birth, initials etc) is considered, either individually 
or in combination, to have the potential to allow 
identification of named individuals. Different 
jurisdictions apply varying criteria to define 'personally 
identifiable data'. In the case of data collected during 
GlaxoSmithKline (GSK) sponsored clinical trials and 
processed via Biometrics and Data Sciences (BDS), the 
true identity of the data of the subject is substituted by a 
code and the "key" linking the code with the true identity 
is held by a third party outside GSK (the investigator). 
These data are generally considered not to be personally 
identifiable.
Placental abruption:
Partial or total placental detachment prior to delivery of 
foetus.
Placenta previa:
Presence of placental tissue overlying or proximate to the 
internal cervical os with or without bleeding, which 
ranges from spotting to haemorrhagic shock.
Post-Authorisation 
Safety Study:
A pharmaco-epidemiological study or a clinical trial 
carried out in accordance with the terms of the marketing 
authorisation, conducted with the aim of identifying or 
quantifying a safety hazard relating to an authorised 
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 authorisation and where 
the investigation of safety is the specific stated objective.
Note: The phrase ‘In accordance with the terms of the 
European marketing authorisation’ 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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Post-partum 
haemorrhage:
Excessive blood loss after delivery i.e. estimated blood 
loss in excess of 500 ml after vaginal delivery and 
estimated blood loss in excess of 1000 ml after Caesarean 
delivery. The other symptoms are ≥10% drop in 
haematocrit, need for blood transfusion, symptomatic 
hypotension, dizziness, pallor and oliguria.
Pre-eclampsia:
An acute pregnancy related hypertensive condition 
characterised by hypertension (>140 and/or >90 mmHg) 
and/or proteinuria (>300 mg in a 24 hour urine specimen) 
occurring after the 20th week of gestation and resumes 
after delivery
Pregnancy/gestational 
duration:
Pregnancy duration will be classified using the gestational 
age according to the duration of pregnancy in number of 
completed weeks:

Preterm will be defined as birth before 37 weeks of 
gestation.

Full term will be defined as birth between 37 and 41 
weeks of gestation.

Post-term will be defined as birth after 41 weeks of 
gestation.
Pregnancy-related 
hypertension:
Blood pressure systolic >140 and/or diastolic >90 mmHg, 
documented in at least two separate measurements after 
20 weeks of gestation, without proteinuria or other 
stigmata of pre-eclampsia, and returning to normal post-
partum. Hypertension usually resolves by 12 weeks post-
partum. For this study, this will include pre-eclampsia, 
eclampsia and HELLP Syndrome.
Premature rupture of 
membranes (PROM):
Spontaneous rupture of foetal membranes that occurs 
before the onset of labour. 
Premature uterine 
contraction:
Uterine contractions without cervical change.
Preterm birth:
Birth before 37 weeks of gestation.
Preterm Premature 
rupture of membranes 
(P-PROM):
Spontaneous rupture of foetal membranes that occurs 
before the onset of labour before 37 weeks of gestation.
Research protocol:
A document that describes the objective(s), design, 
methodology, statistical considerations, and organisation 
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.
 
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Retrospective study:
A study that looks backward in time (e.g., at events that 
occurred in the past; outcomes and exposure can no 
longer be influenced), usually using medical records, 
databases or interviews in order to address one or more 
study objectives. 
Self-contained study:
Study with objectives not linked to the data of another 
study.
Serious Adverse Event 
(SAE):
A SAE is any untoward medical occurrence that:
a.
Results in death,
b.
Is life-threatening,
Note: The term ‘life-threatening’ in the definition of 
‘serious’ refers to an event in which the subject was 
at risk of death at the time of the event. It does not
refer to an event, which hypothetically might have 
caused death, had it been more severe.
c.
Requires hospitalisation or prolongation of existing 
hospitalisation,
Note: In general, hospitalisation signifies that the 
subject has been admitted at the hospital or 
emergency ward for observation and/or treatment 
that would not have been appropriate in the 
physician’s office or in an out-patient setting. 
Complications that occur during hospitalisation are 
also considered AEs. If a complication prolongs 
hospitalisation or fulfils any other serious criteria, the 
event will also be considered serious. When in doubt 
as to whether ‘hospitalisation’ occurred or was 
necessary, the AE should be considered serious.
Hospitalisation for elective treatment of a pre-
existing condition (known or diagnosed prior to 
informed consent signature) that did not worsen from 
baseline is NOT considered an AE.
d.
Results in disability/incapacity, OR
Note: The term disability means a substantial 
disruption of a person’s ability to conduct normal life 
functions. This definition is not intended to include 
experiences of relatively minor medical significance 
such as uncomplicated headache, nausea, vomiting, 
diarrhoea, influenza like illness, and accidental 
trauma (e.g. sprained ankle) which may interfere or 
 
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prevent everyday life functions but do not constitute 
a substantial disruption.
e.
Is a congenital anomaly/birth defect in the offspring 
of a study subject.
Medical or scientific judgement should be exercised in 
deciding whether reporting is appropriate in other 
situations, such as important medical events that may not 
be immediately life-threatening or result in death or 
hospitalisation but may jeopardise the subject or may 
require medical or surgical intervention to prevent one of 
the other outcomes listed in the above definition. These 
should also be considered serious. Examples of such 
events are invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalisation.
Site Monitor:
An individual assigned by the sponsor who is responsible 
for assuring the proper conduct of epidemiological studies 
at one or more investigational sites.
Small for gestational age 
(SGA):
Birth weight less than 10% for infants of same gestational 
age and gender in same population.
Still birth:
Death of the foetus(es) at ≥22 weeks of gestation, 
occurring antepartum or intrapartum.
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.
Subject number:
A unique number identifying a subject, assigned to each 
subject consenting to participate in the study.
 
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Targeted Safety Study:
Studies specifically planned or conducted to examine an 
actual or hypothetical safety concern in a product 
marketed anywhere in the world. This includes any GSK 
sponsored pharmaco-epidemiological study or clinical 
trial conducted anywhere in the world with the aim of 
identifying or quantifying a safety hazard. Although all 
clinical trials collect safety information as a matter of 
routine, only those initiated to examine a specific safety 
concern are considered a targeted safety study.
Vaginal or intrauterine 
haemorrhage:
Vaginal or intrauterine haemorrhage which may be 
caused due to partial or total detachment of placenta or 
due to presence of placental tissue overlying or proximate 
to the internal cervical os with or without bleeding, which 
ranges from spotting to haemorrhagic shock. This 
includes the following diagnosis- placental abruption and 
placenta previa.
 
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Annex 3
Trademarks
The following trademark is used in the present protocol.
Note: In the body of the protocol (including the abstract), the name of the vaccine will be 
written without the superscript symbol ™ and in italics.
Trademark of the GlaxoSmithKline group 
of companies
Generic description
Refortrix™
Combined reduced-antigen-content 
diphtheria, tetanus and acellular pertussis 
(Tdap) vaccine
 
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Annex 4
List of principal and coordinating investigators
The contact details and list of all investigators are available upon request.
 
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Annex 5
Sponsor Information
Sponsor:
GlaxoSmithKline Biologicals
Rue de l’Institut, 89
1330 Rixensart, Belgium
Sponsor Study Monitor:
Refer to the local study contact information document.
 
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Annex 6
Feasibility assessment
The details on feasibility assessment are available upon request.
 
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Annex 7
Definitions and evaluations of selected terms and adverse events of interest in pregnant 
women participating in clinical trials (adapted from Munoz, 2013)
Common terms 
or Adverse 
Events
Definition
Background rates and risk 
factors, if appropriate
Comments
References
PREGNANCY RELATED TERMS
GESTATIONAL 
AGE ESTIMATE
S: Dating of 
Pregnancy
Dating from:
-first day of last menstrual period 
(LMP), 
OR 
-1st trimester ultrasound if no known 
LMP or the ultrasound is not 
consistent with LMP,
OR 
-known date of fertilization (e.g. by 
Assisted Reproductive Technology or 
Intrauterine Insemination).
[ACOG, 2014]
Test for urine or serum β-HCG
-urine test: positive about 10-12 days 
after conception.
-serum test: positive about 5-7 days 
after conception.
The estimated date of conception or 
pregnancy onset is calculated as the 
last menstrual period plus 14 days. 
Ultrasound (US): Gestational age is 
assessed in the 1st trimester (< 14 
weeks) by measurement of crown-rump 
length. In the second trimester (14 to 20 
weeks), the biparietal diameter is used 
(accuracy is within +/- 10 days up to 34 
weeks, then +/- 3 weeks). At term, 
abdominal circumference and femoral 
length are used.
US limited by: insufficient 
standardization, operator variability and 
expertise, lack of large population 
based reference, assumption that all 
fetuses with the same measurements 
have the same gestational age without 
accounting for true differences in fetal 
growth in early gestation or genetic and 
other familiar factors.
-The Committee on Obstetric 
Practice, American Institute of 
Ultrasound in Medicine and Society 
for Maternal-Fetal. Committee 
Opinions: Method for estimating 
Due Date. Number 611, October 
2014 (accessed on-line on 
13/Oct/2014 at: 
http://www.acog.org/Resources-
And-Publications/Committee-
Opinions/Committee-on-Obstetric-
Practice/Method-for-Estimating-
Due-Date).
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Common terms 
or Adverse 
Events
Definition
Background rates and risk 
factors, if appropriate
Comments
References
TRIMESTER OF 
GESTATION 
Pregnancy is divided in three 
trimesters:
-First trimester: up to and including 13 
6/7 weeks of gestation.
-Second trimester: 14 0/7 weeks to 
27 6/7 weeks of gestation.
-Third trimester: 28 0/7 weeks of 
gestation and beyond.
LENGTH OF 
PREGNANCY
Preterm: up to and including 36 6/7 
weeks of gestation.
Term: 37 0/7 weeks through 41 6/7 
weeks of gestation [ACOG, 2013]. 
Early term: Birth at 37 0/7 to <39 
weeks of gestation.
Post-term (S: post-mature): 42 0/7 
weeks of gestation and beyond.
Estimated Date of Delivery (EDD)= 40 
0/7 weeks (280 days) from the first day 
of the last menstrual period or by 
Ultrasound examination.
The American College of 
Obstetricians and Gynecologists 
Committee on Obstetric Practice 
Society for Maternal-Fetal 
Medicine. Committee Opinions: 
Definition of Term Pregnancy. 
Number 579, November 2013 
(accessed on-line on 13/Oct/2014 
at: http://www.acog.org/Resources-
And-Publications/Committee-
Opinions/Committee-on-Obstetric-
Practice/Definition-of-Term-
Pregnancy)
PREGNANCY OUTCOMES
LIVE BIRTH 
S: Live born 
Delivery of a live infant, regardless of 
maturity or birth weight, as 
determined by the presence of 
spontaneous respirations, a 
heartbeat, and spontaneous 
movement
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Common terms 
or Adverse 
Events
Definition
Background rates and risk 
factors, if appropriate
Comments
References
SPONTANEOUS 
ABORTION
S: miscarriage, 
pregnancy loss
Pregnancy ending spontaneously 
before 22 weeks of gestation (i.e. up 
to and including 21 6/7 weeks of 
gestation) [EMEA, 2005]. Includes 
death of embryo/ fetus in utero 
(missed abortion), or blighted ovum 
/anembryonic pregnancy (i.e. 
fertilized ovum whose development 
has ceased at an early stage).
Subgroups:
-Early miscarriage if it occurs during 
the first trimester.
-Late miscarriage when it occurs 
during the second trimester.
Overall rates:  The prevalence of 
spontaneous abortion reported by
several authors among clinical 
pregnancies (i.e. recognized 
pregnancies following a missed 
menstrual period) for all age 
groups combined is about 12-18% 
of all pregnancies in first or second 
trimester.
-Early miscarriage:  Up to 20%of 
pregnancies.
-Late miscarriage:  Up to 2% of 
pregnancies.
Risk factors:  Studies have shown 
that approximately 50% of 
spontaneous abortions are 
associated with fetal chromosome 
abnormalities [Brown 2008].  Many 
studies have shown that maternal 
age is one of the strongest and 
most consistent risk factor.
Note: case definitions vary between 
countries, as definition of viability is 
varied between resource settings (e.g. 
20-24 weeks versus 28 weeks and 
corresponding fetal weight of 500 mgr. 
vs. 1000 mgr).
Document circumstances of fetal loss, 
physical exam/estimated gestational 
age of the product if feasible and/or 
collect results of available studies 
including pathology report of fetus and 
placenta to establish a possible 
etiology, association/causality. Genetic 
testing if available; a karyotype may or 
may not be performed as part of routine 
clinical care. Of note, it may not be 
possible to perform evaluation if the 
subject does not seek medical 
attention. 
- European Medicines Agency 
(Committee for Medicinal Products 
for Human Use). Guideline on the 
Exposure to Medicinal Products 
during Pregnancy: Need for Post-
authorization Data. London, UK: 
EMEA; 2005.
-  Brown S. Miscarriage and its 
associations. Seminars in 
Reproductive Medicine 2008; 26(5): 
391-400.
- Wilcox AJ, Weinberg CR, 
O’Connor JF, Baird DD, Schlatterer 
JP, Canfield RE,et al. Incidence of 
early loss of pregnancy. New 
England Journal of 
Medicine1988;319: 189–94.
- Harlap S, Shiono PH. Alcohol, 
smoking, and incidence of 
spontaneous abortions in the first 
and second trimester. Lancet 1980; 
2:173–6.
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Common terms 
or Adverse 
Events
Definition
Background rates and risk 
factors, if appropriate
Comments
References
STILLBIRTH
S: Stillborn, Fetal 
Demise/Death, 
Deadborn
Delivery of a death fetus after 22 0/7 
weeks of gestation [EMEA, 2005]. 
Categories:
- During pregnancy or antepartum.
- Intrapartum. 
Subgroups:
-Early Stillbirth: Delivery 22 0/7 – <28 
weeks and/or ≥500 -1000 grams.
-Late Stillbirth: Delivery ≥ 28 0/7 
weeks and/or >1,000 grams
Overall rates [ACOG, 2009]:  
6.2/1,000 births or 1 in 160 
deliveries.
-Early stillbirth:  3.2/1,000 births.
-Late stillbirth:  3.1/1,000 births.
Risk factors:  Non-Hispanic black 
race, nulliparity, maternal age >35 
years, hypertension, diabetes, 
obesity BMI >30, multiple 
gestations, smoking, drug and 
alcohol use, infections, growth 
restriction, and placental 
anomalies.
Includes macroscopic examination for 
fetal anomalies, and if available, 
autopsy and karyotype; cord and 
placental examination and pathology. 
Document antepartum events:  
maternal factors, fetal factors (e.g., 
IUGR), external factors (e.g., trauma), 
and peripartum events such as preterm 
premature rupture of membranes 
(PPROM), infection, abruption, cord 
events.
- European Medicines Agency 
(Committee for Medicinal Products 
for Human Use). Guideline on the 
Exposure to Medicinal Products 
during Pregnancy: Need for Post-
authorization Data. London, UK: 
EMEA; 2005.
- American College of Obstetricians 
and Gynecologists. Management of 
stillbirth. ACOG Practice Bulletin 
Number 102. Obstetrics and 
Gynecology2009; 113: 748–61.
(accessed on-line on 13/Oct/2014 
at: 
https://stillbirthmatters.files.wordpre
ss.com/2014/05/acog-
management-of-stillbirth1.pdf)
CONGENITAL 
ANOMALIES
S: Birth defects, 
Malformations
The collection of congenital 
anomalies is based on the Centers 
for Disease Control and Prevention 
(CDC) Metropolitan Atlanta 
Congenital Defects Program 
(MACDP) guidelines [CDC,2007] and 
include morphological, functional, 
chromosomal or genetic anomalies, 
regardless of whether detected at 
birth or not, the fetus is delivered 
dead or alive, or defects are identified 
by prenatal ultrasound, 
amniocentesis or examination of the 
products of conception.
Live-born neonates with transient 
(postural) defects, infectious 
Minor anomaly:  Rates vary widely 
depending on study. Minor 
malformations and developmental 
variants occur in 14 - 40% of 
otherwise normal newborns 
[Leppig, 1987]. 
Major anomaly:  Apparent at birth 
in approximately 3% of population 
[CDC, 2013].
An exact cause or mechanism for a 
major defect can be determined in less 
than 50% of the cases. 
Some agents cause major defects if 
exposure occurs during a specific 
critical period of gestation, but not at 
other times. After organogenesis has 
been completed (about 8 weeks after 
conception or 10 weeks after last 
menstrual period), the observable effect 
may be limited to fetal growth restriction 
or functional rather than gross structural 
defects [Sadler,2009]. 
The primary outcomes relative to stage 
of exposure are as follows:
Pre-implantation: embryonic lethality
Centers for Disease Control. Birth 
defects and genetic diseases 
branch 6-digit code for reportable 
congenital anomalies; 
2007.(accessed on-line on 
13/Oct/2014 at:
http://www.cdc.gov/ncbddd/birthdef
ects/documents/macdpcode0807.p
df)
- Rasmussen SA, Olney RS, 
Holmes LB, Lin AE, Keppler-Noreuil 
KM, MooreCA. Guidelines for case 
classification for the National Birth 
Defects Preven-tion Study. Birth 
Defects Research Part A: Clinical 
and Molecular Teratology2003; 
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Common terms 
or Adverse 
Events
Definition
Background rates and risk 
factors, if appropriate
Comments
References
conditions or certain biochemical 
disorders are classified as being 
without congenital anomalies unless 
there is a reasonable possibility that 
the condition reflects an 
unrecognized congenital birth defect. 
Morphological anomalies: 
Abnormalities of body structure or 
function that are present at birth and 
are of prenatal origin.
Categories:
Minor anomaly:  Anatomic variant or 
defect that do not have serious 
medical, functional or cosmetic 
consequences for the child. Includes 
those found in association with major 
anomalies.
Major anomaly:  Structural or 
functional defect that require 
surgical/medical treatment, have 
serious adverse effects on health or 
development (functional), or have 
significant cosmetic impact. 
[Rasmussen, 2003]. 
Implantation to time of organogenesis: 
morphological defects.
Fetal → neonatal stage: functional 
disorders, growth retardation, 
Carcinogenesis.
A certain pattern of minor 
malformations may have important 
predictive value in identifying more 
serious associated problems, some of 
which may be unrecognizable at an 
early age. Specific patterns of multiple 
minor malformations may be presenting 
signs of a genetic condition or 
malformation syndrome.
67:193–201.
- Leppig KA, Werler MM, Cann CI, 
Cook CA, Holmes LB. Predictive 
value of minor anomalies. 
Association with major 
malformations. Journal of 
Pediatrics1987; 110: 530–7.
-Sadler TW. Langman’s medical 
embryology. 11th ed. Lippincott 
Williams and Q4Wilkins; 2009.
- Centers for Disease Control and 
Prevention. Update on overall 
prevalence of major birth defects-
Atlanta, Georgia, 1978–2005. 
MMWR; 2013. (accessed on-line on 
13/Oct/2014 at: 
http://www.cdc.gov/mmwr/preview/
mmwrhtml/mm5701a2.htm )
ELECTIVE OR 
THERAPEUTIC 
TERMINATION 
OF PREGNANCY
S: Induced 
abortion
Expulsion of products of conception 
with medical or surgical assistance. 
The termination of the pregnancy can 
be elective or therapeutic.
-Elective: performed for personal 
choice/socio-economic reasons, 
excluding maternal or fetal health 
reasons. 
-Therapeutic: performed to preserve 
the health or save the life of a 
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pregnant woman. 
ECTOPIC 
PREGNANCY
S: Extra-uterine 
pregnancy  
Condition in which a fertilized ovum 
implants outside the uterine cavity, 
most often in the fallopian tube 
(97%).
Affects 1.5% to 2% of all 
pregnancies and poses a 
significant threat to women of 
reproductive age. It is the leading 
cause of maternal death during the 
first trimester of pregnancy.
Risk factors: tubal surgery, genital 
tract infections leading to pelvic 
inflammatory disease, previous 
ectopic pregnancy, and in utero 
exposure to diethylstilbestrol 
[ACOG, 2008].
Diagnosis is generally based on: clinical 
symptoms/signs, diagnostic 
transvaginal ultrasonography, abnormal 
serum progesterone level of less than 5 
ng/mL and/or an inappropriate increase 
in hCG.
- Kurt T. Barnhart. Ectopic 
pregnancy. N Engl J Med 2009; 
361:379-87.
- American College of Obstetricians 
and Gynecologists. Medical 
Management of Ectopic Pregnancy. 
ACOG Practice Bulletin Number 94. 
Obstetrics and Gynecology Jun 
2008; 111(6): 1479–85.
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MOLAR 
PREGNANCY
S:  gestational 
trophoblastic 
neoplasia, 
gestational 
trophoblastic 
tumor
Pregnancy marked by a neoplasm 
within the uterus, whereby part or all 
of the chorionic villi are converted into 
a mass of clear vesicles. 
Histologically distinct disease entities 
encompassed by this general 
terminology include: complete and 
partial hydatidiform moles, invasive 
moles, gestational choriocarcinomas, 
and placental site trophoblastic 
tumors.
The incidence is estimated at 1-3 
per 1000 pregnancies for partial or 
complete hydatidiform moles. The 
malignant invasive moles 
(choriocarcinoma and placental 
site trophoblastic 
tumour/epithelioid trophoblastic 
tumour) are very rare, 0.2% of the 
gestational trophoblastic disease 
cases [ESMO, 2013; ACOG, 
2004].
Risk factors:  extremes of maternal 
age and prior molar pregnancy. 
The risk of repeat molar pregnancy 
after 1 mole is about 1%, or about 
10-20 times the risk for the general 
population.
The disease is most frequently 
diagnosed on the basis of increasing or 
plateauing hCG values. Patients should 
be monitored with serial determinations 
of quantitative hCG values. A baseline 
post-evacuation chest X-ray should be 
considered.
-  American College of 
Obstetricians and Gynecologists.  
Diagnosis and Treatment of 
Gestational Trophoblastic Disease.  
ACOG Practice Bulletin Number 53.  
Obstetrics and Gynecology June 
2004; 103 (6):1365-77.
- M. J. Seckl, N. J. Sebire, R. A. 
Fisher, F. Golfier, L. Massuger & C. 
Sessa, on behalf of the ESMO 
Guidelines Working Group. 
Gestational trophoblastic disease: 
ESMO Clinical Practice Guidelines 
for diagnosis, treatment and follow-
up.  Annals of Oncology 2013; 24 
(Supplement 6): vi39–vi50.
PREGNANCY RELATED ADVERSE EVENTS OF INTEREST
VAGINAL OR 
INTRAUTERINE 
HEMORRHAGE 
S: Obstetric 
Hemorrhage, 
Major obstetric 
hemorrhage
Vaginal or intrauterine hemorrhage 
that encompasses antepartum (i.e. 
bleeding from the genital tract after 
24 weeks of gestation), intrapartum, 
and postpartum bleeding (i.e. within 
24 hours post-delivery).  
A major obstetric hemorrhage is 
defined as blood loss from uterus or 
genital tract >1500 mL or a decrease 
Antepartum hemorrhage: has an 
incidence of 2–5% of all 
pregnancies beyond 24 weeks 
[Walfish, 2009]. Infrequent (14% of 
cases occur before 32 weeks 
gestation) and up to 60% between 
32-37 weeks gestation [Munoz, 
2013]. 
Risk factors for placenta previa: 
Given the wide range of definitions 
applied to maternal hemorrhage, it is 
important to combine the clinical 
presentation and objective data, while 
keeping in mind the probability of 
concealed bleeding within the uterus, 
peritoneal cavity, and retroperitoneal 
space, and the relative masking of 
haemodynamic signs of haemorrhagic 
- American College of 
Obstetricians and Gynecologists. 
Cervical insufficiency.  ACOG 
Practice Bulletin No. 76, 
Postpartum Haemorrhage   
International Journal of Gynecology 
and Obstetrics Oct 2006: 108 (4): 
1034-47 (accessed on-line on 
13/Oct/2014 at:
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in hemoglobin of >4 gr/dl or acute 
loss requiring transfusion of >4 units 
of blood, or signs or symptoms of 
hypovolemia. 
Common causes of blood loss:
- Antepartum hemorrhage: placenta 
previa (presence of placental tissue 
overlying or proximate to the internal 
cervical os), placental abruption 
(partial or total placental detachment 
prior to delivery of fetus), uterine 
rupture, bleeding from vaginal or 
cervical lesions, etc.
- Postpartum Hemorrhage: uterine 
atony, retained products of 
conception, abnormal placentation 
(abnormal attachment of the placenta 
to the uterine wall and includes 
accreta, increta, and percreta, 
depending on the extent of uterine 
invasion), genital tract trauma, uterine 
inversion, puerperal sepsis, uterine 
pathology such as fibroids, etc.
prior uterine trauma, multiparity, 
advanced maternal age, previous 
C-section or other uterine surgery, 
and prior placenta previa.
Risk factors for placental 
abruption:   hypertension, pre-
eclampsia, advanced maternal 
age, multiparity, maternal/paternal 
tobacco use, cocaine use, trauma, 
premature rupture of membranes, 
chorioamnionitis, and prior 
abruption.
Risk factors for uterine rupture:  
prior uterine surgery, trauma, 
uterine anomalies, dystocia, use of 
uterotonic drugs, and abnormal 
placentation.
Post-partum hemorrhage: Primary 
postpartum hemorrhage, which 
occurs in 4–6% of pregnancies, is 
caused by uterine atony in 80% or 
more of cases [ACOG,2006].
Risk factors for Postpartum 
Hemorrhage: Prolonged labor, 
Augmented labor, Rapid labor, 
History of postpartum hemorrhage,  
Episiotomy, especially 
mediolateral, Preeclampsia, 
Overdistended uterus 
(macrosomia, twins, hydramnios), 
Operative delivery, Asian or 
Hispanic ethnicity, 
Chorioamnionitis.
Risk factors for abnormal 
shock due to the physiological 
adaptations of pregnancy.
Diagnosis is based on clinical 
presentation; ultrasound and placental 
pathology if available.
https://www.acog.org/~/media/Distri
cts/District%20II/PDFs/Final_Hemor
rhage_Web.pdf
-   Walfish M et al.  Maternal 
haemorrhage. Br. J. Anaesth. 
(2009) 103 (suppl 1): i47-i56.
-Munoz et al.  Research on 
vaccines during pregnancy: 
Protocol design and assessment of 
safety, Vaccine, (2013): 31 (40): 
4274-4279, Appendixes
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placentation: placenta previa with 
or without previous uterine 
surgery, prior myomectomy, prior 
cesarean delivery, Asherman’s 
syndrome, submucous 
leiomyomata, and maternal age 
older than 35 years.
PREMATURE 
RUPTURE OF 
MEMBRANES 
(PROM) 
AND 
PRETERM 
PREMATURE 
RUPTURE OF 
MEMBRANES (P-
PROM)
PROM: Spontaneous rupture of fetal 
membranes that occurs before the 
onset of labor. 
Preterm PROM (P-PROM):
Spontaneous rupture of fetal 
membranes that occurs before the 
onset of labor before 37 weeks 
gestation. 
Term PROM may occur in 8% of 
pregnancies, P-PROM in 
approximately one-third of all 
preterm births or 4% of all births 
[ACOG, 2007].
Risk factors:  Numerous maternal 
and fetal factors involved, 
particularly infection, obstetric 
factors including abruption 
placenta, as well as previous P-
PROM or premature delivery. 
Recurrence for P-PROM is 16-
32%.
Assessment of gestational age and 
assessment of maternal and fetal risks, 
including intrauterine infection, labor, 
fetal compromise. 
-American College of Obstetricians 
and Gynecologists. Premature 
rupture of membranes. ACOG 
Practice Bulletin Number 80. 
Obstetrics and 
Gynecology2007;109:1007–20.
PREMATURE 
UTERINE 
CONTRACTIONS 
AND 
PREMATURE 
LABOR
Premature uterine contractions:  
Uterine contractions without cervical 
change.
Premature labor:  Cervical change in 
the presence of regular uterine 
contractions that occur before 37 
weeks of gestation. 
Refer to incidence of preterm 
delivery: 12% of all live births 
[ACOG, 2012].
Collect any clinical and laboratory 
information that is available. Standard 
work-up may include:  vaginal 
examination, uterine monitoring, and 
fetal monitoring. Work-up to determine 
etiology or association to study product 
may include:  evaluation for infections 
(urine culture, Group B streptococcus, 
Chlamydia, gonococcus, Trichomonas 
vaginalis, bacterial vaginosis), drug 
screen, and ultrasound to rule out 
abruption, cord prolapse, 
oligo/polyhydramnios.
- American College of Obstetricians 
and Gynecologists.  Management 
of preterm labor. ACOG Practice 
Bulletin Number 127. International 
Journal of Gynecology and 
Obstetrics 2012 Jun; 19(6):1308-
17.
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INTRAUTERINE 
GROWTH 
RESTRICTION / 
POOR FETAL 
GROWTH
S: IUGR 
S: Fetal growth 
retardation 
Estimated or actual birth weight 
below the 10th percentile for 
gestational age.
10% of live births [ACOG, 2013].
Risk factors:  Numerous, classified 
as maternal, placental, fetal.
May include ultrasound (specific 
biometric parameters and estimated 
fetal weight), umbilical artery Doppler 
velocimetry, amniocentesis, 
chromosomes, and assessment of 
maternal risk factors (infection, 
hypertension, etc.).
NOTE: curves used to determine %iles 
should account for gender and 
race/ethnicity
- American College of Obstetricians 
and Gynecologists. Fetal Growth 
Restriction. ACOG Committee 
Opinion Number 134. Obstetrics 
and Gynecology May 2013;121: 
1122–33. 
GESTATIONAL 
HYPERTENTION, 
PREECLAMPSIA 
AND ECLAMPSIA
S: Pregnancy 
Related 
Hypertension, 
Pregnancy 
Induced 
Hypertension 
(PIH), Toxemia 
Gestational hypertension:  Blood 
pressure systolic >140 and/or 
diastolic >90 mmHg, documented in 
at least 2 separate measurements 
after 20 weeks of gestation, without 
proteinuria or other stigmata of 
preeclampsia, and returning to 
normal post-partum. Hypertension 
usually resolves by 12 weeks 
postpartum
Pre-eclampsia:  Hypertension (>140 
and/or >90 mmHg) occurring after the 
20th week of gestation, and up to 6 
weeks postpartum, combined with 
other abnormalities such as 
proteinuria (>300 mg in a 24 hr urine 
specimen).
HELLP syndrome:  Form of severe 
pre-eclampsia with associated 
laboratory abnormalities including 
hemolysis (H), elevated liver (EL) 
function tests, and low platelets (LP), 
with or without proteinuria.
Eclampsia:  If the features of pre-
Hypertensive disease occurs in 
12-22% of pregnancies [ACOG, 
2001; ACOG, 2002]. As many as 
25% of women with gestational 
hypertension will develop 
preeclampsia. The reported 
incidence of preeclampsia is 5-8% 
of pregnancies, usually first 
pregnancies. 
Risk factors:  First pregnancy, 
multiple gestation, preeclampsia in 
previous pregnancy, chronic 
hypertension, pre-gestational 
diabetes, vascular and connective 
tissue disorders, nephropathy, 
antiphospholipid antibody 
syndrome, obesity, age >35 years, 
non-Hispanic black race.
Blood pressure elevation should be 
sustained and documented in two 
independent measurements. Additional 
assessments include a random or 24-
hour urine protein determination of 300 
mg/dL, other laboratory testing to 
establish severity and collection of 
available data on fetal well-being.
- American College of Obstetricians 
and Gynecologists. Diagnosis and 
management of preeclampsia and 
eclampsia. ACOG Practice Bulletin 
Number 33.Obstetrics and 
Gynecology 2002; 99:159–67. 
- American College of Obstetricians 
and Gynecologists. Chronic 
hypertension in pregnancy. ACOG 
Practice Bulletin Number 29. 
Obstetrics and Gynecology2001; 
98:177–85.
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eclampsia are accompanied by new 
onset generalized seizures.
Chronic Hypertension with 
superimposed preeclampsia:
Chronic hypertension definition PLUS 
preeclampsia definition
GESTATIONAL 
DIABETES 
MELLITUS
S: Diabetes of 
pregnancy 
Onset or first recognition of abnormal 
glucose tolerance during pregnancy 
(old definition still used by ACOG).
Diagnosis based on administration of 
glucose challenge test at 24-28 
weeks gestation
1% to 14%, with 2-5% being the 
most common figure [ACOG, 
2001]. 
Includes urine glucose measurement 
during routine prenatal care visits; a 
fasting plasma glucose ≥126 mg/dL 
[7.0 mmol/L], or A1C ≥6.5 percent 
using a standardized assay, or a 
random plasma glucose ≥200 mg/dL 
[11.1 mmol/L] that is subsequently 
confirmed by elevated fasting plasma 
glucose or A1C, as noted above. 
Glucose tolerance screening is 
universal at 24-28 weeks of gestation.
- American College of Obstetricians 
and Gynecologists. Gestational 
diabetes. ACOG Practice Bulletin 
Number 30. Obstetrics and 
Gynecology2001;98: 525–38.
MATERNAL 
DEATH
Death of a woman while pregnant or 
within 42 days of termination of 
pregnancy, irrespective of the 
duration and site of the pregnancy, 
from any cause related to or 
aggravated by the pregnancy or its 
management, but not from accidental 
or incidental causes.
Direct obstetric death: death of the 
mother resulting from conditions or 
complications which are unique to 
pregnancy and occur during the 
antepartum, intrapartum, or 
postpartum period.
Indirect obstetric death: A maternal 
death that is not directly due to 
obstetric cause (such as from 
The global maternal mortality rate 
is estimated to be about 210 
maternal deaths per 100,000 live 
births [WHO,2013]. Indirect causes 
and obstetric hemorrhage are the 
largest causes of maternal death 
worldwide. Of the direct causes of 
death, hemorrhage is the leading 
cause of maternal death, followed 
by hypertensive disorders and 
sepsis. Regional estimates varied 
substantially [Say, 2014].
- Trends in Maternal Mortality: 1990 
to 2013. Estimates by WHO, 
UNICEF, UNFPA, The World Bank 
and the United Nations Population 
Division. (accessed on-line on 
13/Oct/2014 at:
http://apps.who.int/iris/bitstream/10
665/112682/2/9789241507226_eng
.pdf?ua=1)
-Lale Say et al, Global causes of 
maternal death: a WHO systematic 
analysis.  Lancet Glob Health 
2014;2: e323–33
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previously existing disease, or 
disease developing during 
pregnancy, labor, or the puerperium 
but that was not unique to 
pregnancy.)
Late Maternal Death: Death of 
woman from direct or indirect causes 
more than 42 days but less than one 
year after termination of pregnancy.
NEONATAL RELATED EVENTS
BIRTH WEIGHT 
(BW) 
Small for gestational age (SGA): Birth 
weight < 10% for newborns of same 
gestational age and gender in same 
population (<2500g at term).
Low birth weight: BW <2500 g (5.5 
lb).
Very low birth weight : BW <1500 g 
(3.3 lb)
Extremely low birth weight:  BW 
<1000 g (2.2 lb).
Large for gestational age (LGA): Birth 
weight > 90% for newborns of same 
gestational age in same population 
(>4000g at term).
High Birth Weight (Macrosomia): BW 
>4000 g (8.13 lb).
SGA newborns are predisposed to 
complications, including 
hypoglycemia, hyperbilirubinemia, 
hypothermia, intraventricular 
hemorrhage, necrotizing 
enterocolitis, seizures, sepsis, 
respiratory distress syndrome, and 
neonatal death.
One of the primary risk factors of 
LGA is poorly-controlled maternal 
diabetes (pre-existing diabetes 
mellitus/gestational). Other risk 
factors in decreasing order of 
importance, are as follows: a 
history of macrosomia, maternal 
weight before pregnancy, weight 
gain during pregnancy, multiparity, 
male fetus, gestational age more 
than 40 weeks, ethnicity, maternal 
birth weight, maternal height, 
maternal age younger than 17 
years and a positive 50g glucose 
screen with a negative result on 
Birth weight: Objective is measurement 
of weight on the day of delivery (OR 
first weight obtained). Varies with 
singleton vs. multiple gestation, 
gestational age, gender, race, ethnicity, 
maternal nutritional status (BMI), and 
maternal health status.
Birth weight is one of the most sensitive 
– and also one of the most important –
measures of the well-being of children. 
Weight at birth is directly influenced by 
the general level of health status of the 
mother. Assessment of Birth Weight is 
in relation to Gestational Age (BW/GA):
-Gestational age should be based on 
best obstetric estimate, usually prenatal 
ultrasound or first day of last menstrual 
period if ultrasound not available; or 
neonatal physical exam.
-Weight should be based on objective 
measurement on the day of birth.
-Estimate of BW/GA should be based 
on population specific curves
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the three-hour glucose tolerance 
test.
PRETERM BIRTH
Birth before 37 weeks of gestation.
Late Preterm: 34 to <37 weeks
Moderate Preterm:  32 to <34 weeks
Very Preterm: 28 to < 32 weeks
Extreme Preterm: < 28 weeks
10-15% of all pregnancies, with 
most recent National Vital 
Statistics Report showing a decline 
to 11.72% in recent years. 
Extreme preterm birth occurs in 
less than 1% of live births [ACOG, 
2003]. 
Includes physical examination and 
determination of gestational age, and 
evaluation for maternal or infant causes 
of premature delivery. Assessment 
requires gestational age assessment by 
best available obstetric estimate, 
usually prenatal ultrasound or first day 
of the last menstrual period if 
ultrasound not available.
Also assessed by pediatric estimate 
through physical and neurological 
examination of newborn at birth. This is 
less desirable as this assessment is 
affected by abnormal fetal growth, 
placental anatomic and functional 
anomalies, maternal nutrition, racial 
and ethnic background, population and 
genetic factors, and birth weight for GA.
-American College of Obstetricians 
and Gynecologists. Management of 
preterm labor. ACOG Practice 
Bulletin Number 43. International 
Journal of Gynaecology and 
Obstetrics 2003;82: 127–35.
NEONATAL 
DEATH
Death of newborn at any time from 
birth to 28 days of life, regardless of 
gestational age.
Subgroups:
Very early neonatal death: < 24hrs
Early neonatal death: from birth to < 7 
days
Late neonatal death: 7 to < 28 days
Intrapartum-related neonatal death 
(previously called: asphyxia deaths): 
neonatal death of term babies with 
The early neonatal death rate is 
estimated to be 8.4 per 1000 
liveborns; 67.1% occur by day 3 of 
life [Vogel, 2014].  Prematurity is 
the main cause of early neonatal 
deaths (~62%).
Causes of death and rates may vary 
according to whether the birth setting 
was in a hospital or in the community
- Vogel JP et al, on behalf of the 
WHO Multicountry Survey on 
Maternal and Newborn Health 
Research Network. Maternal 
complications and perinatal 
mortality: findings of the World 
Health Organization Multicountry 
Survey on Maternal and Newborn 
Health. BJOG 2014; 121 (Suppl. 1): 
76–88.
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neonatal encephalopathy or who 
cannot be resuscitated (or for whom 
resuscitation is not available). Also 
includes babies who die from birth 
injury without hypoxic brain injury)
NEONATAL 
HYPOXIC 
ISCHEMIC 
ENCEPHALOPAT
HY (HIE)
S: HIE, Birth 
Asphyxia, 
Perinatal 
Asphyxia, 
Neonatal 
encephalopathy
A disturbance of neurological function 
in the earliest days of life in the term 
infant manifested by difficulty initiation 
and maintaining respiration, 
depression of tone and reflexes, 
abnormal level of consciousness and 
often seizures, which may follow an 
intrapartum hypoxic insult or be due 
to another cause.
Rates may vary widely.  The 
incidence of HIE in developed 
countries is estimated to be 1.5 
per 1,000 live births [Kurinczuk, 
2010]. Estimates in developing 
countries range from 2.3–26.5 per 
1,000 live births [Horn,2013].
Assessed by clinical and laboratory 
findings: 5 minute Apgar score of 0-3, 
Respiratory distress and Acidosis (pH < 
7.0), altered tone, depressed level of 
consciousness, seizures, multiorgan 
involvement.
Diagnostic tests:
- MRI is preferred imaging study.
- CT can identify focal lesions, 
hemorrhage, diffuse cortical injury
- EKG (ECG) and continuous EKG 
(ECG)
May result in neonatal death or 
permanent damage to the brain and 
other organs.
May be associated with perinatal 
events, rarely to prenatal events.
- Kurinczuk JJ, White-Koning M, 
Badawi N: Epidemiology of 
neonatal encephalopathy and 
hypoxic–ischaemic 
encephalopathy. Early Hum Dev 
2010, 86(6):329-338.
- Horn AR, Swingler GH, Myer L, 
Harrison MC, Linley LL, Nelson C, 
Tooke L, Rhoda NR, Robertson NJ: 
Defining hypoxic ischemic 
encephalopathy in newborn infants: 
benchmarking in a South African 
population. J Perinat Med 2013, 
41(2):211-217. 
FAILURE TO 
THRIVE OR 
GROWTH 
DEFICIENCY
Inability to maintain expected growth 
rate over time, evaluated by plotting 
individual weight gain and growth on 
standard growth charts for the 
population.
Failure to thrive (FTT) is a 
common problem, however 
precise epidemiological data is 
lacking. The population prevalence 
of FTT has been found to range 
anywhere between 1.3% and 
20.9% depending on the definition 
of FTT that is used. FTT accounts 
for 1–5% of paediatric hospital 
admissions under 2 year of age 
[Sullivan, 2004]
Normal newborn weight gain includes 
weight loss of up to 10% of birth weight 
in the first 1-2 weeks of life, with steady, 
predictable weight gain thereafter. 
Progress varies by gestational and 
post-natal age, genetic and 
environmental factors.
Definitions vary. Fall of weight below 
5th percentile for age often used. Olsen 
et al have described multiple different 
anthropometric criteria for failure to 
thrive. These criteria include signs of 
- Olsen EM, Petersen J, Skovgaard 
AM, Weile B, Jorgensen T, Wright 
CM. Failure to thrive: the 
prevalence and concurrence of 
anthropometric criteria in a general 
infant population. Arch Dis Child. 
February2007; 92(2):109-114.
-  Peter B Sullivan. Commentary: 
The epidemiology of failure-to-thrive 
in infants. Int. J. Epidemiol. (2004) 
33 (4): 847-848.
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failure to gain weight (weight < 75% of 
median weight for chronological age, 
weight for chronological age < 5th 
percentile, weight deceleration crossing 
> 2 major percentile lines, etc), failure 
to grow (length for chronological age < 
5th percentile),
and failure to grow and gain weight 
(weight < 80% of
median weight for length, body mass 
index < 5th percentile) [Olsen, 2007]
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Annex 8
Planned variables to be collected in electronic Case 
Report Form (eCRF)
Demographic data:
Age (in years)
Resident
Medical antecedents:
Chronic hypertension
Diabetes mellitus
Anaemia
Nutritional disorders: Malnutrition , overweight, obesity
Infectious diseases (e.g.: Chagas disease, Malaria, HIV, Hepatitis, Tuberculosis)
Other Chronic Diseases: Heart disease, rheumatic disease, epilepsy, renal disease, 
thyroid and other endocrine diseases
Blood transfusion
Accidents
Major surgeries
Neurologic diseases
Gynaecological history 
Menstrual cycles: Duration in days, interval in days and regular
Prior use of contraceptive methods
Sexually transmitted diseases
Gynaecological surgeries (at what age, diagnosis) 
Breast problems
Obstetric Antecedents:
Number of pregnancies :including miscarriage, ectopic pregnancy
Number of deliveries
Type of deliveries: forceps, Caesarean, spontaneous, vaginal
Number of miscarriages including spontaneous, induced, therapeutic
Number of live births
Interval between pregnancies
Number of newborns: Preterm (before 37 weeks), Post tem ( > 42 weeks)
Rh isoimmunization
Number of newborns of low birth weight (less than 2,500 gm) and more than 4000 gm
 
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Early neonatal deaths (if during hospitalisation): Up to seven days of life
Late neonatal deaths (if during hospitalisation): Between 7 and 28 days
Stillbirth (intrauterine foetal death) and gestational age at which the event occurred
Newborns with jaundice, transfusion, hypoglycaemia
Events or complications in previous pregnancies : Haemorrhage, pre-eclampsia, other
Complications in puerperium: Haemorrhage, infections, other
Current Pregnancy History:
Date (first day/month/year) of the last menstrual period 
Weight
Ultrasound scan result
Lab tests: Blood group, Rh, haemoglobin, glycaemia, other
Vaccination(s)
Concomitant medications reported at the time of delivery
Hospitalisation during this pregnancy
Habits: Smoking, alcohol and illicit drugs
Pregnancy events
Gestational diabetes
Pre-eclampsia
Eclampsia
HELLP Syndrome
Placenta abruption
Placenta previa
Vaginal haemorrhage

Ante-partum

Intra-partum

Post-partum
Birth Outcomes
Pre term birth (weeks of gestation)
Small for gestational age (birth weight in grams)
Apgar score
Other events
Premature rupture of membranes
Preterm premature rupture of membranes
 
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Premature uterine contraction
Premature labour
Neonatal death
Maternal death
Still birth
Neonatal hypoxic ischaemic encephalopathy
Congenital anomalies
 
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Annex 9
Recommendations for Refortrix vaccine in Brazil
The recommendation for Refortrix vaccine in Brazil is available upon request.
 
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Annex 10 Protocol Sponsor Signatory Approval
eTrack study number and 
Abbreviated Title
203153 (EPI-PERTUSSIS-037 VS BR)
Date of protocol
Final Version 1: 11 September 2015
Detailed Title
A post-marketing, observational, retrospective, cohort 
study to assess the safety of RefortrixTM (Tdap) when 
administered during pregnancy in a maternal 
immunization program in Brazil.
Sponsor signatory
Laurence Baril, Director, Epidemiology, 
GlaxoSmithKline Biologicals
Rue de l’Institut, 89
1330 Rixensart, Belgium
Signature
Date
 
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Annex 11 Protocol Investigator Agreement
I agree:

To conduct the study in compliance with this protocol, any mutually agreed future 
protocol amendments or protocol administrative changes, with the terms of the study 
agreement and with any other study conduct procedures and/or study conduct 
documents provided by GlaxoSmithKline (GSK) Biologicals.

To assume responsibility for the proper conduct of the study at this site.

That I am aware of, and will comply with, ‘Good Clinical Practice’ (GCP), other 
applicable guidelines and all applicable regulatory requirements. 

To ensure that all persons assisting me with the study are adequately informed about 
study-related duties and functions as described in the protocol.

To co-operate with a representative of GSK Biologicals in the monitoring process of 
the study and in resolution of queries about the data.

That I have been informed that certain regulatory authorities require the sponsor to 
obtain and supply, as necessary, details about the investigator’s ownership interest in 
the sponsor, and more generally about his/her financial ties with the sponsor. GSK 
Biologicals will use and disclose the information solely for the purpose of complying 
with regulatory requirements.
Hence I:

Agree to supply GSK Biologicals with any necessary information regarding 
ownership interest and financial ties (including those of my spouse and dependent 
children).

Agree to promptly update this information if any relevant changes occur during the 
course of the study and for one year following completion of the study.

Agree that GSK Biologicals may disclose any information it has about such 
ownership interests and financial ties to regulatory authorities.

Agree to provide GSK Biologicals with an updated Curriculum Vitae and other 
documents required by regulatory agencies for this study.
 
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eTrack study number and 
Abbreviated Title
203153 (EPI-PERTUSSIS-037 VS BR)
Date of protocol
Final Version 1: 11 September 2015
Detailed Title
A post-marketing, observational, retrospective,
cohort study to assess the safety of RefortrixTM (Tdap) 
when administered during pregnancy in a maternal 
immunization program in Brazil.
Investigator name
Signature
Date
 
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Annex 12 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
1.1.2 End of data collection2
1.1.3 Study progress report(s)
1.1.4 Interim progress report(s)
1.1.5 Registration in the EU PAS register
1.1.6 Final report of study results.
17
17
1
15
Comments:
The EU PASS registration will be updated in the final version.
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)
2.1.2 The objective(s) of the study?
16
16-17
2.1.3 The target population? (i.e. population 
or subgroup to whom the study results 
are intended to be generalised)
2.1.4 Which formal hypothesis(-es) is (are) to 
be tested? 
2.1.5 If applicable, that there is no a priori 
15-17
27
                                                
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)
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, randomised controlled trial, new 
or alternative design) 
16-18
3.2 Does the protocol specify the primary and 
secondary (if applicable) endpoint(s) to be 
investigated?
24-25
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)
23-24
Comments:
Section 4: Source and study populations
Yes
No
N/A
Page 
Number(s)
4.1 Is the source population described?
17
4.2 Is the planned study population defined in 
terms of:
4.2.1 Study time period?
4.2.2 Age and sex?
4.2.3 Country of origin?
4.2.4 Disease/indication? 
17
18
17
 
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Section 4: Source and study populations
Yes
No
N/A
Page 
Number(s)
4.2.5 Co-morbidity?
4.2.6 Seasonality?
17
4.3 Does the protocol define how the study 
population will be sampled from the source 
population? (e.g. event or inclusion/exclusion 
criteria)
19-20
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) 
19-24
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)
29
5.3 Is exposure classified according to time 
windows? (e.g. current user, former user, 
non-use)
19
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? 
23 and 24
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)
29
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)
24
7.2 Does the protocol address known effect 
modifiers? (e.g. collection of data on known 
effect modifiers, anticipated direction of 
effect)
Comments:
 
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Section 8: Data sources
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.) 
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.)
8.1.3 Covariates? 
24
24
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) 
8.2.2 Endpoints? (e.g. date of occurrence, 
multiple event, severity measures 
related to event) 
8.2.3 Covariates? (e.g. age, sex, clinical and 
drug use history, co-morbidity, co-
medications, life style, etc.)
24
24
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)
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) 
 
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Comments:
Section 9: Study size and power
Yes
No
N/A
Page 
Number(s)
9.1 Is sample size and/or statistical power 
calculated? 
25-26
Comments:
Section 10: Analysis plan
Yes
No
N/A
Page 
Number(s)
10.1 Does the plan include measurement of 
excess risks?
27-28
10.2 Is the choice of statistical techniques 
described? 
27-28
10.3 Are descriptive analyses included?
27-28
10.4 Are stratified analyses included?
10.5 Does the plan describe methods for 
adjusting for confounding?
28
10.6 Does the plan describe methods addressing 
effect modification?
Comments:
 
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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?
28
11.2 Does the protocol provide information on data 
storage? (e.g. software and IT environment, 
database maintenance and anti-fraud 
protection, archiving)
29
11.3 Are methods of quality assurance described?
29
11.4 Does the protocol describe possible quality 
issues related to the data source(s)?
29
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?
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)
29
29
12.2 Does the protocol discuss study 
feasibility? (e.g. sample size, anticipated 
exposure, duration of follow-up in a cohort 
study, patient recruitment)
18
12.3 Does the protocol address other 
limitations? 
30
Comments:
 
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Section 13: Ethical issues
Yes
No
N/A
Page 
Number(s)
13.1 Have requirements of Ethics 
Committee/Institutional Review Board 
approval been described?
13.2 Has any outcome of an ethical review 
procedure been addressed?
13.3 Have data protection requirements been 
described?
31
Comments:
The study still has to be submitted to EC/IRB.
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? 
15
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)? 
15.2 Are plans described for disseminating study 
results externally, including publication?
32
Comments:
 
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