A Phase 3b, Non-randomized, Open Label, Multi-country, Cohort Study to Describe the Safety of Study Participants Who Received RSVPreF3 Maternal Vaccination (Any Dose) or Controls From Previous RSV MAT Studies (RSV MAT-001, RSV MAT-004, RSV MAT-010, RSV MAT-011, RSV MAT-009, RSV MAT-012 and RSV MAT-039) During Any Pregnancy Conceived Post Vaccination/Control
Phase: PHASE3
Conditions: Respiratory Syncytial Virus Infections
Sponsor: GlaxoSmithKline

CONFIDENTIAL 
219510 (RSV MAT-015) 
Protocol Amendment 2 Final 
21 Jun 2023 
1 
 
CLINICAL STUDY PROTOCOL 
Primary Study Intervention 
Not applicable 
Other Study Intervention 
Not applicable 
Study Identifier 
219510 (RSV MAT-015) 
Eudra CT number 
2022-003124-41 
Approval Date 
21 Jun 2023 
Title 
A Phase 3b, non-randomized, open label, multi-
country, cohort study to describe the safety of study 
participants who received RSVPreF3 maternal 
vaccination (any dose) or controls from previous 
RSV MAT studies (RSV MAT-001, RSV MAT-004, 
RSV MAT-010, RSV MAT-011, RSV MAT-009, 
RSV MAT-012 and RSV MAT-039) during any 
pregnancy conceived post vaccination/control. 
Brief Title 
A follow-up study to describe the safety of study 
participants who received RSVPreF3 maternal 
vaccination (any dose) or controls from previous 
RSV MAT studies during any pregnancy conceived 
post vaccination/control. 
Sponsor 
GlaxoSmithKline Biologicals S.A.  
Rue De L'Institut 89 
1330 Rixensart 
Belgium 
Sponsor signatory 
Joon Hyung Kim 
Clinical and Epidemiology Project Lead, RSV 
Maternal Portfolio 
Medical monitor name and contact information will be provided separately  
©2023 GSK group of companies or its licensor. 

CONFIDENTIAL 
219510 (RSV MAT-015) 
Protocol Amendment 2 Final 
21 Jun 2023 
2 
Protocol Amendment 2 Investigator Agreement 
I agree: 
• 
To conduct the study in compliance with this protocol, any future protocol 
amendments, with the terms of the clinical trial agreement and with any other study 
conduct procedures and/or study conduct documents provided by GSK. 
• 
To assume responsibility for the proper conduct of the study at this site. 
• 
That I am aware of and will comply with GCP and all applicable regulatory 
requirements.  
• 
That I will comply with the terms of the site agreement. 
• 
To comply with local bio-safety legislation. 
• 
To ensure that all persons assisting me with the study are adequately informed about 
the GSK study intervention and other study-related duties and functions as described 
in the protocol. 
• 
To supervise any individual or party to whom I have delegated study-related duties 
and functions conducted at the study site. 
• 
To ensure that any individual or party to whom I have delegated study-related duties 
and functions conducted at the study site are qualified to perform those study-related 
duties and functions. 
• 
To co-operate with representative(s) of GSK in the monitoring and data management 
processes of the study with respect to data entry and resolution of queries about the 
data. 
• 
To have control of all essential documents and records generated under my 
responsibility before, during, and after the study. 
• 
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 or the study intervention(s), and more generally about their financial 
ties with the sponsor. GSK will use and disclose the information solely for the 
purpose of complying with regulatory requirements. 
Hence, I: 
• 
Agree to supply GSK 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 
study and for 1 year following completion of the study. 
• 
Agree that GSK may disclose any information about such ownership interests and 
financial ties to regulatory authorities. 
• 
Agree to provide GSK with an updated Curriculum Vitae and all other documents 
required by regulatory agencies for this study. 

CONFIDENTIAL 
219510 (RSV MAT-015) 
Protocol Amendment 2 Final 
21 Jun 2023 
3 
Study identifier 
219510 (RSV MAT-015) 
Eudra CT number 
2022-003124-41 
Approval date 
21 Jun 2023 
Title 
A Phase 3b, non-randomized, open label, multi-
country, cohort study to describe the safety of study 
participants who received RSVPreF3 maternal 
vaccination (any dose) or controls from previous 
RSV MAT studies (RSV MAT-001, RSV MAT-
004, RSV MAT-010, RSV MAT-011, RSV MAT-
009, RSV MAT-012 and RSV MAT-039) during 
any pregnancy conceived post vaccination/control. 
Investigator name 
 
 
 
Signature 
 
 
 
Date of signature 
(DD Month YYYY) 
 
 
 
 
Leiter der klinischen Prüfung 
name, function and title 
 
 
 
Signature 
 
 
 
Date of signature 
(DD Month YYYY) 
 

CONFIDENTIAL 
219510 (RSV MAT-015) 
Protocol Amendment 2 Final 
21 Jun 2023 
4 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
DOCUMENT HISTORY 
Document 
Date of Issue 
Amendment 2 
21 Jun 2023 
Amendment 1 
17 January 2023 
Original Protocol 
16 September 2022 
Amendment 2 (21 Jun 2023) 
This amendment is considered substantial based on the criteria defined in Article 
10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union because it significantly impacts the scientific value of the study. 
Overall rationale for the current Amendment: This amendment is being done to 
include details pertaining to the exclusion criteria for women of nonchildbearing 
potential, the timeframe for the primary and secondary objectives and the Phase of the 
study (Phase 3b). It also includes updated information indicating that all the prior studies 
listed are collectively called as ‘prior RSV MAT studies’ for both cohorts, to allow 
participants from any of the prior RSV MAT studies who are pregnant at enrollment to be 
enrolled in the prospective cohort. It further clarifies the method and source of data 
collection in the retrospective and prospective cohorts. 
Additional updates were made in the objectives and endpoints section, schedule of 
activities, study design section, participant discontinuation/withdrawal from the study 
section, safety section, statistical considerations, and appendix.  
The list of abbreviations and references were updated, additional information from the 
current protocol template were included, and some minor edits were made for clarity 
wherever applicable. Some minor typographical and grammatical corrections were also 
made in this amendment. 
LIST OF MAIN CHANGES IN THE PROTOCOL AND THEIR RATIONALE: 
Section # and title 
Description of change 
Brief rationale 
Title 
Phase 3b added in the title. 
Amended as per the request from the 
regulatory authorities (PEI). 
List of abbreviations and 
definitions of terms 
Updated the list of abbreviations. 
Abbreviations were added with regards to 
the update in the protocol. Other 
abbreviations that were not spelled out in 
the previous protocol amendment were 
also updated as per the request from the 
regulatory authorities (PEI/AEMPS). 

CONFIDENTIAL 
219510 (RSV MAT-015) 
Protocol Amendment 2 Final 
21 Jun 2023 
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Section # and title 
Description of change 
Brief rationale 
Table 2: Schedule of activities 
for prospective cohort – 
Adult/Adolescent participant  
Section 5.2: Exclusion criteria 
Section 7.2: Participant 
discontinuation/withdrawal 
from the study 
Updated information regarding the 
women of nonchildbearing potential 
(WONCBP) to explain that 
WONCBP participants will be 
excluded if they do not plan to use 
any additional measures to conceive 
a pregnancy. 
To add clarity that participants who plan to 
conceive during the study will be allowed 
to participate in the study. 
Table 5: Objectives and 
endpoints 
Added the timeframe in the primary 
and secondary objectives. 
To define the timeframe for the analyses 
of data within 2 years. 
Added tertiary (exploratory) 
objectives. 
 
 
Section 9.3: Statistical 
analyses 
Added a timeframe in the endpoints 
and statistical analysis methods for 
primary and secondary endpoint 
analyses. 
To align with the updates in the objectives 
and endpoints section. 
Added new section for exploratory 
analyses. 
Section 1.2: Schema 
Section 4.1: Overall design 
Section 5.1.1: Retrospective 
cohort 
Section 5.1.2: Prospective 
cohort 
Section 10.1.4: Recruitment 
strategy 
Removed all the prior study names 
and mentioned as ‘prior RSV MAT 
studies’ for both cohorts, to allow 
participants from any of the prior 
RSV MAT studies who are pregnant 
at enrollment to be enrolled in the 
prospective cohort. 
To allow follow-up through day 42 post-
delivery for any current study pregnancy 
ongoing at enrollment in the prospective 
cohort. 
Section 8.4.5.2: Retrospective 
data source and data 
collection 
Updated the information to explain 
how retrospective data collection is 
done. 
As per the suggestion from regulatory 
authorities (PEI) this section has been 
updated to explain the method and source 
of retrospective data collection i.e., for 
pregnancies completed (through Day 42 
post-delivery) prior to study enrollment. 
Section 8.4.5.3: Prospective 
data source and data 
collection 
Updated the information to explain 
how prospective data collection is 
done. 
As per the suggestion from regulatory 
authorities (PEI) this section has been 
updated to explain the method and source 
of prospective data collection i.e., for 
participants with ongoing pregnancy at 
enrollment or conceived after enrollment. 
Section 8.4.8.2: Reporting of 
congenital anomalies in 
relation to pregnancy 
outcomes and SAEs and/or 
AESIs 
Added information to report all minor 
congenital anomalies that are 
neither reportable per MACDP nor 
medically attended, in the Adverse 
Event eCRF for infant participants. 
To ensure reporting of minor congenital 
anomalies that are not reportable per 
MACDP or medically attended, such as 
Mongolian spots. 
Section 10.6: Appendix 6: 
Definitions of maternal, fetal, 
and neonatal events of 
interest as per GAIA 
Section 11: References 
Added GAIA references. 
Amended as per the request from the 
regulatory authorities (PEI). 
Section 10.6: Appendix 6: 
Definition of maternal, fetal 
and neonatal events of 
interest as per GAIA 
Some maternal and neonatal events 
of interest have been specified as 
‘Not a study specific AESI’. 
To clarify that some maternal and neonatal 
events of interest are not a study specific 
AESI. 
CCI

CONFIDENTIAL 
219510 (RSV MAT-015) 
Protocol Amendment 2 Final 
21 Jun 2023 
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Section # and title 
Description of change 
Brief rationale 
Table 1: Study activities for 
retrospective cohort 
Table 2: Schedule of Activities 
for prospective cohort – 
Adult/Adolescent participant 
Table 3: Schedule of activities 
for prospective cohort – Infant 
participant 
Explanation added for the collection 
of demographic and lifestyle data for 
mothers and infants. 
For mothers, demography data will 
be collected at enrollment and 
lifestyle data during or at the end of 
each pregnancy.  
For infants, demography data will be 
collected at birth and lifestyle data at 
Day 42 post-delivery. 
Details and timing of data collection 
updated with necessary clarification. 
Information added to clarify the time-
period for the collection of SAE. 
Updated in alignment with Section 8.4.1. 
Table 2: Schedule of Activities 
for prospective cohort – 
Adult/Adolescent participant 
Table 3: Schedule of activities 
for prospective cohort – Infant 
participant 
Added details for the recording of 
MAEs, SAEs, and AEs leading to 
study withdrawal. 
To clarify that AEs (AESI), MAEs and 
SAEs leading to withdrawal will be 
recorded. 
Table 1: Study activities for 
retrospective cohort 
Explanation added for the collection 
of medical and vaccination history. 
To clarify that the information will be 
collected at each pregnancy. 
Table 2: Schedule of Activities 
for prospective cohort – 
Adult/Adolescent participant  
Section 4.1: Overall design 
Section 4.4: End-of-study 
definition 
Information added to define the end 
of study period for participants who 
are pregnant at study enrollment. 
To clarify that if participants are pregnant 
at study enrollment, the study period ends 
at Day 42 post-delivery in the prospective 
cohort. 
Section 7.2: Participant 
discontinuation/withdrawal 
from the study 
Additional criteria included that will 
lead to participant 
discontinuation/withdrawal from the 
study. 
To clarify that criteria which may lead to 
participant discontinuation/withdrawal from 
the study (such as occurrence of AEs 
(AESIs), MAEs, and SAEs (for the 
prospective cohort) and participant 
migration from the study area) will be 
recorded. 
Section 8.1.1: Collection of 
demographic data and 
lifestyle characteristics 
Added text from the current protocol 
template to explain why the 
collection of sex, race and ethnicity 
data is being done in the study. 
To provide the rationale that sex, race, 
and ethnicity data will be collected to 
evaluate and monitor the diversity of 
participants in the study. 
Section 8.3.1: Safety 
monitoring and committee 
Added text to explain the role of 
safety review team. 
Updated in alignment with the current 
protocol template. 
Replaced the term CRDL with CSL. 
The functional designation of the clinical 
scientist in the organization has been 
changed to CSL. 
Section 8.4.1: Time period 
and frequency for collecting 
MAE, SAE, and other safety 
information 
Information added to clarify the time-
period for the collection of SAE. 
Updated in alignment with the current 
protocol template. 
Section 8.4.10: COVID-19 
infection 
Section 11: References 
Updated the reference related to 
WHO case definition for COVID-19. 
To align with the current updated 
reference (July 2022) which explains the 
WHO case definition for COVID-19. 

CONFIDENTIAL 
219510 (RSV MAT-015) 
Protocol Amendment 2 Final 
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Section # and title 
Description of change 
Brief rationale 
Section 9.1: Statistical 
hypotheses 
Section 9.3: Statistical 
analyses 
Removed the ‘Per Protocol Set” for 
both maternal and infant participants 
and “Maternal Set” for maternal 
participants.  
Amended as per the request from the 
regulatory authorities (PEI) to avoid any 
confusion. As this is a safety follow-up 
study, the Full Analysis Set (FAS) will 
contain all the maternal or post-
delivery/birth data and it will be used for 
the analyses. 
Updated the information that primary 
and secondary analyses will be 
performed on the Full Analysis Set. 
Section 10.1.3: Informed 
consent process 
Added information to explain the 
process of obtaining assent from 
minor participants, obtaining 
consent if minor participants 
become legally emancipated during 
the study, and obtaining consent if 
participants are incapacitated. 
To clarify the process of obtaining consent 
for adolescent and incapacitated 
participants prior to enrolling in the study, 
and the process of obtaining reconsent if 
the adolescent participants reach the legal 
age of consent according to the local law 
and regulations during the study. 
Section 10.1.7: Data quality 
assurance 
Added information about quality 
tolerance limit. 
To explain that quality tolerance limit will 
be monitored during the study to identify 
systemic issues that may impact 
participant’s right, safety and/or reliability 
of study results. 
Section 10.1.9: Study and site 
start and closure 
Added text to explain about the start 
of the study and first act of 
recruitment. 
To explain that the start of study is defined 
as first subject first visit (FSFV)/first 
contact and the first act of recruitment is 
defined as first ICF signature date. 
Section 10.2.2: Definition of 
SAE 
Included abnormal pregnancy 
outcomes in the definition of SAE. 
To categorize or collect abnormal 
pregnancy outcomes as SAEs. 
Section 10.2.3.2: Assessment 
of intensity 
Included ‘SAE’ for the assessment 
of intensity. 
To clarify that assessment of intensity will 
be done for SAE. 
Section 10.2.3.6: Updating of 
SAE, SAE due to study 
participation, MAEs and AESI 
information after removal of 
writer access to the 
participant’s eCRF 
Replaced ‘electronic report’ with 
‘paper report’ for collecting 
information related to adverse 
events. 
To clarify that additional adverse events 
will be recorded on the appropriate paper 
report after the write access to the 
participant’s eCRF is removed. 
Section 10.2.4: Reporting of 
SAEs, SAEs due to study 
participation, MAEs, and 
AESIs 
Added text for the reporting of 
poststudy adverse events related to 
any GSK non-IMP if the site 
becomes aware of such adverse 
events. 
Updated in alignment with the current 
protocol template. 
Section 10.3.1.2: Women of 
nonchildbearing potential 
(WONCBP) 
Deleted the text related to the cut-off 
for FSH levels. 
To avoid misunderstanding, as no specific 
cut-off is defined for FSH levels for this 
study. 

CONFIDENTIAL 
219510 (RSV MAT-015) 
Protocol Amendment 2 Final 
21 Jun 2023 
8 
TABLE OF CONTENTS 
PAGE 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ..................................... 4 
List of main changes in the protocol and their rationale: ........................................... 4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ........................................ 14 
1. 
PROTOCOL SUMMARY ........................................................................................ 20 
1.1. 
Synopsis ..................................................................................................... 20 
1.2. 
Schema ...................................................................................................... 21 
1.3. 
Schedule of activities (SoA) ........................................................................ 23 
2. 
INTRODUCTION .................................................................................................... 28 
2.1. 
Study rationale ............................................................................................ 28 
2.2. 
Background ................................................................................................ 28 
2.3. 
Benefit/risk assessment .............................................................................. 29 
3. 
OBJECTIVES AND ENDPOINTS ........................................................................... 30 
4. 
STUDY DESIGN .................................................................................................... 31 
4.1. 
Overall design ............................................................................................. 31 
4.2. 
Scientific rationale for study design ............................................................. 32 
4.2.1. 
Participant input into design ......................................................... 32 
4.3. 
Justification for dose ................................................................................... 32 
4.4. 
End-of-study definition ................................................................................ 32 
4.5. 
Study limitations .......................................................................................... 33 
5. 
STUDY POPULATION ........................................................................................... 33 
5.1. 
Inclusion criteria .......................................................................................... 34 
5.1.1. 
Retrospective cohort .................................................................... 34 
5.1.2. 
Prospective cohort ....................................................................... 35 
5.2. 
Exclusion criteria ......................................................................................... 35 
5.3. 
Lifestyle considerations ............................................................................... 36 
5.4. 
Screen failures ............................................................................................ 36 
5.5. 
Criteria for temporarily delaying enrollment ................................................. 36 
6. 
STUDY INTERVENTION AND CONCOMITANT THERAPY .................................. 36 
7. 
PARTICIPANT DISCONTINUATION/WITHDRAWAL ............................................. 36 
7.1. 
Discontinuation of study intervention ........................................................... 36 
7.2. 
Participant discontinuation/withdrawal from the study ................................. 36 
7.3. 
Lost to follow-up.......................................................................................... 37 
8. 
STUDY ASSESSMENTS AND PROCEDURES ..................................................... 38 
8.1. 
Administrative and general/baseline procedures ......................................... 38 
8.1.1. 
Collection of demographic data and lifestyle 
characteristics .............................................................................. 38 
8.1.2. 
Medical/vaccination history .......................................................... 38 
8.2. 
Immunogenicity assessments ..................................................................... 38 
8.3. 
Safety assessments .................................................................................... 39 
8.3.1. 
Safety monitoring and committee ................................................. 39 

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219510 (RSV MAT-015) 
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8.4. 
MAEs, serious adverse events (SAEs) and SAEs due to study 
participation, AESIs, and other safety reporting .......................................... 39 
8.4.1. 
Time period and frequency for collecting MAE, SAE, and 
other safety information ............................................................... 40 
8.4.2. 
Method of detecting SAEs and SAEs due to study 
participation ................................................................................. 41 
8.4.3. 
Follow-up of SAEs and SAEs due to study participation .............. 41 
8.4.4. 
Adverse events of special interest................................................ 41 
8.4.5. 
Data Source and Data Collection for AESIs ................................. 41 
8.4.5.1. 
List of AESIs ............................................................... 41 
8.4.5.2. 
Retrospective data source and data collection ............ 42 
8.4.5.3. 
Prospective data source and data collection ............... 42 
8.4.6. 
Regulatory reporting requirements for SAEs, SAEs due to 
study participation and AESIs ...................................................... 43 
8.4.7. 
Contact information for reporting SAEs, SAEs due to study 
participation and AESIs ................................................................ 44 
8.4.8. 
Additional reporting guidance for pregnancies reported 
during study period ...................................................................... 44 
8.4.8.1. 
Labor and Delivery ..................................................... 44 
8.4.8.2. 
Reporting of congenital anomalies in relation to 
pregnancy outcomes and SAEs and/or AESIs ............ 44 
8.4.9. 
Treatment of adverse events ....................................................... 46 
8.4.10. 
Covid-19 Infection ........................................................................ 46 
8.5. 
Pharmacokinetics ....................................................................................... 46 
8.6. 
Pharmacodynamics .................................................................................... 46 
8.7. 
Genetics ..................................................................................................... 46 
8.8. 
Biomarkers ................................................................................................. 46 
8.9. 
Immunogenicity assessments ..................................................................... 46 
8.10. 
Health economics or medical resource utilization and health 
economics .................................................................................................. 46 
9. 
STATISTICAL CONSIDERATIONS ........................................................................ 47 
9.1. 
Statistical hypotheses ................................................................................. 47 
9.2. 
Analysis sets ............................................................................................... 47 
9.3. 
Statistical analyses ..................................................................................... 47 
9.3.1. 
General considerations ................................................................ 47 
9.3.2. 
Primary endpoints analysis .......................................................... 48 
9.3.3. 
Secondary endpoints analyses .................................................... 48 
9.3.3.1. 
Pregnancy outcomes and AESIs from any 
study pregnancy ......................................................... 48 
9.3.3.2. 
Selected pregnancy outcomes and AESIs by 
selected risk factors .................................................... 48 
9.3.4. 
Exploratory endpoints analyses ................................................... 49 
9.3.5. 
Other safety analyses .................................................................. 49 
9.4. 
Interim analyses .......................................................................................... 49 
9.5. 
Sample size determination .......................................................................... 49 
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ............................................................................................... 53 
10.1. 
Appendix 1: Regulatory, ethical, and study oversight considerations .......... 53 
10.1.1. 
Regulatory and ethical considerations ......................................... 53 
10.1.2. 
Financial disclosure ..................................................................... 53 

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219510 (RSV MAT-015) 
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10.1.3. 
Informed consent process ............................................................ 54 
10.1.4. 
Recruitment strategy .................................................................... 54 
10.1.5. 
Data protection ............................................................................ 55 
10.1.6. 
Dissemination of Clinical Study Data ........................................... 55 
10.1.7. 
Data quality assurance ................................................................ 56 
10.1.8. 
Source documents ....................................................................... 57 
10.1.9. 
Study and site start and closure ................................................... 57 
10.1.10. Publication policy ......................................................................... 58 
10.2. 
Appendix 2: MAEs and SAEs due to study participation: Definitions 
and procedures for recording, evaluating, follow-up, and reporting ............. 58 
10.2.1. 
Unsolicited AE ............................................................................. 58 
10.2.2. 
Definition of SAE .......................................................................... 59 
10.2.3. 
Recording, assessment and follow-up of MAEs, SAE, SAE 
due to study participation and AESIs ........................................... 59 
10.2.3.1. SAE recording ............................................................ 59 
10.2.3.2. Assessment of intensity .............................................. 60 
10.2.3.3. Assessment of causality ............................................. 60 
10.2.3.4. Assessment of outcomes for SAEs and SAEs 
due to study participation ............................................ 61 
10.2.3.5. Follow-up of SAEs, SAEs due to study 
participation, MAEs and AESIs ................................... 61 
10.2.3.6. Updating of SAE, SAE due to study 
participation, MAEs and AESI information after 
removal of write access to the participant’s 
eCRF .......................................................................... 62 
10.2.4. 
Reporting of SAEs, SAEs due to study participation, MAEs 
and AESIs .................................................................................... 62 
10.2.4.1. Medically attended visits ............................................. 63 
10.3. 
Appendix 3: Definition of childbearing potential ........................................... 63 
10.3.1. 
Definitions .................................................................................... 63 
10.3.1.1. Woman of Childbearing Potential (WOCBP) ............... 63 
10.3.1.2. Woman of Nonchildbearing Potential 
(WONCBP) ................................................................. 63 
10.4. 
Appendix 4: Country-specific requirements. ................................................ 64 
10.5. 
Appendix 5: Gestational Age Assessment .................................................. 65 
10.5.1. 
GAIA GESTATIONAL AGE ASSESSMENT FORM ..................... 65 
10.5.2. 
METHODS OF GESTATIONAL AGE ASSESSMENT AND 
ESTIMATION OF DUE DATE ...................................................... 66 
10.6. 
Appendix 6: Definitions of maternal, fetal and neonatal events of 
interest as per GAIA ................................................................................... 66 
10.7. 
Appendix 7: Protocol amendment history .................................................. 105 
11. REFERENCES ..................................................................................................... 107 
 

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219510 (RSV MAT-015) 
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LIST OF TABLES 
PAGE 
Table 1 
Study activities for retrospective cohort .................................................. 23 
Table 2 
Schedule of Activities for prospective cohort – Adult/Adolescent 
participant .............................................................................................. 24 
Table 3 
Schedule of Activities for prospective cohort – Infant participant ............ 26 
Table 4 
Intervals between study contacts for prospective cohort......................... 27 
Table 5 
Objectives and Endpoints ....................................................................... 30 
Table 6 
Collection and reporting of safety information ......................................... 40 
Table 7 
Timeframes for submitting SAE due to study participation and 
other events reports to GSK ................................................................... 43 
Table 8 
Contact information for reporting SAEs, SAEs due to study 
participation and AESIs .......................................................................... 44 
Table 9 
Reporting pregnancy outcomes with or without congenital 
anomalies as AESIs and/or SAEs .......................................................... 44 
Table 10 
Maternal Participants ............................................................................. 47 
Table 11 
Infant Participants .................................................................................. 47 
Table 12 
Sample size, event rate and probability .................................................. 51 
Table 13 
95% CI on the percentage of participants with event(s) of interest ......... 52 
Table 14 
Fetal death / Stillbirth ............................................................................. 68 
Table 15 
Maternal Death ...................................................................................... 71 
Table 16 
Hypertensive disorders of pregnancy (Gestational hypertension, 
Pre-eclampsia, Pre-eclampsia with severe features including 
eclampsia) .............................................................................................. 72 
Table 17 
Antenatal Bleeding ................................................................................. 74 
Table 18 
Postpartum hemorrhage ......................................................................... 75 
Table 19 
Fetal growth restriction ........................................................................... 76 
Table 20 
Gestational diabetes mellitus (pregnancy induced 
hyperglycemia) ....................................................................................... 77 
Table 21 
Non-reassuring fetal status .................................................................... 79 

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219510 (RSV MAT-015) 
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Table 22 
Pathways to preterm birth ...................................................................... 80 
Table 23 
Chorioamnionitis .................................................................................... 82 
Table 24 
Standard Definitions for Maternal Events of interest not defined 
as events in GAIA .................................................................................. 84 
Table 25 
Small for Gestational Age ....................................................................... 86 
Table 26 
Low Birth Weight (LBW) ......................................................................... 88 
Table 27 
Neonatal encephalopathy ....................................................................... 89 
Table 28 
Congenital Microcephaly ........................................................................ 90 
Table 29 
Major Congenital anomalies ................................................................... 93 
Table 30 
Neonatal Death ...................................................................................... 96 
Table 31 
Neonatal Infections ................................................................................ 98 
Table 32 
Respiratory Distress in the Neonate ..................................................... 101 
Table 33 
Preterm Birth ........................................................................................ 102 
Table 34 
Failure to Thrive ................................................................................... 103 
Table 35 
Standard Definitions for Neonatal Events of interest not defined 
as events in GAIA ................................................................................ 104 

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LIST OF FIGURES 
PAGE 
Figure 1 
Overall Study design overview ............................................................... 21 
Figure 2 
Study design overview- Prospective cohort ............................................ 22 

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219510 (RSV MAT-015) 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS  
AC 
Abdominal circumference 
ACOG 
American College of Obstetricians and Gynecologists 
AE 
Adverse Event 
AEMPS 
The Spanish Agency of Medicines and Medical Devices 
AESI 
Adverse Event of Special Interest 
AFI 
Amniotic fluid index 
AFLP 
Acute fatty liver of pregnancy 
BPD 
Biparietal diameter 
CDC 
Centers for Disease Control and Prevention 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences 
CRDL 
Clinical Research and Development Lead 
CRF/eCRF 
Case report form/electronic case report form 
CRL 
Crown-rump length 
CSL 
Clinical Science Lead 
CSR 
Clinical Study Report 
EDD 
Estimated Delivery Date 
ELBW 
Extremely low birth weight 
ET 
Embryo transfer 
FAS 
Full Analysis Set 
FH 
Fundal height 
FHR 
Fetal heart rate 
FL 
Femur length 
FSFV 
First subject first visit 
FSH 
Follicle stimulating hormone 
FTT 
Failure to thrive 
GA 
Gestational age 
GAIA 
Global Alignment of Immunization safety Assessment in 
pregnancy 
GCP 
Good Clinical Practice 

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GDM 
Gestational diabetes mellitus 
GSK 
GlaxoSmithKline 
HC 
Head Circumference 
HCP 
Health Care Provider 
HIPAA 
Health Insurance Portability and Accountability Act 
HRT 
Hormonal replacement therapy 
IADPSG 
International Association of Diabetes and Pregnancy Study 
Groups 
IAF 
Informed Assent Form 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonization 
ICMJE 
International Committee of Medical Journal Editors 
ICP 
Intrahepatic Cholestasis of Pregnancy 
ICSR 
Individual case safety report 
IgM 
Immunoglobulin M 
IHD 
Individual Human Data 
IRB/IEC 
Institutional Review Board/Independent Ethics Committee 
IRM 
Individual Rights Management 
IUI 
Intrauterine Insemination 
IVF 
In vitro fertilization 
LAR 
Legally acceptable representative 
LBW 
Low birth weight 
LMP 
Last menstrual period 
LRTI 
Lower respiratory tract illnesses 
LSLV 
Last Subject Last Visit 
MACDP 
Metropolitan Atlanta Congenital Defects Program 
MAE 
Medically attended adverse event 
MAP 
Mean arterial pressure 
MedDRA 
Medical Dictionary for Regulatory Activities 
MUAC 
Mid Upper Arm Circumference 
NDDG 
National Diabetes Data Group 
NICE 
The National Institute of Health and Care Excellence 

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Non-IMP 
Non-investigational medicinal product 
OGTT 
Oral glucose tolerance test 
PEI 
Paul-Ehrlich Institute 
qSOFA 
Quick SOFA 
QTL 
Quality tolerance limit 
RSV 
Respiratory Syncytial Virus 
SAE 
Serious adverse event 
SD 
Standard Deviation 
SoA 
Schedule of activities 
SOFA 
Sequential [Sepsis-related] Organ Failure Assessment 
SRT 
Safety Review Team 
U/S 
Ultrasound examination 
URI 
Upper respiratory infection 
US 
United States 
VLBW 
Very low birth weight 
WHO 
World Health Organization 
WOCBP 
Woman of Childbearing Potential 
WONCBP 
Woman of nonchildbearing potential 
YOA 
Years of age 
 

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Term 
Definition 
Child in care 
A child who has been placed under the control or 
protection of an agency, organization, institution or 
entity by the courts, the government or a government 
body, acting in accordance with powers conferred on 
them by law or regulation. The definition of a child in 
care can include a child cared for by foster parents or 
living in a care home or institution, provided that the 
arrangement falls within the definition above. The 
definition of a child in care does not include a child who 
is adopted or has an appointed legal guardian. 
Eligible 
Qualified for enrollment into the study based upon strict 
adherence to inclusion/exclusion criteria. 
Essential documents 
Documents which individually and collectively permit 
evaluation of the conduct of a study and the quality of 
the data produced. 
GAIA 
Global Alignment of Immunization Safety Assessment 
in pregnancy. A project that aims to improve the 
quality of outcome data from clinical vaccine trials in 
pregnant women with a specific focus on the needs 
and requirements for safety monitoring in low to 
middle income countries. 
Investigator 
A person responsible for the conduct of the clinical 
study at a study site. If a study is conducted by a team of 
individuals at a study site, the investigator is the 
responsible leader of the team and may be called the 
principal investigator.  
The investigator can delegate study-related duties and 
functions conducted at the study site to qualified 
individual or party to perform those study-related duties 
and functions. 
Legally acceptable 
representative 
An individual, judicial or other body authorized under 
applicable law to consent on behalf of a prospective 
participant to the participant's participation in the 
clinical study. 
The terms legal representative or legally authorized 
representative are used in some settings. 

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Term 
Definition 
Participant 
Term used throughout the protocol to denote an 
individual who has been contacted to participate or who 
participates in the clinical study as a recipient of the 
study intervention (vaccine(s)/product(s)/control). 
Synonym: subject 
Participant number 
A unique identification number assigned to each 
participant who consents to participate in the study. 
Primary Completion Date 
The date on which the last participant in a clinical study 
was examined or received an intervention to collect final 
data for the primary outcome measure. 
Whether the clinical study ended according to 
the protocol or was terminated does not affect this date. 
For clinical studies with more than one primary outcome 
measure with different completion dates, this term refers 
to the date on which data collection is completed for all 
the primary outcome measures.  
Provisional Lost to Follow-
Up:  
A sustained inability of the site to make any contact 
with the participant (or parent(s)/LAR(s)) over the 
period of three contact attempts and/or after a final 
attempt has been made by mail (in accordance with 
local regulations/preferred site practices), but the 
participant is still within the study follow-up period. 
A provisional lost to follow-up participant who 
subsequently contacts the site and wants to resume 
follow-up may resume study activities, provided that the 
participant has not reached the end of the study follow-
up period. 
Remote visit 
This term refers to the visit conducted in the place other 
than the study site. 
Self-contained study 
Study with objectives not linked to the data of another 
study. 
Source data 
All information in original records and certified copies 
of original records of clinical findings, observations, or 
other activities in a clinical study necessary for the 
reconstruction and evaluation of the study. Source data 
are contained in source documents (original records or 
certified copies). 

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Term 
Definition 
Study completion date 
The date on which the last participant in a clinical study 
to collect final data for the primary outcome 
measures, secondary outcome measures, and adverse 
events (that is, the last participant's last visit or LSLV). 
Study monitor 
An individual assigned by the sponsor and responsible 
for assuring proper conduct of clinical studies at 1 or 
more investigational sites. 
Telemedicine 
The use of electronic information and 
telecommunications technologies (both video-based and 
audio-only) to facilitate remote health care delivery, 
participant and professional health-related education, 
public health and health administration. 
Virtual visit 
This term refers to study visits conducted using 
multimedia or technological platforms. 

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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Protocol Title:  
A Phase 3b, non-randomized, open label, multi-country, cohort study to describe the 
safety of study participants who received RSVPreF3 maternal vaccination (any dose) or 
controls from previous RSV MAT studies (RSV MAT-001, RSV MAT-004, RSV MAT-
010, RSV MAT-011, RSV MAT-009, RSV MAT-012 and RSV MAT-039) during any 
pregnancy conceived post vaccination/control. 
Brief Title: 
A follow-up study to describe the safety of study participants who received RSVPreF3 
maternal vaccination (any dose) or controls from previous RSV MAT studies during any 
pregnancy conceived post vaccination/control. 
Rationale: Refer to Section 2.1. 
Objectives, Endpoints, and Estimands: Refer to Section 3. 
Overall Design: Refer to Section 4.1. 
Number of Participants: Refer to Section 9.5. 
Data Monitoring/Other Committee: Refer to Section 8.3.1. 

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1.2. 
Schema 
Figure 1 
Overall Study design overview 
 
AESI: Adverse Events of Special Interest; SAE: Serious Adverse Event; MAEs: Medically attended Adverse Events 
*2 years+2 months post vaccine/control to give time for the participant to be aware of a pregnancy if it is conceived very close to 2 years post-vaccination. The retrospective cohort will 
also include participants who have not reached 2 years+2 months post vaccine/control prior to/at enrollment but are a Woman of Nonchildbearing Potential (WONCBP) as defined 
in Section 10.3.1.2 at study enrollment, or recipient of bilateral tubal ligation prior to study enrollment. 
**For participants enrolled in prior studies of pregnant women (i.e., MAT-004, MAT-009, MAT-012), this study will include pregnancies conceived after the prior study pregnancy in 
which RSVPreF3 vaccination (or control) was administered. 
*** For participants enrolled in prior RSV MAT studies i.e., RSV MAT-001, RSV MAT-004, RSV MAT-009, RSV MAT-010, RSV MAT-011, RSV MAT-012 and RSV MAT-039. 

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Figure 2 
Study design overview- Prospective cohort 
 
 
*Contacts every 6 months up to 2 years (+2 months) post-vaccine/control (received as part of prior RSV MAT study participation), unless a pregnancy conceived post-vaccine/control is 
reported.  
** Once a pregnancy is reported, the participant is followed monthly during pregnancy until delivery, then again at Day 42 post-delivery. Pregnancy follow-up will include all pregnancies 
ongoing at enrollment or newly conceived during follow-up within 2 years post vaccine/control. If Day 42 post-delivery is <2 years+2 months, the woman returns to contacts every 
6 months until 2 years (+2 months) post-vaccine/control. 
***In addition to the planned study contacts, additional unplanned visits or medical procedures can be done as per the investigator’s discretion. 

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1.3. 
Schedule of activities (SoA) 
Table 1 
Study activities for retrospective cohort 
Type of contact 
Visit 1/Contact 1 
Notes 
Timepoint 
Day 1c 
 
Participant Contact a 
● 
 
Informed consent 
● 
Maternal and infant informed 
consent 
Inclusion and exclusion criteria 
● 
 
Demography and lifestyle characteristics 
● 
Mothers: Demography at 
enrollment, and lifestyle during or 
at the end of each pregnancy 
Infants: Demography at birth, and 
lifestyle at Day 42 post-delivery 
Medical and vaccination history 
● 
Collect information prior to start of 
study pregnancies (for each 
pregnancy) 
Contact information for all HCPs seen by mother or infant 
from start of current study pregnancies through day 42 post-
delivery 
○ 
 
Safety assessments during current study pregnancies 
(from medical record review) 
 
 
Record concomitant medications/vaccinations  
● 
One month prior to conception to 
Day 42 post-delivery 
Record medically attended AEs b until Day 42 post-delivery 
● 
Mothers: conception to Day 42 post-
delivery 
Infants: birth to Day 42 post-delivery 
Record pregnancy outcomes, pregnancy AESIs until Day 42 
post-delivery and infant AESIs until Day 42 post-delivery 
● 
 
Infant SAEs from birth until Day 42 post-delivery 
● 
 
Infant MAEs from birth until Day 42 post-delivery 
● 
 
SAEs during pregnancy until Day 42 post-delivery 
● 
 
Record SAEs related to study participation or related to a 
GSK product d 
● 
 
Final Activities 
 
 
Study conclusion 
● 
 
● Is used to indicate a study procedure that requires documentation in the individual eCRF. 
○ Is used to indicate a study procedure that does not require documentation in the individual eCRF. 
a Contact may be via telephone, SMS, email, video-telephone/telemedicine or other means, depending on local best 
practice. If the study site is the participant’s primary healthcare facility, contact with study personnel may also be 
made in the context of a visit for routine or event-driven care 
b events reported in the context of routine follow-up or unrelated to the event causing an event-driven visit will not be 
counted as ‘medically attended’ (e.g., a minor URI noted in the context of a routine prenatal visit would not be a 
‘medically attended event’)  
c All information needed for retrospective cohort participants can likely be collected on a single day, but it is possible 
that study personnel may need to re-contact participants to complete/clarify data collection. 
d Any SAEs assessed as related to study participation (e.g., protocol-mandated procedures) or related to a 
GSK product will be recorded from the time a participant consents to participate in the study. 
 

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Table 2 
Schedule of Activities for prospective cohort – Adult/Adolescent participant 
Type of contact 
Visit 1/Contact 1 
a 
Follow-up contact a 
Unscheduled 
contact a 
Initial 
Pregnancy 
Contact a, b 
Pregnancy 
contacts 
Delivery 
b 
Day 42 
Contact 
b 
Notes 
Timepoints 
Day 1 
Bi-annual, to 2 years+2 
months post 
vaccine/control 
 
 
Monthly until 
delivery** 
 
Day 42 
post-
delivery 
Informed consent/Informed Assent 
● 
 
 
 
 
 
 
 
Inclusion and exclusion criteria 
● 
 
 
 
 
 
 
 
Demography and lifestyle 
characteristics 
● 
 
 
 
 
● 
 
Demography at 
enrollment, and lifestyle 
during or at the end of 
each pregnancy 
Medical and vaccination history prior to 
pregnancy 
● 
 
 
● 
 
 
 
Collect information prior to 
start of study pregnancies 
Spontaneous pregnancy reporting by 
participants 
● 
● 
● 
● 
● 
● 
● 
 
Contact information for all HCPs seen 
from start of current study pregnancies 
through day 42 post-delivery 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
 
Safety assessments during current 
study pregnancies (from medical 
record review) 
 
 
 
 
 
 
 
 
Record medications/vaccinations  
● 
 
 
● 
● 
● 
● 
One month prior to 
conception to Day 42 
post-delivery 
Record medically attended AEs until 
Day 42 post-delivery 
● 
 
 
● 
● 
● 
● 
Conception to Day 42 
post-delivery 
Record pregnancy outcomes, 
pregnancy related AESIs until Day 42 
post-delivery 
● 
 
● 
● 
● 
● 
● 
 
SAEs during pregnancy until Day 42 
post-delivery 
● 
 
 
● 
● 
● 
● 
 

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Type of contact 
Visit 1/Contact 1 
a 
Follow-up contact a 
Unscheduled 
contact a 
Initial 
Pregnancy 
Contact a, b 
Pregnancy 
contacts 
Delivery 
b 
Day 42 
Contact 
b 
Notes 
Timepoints 
Day 1 
Bi-annual, to 2 years+2 
months post 
vaccine/control 
 
 
Monthly until 
delivery** 
 
Day 42 
post-
delivery 
Record SAEs related to study 
participation or related to a GSK 
product d 
● 
● 
● 
● 
● 
● 
● 
 
MAEs, SAEs and AEs (AESIs) 
leading to study withdrawal  
● 
● 
● 
● 
● 
● 
● 
 
Final Activities 
 
 
 
 
 
 
 
 
Study conclusion 
 
●c 
 
 
 
 
●c 
 
● Is used to indicate a study procedure that requires documentation in the individual eCRF. 
○ Is used to indicate a study procedure that does not require documentation in the individual eCRF. 
a Any study contact may be via telephone, SMS, email, video-telephone/telemedicine or other means, depending on local best practice. If the study site is the participant’s primary 
healthcare facility, contact with study personnel may also be made in the context of a visit for routine or event-driven care. 
b May be combined with another contact where pregnancy is first reported [e.g., combined with Visit 1/Contact 1 (for past/ongoing pregnancies at enrollment), follow-up contact, 
unscheduled contact.] 
c For participants who are not pregnant at 2 years post vaccine/control, the study conclusion will be completion of the last bi-annual contact, at least 2 months after 2 years post-
vaccine/control. If the participant is pregnant at 2 years post vaccine/control or at study enrollment, study conclusion will be completion of Day 42 post-delivery. WONCBP at study 
enrollment, or recipient of bilateral tube ligation prior to study enrollment will be excluded from the study if she has not conceived a pregnancy post-vaccine/control and 
does not plan to use any additional measures to attempt to conceive a pregnancy (e.g., sterilization reversal or in vitro fertilization (IVF)). 
d Any SAEs assessed as related to study participation (e.g., protocol-mandated procedures) or related to a GSK product will be recorded from the time a participant 
consents to participate in the study. 

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Table 3 
Schedule of Activities for prospective cohort – Infant participant 
Type of contact a 
Delivery b 
Day 42 Contact b 
Notes 
Timepoints 
Day 1 
Day 42 
Informed consent 
● 
 
Infant informed consent is anticipated at delivery, but may be 
done at any time up to the delivery contact if allowed at the site 
(or at Visit 1/Contact 1 for an infant born from a past pregnancy) 
Inclusion and exclusion criteria 
● 
 
 
Demography and lifestyle characteristics 
● 
● 
Demography at birth, and lifestyle at Day 42 post-delivery 
Contact information for all HCPs seen by infant from birth 
through Day 42  
○ 
○ 
 
Safety assessments (from medical record review) 
 
 
 
Record medications/vaccinations  
● 
● 
 
Record medically attended AEs until Day 42 
● 
● 
 
Infant AESIs from birth until Day 42 
● 
● 
 
Infant SAEs from birth until Day 42 
● 
● 
 
Record SAEs related to study participation or related to a 
GSK product c 
● 
● 
 
MAEs, SAEs and AEs (AESIs) leading to study withdrawal 
● 
● 
 
Final Activities 
 
 
 
Study conclusion 
 
● 
 
● Is used to indicate a study procedure that requires documentation in the individual eCRF. 
○ Is used to indicate a study procedure that does not require documentation in the individual eCRF. 
a Any study contact may be via telephone, SMS, email, video-telephone/telemedicine or other means, depending on local best practice. If the study site is the participant’s primary 
healthcare facility, contact with study personnel may also be made in the context of a visit for routine or event-driven care. 
b May be combined in one contact where delivery and day 42 have already occurred at the time of maternal enrollment. 
c Any SAEs assessed as related to study participation (e.g., protocol-mandated procedures) or related to a GSK product will be recorded from the time a participant 
consents to participate in the study. 

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Table 4 
Intervals between study contacts for prospective cohort 
Contact(s) 
Planned contact interval  
Allowed interval range 
Visit 1/Contact 1→Bi-annual contacts 
Bi-annual contact→ next Bi-annual contact 
180 days* 
135-225 days1 
 
Prior study vaccination→ last Bi-annual contact/Study Conclusion 
2 years+2 months (790 days)** 
790 days-835 days2 
Monthly contacts until delivery 
Every 30 days 
15-45 days3 
Delivery contact*** 
Delivery+3 days 
Delivery – Day 42 post-delivery 
Day 42 contact 
Day 43 post-delivery 
Day 43-Day 584 
* This contact interval does not apply while the participant is pregnant. 
** The study conclusion visit interval is planned at least 2 months after 2 years post-vaccine/control, to give time for the participant to be aware of a pregnancy if it is conceived very 
close to the end of 2 years post-vaccine/control; Once a participant reaches 2 years+2 months the study conclusion can occur at any time (the last Bi-annual contact does not 
need to be 180 days from the prior contact. For participants who are not pregnant at 2 years post vaccine/control, the study conclusion will be completion of the last bi-annual 
contact, at least 2 months after 2 years post-vaccine/control. If the participant is pregnant at 2 years post vaccine, study conclusion will be completion of Day 42 post-delivery. 
1Maximum Allowed interval range is +/- 3 months. 
2Maximum interval range 880 days. 
3Maximum interval range can be +59 days. 
4Maximum interval range can be Day 133*** The delivery contact will be based on expected delivery date. 

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2. 
INTRODUCTION 
2.1. 
Study rationale 
The study is designed to describe the safety during pregnancies conceived after the prior 
study vaccination (or control) and to collect all the medically related information in 
subsequent pregnancies in women who previously were administered RSVPreF3 
maternal vaccine or control from any RSV MAT study.  
2.2. 
Background 
GSK was developing an investigational Respiratory Syncytial Virus (RSV) vaccine for 
administration to pregnant women, with the aim of preventing medically assessed, RSV-
associated lower respiratory tract illnesses (LRTIs) in their infants by transfer of maternal 
antibodies. The primary endpoint for efficacy in the development program was their 
infants’ protection from RSV for first 6 months of life. The vaccine candidate is an 
engineered version of the RSV fusion (F) surface glycoprotein, stabilized in the pre-
fusion conformation (RSVPreF3).  
Several Phase I to Phase III studies were conducted in pregnant and non-pregnant 
women; throughout this document these studies are collectively referenced as the ‘prior 
RSV MAT studies’. Briefly, these were:  
• 
RSV MAT-001: RSVPreF3 in non-pregnant women, first time in human, safety and 
immunogenicity 
• 
RSV MAT-004: RSVPreF3 first time in pregnant women, safety and dose 
confirmation 
• 
RSV MAT-010: RSVPreF3 co-administration with influenza vaccination, lot-to-lot 
consistency 
• 
RSV MAT-011: RSVPreF3 co-administration with Tdap (Boostrix) vaccination, 
second dose of RSVPreF3 
• 
RSV MAT-009: Efficacy in infants of RSVPreF3-vaccinated pregnant women 
• 
RSV MAT-012: RSVPreF3 in high-risk (high-risk adult women + healthy 
adolescents 15-17 years) pregnancies 
• 
RSV MAT-039: RSVPreF3 in healthy non-pregnant girls ages 9-17 years and non-
pregnant adult women ages 18-49 years 
In all studies, the study participants received one dose of RSV MAT vaccine (or control) 
except in RSV MAT-011 study, where some participants received a second dose. For 
participants in MAT-011 study who received a second dose, any pregnancy conceived 
after first dose will be considered in this study; MAT-011 participants enrolled in the 
prospective cohort will be followed for pregnancies conceived up to 2 years post last 
dose. In studies with non-pregnant women, the study participants were followed up to 6 
months post-vaccination. In studies including pregnant women, safety of the candidate 

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vaccine was evaluated in maternal participants for up to 6 months after delivery. Safety in 
infants was evaluated for up to 12 months after birth. Safety evaluation included 
assessment of medically attended AEs, serious adverse events, pregnancy outcomes, and 
pregnancy-related and infant adverse events of special interest (AESIs). 
Following review of the data collected from the RSV MAT-009 study in pregnant 
women, a safety signal was identified. An imbalance in the proportion of preterm births 
was observed in infants born to vaccinated mothers who received RSV maternal vaccine 
versus those who received placebo. The safety signal was investigated and based on the 
above observations, GSK decided to stop enrollment and vaccination for all actively 
enrolling RSV MAT studies as of 28 February 2022. From this date, no new pregnant or 
non-pregnant women were enrolled or vaccinated in the studies. Children born to 
participating pregnant women who were vaccinated were continued to be followed-up in 
these studies. Safety monitoring of all enrolled participants continued during the rest of 
the study period. 
As the identified safety signal is pregnancy-related and related to neonatal events, GSK 
decided to continue to evaluate safety of RSVPreF3 in pregnancies conceived after the 
prior study vaccination. This current study will enroll women who were enrolled in the 
RSV MAT-001, RSV MAT-004, RSV MAT-010, RSV MAT-011, RSV MAT-009, RSV 
MAT-012 or RSV MAT-039 studies and record information about their pregnancies 
conceived post-study vaccination (if they occur prior to/during the current study period). 
To clarify, for those enrolled in prior studies of pregnant women (i.e., RSV MAT-004, 
RSV MAT-009, RSV MAT-012), this study will follow-up the subsequent pregnancies 
conceived after the prior study pregnancy in which RSVPreF3 vaccination (or control) 
was administered. 
2.3. 
Benefit/risk assessment 
No intervention will be administered in this study. 
Detailed information about the known benefits and risks and expected AEs of RSV 
Maternal Vaccine (RSVPreF3) can be found in the IB. 

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3. 
OBJECTIVES AND ENDPOINTS  
Table 5 
Objectives and Endpoints  
Objectives 
Endpoints 
Primary 
To describe the incidence of pregnancy outcomes, 
pregnancy related adverse events of special interest 
(AESIs) and infant AESIs during the first pregnancy 
conceived within 2 years post-vaccination in 
participants enrolled in RSV MAT studies (by study arm, 
those previously received RSVPreF3 and control) up to 
Day 42 post-delivery. 
Incidence of pregnancy outcomes, pregnancy related 
AESIs and infant AESIs during the first pregnancy 
conceived within 2 years post-vaccination in 
participants enrolled in RSV MAT studies (by study arm, 
those previously received RSVPreF3 and control) up to 
Day 42 post-delivery. 
Secondary 
To describe the incidence of pregnancy outcomes, 
pregnancy related adverse events of special interest 
(AESIs) and infant AESIs during any pregnancy 
conceived within 2 years post-vaccination in 
participants enrolled in RSV MAT studies (by study arm, 
those previously received RSVPreF3 and control) up to 
Day 42 post-delivery. 
Incidence of pregnancy outcomes, pregnancy related 
AESIs and infant AESIs during any pregnancy 
conceived within 2 years post-vaccination in 
participants enrolled in RSV MAT studies (by study arm, 
those previously received RSVPreF3 and control) up to 
Day 42 post-delivery. 
To describe the incidence of selected pregnancy 
outcomes, pregnancy related AESIs and infant AESIs by 
risk status and by selected risk factors for or causes of 
those events/outcomes during pregnancies conceived 
within 2 years post-vaccination in participants enrolled 
in RSV MAT studies (by study arm, those previously 
received RSVPreF3 and control) up to day 42 post-
delivery. 
Incidence of selected pregnancy outcomes, pregnancy 
related AESIs and infant AESIs by risk status and by 
selected risk factors for or causes of those 
events/outcomes during any pregnancy conceived 
within 2 years post-vaccination in participants enrolled 
in RSV MAT studies (by study arm, those previously 
received RSVPreF3 and control) up to Day 42 post-
delivery. 
Incidence of selected pregnancy outcomes, pregnancy 
related AESIs and infant AESIs by risk status and by 
selected risk factors for or causes of those 
events/outcomes during the first pregnancy conceived 
within 2 years post-vaccination in participants enrolled 
in RSV MAT studies (by study arm, those previously 
received RSVPreF3 and control) up to Day 42 post-
delivery. 
Tertiary (Exploratory) 
CCI

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4. 
STUDY DESIGN 
4.1. 
Overall design 
See Section 1.2 for the study schematic diagram. 
This study will be a combination of retrospective and prospective cohort design with two 
groups. RSVPreF3 vaccine group will include participants who received RSVPreF3 
vaccine in RSV MAT studies and control group will include participants who received 
any control (placebo, Tdap or influenza vaccine) during prior RSV MAT studies. 
• 
Retrospective cohort  
• 
Current study participants who are more than 2 years after vaccination/control 
and are not currently pregnant at the time of study enrollment will be included in 
this study cohort. 
• 
Participants previously enrolled in prior RSV MAT studies will be included 
in this cohort. 
• 
For participants enrolled in prior studies of pregnant women (i.e., MAT-
004, MAT-009, MAT-012), data collection for this cohort will not include 
the prior study pregnancy. 
• 
Medical data related to any pregnancy conceived post RSVPreF3 vaccine or any 
control (placebo, Tdap or influenza vaccine) through study enrollment (even if 
the pregnancy was conceived after 2 years post-vaccine/control) will be 
collected retrospectively from the date of start of current study pregnancy up to 
Day 42 (approximately 6 weeks) post-delivery. 
• 
Infants will be enrolled with the maternal participants at Visit 1 and all relevant 
medical data until Day 42 post-delivery will be retrieved. 
• 
Prospective cohort: 
• 
Current study participants who are within 2 years+2 months after 
vaccination/control or with ongoing pregnancies (pregnancies prior to Day 42 
post-delivery) at the time of study enrollment will be included in this study 
cohort. 
• 
Study participants enrolled in prior RSV MAT studies will be included in this 
study cohort. 
• 
For participants enrolled in prior studies of pregnant women (i.e., MAT-
004, MAT-009, MAT-012), data collection for this cohort will not include 
the prior study pregnancy. 
• 
All participants will be followed up for 2 years+2 months post RSVPreF3 or 
control vaccination to record any pregnancy conceived within 2 years post 
vaccine/control. If the participant is pregnant at 2 years post-vaccine/control, 
study follow-up will continue until day 42 post-delivery. 

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Note: Pregnancies reported during prospective follow-up at approximately 2 
years+2 months that were conceived after 2 years post-vaccine/control will not be 
included in the study.  
• 
Medical data related to any pregnancy conceived post RSV MAT (RSVPreF3) 
vaccine and any control (placebo, Tdap or influenza vaccine) will be collected 
from the date of start of current study pregnancy up to day 42 (approximately 6 
weeks) post-delivery. 
• 
Infants will be enrolled at Delivery and all relevant medical data until Day 42 
post-delivery will be collected. 
• 
Type of study and design: A safety follow-up cohort study. 
• 
Study period: The study period starts from the date of start of any pregnancy 
conceived after RSV MAT vaccination (RSVPreF3) or control vaccination in RSV 
MAT studies or from the date of current study enrollment, whichever date is earlier. 
The study period ends at current study enrollment for retrospective cohort 
participants. The study period ends at 2 years+2 months post vaccine/control for 
prospective cohort participants who are not pregnant at 2 years post vaccine/control. 
The study period ends at Day 42 post-delivery for prospective cohort participants 
who are pregnant at 2 years post vaccine/control or at study enrollment. 
• 
Number of participants: All adolescent or adult study participants (approximately 
8240) from the above-mentioned RSV MAT studies will be considered for 
enrollment based on the eligibility criteria. Approximately 650 enrolled study 
participants are estimated to have at least one pregnancy of interest for this study 
(see Section 9.5 for detailed calculations). Even approximately 300 participants with 
pregnancy information included in the study would still provide reasonable precision 
to detect and estimate most of the events of interest in the study.  
4.2. 
Scientific rationale for study design 
See Section 2.1 and Section 2.2. 
4.2.1. 
Participant input into design 
Not applicable 
4.3. 
Justification for dose 
Not applicable 
4.4. 
End-of-study definition 
A participant is considered to have completed the study if the participant has completed 
all periods of the study including the last contact (study conclusion). This last contact can 
be either 1) at current study enrollment for retrospective cohort participants, 2) at 2 
years+2 months post vaccine/control for prospective cohort participants who are not 
pregnant at 2 years post vaccine/control, or 3) at Day 42 post-delivery for prospective 

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cohort participants who are pregnant at 2 years post vaccine/control or who are pregnant 
at enrollment. The study may be terminated earlier if other research demonstrates no 
impact of vaccination on pregnancies conceived post-vaccination. 
4.5. 
Study limitations 
• 
The study participants who decide to enroll in this study are already aware whether 
they received RSVPreF3 or control. Study participants from prior RSV MAT 
pregnancy studies who experienced an adverse pregnancy outcome or a 
pregnancy/infant event from a prior pregnancy, may choose to participate in the 
current study at different rates than those who did not. This may lead to selection 
bias. As we have information on prior vaccination/control and prior adverse 
events/outcomes, we can evaluate whether this occurs and consider statistical 
analysis approaches to adjust for this. 
• 
Comparison between incidence of events or outcomes in this study and events or 
outcomes in previous RSV MAT studies likely cannot be made directly because of 
the following possible limitations: 1) the expected sample size for this study is too 
small for the study to be adequately powered for comparisons, 2) this study has 
different inclusion and exclusion criteria, 3) this study has different timepoint of 
pregnancy at enrollment (as early as possible), and 4) different risk factors for 
participants in this study, such as a relatively short inter-pregnancy interval for 
pregnancies included in this study. 
• 
This study includes two cohorts, one for which all data will be collected 
retrospectively and the other cohort for which data will be collected prospectively 
(with some retrospective data collection). This approach was taken so that the 
number of enrolled participants can be maximized. However, this may result in 
underestimation of the true incidence of AESIs in a pooled cohort (retrospective and 
prospective), as the retrospective cohort is more subject to recall bias. 
• 
This study is conducted with a proportion of the same participants enrolled in 
previous RSV MAT studies which uncovered a safety signal, as described in Section 
2.2. As there is still no plausible mode of action or known imbalance in risk factors 
across RSVPreF3 vs. control groups identified that explains the safety signal, the 
possibility remains there is unknown confounding (an unmeasured risk factor or 
exposure) leading to the safety signal. If there is unknown confounding, that may 
lead to a similar safety finding in this study. 
5. 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, 
also known as protocol waivers or exemptions, is not permitted. 
The study population will include up to 8240 participants (those who had conceived 
before study enrollment, those with ongoing pregnancy or who at enrollment may not 
have conceived but are followed for conception within 2 years post vaccine/control) 
from RSV MAT studies to collect pregnancy outcome, pregnancy related AESIs and 
infant AESIs for any pregnancy conceived post-vaccination (refer Section 9.5). 

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All study participants who have received either RSVPreF3 vaccine or control (placebo, 
Tdap only, influenza vaccine only) will be included in this study. 
Study participants with any pregnancy conceived after vaccination with Day 42 post-
delivery at or before study start (i.e., any pregnancy conceived after vaccination is a past 
pregnancy) will be included in the retrospective cohort and retrospective data will be 
collected from medical records. 
Study participants with any pregnancy conceived after vaccination ongoing at study start 
(pregnancy prior to Day 42 post-delivery) or newly reported during current study follow-
up will be included in the prospective cohort and relevant data will be collected from 
medical records, as identified through structured follow-up contacts. 
5.1. 
Inclusion criteria 
5.1.1. 
Retrospective cohort 
Adult/Adolescent Participant: 
• 
Adult/Adolescent study participant, from any of the prior RSV MAT studies who 
have either received RSV MAT vaccine or control (placebo, Tdap or influenza 
vaccine). 
• 
Study participant:  
• 
Who has reached 2 years+2 months post vaccine/control prior to/at enrollment 
or  
• 
who has not reached 2 years+2 months post vaccine/control prior to/at 
enrollment but is a Woman of Nonchildbearing Potential (WONCBP) as defined 
in Section 10.3.1.2 at study enrollment, or recipient of bilateral tubal ligation 
prior to study enrollment. 
• 
Study participant with any pregnancy conceived post-vaccination/control, that has 
reached Day 42 post-delivery prior to/at enrollment. 
• 
Provide signed and dated informed consent form. 
• 
Be willing to comply with all study requirements and be available for the duration of 
the study. 
Infant Participant: 
• 
Participant live born as the result of a pregnancy followed in an adult/adolescent 
participant in this study. 
• 
Signed and dated informed consent form obtained from the participant’s 
parent(s)/LAR(s) prior to performance of any study-specific procedure. 

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5.1.2. 
Prospective cohort 
Adult/Adolescent Participant: 
• 
Adult/adolescent study participant from any of the prior RSV MAT studies who 
have either received RSV MAT vaccine or control (placebo, Tdap or influenza 
vaccine). 
• 
Study participant: 
• 
Who has not reached 2 years+2 months post vaccine/control prior to/at 
enrollment or 
• 
Who has reached at least 2 years+2 months post vaccine/control but has an 
ongoing pregnancy (prior to Day 42 post-delivery) at enrollment. Participants 
who have reached 2 years post-vaccine/control before enrollment but are 
pregnant at enrollment will be enrolled and followed until Day 42 post-delivery 
for the pregnancy ongoing at enrollment. 
• 
Female participants of childbearing potential. 
• 
Provide signed and dated informed consent form. 
• 
Be willing to comply with all study procedures and be available for the duration of 
the study. 
Infant Participant: 
• 
Participant live born as the result of a pregnancy followed in an adolescent/adult 
participant in this study. 
• 
Participant’s parent(s)/LAR(s), in the opinion of the investigator, can and will 
comply with the requirements of the protocol. 
• 
Signed and dated informed consent form obtained from the participant’s 
parent(s)/LAR(s) prior to performance of any study-specific procedure. 
5.2. 
Exclusion criteria 
Participants are excluded from the study if any of the following criteria apply: 
Adult/adolescent participant otherwise eligible for the prospective cohort: 
• 
Woman of Nonchildbearing Potential (WONCBP) as defined in Section 10.3.1.2 at 
study enrollment, or recipient of bilateral tubal ligation prior to study enrollment, if 
she has not conceived a pregnancy post-vaccine/control and does not plan to use 
any additional measures to attempt to conceive a pregnancy (e.g., sterilization 
reversal or IVF). 
Infant participant: 
• 
Child in care. 

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5.3. 
Lifestyle considerations 
No lifestyle restrictions are required for this study. 
5.4. 
Screen failures 
No screen failures are expected. 
5.5. 
Criteria for temporarily delaying enrollment 
Not applicable. 
6. 
STUDY INTERVENTION AND CONCOMITANT THERAPY 
Not applicable. 
7. 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1. 
Discontinuation of study intervention 
Not applicable. 
7.2. 
Participant discontinuation/withdrawal from the study  
A participant may withdraw from the study at any time at the participant’s own request 
for any reason (or without providing any reason). 
A participant may be withdrawn at any time at the discretion of the investigator for 
compliance reasons. Investigators may also withdraw participants from the prospective 
cohort who become a WONCBP as defined in Section 10.3.1.2 or receive bilateral tubal 
ligation during the prospective follow-up, if they do not plan to use any additional 
measures to attempt to conceive a pregnancy (e.g., sterilization reversal, or IVF). 
Investigators will attempt to contact participants who do not respond to or complete 
scheduled follow-up contacts.  
All data collected up to and including the date of withdrawal of/last contact with the 
participant will be included in the study analyses. If the participant withdraws consent for 
disclosure of future information, the sponsor may retain and continue to use any data 
collected before such a withdrawal of consent. 
The primary reason for participant discontinuation/ withdrawal from the study will be 
documented in the eCRF based on the list below: 
• 
Adverse event requiring expedited reporting (AESI and SAE) (prospective cohort 
only) 
• 
Non-serious adverse event (MAE) (prospective cohort only) 

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• 
Death 
• 
Lost to follow-up 
• 
Physician decision 
• 
Protocol deviation 
• 
Site terminated by Sponsor 
• 
Study terminated by Sponsor 
• 
Withdrawal by participant 
• 
Migrated/moved from the study area 
• 
Other (specify). 
Participants who are withdrawn from the study because of MAEs/SAEs must be clearly 
distinguished from participants who are withdrawn for other reasons. Investigator will 
follow participants who are withdrawn from the study due to a MAE/SAE until the 
event is resolved (see Section 10.2.3.5). 
7.3. 
Lost to follow-up  
A participant will be considered lost to follow-up if the participant repeatedly fails to 
complete follow-up contacts (or scheduled visits) and is unable to be contacted by the 
study site. 
A participant will be considered ‘provisional lost to follow-up’ if the participant is 
considered lost to follow-up but has not reached the end of the study follow-up period. 
Unless there is a compelling reason, participants with a provisional lost to follow-up 
status should not receive further study-related contact from the study sites. A provisional 
lost to follow-up participant who subsequently contacts the site and wants to resume 
follow-up may resume study activities, provided that the participant has not reached the 
end of the study follow-up period. 
The following actions must be taken if a participant fails to complete a follow-up contact 
(or fails to return to the clinic for a required study visit): 
1. The site must attempt to contact the participant and reschedule the missed visit or 
follow-up contact as soon as possible, counsel the participant on the importance of 
maintaining the assigned visit schedule or follow-up contact and ascertain whether 
the participant wishes to and/or should continue in the study. 
2. Before a participant is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, [3] 
telephone calls, and if necessary, a certified letter to the participant’s last known 
mailing address or local equivalent methods). These contact attempts should be 
documented in the participant’s medical record. 
3. The site will then mark the participant as provisional lost to follow-up. This 
designation can be removed if the participant recontacts the site to resume study 
follow-up before the end of their study follow-up period. 

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4. Should the participant continue to be unreachable, the participant will be considered 
to have withdrawn from the study.  
5. Final lost to follow-up status should be determined at the end of the study when a 
participant has reached the end of the study follow-up period (e.g., 2 years post-
vaccine/control + 2 months) without returning for or responding to one or more of 
his/her final study visits or study contacts. The date of last participant contact will be 
considered to be the date of study withdrawal for lost to follow-up. 
8. 
STUDY ASSESSMENTS AND PROCEDURES 
6. Study procedures and their timing are summarized in the Schedule of Activities 
(SoA) (Section 1.3). Protocol waivers or exemptions are not allowed. 
7. Adherence to the study design requirements, including those specified in the SoA 
(Section 1.3), is essential and required for study conduct. 
8. All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. 
9. In the event of a significant study-continuity issue (e.g., caused by a pandemic), 
alternate strategies for participant visits and monitoring may be implemented by the 
sponsor or the investigator, as per local health authority/ethics requirements. 
8.1. 
Administrative and general/baseline procedures 
8.1.1. 
Collection of demographic data and lifestyle characteristics 
Record demographic data such as date of birth, sex (for infant participants), race, and 
ethnicity in the participant’s eCRF. Record lifestyle characteristics data such as smoking 
and substance use in the participant’s eCRF will be collected towards the end of 
pregnancy. 
Collection of sex, race and ethnicity data is necessary to assess and monitor the 
diversity of the participants, and to determine if the participants are truly representative 
of the impacted population. 
8.1.2. 
Medical/vaccination history 
Obtain the participant’s medical/vaccination history prior to the current study pregnancy 
follow-up by interviewing the participant/parent(s)/LAR(s) and/or review of the 
participant’s medical records. Record any vaccinations received from one month prior to 
the current pregnancy. Record any pre-existing conditions, signs and/or symptoms 
present prior to the current pregnancy in the eCRF. 
8.2. 
Immunogenicity assessments 
Not applicable. 

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8.3. 
Safety assessments 
Planned timepoints for all safety assessments are provided in the SoA (Section 1.3). 
8.3.1. 
Safety monitoring and committee 
Safety evaluations will include those performed by investigators, as well as those by a 
SRT composed of GSK RSV team members.  
A SRT is in place for each GSK product. It comprises of a global cross-functional team 
responsible for the ongoing assessment of benefit-risk for a product. The SRT 
contribute to the continual assessment of incoming new efficacy and safety 
information. 
If the SRT’s decision(s) after a safety evaluation require(s) them to take some action 
(e.g., to suspend, modify, or continue the conduct of the study for all groups or for 
selected groups), the SRT Chair (or his/her representative) will notify the study CSL. The 
study CSL will be accountable for notifying investigators in writing of the SRT’s 
decision(s). 
An external case adjudication committee will provide an independent, objective, blinded 
review and judgement on cases of preterm births. The scope of review by this committee 
will be limited to only review of gestational age at birth (to determine status of preterm 
birth cases) and preterm birth cases but may be expanded at the discretion of the GSK 
clinical study team. The details of structure and scope of this committee will be included 
in external case adjudication committee charter. 
8.4. 
MAEs, serious adverse events (SAEs) and SAEs due to 
study participation, AESIs, and other safety reporting 
For definitions relating to safety information see Section 10.2. 
The investigator and any qualified designees are responsible for detecting, documenting, 
and recording events that meet the definition of a MAE, SAEs, AESI (see Section 10.2) , 
SAE due to study participation and other safety information and remain responsible for 
following up all MAEs, SAEs, AESIs, SAEs considered related to the study participation 
that caused the participant to discontinue the study (see Section 7). This includes events 
reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant’s legally authorized representative). 
SAEs due to study participation, defined as SAEs which in the opinion of the investigator 
are related to the study participation (e.g., accident during any of the study contact and/or 
study visit) will be recorded throughout the study period. 
The method of recording, evaluating, and assessing causality of SAEs and SAEs due to 
study participation and the procedures for completing and transmitting SAE due to study 
participation reports are provided in Section 10.2 and/or Section 8.4.6. 

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8.4.1. 
Time period and frequency for collecting MAE, SAE, and other 
safety information  
All SAEs due to study participation will be collected from the signing of the ICF and/or 
IAF until Day 42 post-delivery or study conclusion at the time points specified in the 
SoA (Section 1.3).  
SAEs assessed as related to study participation (e.g., protocol-mandated procedures) or 
related to a GSK product (non-IMP) will be recorded from the time a participant 
consents to participate in the study. 
MAEs and SAEs for maternal participants will be collected during pregnancy until Day 
42 post-delivery at the time points specified in the SoA (Section 1.3). 
Table 6 
Collection and reporting of safety information  
Event 
 Visit 1 
Bi-annual 
contacts for 2 
years until 
pregnancy 
 Initial 
Pregnancy 
Contact 
Monthly 
contacts until 
Delivery 
Delivery 
Contact 
Day 42 
post-
delivery 
Study 
Conclusion 
 
D1 
 
 
 
 
 
SAEs related to 
study 
participation** or 
related to a GSK 
product  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy 
outcome 
 
 
 
 
 
 
 
 
MAEs  
 
 
 
 
 
 
 
 
SAEs 
 
 
 
 
 
 
 
 
Pregnancy 
related AESIs 
 
 
 
 
 
 
 
 
Infant AESIs 
 
 
 
 
 
 
 
 
Infant MAEs 
 
 
 
 
 
 
 
 
Infant SAEs 
 
 
 
 
 
 
 
 
* i.e., consent obtained; D: Day, M: Month 
** Any SAEs assessed as related to study participation (e.g., protocol-mandated procedures) or related to a GSK 
product will be recorded from the time a participant consents to participate in the study. 
The shaded regions in the table indicate time period of data collection 
All SAEs, AESIs and SAEs related to study participation will be recorded and reported to 
the sponsor or designee immediately and under no circumstance should this exceed 24 
hours, as indicated in Section 10.2. The investigator will submit any updated SAE data to 
the sponsor within 24 hours of it being available and/or awareness. 
A poststudy SAE is defined as any event that occurs outside of the SAE reporting 
period defined in Section 8.4.1 and Table 6. 

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Investigators are not obligated to actively seek information on SAEs after conclusion of 
the study participation. However, if the investigator learns of any SAE, including a 
death, after a participant has been discharged from the study, the investigator must 
record it in the medical records. If the investigator considers the event to be reasonably 
related to study participation, the investigator must promptly notify the sponsor. 
8.4.2. 
Method of detecting SAEs and SAEs due to study participation 
Care will be taken not to introduce bias when detecting SAEs and SAEs due to study 
participation. Open-ended and nonleading verbal questioning of the 
participant/participants’ parent(s)/LAR(s) is the preferred method to inquire about SAEs 
and SAEs due to study participation occurrences. 
8.4.3. 
Follow-up of SAEs and SAEs due to study participation  
After the initial SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs and SAEs due to study participation 
will be followed until resolution, stabilization, the event is otherwise explained, or the 
participant is lost to follow-up (as defined in Section 7.3). Further information on follow-
up procedures is provided in Section 10.2.3.5. 
8.4.4. 
Adverse events of special interest 
All pregnancy related AESIs will be collected during pregnancy until Day 42 post-
delivery at the time points specified in the SoA (Section 1.3). 
Infant AESIs will be collected from birth until Day 42 post-delivery at the time points 
specified in the SoA (Section 1.3). 
8.4.5. 
Data Source and Data Collection for AESIs 
8.4.5.1. 
List of AESIs  
Pregnancy-related AESIs  
Infant AESIs 
• 
Hypertensive disorders of pregnancy: 
o 
gestational hypertension, 
o 
pre-eclampsia, 
o 
pre-eclampsia with severe features 
including eclampsia; 
• 
Fetal growth restriction; 
• 
Pathways to preterm birth: 
o 
premature preterm rupture of 
membranes, 
o 
preterm labor, 
o 
insufficient cervix 
o 
provider-initiated preterm birth; 
• 
Gestational diabetes mellitus; and 
• 
Chorioamnionitis. 
• 
Small for gestational age, 
• 
Low birth weight including very low 
and extremely low birth weight (<2500 g, 
<1500 g, <1000 g), 
• 
Congenital anomalies: 
o 
major external structural 
defects, 
o 
internal structural defects, 
o 
functional defects, 
• 
Neonatal death 
o 
in a non-viable live birth [<22 
weeks gestation] 
o 
in an extremely pre-term birth 
[22.GA<28 weeks], 

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Pregnancy-related AESIs  
Infant AESIs 
o 
in a preterm live birth 
[28.GA<37 weeks], 
o 
in a term live birth, 
• 
Preterm birth 
8.4.5.2. 
Retrospective data source and data collection 
For pregnancies completed (through Day 42 post-delivery) prior to enrollment, medical 
data related to pregnancy outcome, pregnancy related AESIs and infant AESIs of any 
pregnancy conceived post-RSVPreF3 or control vaccination, based on medical records, 
will be retrospectively collected. Data collection will be done through a single 
structured participant contact to retrospectively collect information about any 
healthcare received by the mother and infant during pregnancy up to Day 42 post-
delivery. This will identify the medical records for review, so that information about 
any outcome, medically attended event, SAE, or event of special interest is obtained 
directly from medical records. 
All relevant data collected in the medical records will be recorded in an electronic case 
report form (eCRF). 
8.4.5.3. 
Prospective data source and data collection 
For participants in the prospective cohort, prospective data collection related to 
pregnancy outcome, pregnancy related AESIs and infant AESIs of any pregnancy 
conceived post-vaccination and ongoing at enrollment or conceived after enrollment 
will be done through multiple structured participant follow-up contacts to collect 
information about any healthcare received by the mother and infant during pregnancy 
up to Day 42 post-delivery. This will identify the medical records for review, so that 
information about any outcome, medically attended event, SAE or event of special 
interest is obtained directly from medical records. 
• 
Follow-up contact every six months if not pregnant, up to 2 years (+2 months) post-
vaccination/control. 
• 
A follow-up Contact or Visit at the start of the pregnancy. 
• 
Spontaneous reporting of pregnancy by study participants. 
• 
Monthly contacts during any pregnancies conceived within 2 years post-
vaccination/control, until Day 42 post-delivery. 
• 
Follow-up Contact at Delivery. 
• 
Follow-up Contact at Day 42 (~6 weeks) post-delivery. 
All relevant data collected in the medical records will be recorded in an electronic case 
report form (eCRF). 

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8.4.6. 
Regulatory reporting requirements for SAEs, SAEs due to study 
participation and AESIs 
• 
Prompt notification by the investigator to the sponsor of an SAE, SAE due to study 
participation and AESI is essential so that legal obligations and ethical 
responsibilities toward the safety of participants and the safety of a study 
intervention under clinical investigation are met. See Section 8.4.1 for reporting 
timeframes. 
• 
For SAEs, SAEs due to study participation and AESI, the investigator must always 
provide an assessment of causality at the time of the initial report, as defined in the 
Section 10.2.3.3. 
• 
An investigator who receives an investigator safety report describing an SAE due to 
study participation or other specific safety information (e.g., summary or listing of 
SAEs) from the sponsor will review and then file it along with the IB and will notify 
the IRB/IEC, if appropriate according to local requirements. 
Table 7 
Timeframes for submitting SAE due to study participation and other 
events reports to GSK  
Type of event 
Initial reports 
Follow-up of relevant information on a 
previous report 
Timeframe 
Documents 
Timeframe 
Documents 
SAEs  
24 hours* ‡ 
Electronic Adverse Events 
Report 
24 hours* 
[paper/electronic] Adverse 
Events Report 
SAEs due to 
study participation 
24 hours* ‡ 
Electronic Adverse Events 
Report 
24 hours* 
[paper/electronic] Adverse 
Events Report 
AESIs 
24 hours* ‡ 
Electronic Adverse Events 
Report 
24 hours* 
[paper/electronic] Adverse 
Events Report 
* Timeframe allowed after receipt or awareness of the information by the investigator/site staff. 
‡ Paper Adverse Events Report will be dated and signed by the investigator (or designee). For each SAE due to study 
participation, the investigator(s) must document in the medical notes that they have reviewed the SAE due to study 
participation and have provided an assessment of causality 

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8.4.7. 
Contact information for reporting SAEs, SAEs due to study 
participation and AESIs 
Table 8 
Contact information for reporting SAEs, SAEs due to study 
participation and AESIs 
Study contact for questions regarding SAEs, SAEs due to study participation and 
AESIs 
Contact GSK’s local and/or medical contacts 
Contacts for reporting SAEs due to study participation 
Available 24/24 hours and 7/7 days 
ogm28723@gsk.com  
8.4.8. 
Additional reporting guidance for pregnancies reported during 
study period 
8.4.8.1. 
Labor and Delivery  
• 
An uncomplicated vaginal delivery or planned cesarean section expected to occur in 
a hospital setting should NOT be reported as an AE, MAE or SAE. 
• 
A medical complication that requires a cesarean section or an emergency induction 
may be reported as an SAE/AESI (as applicable), using the corresponding Expedited 
AE report form.  
8.4.8.2. 
Reporting of congenital anomalies in relation to pregnancy outcomes 
and SAEs and/or AESIs 
Table 9 summarizes the requirements for AESI/SAE reporting of adverse pregnancy 
outcomes when congenital anomalies are/are not present. 
Table 9 
Reporting pregnancy outcomes with or without congenital 
anomalies as AESIs and/or SAEs  
 
 
Fetal death 
Elective / Therapeutic 
Termination 
 
Live birth 
/stillbirth 
Congenital anomalies* 
AESI 
SAE 
AESI 
SAE 
AESI 
SAE 
None 
- 
- 
- 
X 
- 
X 
Major1  
X 
if reportable per 
MACDP3 
- 
X 
- 
X 
Minor2  
- 
if reportable per 
MACDP3 
- 
X 
- 
X 
* In the event of infant’s participation in the study, congenital anomalies are to be reported in the infant’s eCRF. 
However, when there is no live birth, or no signed informed consent for the infant or the congenital anomaly is being 
reported for a subsequent pregnancy, it will be encoded in the maternal participant’s eCRF.  
1Structural or functional defects that require surgical and/or medical treatment and that have serious adverse effects on 
health or development (functional) or have significant cosmetic impact. 
2Anatomic variants or defects that do not have serious medical, functional or cosmetic consequences for the child.  
3 Metropolitan Atlanta Congenital Defects Program (MACDP) 6-Digit Code Defect List 

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Additional guidance when congenital anomalies are present are as follows: 
The term “congenital anomaly” is broad. GSK uses the case definitions provided in the 
Centers for Disease Control and Prevention (CDC) Metropolitan Atlanta Congenital 
Defects Program guidelines, with specific reference to the MACDP 6-Digit Code Defect 
List [MACDP, 2021] to ensure that the collection and recording of these data is complete 
and consistent across studies and projects. 
To report a pregnancy outcome of live birth with congenital anomaly as an SAE per these 
guidelines, an infant must have a birth defect that is included in MACDP surveillance 
data per the MACDP 6-Digit Code Defect List. (Congenital anomalies that are not 
included in MACDP surveillance data may be reported as medically attended or serious 
adverse events, if appropriate). 
The characterization of major and minor congenital anomalies will follow CDC 
definitions [CDC, 2019]. Major congenital anomalies are structural or functional defects 
that require surgical and/or medical treatment and that have serious adverse effects on 
health or development (functional) or have significant cosmetic impact. They are always 
reported as AESIs, even if they are not reportable as SAEs.  
Minor congenital anomalies are anatomic variants or defects that do not have serious 
medical, functional or cosmetic consequences for the child. Minor congenital anomalies 
are not to be reported as AESIs, even if they are reportable as SAEs.  
If minor congenital anomalies are not reportable as per MACDP, they should be recorded 
on the infant AE eCRF. Whether the event was medically attended or not should also be 
recorded in the infant AE eCRF. If they are not medically attended, they should be 
reported in the infant AE eCRF as medically attended event category “none”. 
For example: 
• 
Cleft palate is a major congenital anomaly and should be reported as an AESI. Per 
the MACDP 6 Digit Code Defect list, cleft palate is always included in MACDP 
surveillance data and should therefore also be reported as an SAE.  
• 
If congenital aortic valve insufficiency or regurgitation meets the criteria for a major 
congenital anomaly, it is an AESI. Per the MACDP 6-digit code list, congenital 
aortic valve insufficiency or regurgitation is only included in MACDP surveillance 
data and should only be reported as an SAE if designated as moderate or severe, or 
(if the degree is not specified) if another heart defect is present. Other cases could be 
reported as medically attended or serious adverse events if the infant meets any other 
protocol criterion for a medically attended or serious AE because of the condition. 
• 
Mongolian spots, in the absence of any associated findings represent a minor 
congenital anomaly. Per the MACDP 6-digit code list, they are never included in 
MACDP surveillance data. They are neither an AESI nor an SAE. They do not 
typically satisfy the criteria for a medically attended AE and so, in general, would 
only be recorded on the infant AE eCRF. 

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8.4.9. 
Treatment of adverse events 
• 
Any medication administered for the treatment of an SAE/AESI should be recorded 
on the Expedited Adverse Event Report of the participant’s eCRF screen. 
8.4.10. 
Covid-19 Infection  
Maternal and infant COVID-19 cases identified during the study (as per standard of care) 
will be captured and reported using standard medically attended AE or SAE criteria, as 
outlined in Section 10.2. Additionally, all reported COVID-19 infections during a study 
pregnancy will be captured and reported on a COVID-19 screen of the eCRF. 
COVID-19 cases should be reported in the eCRF according to the WHO Case Definition 
[WHO, 2022] using one of the following terms:  
• 
Suspected COVID-19 infection 
• 
Probable COVID-19 infection 
• 
Confirmed COVID-19 infection. 
8.5. 
Pharmacokinetics 
PK is not evaluated in this study. 
8.6. 
Pharmacodynamics 
PD is not evaluated in this study. 
8.7. 
Genetics 
Genetics are not evaluated in this study.  
8.8. 
Biomarkers 
Biomarkers are not evaluated in this study. 
8.9. 
Immunogenicity assessments 
Not applicable for this study. 
8.10. 
Health economics or medical resource utilization and health 
economics 
Not applicable for this study. 

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9. 
STATISTICAL CONSIDERATIONS 
The statistical analysis plan will be finalized prior to database lock and it will include a 
more technical and detailed description of the statistical analyses described in this 
section. This section is a summary of the planned statistical analyses of the most 
important endpoints including primary and key secondary endpoints. 
9.1. 
Statistical hypotheses 
This study is descriptive without statistical hypotheses. The primary and secondary 
objectives, as outlined in Section 3, are planned to be addressed using descriptive 
statistics. 
9.2. 
Analysis sets 
Table 10 
Maternal Participants 
Analysis Set 
Definition / Criteria 
Screened  
All participants who were screened for eligibility. 
Enrolled 
All maternal subjects who completed the informed consent process and signed the 
informed consent form and were determined eligible for study participation. 
Note screening failures (who never passed screening even if rescreened) are 
excluded from the Enrolled analysis set as they did not enter the study. 
Full Analysis Set (FAS) 
All maternal subjects who had pregnancy defined by this study (defined in 
Section 5.1).  
Table 11 
Infant Participants 
Analysis Set 
Definition / Criteria 
Enrolled Infant 
Infants live born to the maternal set, whose parents/LARs completed the informed 
consent process and signed the informed consent form. 
Full Analysis Set (FAS) 
All infant subjects in the infant set who have post-delivery/birth data.  
9.3. 
Statistical analyses 
9.3.1. 
General considerations 
All statistical analyses are descriptive. Besides the primary analyses, sub-group analyses 
may be conducted. 
All primary and secondary analyses will be performed on the Full Analysis Set. 

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9.3.2. 
Primary endpoints analysis  
 
Primary Endpoints  
Statistical Analysis Methods 
Maternal 
participants 
Number and percentage of maternal 
participants reporting pregnancy outcomes 
and pregnancy related AESIs within the 
first pregnancy conceived within 2 years 
post-vaccination in participants 
enrolled in prior RSV MAT studies up to 
Day 42 post-delivery. 
The number and percentage of maternal participants 
reporting pregnancy outcomes and pregnancy 
related AESIs within the first pregnancy conceived 
within 2 years post-vaccine/control will be tabulated 
with its exact 95% CI by study arms. 
By participant listings of pregnancy related 
outcomes and AESIs will be prepared 
Infant 
participants 
Number and percentage of infant 
participant reporting infant AESIs from the 
first pregnancy conceived within 2 years 
post-vaccination in participants 
enrolled in prior RSV MAT studies up to 
Day 42 post-delivery. 
The Number and percentage of infant participant 
reporting infant AESIs from the first study pregnancy 
conceived within 2 years post-vaccine/control will 
be tabulated with its exact 95% CI by study arms. 
By participant listings of infant AESIs will be 
prepared. 
Pregnancy outcomes include (not limited to) spontaneous abortion, stillbirth, and preterm 
birth. The pregnancy related adverse events of special interest (AESIs) and infant AESIs 
are listed in Section 8.4.5.1. 
9.3.3. 
Secondary endpoints analyses  
9.3.3.1. 
Pregnancy outcomes and AESIs from any study pregnancy 
 
Secondary Endpoints  
Statistical Analysis Methods 
Maternal 
participants 
Number and percentage of maternal 
participants reporting pregnancy outcomes 
and pregnancy related AESIs during any 
study pregnancy conceived within 2 
years post-vaccination in participants 
enrolled in prior RSV MAT studies up to 
Day 42 post-delivery. 
The number and percentage of maternal 
participants reporting pregnancy outcomes and 
pregnancy related AESIs during any pregnancy 
conceived within 2 years post-vaccination in 
participants enrolled in prior RSV MAT studies 
up to Day 42 post-delivery, will be tabulated with 
its exact 95% CI by study arms on subject level. 
By participant listings of pregnancy related 
outcomes and AESIs will be prepared. 
Infant 
participants 
Number and percentage of infant 
participant reporting infant AESIs from any 
study pregnancy conceived within 2 
years post-vaccination in participants 
enrolled in prior RSV MAT studies up to 
Day 42 post-delivery. 
The Number and percentage of infant participant 
reporting infant AESIs from any pregnancy 
conceived within 2 years post-vaccination in 
participants enrolled in prior RSV MAT studies 
up to Day 42 post-delivery, will be tabulated with 
its exact 95% CI by study arms on subject level. 
By participant listings of infant AESIs will be 
prepared. 
9.3.3.2. 
Selected pregnancy outcomes and AESIs by selected risk factors 
The number and percentage of selected pregnancy outcomes, pregnancy related AESIs 
and infant AESIs by study arms, stratified by selected risk factors, will be tabulated with 
exact 95% CIs for both first and any study pregnancy conceived within 2 years post-
vaccination in participants enrolled in prior RSV MAT studies up to Day 42 post-
delivery. Their relative risk estimates with 95% CIs and observed p-values will be 
reported for all comparisons accordingly.  

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Regarding preterm birth outcome, the comparisons will be conducted by study arms and 
by the combination of study arms and preterm birth history (Yes/No) in prior MAT study. 
The risk factors to be explored may include maternal smoking/household smoke 
exposure, maternal substance abuse, infections during pregnancy, COVID infection 
during pregnancy, prior preterm delivery, multiple gestation pregnancy, and short inter-
pregnancy interval (less than 18 months between pregnancies), pregnancy complications 
such as preeclampsia and fetal distress. 
9.3.4. 
Exploratory endpoints analyses 
Exploratory analyses of pregnancy outcomes, pregnancy related adverse events of 
special interest (AESIs), infant AESIs, and any other analysis (as applicable) will be 
described in the statistical analysis plan and may be summarized in one or more 
annexes to the clinical study report. 
9.3.5. 
Other safety analyses 
For medically attended AEs until Day 42 post-delivery (Mothers: conception to Day 42 
post-delivery; Infants: birth to Day 42), the number and percentage of maternal or infant 
participants with each medically attended AE with exact 95% CIs will be tabulated by 
study arms and by Medical Dictionary for Regulatory Activities (MedDRA) preferred 
term. By-participant listings will be prepared. 
For SAEs due to study participation, the number and percentage of participants with each 
SAE with exact 95% CIs will be tabulated by study arms and by Medical Dictionary for 
Regulatory Activities (MedDRA) preferred term. By-participant listings will be prepared. 
9.4. 
Interim analyses 
Not applicable. 
9.5. 
Sample size determination 
All analyses will be descriptive and thus no hypothesis driven sample size calculation 
was conducted.  
As noted in Section 4.1, all study participants (approximately 8240) from prior RSV 
MAT studies will be considered for enrollment in this study based on the eligibility 
criteria. Assuming the study will start on December 7th, 2022, the study potential 
subjects include: (1) those who had deliveries defined in Section 5.1.1 (to be enrolled to 
Retrospective cohort); (2) those with ongoing pregnancy, or who at enrollment have not 
conceived but subsequently conceive within two years since the vaccination/control in 
previous RSV MAT studies as defined in in Section 5.1.2 (to be enrolled to Prospective 
cohort). The actual sample size will mainly depend on: (1) the enrollment rate of those 
subjects who participated in the previous RSV MAT studies; (2) the incidence rate of 
pregnancy conceived post RSVPreF3 (or control) vaccination during study period. 

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To estimate the incidence rate of first pregnancy conceived post RSVPreF3 (or control) 
vaccination, we considered the likelihood of pregnancy among participants in prior 
studies of non-pregnant women and pregnant women separately (approximately 8240 
total). Among non-pregnant women (approximately 2540), we estimate approximately 
10% will have a pregnancy during the time period of this study [Curtin, 2013]. Assuming 
60% enroll in this study, we estimate approximately 150 non-pregnant women in prior 
studies who enroll in this study will have a pregnancy. Among pregnant women 
(approximately 5700), we estimated approximately 50% would have another pregnancy. 
From data on inter-pregnancy intervals in US women, we estimated approximately 30% 
of those subsequent pregnancies will occur during the time period of this study [Thoma, 
2016]. Assuming 60% enroll in this study, we estimate approximately 500 non-pregnant 
women in prior studies who enroll in this study will have a pregnancy. In total, we 
estimate approximately 650 enrolled study participants will have at least one pregnancy 
of interest for this study and contribute to the total number of pregnancies from which 
incidence rates for events will be calculated. 
The lowest rate of the safety signal observed in a MAT-009 study group was 
approximately 5% (see Section 2.2). A sample size of 300 pregnancy participants will 
provide 100% probability to detect at least one event (e.g., preterm birth event), 
providing the true rate is 5%. Assuming only 100 of 300 pregnancy participants are from 
the previous RSVPreF3 group, it can provide 99.4% probability to detect at least one 
event on the condition of the true event rate at 5%. For a sample size of 300 pregnancy 
participants, it will still provide a probability of 78%, 95% or 99% to observe at least one 
participant with event of interest, even if the true event rate is as low as 0.5%, 1% or 
1.5%, respectively. A sample size of 650 pregnancy participants will provide a 
probability of 96% or 100% to observe at least one participant with event of interest, even 
if the true event rate is as low as 0.5% or 1%, respectively. The table below presents more 
scenarios of sample size consideration regarding event rates. 

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Table 12 
Sample size, event rate and probability  
Sample size 
Event Rate 
Probability to observe at least one event 
300 
0.5% 
78% 
1% 
95% 
1.5% 
99% 
3% 
100% 
5% 
100% 
7% 
100% 
500 
0.5% 
92% 
1% 
99% 
1.5% 
100% 
3% 
100% 
5% 
100% 
7% 
100% 
650 
0.5% 
96% 
1% 
100% 
1.5% 
100% 
3% 
100% 
5% 
100% 
7% 
100% 
1000 
0.5% 
99% 
1% 
100% 
1.5% 
100% 
3% 
100% 
5% 
100% 
7% 
100% 
In consideration of the precision of 95% Clopper-Pearson confidence interval (CI) for the 
event rate, if observed 5% participants experienced a pregnancy outcome AESI among 
300 participants, the two-sided 95% CI would be within (2.8%, 8.1%). And among 650 
participants, the two-sided 95% CI would be within (3.5%, 7%). The table below presents 
the precision one can get in more scenarios. Even approximately 300 participants with 
pregnancy information are included in the study would still provide reasonable precision 
to detect and estimate most of the events of interest in the study. 

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Table 13 
95% CI on the percentage of participants with event(s) of interest  
Sample size 
Number of Event(s) 
% of Event 
95% CI 
Lower Limit 
Upper Limit 
300 
1 
0.33 
0.0 
1.8 
3 
1 
0.2 
2.9 
5 
1.67 
0.5 
3.8 
9 
3 
1.4 
5.6 
15 
5 
2.8 
8.1 
21 
7 
4.4 
10.5 
30 
10 
6.8 
14.0 
500 
1 
0.2 
0.0 
1.1 
5 
1 
0.3 
2.3 
10 
2 
1.0 
3.6 
15 
3 
1.7 
4.9 
25 
5 
3.3 
7.3 
35 
7 
4.9 
9.6 
50 
10 
7.5 
13.0 
650 
1 
0.15 
0.0 
0.9 
7 
1 
0.4 
2.1 
10 
1.5 
0.7 
2.8 
20 
3 
1.8 
4.6 
33 
5 
3.5 
7.0 
46 
7 
5.2 
9.2 
65 
10 
7.8 
12.6 
1000 
5 
0.5 
0.2 
1.2 
10 
1 
0.5 
1.8 
15 
1.5 
0.8 
2.5 
30 
3 
2.0 
4.3 
50 
5 
3.7 
6.5 
70 
7 
5.5 
8.8 
100 
10 
8.2 
12.0 
Note: Precision estimation using PASS2019 19.0.1 (Clopper-Pearson Confidence Intervals for One Proportion). 
Participants who withdraw from the study will not be replaced. 

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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1. 
Appendix 1: Regulatory, ethical, and study oversight 
considerations 
10.1.1. 
Regulatory and ethical considerations 
• 
This study will be conducted in accordance with the protocol and with the following: 
− 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) international ethical guidelines 
− 
Applicable ICH GCP guidelines 
− 
Applicable laws and regulations 
• 
The protocol, protocol amendments, ICF, IAF (if applicable), IB, and other relevant 
documents must be submitted to an IRB/IEC by the investigator and reviewed and 
approved by the IRB/IEC before the study is initiated.  
• 
Substantial amendments to the protocol will require IRB/IEC approval before 
implementation of changes made to the study design, except for changes necessary to 
eliminate an immediate hazard to study participants.  
• 
Protocols and any substantial amendments to the protocol will require health 
authority approval prior to initiation except for changes necessary to eliminate an 
immediate hazard to study participants. 
• 
The investigator will be responsible for the following, as applicable: 
− 
Providing written summaries of the status of the study to the IRB/IEC annually 
or more frequently in accordance with the requirements, policies, and 
procedures established by the IRB/IEC 
− 
Notifying the IRB/IEC of SAEs or other significant safety findings as required 
by IRB/IEC procedures 
− 
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 
536/2014 for clinical studies (if applicable), and all other applicable local 
regulations 
10.1.2. 
Financial disclosure 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study. 

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10.1.3. 
Informed consent process 
• 
The investigator or the investigator’s representative will explain the nature of the 
study, including the risks and benefits, to the participants/participants’ 
parent(s)/LAR(s) and answer all questions regarding the study. 
• 
Potential participants/participants’ parent(s)/LAR(s) must be informed that their 
participation is voluntary. They or their LAR will be required to physically or 
digitally sign a statement of informed consent that meets the requirements of 21 CFR 
50, local regulations, ICH guidelines, Health Insurance Portability and 
Accountability Act (HIPAA) requirements, privacy and data protection 
requirements, where applicable, and the IRB/IEC or study center. 
• 
The medical record must include a statement that physical or digital informed 
consent was obtained before the participant was enrolled in the study and the date the 
physical or digital consent was obtained. The authorized person obtaining the 
informed consent must also sign the ICF. 
• 
Participants must be reconsented to the most current version of the ICF(s) during 
their participation in the study. 
• 
A physical or digital copy of the ICF(s) must be provided to the participant or their 
LAR. 
• The investigator must obtain assent from the minor participant in addition to the 
consent provided by the participants’ parent(s)/LAR(s) when a minor can assent to 
participate in a study. The investigator is also accountable for determining a 
minor's capacity to assent to participation in a research study according to the local 
laws and regulations. 
• In accordance with local laws and regulations, participants who become legally 
emancipated during the study, i.e., reach the legal age of consent, must be 
reconsented.  
• The participant must provide consent by signing an ICF, which summarizes the 
study, includes a consent statement and provides documentation that the 
participant agrees to continue participating in the study.  
• If the participant is incapacitated and cannot provide consent, the parent(s)/LAR(s) 
can provide consent by signing the ICF on their behalf. 
10.1.4. 
Recruitment strategy 
This study will contact approximately 8240 female participants who were enrolled in one 
of the prior RSV MAT studies for participation into this follow-up study. Pre-screening 
and screening will be tracked on a routine basis and projected enrollment per country will 
be discussed with the central team on a regular basis. 

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10.1.5. 
Data protection 
• 
Participants will be assigned a unique identifier by the investigator. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier only; 
participant names or any information which would make the participant identifiable 
will not be transferred. 
• 
GSK will ensure protection of the personal data of the investigator and site staff 
which is collected within the framework of and for the purpose of the study. 
• 
The participant/participants’ parent(s)/LAR(s) must be informed that their 
personal/their child’s study-related data will be used by the sponsor in accordance 
with local data protection law. The level of disclosure must also be explained to the 
participant/participants’ parent(s)/LAR(s) that their/their child’s data will be used as 
described in the informed consent  
• 
The participant/participants’ parent(s)/LAR(s) must be informed that their/their 
child’s medical records may be examined by Clinical Quality Assurance auditors or 
other authorized personnel appointed by the sponsor, by appropriate IRB/IEC 
members, and by inspectors from regulatory authorities. 
• 
The contract between sponsor and study sites specifies responsibilities of the parties 
related data protection, including handling of data security breaches and respective 
communication and cooperation of the parties. 
• 
Information technology systems used to collect, process, and store study-related data 
are secured by technical and organizational security measures designed to protect 
such data against accidental or unlawful loss, alteration, or unauthorized disclosure 
or access. GSK and/or trusted third parties working on behalf of GSK and/or 
institutions working with GSK for the purposes of this study are contractually bound 
to protect participant coded data. GSK will protect participant coded data and will 
only share it as described in the ICF. 
10.1.6. 
Dissemination of Clinical Study Data 
• 
The key design elements of this protocol and results summaries will be posted on 
www.ClinicalTrials.gov and/or GSK Clinical Study Register in compliance with 
applicable regulations/GSK policy. GSK will aim to register protocols summaries 
prior to study start and target results summaries submission within 12 months of 
primary/ study completion date. Where external regulations require earlier 
disclosure, GSK will follow those timelines.  
• 
Where required by regulation, summaries will also be posted on applicable national 
or regional clinical study registers. 
• 
Where required by applicable regulatory requirements, an investigator signatory will 
be identified for the approval of the study report, and provided reasonable access to 
statistical tables, figures, and relevant reports. GSK will also provide the investigator 
with the full summary of the study results, including a summary of trial results 
understandable to laypersons. The investigator is encouraged to share the plain 
language summary with the study participants, as appropriate. The full study report 

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will be made available upon request, after decision on marketing authorization by 
regulatory authorities.   
• 
GSK will provide the investigator with the randomization codes and participant-level 
line listings for their site only after completion of the full statistical analysis. 
• 
GSK intends to make anonymized participant-level data from this study available to 
external researchers for scientific analyses or to conduct further research that can 
help advance medical science or improve patient care. This helps ensure the data 
provided by study participants are used to maximum effect in the creation of 
knowledge and understanding. 
10.1.7. 
Data quality assurance 
• 
All participant data relating to the study will be recorded on printed or electronic 
CRFs unless transmitted to the sponsor or designee electronically (e.g., laboratory 
data). The investigator is responsible for verifying that data entries are accurate and 
correct by physically or electronically signing the CRF. 
• 
Guidance on completion of eCRFs will be provided in eCRF completion guidelines. 
• 
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source documents. 
• 
QTLs will be predefined in the QTL report to identify systematic issues that can 
impact participant right, safety and/or reliability of study results. These predefined 
parameters will be monitored during the study, and important deviations from the 
QTLs and remedial actions taken will be summarized in the CSR. 
• 
Monitoring details describing strategy, including definition of study critical data 
items and processes (e.g., risk-based initiatives in operations and quality such as risk 
management and mitigation strategies and analytical risk-based monitoring), 
methods, responsibilities, and requirements, including handling of noncompliance 
issues and monitoring techniques (central, remote, or on-site monitoring) are 
provided in the monitoring plan. 
• 
The sponsor or designee is responsible for the data management of this study, 
including quality checking of the data. 
• 
The sponsor assumes accountability for actions delegated to other individuals (e.g., 
contract research organizations). 
• 
Records and documents, including signed ICF, pertaining to the conduct of this study 
must be retained by the investigator for 25 years from the issue of the final CSR/ 
equivalent summary unless local regulations or institutional policies require a 
different retention period. No records may be destroyed during the retention period 
without the written approval of the sponsor. No records may be transferred to 
another location or party without written notification to the sponsor.  

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10.1.8. 
Source documents 
• 
Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site. 
• 
Data reported on the eCRF/or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must 
be explained. The investigator may need to request previous medical records or 
transfer records, depending on the study. Also, medical records must be available. 
• 
Definition of what constitutes source data and its origin can be found in [e.g. source 
data acknowledgment or monitoring guidelines]. 
• 
The investigator must maintain accurate documentation (source data) that supports 
the information entered in the eCRF. 
• 
The sponsor or designee will perform monitoring to confirm that data entered into 
the eCRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and 
that the study is being conducted in accordance with the currently approved protocol 
and any other study agreements, ICH GCP, and all applicable regulatory 
requirements. 
10.1.9. 
Study and site start and closure 
Start of Study and First Act of Recruitment 
The start of study and the first act of recruitment are defined as first subject first visit 
(FSFV)/first contact and first ICF signature date at a country-level. 
Study/Site Termination 
GSK or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of GSK. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to: 
For study termination: 
• 
Discontinuation of further study intervention development 
For site termination: 
• 
Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor’s procedures, or GCP guidelines 

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• 
Inadequate or no recruitment (evaluated after a reasonable amount of time) of 
participants by the investigator 
• 
Total number of participants included earlier than expected 
If the study is prematurely terminated or temporarily suspended, the sponsor shall 
promptly inform the investigators, the IECs/IRBs, the regulatory authorities, and any 
contract research organization(s) used in the study of the reason for termination or 
temporary suspension, as specified by the applicable regulatory requirements. The 
investigator shall promptly inform the participant and should assure appropriate 
participant therapy and/or follow-up. 
10.1.10. 
Publication policy 
The results of this study may be published in peer reviewed scientific literature and/or 
presented at scientific meetings. The sponsor will comply with the requirements for 
publication of study results in accordance with standard editorial and ethical practice and 
as per the sponsor’s internal policy. Authorship will be determined by mutual agreement 
and in line with ICMJE authorship requirements. 
10.2. 
Appendix 2: MAEs and SAEs due to study participation: 
Definitions and procedures for recording, evaluating, follow-
up, and reporting 
10.2.1. 
Unsolicited AE 
• 
Definition of unsolicited AE 
• 
An unsolicited AE is an AE that was either not included in the list of solicited 
events or could be included in the list of solicited events but with an onset outside 
the specified period of follow-up for solicited events. Unsolicited AEs must have 
been communicated by participants/ participant’s parent(s)/LAR(s) who has 
signed the informed consent. Unsolicited AEs include both serious and nonserious 
AEs. 
• 
Potential unsolicited AEs may be medically attended (i.e., symptoms or illnesses 
requiring a hospitalization, emergency room visit, or visit to/by a healthcare 
provider). The participants/ participant’s parent(s)/LAR(s) will be instructed to 
contact the site as soon as possible to report medically attended event(s), as well as 
any events that, though not medically attended, are of [participant/ participant’s 
parent(s) /LAR(s)] concern. Detailed information about reported unsolicited AEs 
will be collected by qualified site personnel and documented in the participant’s 
records. 
• 
Unsolicited AEs that are not medically attended nor perceived as a concern by the 
participant/participant’s parent(s)/LAR(s) will be collected during an interview 
with the participants/participant’s parent(s)/LAR(s) and by review of available 
medical records at the next visit. 

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10.2.2. 
Definition of SAE 
An SAE is defined as any untoward medical occurrence that, at any dose, meets one or 
more of the criteria listed: 
a. 
Results in death 
b. Is life-threatening 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe. 
c. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
In general, hospitalization signifies that the participant has been admitted (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting. Complications that occur during 
hospitalization are AE. If a complication prolongs hospitalization or fulfills any 
other serious criteria, the event is serious. When in doubt as to whether 
“hospitalization” occurred or was necessary, the AE should be considered serious. 
• 
Hospitalization for elective treatment of a pre-existing condition that did not 
worsen from baseline is not considered an AE. 
d. Results in persistent or significant disability/incapacity 
• 
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, diarrhea, 
influenza, and accidental trauma (e.g., sprained ankle) that may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption. 
e. 
Is a congenital anomaly/birth defect in the offspring of a study participant. 
f. 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, 
stillbirth, congenital anomalies*, ectopic pregnancy)  
*Refer to Section 8.4.8.2 for additional information. 
10.2.3. 
Recording, assessment and follow-up of MAEs, SAE, SAE due to 
study participation and AESIs 
10.2.3.1. 
SAE recording 
• 
When an SAE and/or SAE due to study participation occurs, it is the responsibility of 
the investigator to review all documentation (e.g., hospital progress notes, laboratory 
reports, and diagnostics reports) related to the event. 

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• 
The investigator will then record all relevant SAE and/or SAE due to study 
participation information. 
• 
It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to the sponsor in lieu of completion of the required form. 
• 
There may be instances when copies of medical records for certain cases are 
requested by the sponsor. In this case, all participant identifiers, with the exception 
of the participant number, will be redacted on the copies of the medical records 
before submission to the sponsor. 
• 
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the SAE and/or SAE due to 
study participation. 
10.2.3.2. 
Assessment of intensity 
The investigator will make an assessment of intensity for each MAE, AESI, SAE and 
SAE due to study participation reported during the study and assign it to one of the 
following categories:  
• 
Mild: 
A type of adverse event that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not generally interfere with 
usual activities of daily living. 
• 
Moderate:  
A type of adverse event that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing 
discomfort but poses no significant or permanent risk of harm to the research 
participant. 
• 
Severe 
A type of adverse event that interrupts usual activities of daily living, or significantly 
affects clinical status, or may require intensive therapeutic intervention. 
10.2.3.3. 
Assessment of causality 
• 
The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each SAE. The investigator will use clinical judgment to 
determine the relationship. 
• 
A reasonable possibility of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration, will be considered and investigated. 
• 
For causality assessment, the investigator will also consult the IB and/or product 
information, for marketed products. 

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• 
The investigator must review and provide an assessment of causality for each 
MAE/SAE and document this in the medical notes. There may be situations in which 
an SAE has occurred and the investigator has minimal information to include in the 
initial report to the sponsor. However, it is very important that the investigator 
always make an assessment of causality for every event before the initial 
transmission of the SAE data to sponsor. 
• 
The investigator may change their opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment. 
• 
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
10.2.3.4. 
Assessment of outcomes for SAEs and SAEs due to study 
participation 
The investigator will assess the outcome of all SAEs and/or SAEs due to study 
participation recorded during the study as: 
• 
Recovered/resolved 
• 
Recovering/resolving 
• 
Not recovered/not resolved 
• 
Recovered with sequelae/resolved with sequelae 
• 
Fatal (SAEs only). 
10.2.3.5. 
Follow-up of SAEs, SAEs due to study participation, MAEs and AESIs 
• 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by sponsor 
to elucidate the nature of the SAE and SAE due to study participation as fully as 
possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care professionals. 
• 
New or updated information will be recorded in the originally submitted documents. 
• 
The investigator will submit any updated SAE data to sponsor within 24 hours of 
receipt of the information. 
After the initial SAE, SAE due to study participation or AESIs, the investigator is 
required to proactively follow each participant at subsequent visits/contacts. All SAEs, 
SAEs due to study participation and events of special interest, will be followed until the 
event is resolved, stabilized, otherwise explained, or the participant is lost to follow-up. 
Follow-up during the study 
AESIs, SAEs, MAEs and SAEs due to study participation documented at a previous 
visit/contact and defined as not recovered/not resolved or recovering/resolving will be 
reviewed at subsequent visits/contacts until end of the study. 

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If a participant dies during their participation in the study or during a recognized follow-
up period, GSK will be provided with any available post-mortem findings, including 
histopathology. 
10.2.3.6. 
Updating of SAE, SAE due to study participation, MAEs and AESI 
information after removal of write access to the participant’s eCRF 
When additional SAE, SAE due to study participation, MAEs and AESI information is 
received after write access to the participant’s eCRF is removed, new or updated 
information should be recorded on the appropriate paper report, with all changes signed 
and dated by the investigator. The updated report should be sent to the Study contact for 
reporting SAEs (refer to Section 8.4.3). 
10.2.4. 
Reporting of SAEs, SAEs due to study participation, MAEs and 
AESIs 
SAE Reporting to GSK via an Electronic Data Collection Tool 
• 
The primary mechanism for reporting an SAE, AESIs, MAEs and/or SAEs due to 
study participation to the sponsor will be the electronic data collection tool. 
• 
If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool to report the event within 24 hours. 
• 
The site will enter the SAE, AESIs, MAEs and/or SAEs due to study participation 
data into the electronic system as soon as it becomes available. 
• 
After the study is completed at a given site, the electronic data collection tool will be 
taken offline to prevent the entry of new data or changes to existing data. 
• 
If a site receives a report of a new SAE, AESIs, MAEs and/or SAEs due to study 
participation from a study participant or receives updated data on a previously 
reported SAE, AESIs, MAEs and/or SAEs due to study participation after the 
electronic data collection tool has been taken offline, then the site can report this 
information on a paper SAE form or to the medical monitor/SAE coordinator by 
telephone. 
• 
If the site during the course of the study or poststudy becomes aware of any serious, 
nonserious AEs, pregnancy exposure, related to any GSK non-IMP they will report 
these events to GSK or to the concerned competent authority via the national 
spontaneous reporting system.  These will be classified as spontaneous ICSRs. 
• 
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE data collection tool within the designated reporting 
timeframes. 
• 
Contacts for SAE, AESIs and/or SAEs due to study participation reporting can be 
found in section 8.4.7. 

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10.2.4.1. 
Medically attended visits 
For each unsolicited symptom the participant experiences, the participant/participant’s 
parent(s)/LAR(s) will be asked if he/she/the participant received medical attention 
defined as hospitalization, or an otherwise unscheduled visit to or from medical personnel 
for any reason, including emergency room visits. This information will be recorded in the 
eCRF.  
10.3. 
Appendix 3: Definition of childbearing potential  
10.3.1. 
Definitions 
10.3.1.1. 
Woman of Childbearing Potential (WOCBP) 
Women in the following categories are considered WOCBP (fertile): 
Adolescents of childbearing potential: Tanner stage ≥2 (post-thelarche) irrespective of the 
occurrence of menarche or following menarche. 
From the time of menarche until becoming postmenopausal unless permanently sterile 
(see below) 
Note: Menarche is the first onset of menses in a young female. Menarche is normally 
preceded by several changes associated with puberty including breast development and 
pubic hair growth.  
10.3.1.2. 
Woman of Nonchildbearing Potential (WONCBP) 
Women in the following categories are considered WONCBP: 
Premenarchal: Tanner stage 1 (prepubertal) 
Permanently sterile due to one of the following procedures: 
a. 
Documented hysterectomy 
b. Documented bilateral salpingectomy 
c. 
Documented bilateral oophorectomy 
For permanently sterile individuals due to an alternate medical cause other than the 
above, (e.g., Mullerian agenesis, androgen insensitivity, gonadal dysgenesis), 
investigator discretion should be applied to determining study entry. If reproductive 
status is questionable, additional evaluation should be considered. 
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview. 

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Postmenopausal female 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
• 
A high follicle stimulating hormone (FSH) level in the postmenopausal range may be 
used to confirm a postmenopausal state in women not using hormonal contraception 
or hormonal replacement therapy (HRT). However, in the absence of 12 months of 
amenorrhea, confirmation with more than one FSH measurement is required. 
• 
Females on HRT and whose menopausal status is in doubt must discontinue HRT to 
allow confirmation of postmenopausal status before study enrollment. 
Note: the information above is a standard definition of WONCBP for interventional 
studies. No additional medical examination or medical procedures will be conducted to 
determine if someone is a WONCBP for the purposes of this study. 
10.4. 
Appendix 4: Country-specific requirements. 
France specific requirements are included in the additional appendix provided with this 
protocol. 

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10.5. 
Appendix 5: Gestational Age Assessment 
10.5.1. 
GAIA GESTATIONAL AGE ASSESSMENT FORM  
Based on Quinn, JA, Munoz FM, Gonik B et al. Preterm birth: Case definition & 
guidelines for data collection, analysis, and presentation of immunization safety data. 
Vaccine. 2016; 34: 6047 – 6056. 
LEVELS OF CERTAINTY OF GESTATIONAL AGE ASSESSMENT 
Level 
Description 
Level 1 
Highest level of 
certainty 
Certain LMP or IUI date or ET WITH confirmatory 1st trimester U/S 1 
or 
1st trimester U/S 
Level 2A 
Certain LMP WITH 2nd trimester U/S 1 
or 
Certain LMP WITH 1st trimester physical examination2 
Level 2B 
Uncertain LMP WITH 2nd trimester U/S 1 
Level 3A 
Certain LMP WITH 3rd trimester U/S,  
or 
Certain LMP WITH confirmatory 2nd trimester FH, 
or 
Certain LMP WITH birth weight, 
or 
Uncertain LMP WITH 1st trimester physical examination 
Level 3B 
Lowest level of 
certainty 
Uncertain LMP WITH FH, 
or 
Uncertain LMP WITH neonatal physical assessment (New Ballard score), 
or 
Uncertain LMP WITH birth weight 
1st trimester U/S: ≤136/7 weeks, 2nd trimester U/S: 140/7 to 276/7 weeks, 3rd trimester U/S: ≥280/7 weeks. 
GA: gestational age; U/S: ultrasound examination; LMP: last menstrual period; IUI: intrauterine insemination; ET: 
embryo transfer, FH: fundal height;  
1 If LMP and U/S do not correlate, default to U/S GA assessment 
2 For singleton pregnancies only. Unreliable if obesity, or uterine anomalies. 

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10.5.2. 
METHODS OF GESTATIONAL AGE ASSESSMENT AND 
ESTIMATION OF DUE DATE 
Adapted from: The American College of Obstetricians and Gynecologists (ACOG) 
Committee on Obstetric Practice, American Institute of Ultrasound in Medicine and 
Society for Maternal-Fetal. Committee Opinions: Method for estimating Due Date. 
Number 700, May 2017 (accessed on-line on 05/Mar/2020 at: 
https://www.acog.org/clinical/clinical-guidance/committee-
opinion/articles/2017/05/methods-for-estimating-the-due-date). 
Gestational age range 
Method of measurement 
Discrepancy between U/S dating and LMP (or 
IUI or ET dating) prompting re-dating of EDD 
considering U/S 
1st trimester ≤136/7 weeks 
≤86/7 weeks 
90/7 to 136/7 weeks 
CRL 
> 5 days 
> 7 days 
2nd trimester 140/7 to 276/7 weeks 
140/7 to 156/7 weeks 
BPD, HC, AC, FL 
> 7 days 
160/7 to 216/7 weeks 
> 10 days 
220/7 to 276/7 weeks 
> 14 days 
3rd trimester 
280//7 weeks and beyond 
BPD, HC, AC, FL 
> 21 days 
U/S: ultrasound examination; LMP: last menstrual period; IUI: intrauterine insemination; ET: embryo transfer; CRL: 
crown-rump length; BPD: biparietal diameter; HC: head circumference; AC: abdominal circumference; FL: femur 
length; , EDD: estimated date of delivery 
* Based on LMP (or, if applicable, IUI/ET date) 
10.6. 
Appendix 6: Definitions of maternal, fetal and neonatal 
events of interest as per GAIA 
• 
Section 8.4.5.1 lists events of interest per GAIA that must be reported as AESIs.  
• 
Other GAIA events of interest that meet the SAE definition should be reported with 
enough detail in the SAE narrative to permit level of diagnostic certainty assessment 
by GAIA criteria. 
• 
Articles that discuss GAIA events of interest in detail can be found in the following 
issues of Vaccine [Bauwens, 2016; Jones, 2016a; Jones, 2016b; Kochhar, 2017]: 
− 
Bauwens J, Bonhoeffer J, Chen RT, editors. Harmonizing Immunisation Safety 
Assessment in Pregnancy. Vaccine. 2016. 34 (49): 5991 – 6110. 
− 
Kochhar S, Bauwens J, Bonhoeffer J, editors. Harmonizing Immunization 
Safety Assessment in Pregnancy – Part II. Vaccine. 2017. 35 (48): 6469-6582. 

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− 
Jones CE, Munoz FM, Spiegel HM, et. al. Guideline for collection, analysis 
and presentation of safety data in clinical trials of vaccines in pregnant 
women. Vaccine. 2016a;34(49):5998-6006. 
− 
Jones CE, Munoz FM, Kochhar S, et. al. Guidance for the collection of case 
report form variables to assess safety in clinical trials of vaccines in 
pregnancy. Vaccine. 2016b;34(49):6007-14. 
• 
Definitions and Levels of Diagnostic Certainty are presented in the following Tables. 
References specific to each event of interest are given at the end of the relevant Table. 
Pregnancy Outcomes 
Fetal Death / Stillbirth 
Table 14 
Maternal Events of Interest 
Maternal Death (Not a study specific AESI) 
Table 15 
Hypertensive Disorders of Pregnancy 
Table 16 
Antenatal bleeding (Not a study specific AESI) 
Table 17 
Postpartum hemorrhage (Not a study specific AESI) 
Table 18 
Fetal Growth restriction 
Table 19 
Gestational Diabetes Mellitus 
Table 20 
Non-reassuring fetal status (Not a study specific AESI) 
Table 21 
Pathways to Preterm Birth 
Table 22 
Chorioamnionitis 
Table 23 
Standard definitions for events of interest not defined as such in GAIA (Oligohydramnios, 
Polyhydramnios, Intrahepatic Cholestasis of Pregnancy (ICP), Acute Fatty Liver of Pregnancy, 
Maternal Sepsis) (Not a study specific AESI) 
Table 24 
Neonatal Events of Interest 
Small for Gestational Age 
Table 25 
Low Birth Weight 
Table 26 
Neonatal encephalopathy (Not a study specific AESI) 
Table 27 
Congenital Microcephaly (Not a study specific AESI) 
Table 28 
Congenital Anomalies 
Table 29 
Neonatal Death 
Table 30 
Neonatal Infections (Not a study specific AESI) 
Table 31 
Respiratory Distress in the Neonate (Not a study specific AESI) 
Table 32 
Preterm Birth 
Table 33 
Failure to thrive (Not a study specific AESI) 
Table 34 
Standard definitions for events of interest not defined as such in GAIA (large for gestational age, 
macrosomia) (Not a study specific AESI) 
Table 35 

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Table 14 
Fetal death / Stillbirth 
Fetal death occurring before birth after 20 to 28 weeks of gestation (variation due to 
country definitions). 
Antepartum Stillbirth (Fetal death occurs prior to the evidence of labor.) 
Level 
Description 
1 
Delivery of an infant with no of signs of life at birth (No spontaneous movements, no umbilical cord pulse, 
no heartbeat, no respirations, Apgar score of 0 at 1 and 5 min) determined by physical examination after 
delivery (with or without electronic monitoring of heart rate, respiratory rate, and pulse oximetry).  
AND  
1. 
Prenatal ultrasound examination documenting lack of fetal cardiac activity or movement before the 
onset of labor.  
OR 
2. 
Auscultation for fetal heart tones (using electronic devices or non-electronic devices) documenting 
lack of fetal heartbeat.  
AND 
3. 
Maternal report of lack of fetal movement for 24 h or more.  
OR 
4. 
Maternal physical examination confirming lack of fetal movement.  
OR 
5. 
Radiology findings consistent with intrauterine fetal death.  
AND 
6. 
Attended delivery followed by fetal physical examination afterbirth consistent with antepartum 
death, by obstetrician, neonatologist, pediatrician, maternal-fetal medicine specialist, or pathologist. 
In the setting where access to a specialist is not feasible, diagnosis by a health care provider 
trained or experienced to make the diagnosis is acceptable (e.g. general practice physician, mid-
wife, nurse practitioner, a physician’s assistant or other qualified trained practitioner).  
OR 
7. 
Fetal/placental pathology report consistent with antepartum death.  
AND 
Gestational age within pre-defined range for selected stillbirth definition as assessed by maternal and/or 
fetal parameters (Level1 or 2 in GA assessment algorithm). 
2 
Delivery of an infant with no of signs of life at birth (No spontaneous movements, no umbilical cord pulse, 
no heartbeat, no respirations, Apgar score of 0 at 1 and 5 min) determined physical examination after 
delivery. 
AND 
1. 
Maternal report of lack of fetal movement for 24 h or more. 
OR 
2. 
Maternal physical examination confirming lack of fetal movement.  
OR 
3. 
Auscultation for fetal heart tones (using electronic or non-electronic devices) documenting lack of 
fetal heartbeat.  
AND 
4. 
Attended delivery followed by physical examination after birth consistent with antepartum death, by 
specialist or qualified trained practitioner appropriate to the health care setting.  
OR 
5. 
Fetal/placental pathology report consistent with antepartum death.  
AND 
Gestational age within pre-defined range for selected stillbirth definition as assessed by maternal and/or 
fetal parameters (Level1–2 in GA assessment algorithm). 

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Antepartum Stillbirth (Fetal death occurs prior to the evidence of labor.) (continued) 
Level 
Description 
3 
Delivery of an infant reported to have no of signs of life at birth (No spontaneous movements, no umbilical 
cord pulse, no heart-beat, no cry or spontaneous respirations, no chest movement, and whole body 
cyanosis). AND 
1. 
Maternal report of lack of fetal movement for 24 h or more prior to delivery.  
OR 
2. 
Report of auscultation for fetal heart tones (using electronic or non-electronic devices) documenting 
lack of fetal heartbeat.  
AND 
3. 
Non-attended delivery followed by physical examination of the fetus after birth consistent with 
antepartum death by a healthcare professional appropriate to the level of standard of care in the 
health care setting.  
OR 
4. 
Verbal history by a trained health care provider, non-medical witness or the mother of a fetus born 
with no signs of life or unresponsive to resuscitation efforts immediately after birth and with physical 
features consistent with antepartum death.  
AND 
Gestational age within pre-defined range for selected stillbirth definition as assessed by maternal and/or 
fetal parameters (Level2–3 in GA assessment algorithm). 
4 
Report of stillbirth but fetus is not available for physical examination after birth (no objective assessment 
can be made) 
Maternal information insufficient to assess gestational age 
Intrapartum stillbirth (Fetal death occurs during labor and before delivery) 
Level 
Description 
1 
Delivery of an infant with no of signs of life at birth, including: No spontaneous movements, no umbilical 
cord pulse, no heartbeat, no respirations, and Apgar score of 0 at 1 and 5 min 
Determination of the absence of signs of life is made by physical examination after delivery, with or 
without electronic monitoring of heart rate, respiratory rate, and pulse oximetry.  
AND 
Evidence of live fetus prior to onset of labor (documentation of fetal movement and of fetal heart tones by 
ultrasound prior to onset of labor) (Note: in the absence of evidence of a live fetus prior to the onset of 
labor, the fetal death should be reported as a stillbirth or an antepartum stillbirth). 
AND 
Attended delivery followed by physical examination afterbirth consistent with intrapartum death by 
obstetrician, neonatologist, pediatrician, maternal-fetal medicine specialist, pathologist. In the setting 
where access to a specialist is not feasible, diagnosis by a health care provider trained or experienced to 
make the diagnosis is acceptable (e.g. general practice physician, midwife, or other qualified trained 
practitioner). 
AND 
Gestational age within pre-defined range for selected stillbirth definition as assessed by maternal and/or 
fetal-neonatal parameters (Level 1 in GA assessment algorithm) 

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Intrapartum stillbirth (Fetal death occurs during labor and before delivery) (continued) 
Level 
Description 
2 
Delivery of an infant with no of signs of life at birth, including: No spontaneous movements, no umbilical 
cord pulse, no heartbeat, no respirations, and Apgar score of 0 at 1 and 5 min. 
Determination of the absence of signs of life is made by physical examination after delivery, with or 
without electronic monitoring of heart rate, respiratory rate, and pulse oximetry OR documentation of lack 
of response to resuscitation efforts.  
AND 
Evidence of live fetus prior to onset of labor (maternal report of fetal movement prior to onset of labor and 
documentation of fetal heart tones by auscultation or hand held Doppler) (Note: in the absence of 
evidence of a live fetus prior to the onset of labor, the fetal death should be reported as a stillbirth or an 
antepartum stillbirth).  
AND 
Attended delivery followed by physical examination after birth consistent with intrapartum death by a 
health care professional appropriate to the level of standard of care in the health care setting.  
AND 
Gestational age within pre-defined range for selected stillbirth definition as assessed by maternal and/or 
fetal parameters (Level1–2 in GA assessment algorithm). 
3 
Delivery of an infant reported to have no of signs of life at birth, including: No spontaneous movements, 
no umbilical cord pulse, no heartbeat, no cry, no spontaneous respirations or chest movement, and whole 
body cyanosis. AND 
Evidence of live fetus prior to onset of labor (maternal report of fetal movement prior to onset of labor OR 
auscultation of fetal heart tones) (Note: in the absence of evidence of a live fetus prior to the onset of 
labor, the fetal death should be reported as a stillbirth or an antepartum stillbirth). AND 
Non-attended delivery followed by physical examination of the fetus after birth consistent with intrapartum 
death by a healthcare professional appropriate to the level of standard of care in the health care setting 
OR verbal history by a trained health care provider, non-medical witness or the mother of a fetus born 
with no signs of life or unresponsive to resuscitation efforts immediately after birth. AND 
Gestational age within pre-defined range for selected stillbirth definition as assessed by maternal and/or 
fetal parameters (Level2–3 in GA assessment algorithm). 
4 
Report of stillbirth but fetus is not available for physical examination after birth (no objective assessment 
can be made). 
Maternal information insufficient to assess gestational age. 
Reference [DaSilva, 2016]: DaSilva FT, Gonik B, McMillan M, et al. Stillbirth: Case definition and guidelines for data 
collection, analysis, and presentation of maternal immunisation safety data. Vaccine. 2016; 34(49):6057-6068. 

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Table 15 
Maternal Death 
The 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. (As ICD-10 terminology). 
In the context of immunization: “Death of a woman during pregnancy, childbirth and the 
puerperium that is closely related temporally to an immunization event of the mother 
which is likely the single or contributory cause.” 
Levels of Diagnostic Certainty 
(Highest level (1) to lowest level of certainty) 
Level 
Description 
1 
Diagnosis of pregnancy established by any of the following documented criteria: 
1. 
Ultrasound examination 
2. 
Fetal heart tones 
3. 
Positive serum or urine human chorionic gonadotropin pregnancy test 
4. 
Delivery of a neonate or other products of conception (abortus, stillborn)  
AND 
5. 
Death of the mother while pregnant or within 42 days of termination of pregnancy, irrespective of the 
duration and site of the pregnancy  
AND 
Documentation of Cause of death as: 
6. 
Direct: abortive outcome, hypertensive disorder, obstetric hemorrhage, pregnancy related infection, 
other obstetric complications, unanticipated complications  
7. 
Indirect: non obstetric complications  
8. 
Death during pregnancy, childbirth and the puerperium: other or coincidental 
2 
Diagnosis of pregnancy established by any of the following criteria in the absence of Level 1 criteria: 
1. 
LMP date 
2. 
Serial Symphysio Fundal Height examinations 
AND 
Death of the mother while pregnant or within 42 days of termination of pregnancy, irrespective of the 
duration and site of the pregnancy And  
Documentation of Cause of death as: 
3. 
Direct: abortive outcome, hypertensive disorder, obstetric hemorrhage, pregnancy related infection, 
other obstetric complications, unanticipated complications 
4. 
Indirect: non-obstetric complications  
5. 
Death during pregnancy, childbirth and the puerperium: other or coincidental 
6. 
Unspecified: unknown or undetermined 
3 
Absence of Level 1 or 2 criteria for establishing diagnosis of pregnancy and: 
1. 
Unsure LMP 
2. 
No clinical examination documented  
AND 
Death of the mother temporal to pregnancy, childbirth or the postpartum period when exact timing of 
death is unknown 
AND 
Documentation of cause of death as: 
3. 
Direct: abortive outcome, hypertensive disorder, obstetric hemorrhage, pregnancy related infection, 
other obstetric complications, unanticipated complications 
4. 
Indirect: non-obstetric complications 
5. 
Death during pregnancy, childbirth and the puerperium: other or coincidental 
6. 
Unspecified: unknown or undetermined. 
Reference [Patwardhan, 2016]: Patwardhan M, Eckert LO, Spiegel H, et al. Maternal death: Case definition and 
guidelines for data collection, analysis, and presentation of immunization safety data. Vaccine. 2016;34(49):6077-6083. 

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Table 16 
Hypertensive disorders of pregnancy (Gestational hypertension, 
Pre-eclampsia, Pre-eclampsia with severe features including 
eclampsia) 
Levels of Diagnostic Certainty (Highest level (1) to lowest level of certainty) 
Gestational Hypertension  
Level 
Description 
All 
Clinical syndrome characterized by pregnancy ≥20 weeks 
AND 
New onset hypertension (systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg) 
sustained on two measurements over a minimum of 1 h 
WITHOUT severe features (see preeclampsia with severe features category) and WITHOUT proteinuria 
1 
No proteinuria (as defined by 24 h urine collection < 300 mg, spot protein:creatinine ratio <0.3) 
2 
No proteinuria (as defined by urine dipstick negative or trace)  
In Ev 
Blood pressure cannot be measured OR 
No proteinuria evaluation is available 
Preeclampsia has conventionally been defined as the development of gestational hypertension and proteinuria 
after 20 weeks gestation. Proteinuria can be quantified by: - 24 h urine collection, - a spot protein:creatinine ratio, or 
- with urinary dipstick. Proteinuria of ≥300 mg in a 24 h urine specimen (the gold standard for measurement of 
proteinuria), or ≥0.30 on a spot protein:creatinine ratio, or ≥1+ on a dipstick meets the criteria for preeclampsia. 
Level 
Description 
All 
Clinical syndrome characterized by pregnancy ≥20 weeks  
AND  
New onset hypertension (systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg) 
sustained on two measurements over a minimum of 1 h  
AND  
New onset proteinuria  
1 
Proteinuria diagnosed with ≥300 mg of protein on 24 h urine collection OR ≥0.3 on spot protein:creatinine 
ratio  
2 
Proteinuria diagnosed with ≥1+ protein on urine dipstick 
In Ev. 
Blood pressure cannot be measured  
OR  
no proteinuria evaluation is available (note diagnosis of preeclampsia with severe features does not 
require proteinuria, see definition below) 
In Ev = Insufficient Evidence 

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Hypertensive Disorders of Pregnancy Continued 
Preeclampsia with severe features NOTE: can be diagnosed in the presence or absence of proteinuria. 
Vascular: 
Severely elevated blood pressures, with systolic blood pressure≥160 mmHg and/or diastolic blood pressure ≥110 
mmHg, which is confirmed after only minutes (to facilitate timely anti-hypertensive treatment) 
Neurologic: 
Development of a severe headache (which can be diffuse, frontal, temporal or occipital) that generally does not 
improve with over the counter pain medications (such as acetaminophen/paracetamol) 
Eclampsia 
Development of visual changes (including photopsia, scotomata, cortical blindness) 
Hematologic: 
New onset thrombocytopenia, with platelet count <100,000/L 
Gastrointestinal: 
New onset of nausea, vomiting, epigastric pain 
Transaminitis (AST and ALT elevated to twice the upper limit of normal) 
Liver capsular hemorrhage or liver rupture 
Renal: 
Worsening renal function, as evidenced by serum creatinine level greater than 1.1 mg/dL or a doubling of the serum 
creatinine (absent other renal disease) 
Oliguria (urine output <500 mL/24 h) 
Respiratory: 
Pulmonary edema (confirmed on clinical exam or imaging) 
Level 
Description 
All 
Clinical syndrome characterized by pregnancy ≥20 weeks  
AND  
New onset hypertension (systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg) 
sustained on two measurements over a minimum of 1 h  
AND  
At least one of the criteria for severe disease: 
1 
At least one of the following:  
1. 
Systolic blood pressure ≥160 mmHg and/or diastolic blood pressure ≥110mmHg, which is confirmed 
after only minutes OR  
2. 
Development of severe, persistent headache OR 
3. 
Development of visual changes OR  
4. 
Eclampsia* OR  
5. 
New onset thrombocytopenia (platelets <100,000/L) OR 
6. 
New onset unremitting epigastric pain OR 
7. 
AST and ALT elevated to twice upper limit of normal OR 
8. 
Evidence of liver capsular hematoma or liver rupture (diagnosed on clinical exam or with imaging) OR 
9. 
Worsening renal function, as evidenced by serum creatinine level greater than 1.1 mg/dL or a doubling 
of the serum creatinine (absent other renal disease) or oliguria (<500 cc/24 h) OR 
Pulmonary edema (confirmed on imaging with chest X-ray, or on clinical exam) 
2 
New onset nausea and vomiting  
In Ev 
Blood pressure cannot be measured 
◦* ECLAMPSIA, or new-onset grand mal seizures in a patient with pre-eclampsia, without other provoking factors (such 
as evidence of cerebral malaria or pre-existing seizure disorder). Seizures are often preceded by headaches, visual 
changes or altered mental status: 
In Ev = Insufficient Evidence 
Reference [Rouse, 2016]: Rouse CE, Eckert LO, Wylie BJ, et al. Hypertensive disorders of pregnancy: Case 
definitions &amp; guidelines for data collection, analysis, and presentation of immunization safety data. Vaccine. 
2016;34(49):6069-6076. 

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Table 17 
Antenatal Bleeding  
Antenatal bleeding is a clinical syndrome characterized by bleeding in the second or third 
trimester of pregnancy. Pathologic etiologies attributable to the pregnant state include 
placenta previa, vasa previa and intra-abdominal pregnancy, and morbidly adherent 
placentation, placental abruption, cesarean scar pregnancy and uterine rupture. 
For both levels of diagnostic certainty for each etiology of antenatal bleeding: 
Bleeding is either documented vaginally or suspected to be occurring intrauterine, 
intraperitoneally, or (rarely) retroperitoneally, based on clinical signs and symptoms. 
In the case of ultrasound-based diagnosis, transvaginal ultrasound is more specific than 
transabdominal ultrasound, and transvaginal ultrasound is recommended where available. 
Levels of Diagnostic Certainty (Highest level (1) to lowest level of certainty) 
Morbidly adherent placenta 
Level 
Description 
1 
There are two definitions of equal specificity. 
1. 
Second- or third-trimester ultrasound or MRI evidence of placenta previa, 
AND  
One of the following ultrasound features:  
• 
Greyscale: loss of the retroplacental sonolucent zone, irregular retroplacental sonolucent zone, 
thinning or disruption of the hyperechoic serosa–bladder interface, presence of focal exophytic 
masses invading the urinary bladder, abnormal placental lacunae  
• 
Color Doppler: diffuse or focal lacunar flow, vascular lakes with turbulent flow (peak systolic velocity 
over 15 cm/s), hypervascularity of serosa–bladder interface, markedly dilated vessels over peripheral 
sub placental zone 
• 
3D Power Doppler: numerous coherent vessels involving the whole uterine serosa–bladder junction 
(basal view), hypervascularity (lateral view), inseparable cotyledonal and intervillous circulations, 
chaotic branching, detour vessels (lateral view) 
AND  
One of the risk factors: prior cesarean delivery, prior uterine surgery (including endometrial ablation or 
dilation and curettage) or cesarean scar pregnancy 
OR 
2. 
Morbidly adherent placentation found on histology in a hysterectomy or partial wedge resection 
specimen. 
2 
There are two definitions of equal specificity. 
Ultrasound evidence of placenta previa, 
AND  
hypervascularity at the site of the uteroplacental interface, diagnosed at laparotomy. 
OR 
1. 
Difficulty with placental separation after delivery of the infant, at either a vaginal or cesarean delivery 
with resultant hemorrhage due to partial separation. 
 
Antenatal Bleeding continued 
Placental abruption 
Level 
Description 
1 
There are two definitions of equal specificity. 
1. 
In the absence of placenta previa on ultrasound, vaginal bleeding in the second or third trimester, 
AND one of the following: 
Either uterine irritability or labor, 
Or  
clinical signs of hypovolemic shock or coagulopathy. 
OR 
2. 
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Antenatal Bleeding continued 
2 
There are two definitions of equal specificity. 
1. 
Vaginal bleeding in the second or third trimester, 
AND  
uterine irritability or labor, without clinical signs of hypovolemic shock or coagulopathy 
OR 
2. 
Vaginal bleeding in the second or third trimester, 
AND  
Clinical evidence of retroplacental clot or visually evident placental infarcts at the time of delivery. 
Cesarean Scar Pregnancy 
Level 
Description 
1 
There are two definitions of equal specificity. 
1. 
Transvaginal ultrasound with the following characteristics: empty uterine cavity,  
AND  
Empty cervical canal, without contact with the gestational sac, AND  
Presence of gestational sac, +/- fetal pole, +/- cardiac activity, in the anterior uterine segment 
adjacent to the cesarean scar, AND  
Absence or defect in myometrium between bladder and gestational sac,  
AND  
Gestational sac well perfused on Doppler ultrasound (to differentiate from an expulsing, avascular 
gestational sac). 
OR 
2. 
Hysterectomy specimen with evidence of pregnancy implanted into the cesarean scar. 
2 
There is no Level 2 definition for this event. 
Uterine Rupture 
Level 
Description 
1 
Complete uterine disruption at the time of laparotomy in the context of vaginal or intra-abdominal bleeding. 
2 
There is no Level 2 definition for this event. 
Reference [Prabhu, 2017]: Prabhu M, Eckert LO, Belfort M et al. Antenatal bleeding: Case definition and guidelines for 
data collection, analysis, and presentation of immunization safety data. Vaccine. 2017; 35: 6529-6537. 
Table 18 
Postpartum hemorrhage 
Genital tract bleeding after delivery (up to 42 days) of a fetus or infant that leads to an 
adverse clinical outcome, such as hypovolemia or anemia e.g., exertional dyspnea, 
postural presyncope, tiredness or reduced consciousness. At the furthest extreme 
uncorrected hypovolemic shock can lead to organ-dysfunction and maternal death. 
ICD-10 definition: “hemorrhage after delivery of a fetus or infant” 
Levels of Diagnostic Certainty (Highest level (1) to lowest level of certainty) 
Level 
Description 
1 
Genital bleeding after delivery leading to severe maternal out-come (maternal death or maternal near 
miss) as defined by WHO1.  
2 
Genital bleeding after delivery with at least one of the following: measured abnormal bleeding (1000 ml or 
more), or any bleeding leading to hypotension or blood transfusion. 
3 
Genital bleeding after delivery estimated at 1000 ml or more 
Reference [Kerr, 2016]: Kerr R, Eckert LO, Winikoff B, et al. Postpartum hemorrhage: Case definition and guidelines 
for data collection, analysis, and presentation of immunization safety data. Vaccine. 2016;34(49):6102-6109. 
1 Can be found in Kerr (op cit), Table 1.  

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Table 19 
Fetal growth restriction 
A fetus with a sonographic estimation of fetal weight below the tenth percentile for a 
given gestational age with increasing specificity for adverse perinatal outcomes below the 
third percentile. 
Levels of Diagnostic Certainty (Highest level (1) to lowest level of certainty) 
Level 
Description 
 
Fetal growth restriction is a sonographic finding characterized by: 
1a 
Level 1* evidence of pregnancy dating  
AND 
• 
Estimated fetal weight below 3% using locally-accepted growth curve  
OR 
• 
Estimated fetal weight below 10% using locally-accepted growth curve  
AND 
• 
Absent or reversed end-diastolic flow of the umbilical artery Doppler  
OR 
• 
Oligohydramnios as defined as amniotic fluid index (AFI) < 8 cm or deepest vertical pocket (DVP) < 
2 cm in the presence of intact membranes without concern for fetal anomalies contributing to its 
etiology 
1b 
Level 1* evidence of pregnancy dating  
AND 
Estimated fetal weight below 10%ile using locally-accepted growth curve  
AND 
Lack of absent or reversed end-diastolic flow of the umbilical artery or oligohydramnios (as defined above, 
cfr. Level 1a) 
2a  
Level 2 evidence of pregnancy dating  
AND 
• 
Estimated fetal weight below 3% using locally-accepted growth curve  
OR 
• 
Estimated fetal below 10% using locally-accepted growth curve  
AND 
• 
Absent or reversed end-diastolic flow of the umbilical artery Doppler.  
OR 
• 
Oligohydramnios (as defined above, cfr. Level 1a). 
2b 
• 
Level 2 evidence of pregnancy dating  
AND 
Estimated fetal weight below 10%ile using locally-accepted growth curve  
AND 
No findings of absent or reversed end-diastolic flow of the umbilical artery or oligohydramnios (as defined 
above, cfr Level 1a).  
OR 
• 
Level 1* evidence of pregnancy dating  
AND 
Estimated fetal weight below 10% using locally-accepted growth curve with no findings of oligohydramnios 
(as defined above, cfr. Level 1a) with inability to assess umbilical artery Doppler. 
In Ev 
Absence of ultrasound for use in assessment of estimated fetal weight. 
*Level 1 evidence of pregnancy dating as defined by the Preterm Birth Working Group of the Brighton Collaboration. 
Level 1 pregnancy dating depends on a confirmatory ultrasound performed ≤13 6/7 weeks gestation 
In Ev = Insufficient Evidence 
Reference [Easter, 2017]: Easter SR, Eckert LO, Boghossian N, et al. Fetal growth restriction: Case definition & 
guidelines for data collection, analysis, and presentation of immunization safety data. Vaccine. 2017; 35: 6546-6554. 

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Table 20 
Gestational diabetes mellitus (pregnancy induced hyperglycemia) 
Gestational diabetes mellitus (GDM) is a clinical syndrome characterized by the absence 
of pre-gestational diabetes diagnosis, defined by 
• 
Previous diagnosis of diabetes while not pregnant 
OR 
• 
First trimester hemoglobin A1c level of ≥ 6.5% (47.5 mmol/mol)  
OR 
• 
First trimester fasting blood glucose 126 mg/dL / ≥ 7mmol/L  
AND 
Identification of sustained hyperglycemia during pregnancy not due to other known 
causes (i.e. corticosteroids, beta-mimetics, etc.) 
Levels of Diagnostic Certainty (Highest level (1) to lowest level of certainty) 
Level 
Description 
1 
Absence of pre-gestational diabetes mellitus diagnosis in the first trimester as defined above with level 1-
2 certainty for gestational age using GAIA definition for gestational age  
AND 
Diagnosis of gestational diabetes based on a positive internationally recognized oral glucose tolerance 
test (“major criteria” 1,2) using venous blood sample/samples 
2 
Absence of pre-gestational diabetes mellitus diagnosis in the first trimester as defined above with at least 
level 1-2 certainty for gestational age using GAIA definition for gestational age  
AND 
Diagnosis of gestational diabetes based on positive internationally recognized oral glucose tolerance test 
(“major criteria” 1,2) using capillary blood sample/samples 
3 
Absence of pre-gestational diabetes mellitus diagnosis in the first trimester as defined above with at least 
level 3 certainty for gestational age using GAIA definition for gestational age  
AND 
Diagnosis of gestational diabetes based on positive internationally recognized oral glucose tolerance test 
(see below ‘‘major criteria”1,2) using venous blood or capillary blood sample/samples 
OR 
Diagnosis of gestational diabetes based on fasting plasma glucose of 5.1-6.9 mmol/l (92-125 mg/dL) 
using venous or capillary blood samples. 
In Ev 
Blood glucose cannot be measured  
OR 
Elevated postprandial blood glucose level without confirmatory 
fasting venous blood or capillary glucose level 
OR 
Use of Hemoglobin A1c alone for the diagnosis of GDM without a diagnostic oral glucose tolerance test 
(OGTT) or elevated fasting plasma glucose level.  
OR 
Clinical and laboratory findings such as glucosuria, fundal height greater than dates, obesity, prior history 
of GDM or family history for the diagnosis of gestational diabetes mellitus without a diagnostic test. 
In Ev = Insufficient Evidence 
Reference(s) [Kachikis, 2017]: Kachikis A, Eckert LO, Walker C, et al. Gestational diabetes mellitus: Case definition & 
guidelines for data collection, analysis, and presentation of immunization safety data. Vaccine. 2017; 35:6555-6562. 

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1 Major criteria (presented in Kachikis op cit) 
 
2 Further details regarding oral glucose tolerance tests presented in footnote 1 (Major Criteria); also presented in 
Kachikis (op cit) 
 

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Table 21 
Non-reassuring fetal status 
Indicator of underlying event resulting in temporary or permanent oxygen deprivation to 
the fetus which may lead to fetal hypoxia and metabolic acidosis 
Levels of Diagnostic Certainty (Highest level (1) to lowest level of certainty) 
Level 
Description 
1 
• 
Category III fetal heart rate tracings detected via continuous cardiotocography as defined by 
NICHD  
− 
Absent baseline fetal heart rate variability AND any of the following: 
recurrent late decelerations 
recurrent variable deceleration 
bradycardia (<110 bpm)  
OR 
− 
Sinusoidal pattern  
AND 
• 
Umbilical cord blood analysis consistent with metabolic acidosis (pH < 7.0 and Base deficit >12 
mmol/L) 
2 
• 
Category III fetal heart rate tracings detected via continuous cardiotocography as defined by 
NICHD  
− 
Absent baseline fetal heart rate variability AND any of the following: 
recurrent late decelerations 
recurrent variable deceleration 
bradycardia (<110 bpm) 
OR 
− 
Sinusoidal pattern 
3 
• 
Fetal heart pattern detected via intermittent auscultation suggestive of fetal hypoxia  
− 
Baseline Fetal Heart rate (FHR) <110 bpm or >160 bpm 
− 
Presence of repetitive or prolonged (>3 min) decelerations 
More than 5 contractions in a 10 min period 
Reference [Gravett, 2016]: Gravett C, Eckert LO, Gravett MG, et al. Non-reassuring fetal status: Case definition & 
guidelines for data collection, analysis, and presentation of immunization safety data. Vaccine. 2016;34(49):6084-6092. 

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Table 22 
Pathways to preterm birth  
Premature preterm rupture of membranes; Preterm labor; Insufficient cervix; Provider-
initiated preterm birth 
Preterm = Birth at less than 37 gestation-completed weeks (less than 259 days). 
Levels of Diagnostic Certainty (Highest level (1) to lowest level of certainty) 
Preterm rupture of membranes 
Level 
Description 
All 
Patient is determined to be preterm as defined above.  
• 
On presentation, patient is determined to not be in preterm labor, having ≤4 contractions per hour 
documented clinically or on tocodynometer, with <2 cm cervical dilation (greater than 4 contractions 
per hour would qualify the patient as having preterm labor)  
• 
Fluid can be noted to be clear, blood-tinged, meconium-tinged (fetal stool), purulent-tinged 
(yellowish, suggesting infection) 
1 
• 
Clinical history of rupture of membranes  
AND 
• 
Visible leakage of fluid on vaginal speculum exam  
AND 
• 
Visible arborization (ferning) on microscopy of amniotic fluid  
OR 
• 
Ultrasound with oligohydramnios (AFI <5 or MVP <2)  
AND 
• 
Documented membrane rupture by a diagnostic test (one of the below options): 
1. 
Positive intra-amniotic dye-injection method 
2. 
Positive result on amniotic fluid alpha-fetoprotein test kit  
3. 
Amniotic fluid pH measurement (nitrazine paper test) 
4. 
Amniotic fluid placental alpha macroglobulin-1 protein assay (PAMG-1) test (AmniSure test)  
5. 
Amniotic fluid insulin-like growth factor binding protein (IGFBP-1) test (Actim PROM test) 
2 
• 
Clinical history of rupture of membranes  
AND 
• 
Visible leakage of fluid on vaginal speculum examination  
AND 
• 
Visible arborization (ferning) on microscopy of amniotic fluid  
OR 
• 
Documented membrane rupture by a diagnostic test (one of those listed above)  
OR  
• 
Ultrasound with oligohydramnios (AFI <5 or MVP <2) 
3 
• 
Clinical history of rupture of membranes  
AND 
• 
Visible leakage of presumed amniotic fluid; this may be on vaginal speculum examination (pooling 
in vagina), on inspection of the perineum (wet perineum due to leakage of fluid from the vagina), or 
fluid soaked cloth/clothes/sanitary pad. 
 

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Preterm labor 
Level 
Description 
All 
Patient is determined to be have delivered preterm (at less than 37 gestation-completed weeks (less than 
259 days)).  
1 
• 
On presentation, >4 documented uterine contractions per hour as determined by a tocodynometer  
AND 
• 
Documented change in length or dilation of cervix by physical examination or transvaginal 
ultrasound over a two hour period, with clinical criteria for documenting cervical change by exam 
including: 
− 
Cervical dilation 2 cm or greater at the internal os by digital examination  
− 
Cervical length of 1 cm or less by digital examination 
− 
50% or greater effacement by digital examination 
2 
• 
Greater than 4 uterine contractions per hour as determined by a tocodynometer or clinical 
assessment  
AND 
• 
Documented change in length or dilation of cervix by physical examination, with clinical criteria 
including:  
− 
Cervical dilation 2 cm or greater at the internal os by digital examination 
− 
Cervical length of 1 cm or less by digital examination 
− 
50% or greater effacement by digital examination 
3 
• 
Greater than 4 documented uterine contractions per hour determined by clinical assessment  
AND 
• 
Documented change in cervical examination (change in dilation or effacement) over a two hour 
period 
Insufficient cervix 
Level 
Description 
All 
Patient is determined to: 
• 
be ≥16 weeks and <24 weeks gestation per definitions of gestational age in Section 10.5 
• 
have advanced cervical dilation (>2 cm) resulting in either treatment with a cerclage (cervical stitch) 
or preterm delivery 
• 
not be in preterm labor, having ≤4 contractions per hour documented clinically or on tocodynometer 
(with anything >4 contractions per hour falling into the category of preterm labor) 
1 
• 
Internal cervical os dilation (>2 cm) with ≤4 contractions/h, as determined by transvaginal 
ultrasound  
AND 
• 
digital examination  
2 
• 
Internal cervical os dilation (>2 cm) with ≤4 contractions/h, as determined by digital examination  
3 
• 
Patient reports fetal delivery without any painful contractions 
• 
History excludes other causes of mid-trimester delivery 

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Provider-initiated preterm birth 
Level 
Description 
All 
Patient is determined to be preterm (birth at less than 37 gestation-completed weeks (less than 259 
days).  
1 
• 
Documentation in the healthcare record by a patient’s delivering provider that there were no signs 
or symptoms of the spontaneous onset of preterm labor  
AND 
• 
Documentation in the healthcare record by a patient’s delivering provider that the patient needed to 
undergo induction of labor or cesarean delivery which led to the preterm delivery  
2 
• 
From recall, delivering provider confirms that there was an absence of any signs or symptoms of 
the spontaneous onset of preterm labor  
AND 
• 
Delivering provider reports from recall that he or she decided that the patient needed to undergo 
induction of labor or cesarean delivery 
3 
• 
From recall, patient confirms that there was an absence of any signs or symptoms of the 
spontaneous onset of preterm labor  
AND 
• 
Patient reports from recall that the healthcare provider indicated that she needed to undergo 
induction of labor or cesarean delivery 
Reference [Harrison, 2016]: Harrison MS, Eckert LO, Cutland C, et al. Pathways to preterm birth: Case definition and 
guidelines for data collection, analysis, and presentation of immunization safety data. Vaccine. 2016;34(49):6093-6101. 
Table 23 
Chorioamnionitis 
Chorioamnionitis encompasses a broad spectrum of disease during pregnancy that is 
characterized by inflammation and/or infection of intrauterine structures such as the 
placenta, the chorion and amnion.  
This case definition focuses on the infectious manifestation of chorioamnionitis, intra-
amniotic infection. Four definitions of chorioamnionitis have been developed based on 
systematic literature review, are summarized below, and must be considered when 
applying the case definitions.  
It is important to rule out other obvious sources of acute systemic infection (i.e. 
pyelonephritis) prior to chorioamnionitis diagnosis. 
Level 
Description 
All 
levels 
Clinical Definition A: 
Maternal fever ≥ 38 degrees Celsius on one occasion plus one or more of:  
• 
Baseline fetal tachycardia (FHR > 160 bpm for 10 min or longer, excluding accelerations, 
decelerations and periods of marked variability or, where continuous monitoring is not available, an 
FHR exceeding 160 bpm during and after at least three consecutive contractions) 
• 
Maternal WBC ≥ 15,000 per mm3 in the absence of corticosteroids. 
• 
Definite purulent fluid from the cervical os. 
Clinical Definition B 
Maternal fever ≥ 38 degrees Celsius on one occasion plus two of:  
• 
Maternal tachycardia (HR > 100 bpm) 
• 
Baseline fetal tachycardia (FHR > 160 bpm for 10 min or longer, excluding accelerations, 
decelerations and periods of marked variability or, where continuous monitoring is not available, an 
FHR exceeding 160 bpm during and after at least three consecutive contractions 
• 
Purulent fluid from the cervical os. 
• 
Uterine tenderness 
• 
Maternal WBC ≥ 15,000 per mm3 in the absence of corticosteroids 

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Level 
Description 
Histologic diagnosis: 
• 
Positive finding of invasion of maternal polymorphonuclear leukocytes into the placental plate, the 
chorion and/or amnion which meets criteria based on a widely accepted histopathologic staging and 
grading system [such as Blanc1 Redline2, or Salafia3 criteria]. 
Culture criteria: 
• 
Positive culture of amniotic fluid (via amniocentesis), and/or 
• 
Positive culture of placental membranes (between chorion/amnion) 
GAIA gestational age level 1–2 criteria denote higher gestational age certainty including a combination 
of certain last menstrual period (LMP), first or second trimester ultrasound or first trimester exam 
confirmation. Level 3 diagnostic certainty for gestational age has a lower accuracy compared to levels 1–
2.  
1a 
Clinical Definition A 
AND 
Confirmation via histopathology or culture  
AND 
Gestational age ≥ 22–0/7 weeks by GAIA gestational age level 1–2 criteria  
1b 
Clinical Definition A 
AND 
Confirmation via histopathology or culture 
AND 
Gestational age ≥ 22–0/7 weeks by ANY GAIA gestational age criteria 
2a 
Clinical Definition A  
OR 
Chorioamnionitis via histopathology or culture  
AND 
Gestational age ≥ 22–0/7 weeks by GAIA gestational age level 1–2 criteria  
2b 
Clinical Definition B  
AND 
Gestational age ≥ 22–0/7 weeks by GAIA gestational age level 1–2 criteria 
2c 
Clinical Definition A or B 
OR 
Chorioamnionitis via histopathology or culture  
AND 
Gestational age ≥22–0/7 weeks by any GAIA gestational age criteria 
3a 
Clinical definition A or B with report of fever or maternal feeling of ‘‘feverishness.” 
AND 
Gestational age ≥ 22–0/7 weeks by any GAIA gestational age criteria  
3b 
Clinical definition B without fever (documented or reported) 
AND 
Gestational age ≥ 22–0/7 weeks by any GAIA gestational age criteria 
1W.A. Blanc Pathology of the placenta, membranes, and umbilical cord in bacterial, fungal, and viral infections in man. 
Monogr Pathol, 22 (1981), pp. 67-132 
2R.W. Redline, O. Faye-Petersen, D. Heller, F. Qureshi, V. Savell, C. Vogler Amniotic infection syndrome: nosology 
and reproducibility of placental reaction patterns. Pediatric Dev Pathol: Off J Soc Pediatric Pathol Paediatric Pathol 
Soc, 6 (5) (2003), pp. 435-448 
3C.M. Salafia, C. Weigl, L. Silberman The prevalence and distribution of acute placental inflammation in uncomplicated 
term pregnancies. Obstet Gynecol, 73 (3 Pt 1) (1989), pp. 383-389 
Reference [Kachikis, 2019]: Kachikis, A, Eckart L, Walker C et al. Chorioamnionitis: Case definition & guidelines for 
data collection, analysis, and presentation of immunization safety data. Vaccine. 2019; 7610–7622 

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Table 24 
Standard Definitions for Maternal Events of interest not defined as 
events in GAIA  
Event of 
Interest 
Definition 
Oligohydramnios 
Amniotic fluid index (AFI) < 8 cm or deepest vertical pocket (DVP) < 2 cm in the presence of 
intact membranes without concern for fetal anomalies contributing to its etiology 
Polyhydramnios 
Polyhydramnios is the presence of excess amniotic fluid in the uterus. By definition, 
polyhydramnios is diagnosed if the deepest vertical pocket is more than 8 cm or amniotic fluid 
index (AFI) is more than 95th percentile for the corresponding gestational age 
Gestational liver 
disease 
(Intrahepatic 
Cholestasis of 
Pregnancy or 
ICP)1 
Intrahepatic cholestasis also called obstetric cholestasis should be suspected when pruritis 
develops during pregnancy in the absence of a rash. Lab evidence of cholestasis includes 
elevated bile acids (Glyco and Taurochenodeoxycholic Acid) (> 10 umol/L). Up to 60% of 
patients will have elevated transaminases and 20% of patients will have increased direct 
bilirubin levels. 
Jaundice may or may not be present. ICP typically is transient and resolves after delivery. 
Women that had ICP in previous pregnancy have higher risk to developing ICP in the following 
pregnancies or other hepatobiliary disorders in later life. ICP is associated with adverse fetal 
outcome like meconium-stained liquor, fetal asphyxia, spontaneous preterm delivery 
and intrauterine death.  
Gestational liver 
disease (Acute 
Fatty Liver of 
Pregnancy)2 
Acute fatty liver of pregnancy (AFLP) is a rare, potentially fatal complication that occurs in the 
third trimester or early postpartum period. AFLP is characterized by microvesicular fatty 
infiltration of hepatocytes without any inflammation or necrosis. Most frequent signs and 
symptoms are the following: 
• 
Jaundice 
• 
Abdominal Pain (usually right upper quadrat, midepigastric or radiating to back) 
• 
Central nervous system (altered sensorium, confusion, disorientation, psychosis, 
restlessness, seizures or even coma) 
• 
Disseminated intravascular coagulation 
• 
Nausea and vomiting 
• 
Gastrointestinal bleeding 
• 
Acute renal failure 
• 
Oliguria 
• 
Tachycardia 
• 
Late onset pyrexia 
• 
Hypoglycemia 
• 
ALT<500 U/L 
• 
Hyperbilirubinemia, elevated ammonia, leukocytosis, hypofibrinogenemia 
Ultrasound examination and computed tomography may demonstrate fatty infiltration of the 
liver but are not sufficient for diagnosis 

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Event of 
Interest 
Definition 
Maternal Sepsis3 
Maternal sepsis is a life-threatening condition defined as organ dysfunction resulting from 
infection during pregnancy, child-birth, post-abortion, or post-partum period.  
Organ dysfunction can be identified as an acute change in total SOFA score ≥2 points 
consequent to the infection. 
The baseline SOFA score can be assumed to be zero in patients not known to have preexisting 
organ dysfunction 
A SOFA score ≥2 reflects an overall mortality risk of approximately 10% in a general hospital 
population with suspected infection. Even patients presenting with modest dysfunction can 
deteriorate further, emphasizing the seriousness of this condition and the need for prompt and 
appropriate intervention, if not already being institute. 
 
 
 
MAP = mean arterial pressure; qSOFA = quick SOFA; SOFA = Sequential [Sepsis-related] 
Organ Failure Assessment 
References [Ko, 2006; Geenes, 2016; Bonet, 2017]: 
1 Geenes V. Williamson C, Chappell L. Intrahepatic cholestasis of pregnancy. The Obstetrician and Gynecologist. 
2016; 18:273-81. 
2 Ko H, Yoshida E. Acute Fatty Liver of Pregnancy. Can J Gastroenterol. 2006; 20:25-30. 
3 Bonet M, Pileggi V, Rijken M et al. Towards a concensus definition of maternal sepsis: results of a systematic review 
and expert consultation. Reproductive Health. 2017; 14:67. 

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Small for Gestational Age 
Weight below 10th percentile for gestational age as assessed against a validated global, 
regional or local standard. 
Levels of Diagnostic Certainty (1 highest level to 4 lowest level of certainty 
Level 
Description 
1 
• 
Weight below 10th percentile for gestational age 
AND 
• 
The following used in assessment of weight: 
− 
Newborn weighed within 24 hours of birth 
− 
Weight assessed using a calibrated electronic scale with 10 g resolution 
AND 
• 
The following for assessment of gestational age: 
− 
Certain LMP or IUI or embryo transfer date AND confirmatory ultrasound in first trimester  
OR 
− 
First trimester ultrasound 
2a 
• 
Weight below 10th percentile for gestational age  
AND 
• 
The following used in assessment of weight:  
− 
Newborn weighed within 24 hours of birth on any scale with a < 50 g resolution, tared to zero 
and calibrated  
AND 
• 
The following for assessment of gestational age: 
− 
Certain LMP with first or second trimester ultrasound  
OR 
− 
Certain LMP with first trimester physical exam 
2b 
• 
Weight below 10th percentile for gestational age  
AND 
• 
The following used in assessment of weight:  
− 
Newborn weighed within 24 hours of birth on any scale with a < 50 g resolution, tared to zero 
and calibrated  
AND 
• 
The following assessment of gestational age:  
− 
Uncertain LMP with second trimester ultrasound 
3a 
• 
Weight below 10th percentile for gestational age  
AND 
• 
The following used in assessment of weight: 
− 
Infant weighed within the first 48 hours of life 
− 
Newborn weighed on any scale with a < 50 g resolution, tared to zero and calibrated  
AND 
• 
The following assessment of gestational age: 
− 
Certain LMP with third trimester ultrasound  
OR 
− 
Certain LMP with confirmatory 2nd trimester fundal height  
OR 
− 
Certain LMP with birthweight  
OR 
− 
Uncertain LMP with first trimester physical exam  
 

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Small for Gestational Age (continued) 
Level 
Description 
3b 
• 
Weight below 10th percentile for gestational age  
AND 
• 
The following used in assessment of weight:  
− 
Infant weighed within the first 48 hours of life 
− 
Newborn weight assessed by measuring the difference between an adult holding the infant 
and the adult being weighed alone on any scale 
AND 
• 
The following assessment of gestational age: 
− 
Uncertain LMP with fundal height  
OR 
− 
Uncertain LMP with newborn physical assessment  
OR 
− 
Uncertain LMP with birthweight 
4 
• 
Baby noted to be small, but no actual weight 
• 
Baby with GA assessed only by infant examination 
• 
Diagnosis extracted from billing codes or chart, with no documentation of actual birth weight or GA 
Reference [Schlaudecker, 2017]: Schlaudecker EP, Munoz FM, Bardají A, et al. Small for gestational age: Case 
definition & guidelines for data collection, analysis, and presentation of maternal immunisation safety data. Vaccine. 
2017; 35:6518-6528. 

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Table 26 
Low Birth Weight (LBW) 
Regardless of gestational age:  
• 
Low birth weight (LBW): <2500 grams.  
• 
Very low birth weight (VLBW): <1500 grams  
• 
Extremely low birth weight (ELBW): <1000grams 
Levels of Diagnostic Certainty (1 highest level to 4 lowest level of certainty 
Level 
Description 
1 
Newborn infant weighed within 24 hours of birth  
AND 
Use electronic scale which is graduated to 10 grams  
AND 
Scale is calibrated at least once a year  
AND 
Scale placed on level, hard surface  
AND 
Scale tared to zero grams  
AND 
Weight recorded as <2500 grams  
OR 
Birth weight recorded as <2500 grams  
AND 
Birth weight assessed as per health care facility’s standard operating procedure, which fulfills criteria 1 to 
5 above. 
2 
Newborn infant weighed within 24 hours of birth  
AND 
Scale (electronic/spring) is graduated to at least 50 grams  
AND 
Scale is calibrated at least once a year, or more often if moved  
AND 
Scale tared to zero grams or 0.00kg  
AND 
Weight recorded as <2500 grams  
OR 
Birth weight recorded as <2500 grams AND 
Birth weight assessed as per health care facility’s standard operating procedure, which fulfills criteria 1 to 
4 above. 
(Scale used could be electronic or spring scale, including color-coded scale) 
3 
Newborn infant weighed on day 1 or 2 of life (first 48 hours of life)  
AND 
Weight measured using dial/spring/color-coded scale  
AND 
Weight assessed as <2500 grams 
4 
Newborn weight assessed between day 1 and 2 of life (first 48 hours)  
AND 
Proxy measure (newborn foot length, chest circumference, mid upper arm circumference) of birth weight 
used  
AND 
Weight CATEGORY assessed as <2500 grams 
Reference [Cutland, 2017]: Cutland CL, Lackritz EM, Mallett-Moore T, et al. Low birth weight: Case definition & 
guidelines for data collection, analysis, and presentation of maternal immunization safety data. Vaccine. 2017; 
35:6492-6500. 

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Table 27 
Neonatal encephalopathy 
Disease, malfunction of damage of the brain in a newborn (1–28 days) born at or beyond 
35 weeks of gestation, that may be due to a variety of etiologies including but not limited 
to hypoxia/ischemia, metabolic disturbance, infection and traumatic processes 
Levels of Diagnostic Certainty (1 highest level to 4 lowest level of certainty 
Level 
Description 
1 
(Definite) 
Abnormal level of alertness or seizures AND 
Difficulty with initiating and maintaining respiration AND 
Depression of tone 
2 
(Probable) 
Abnormal level of alertness or seizures  
AND 
Difficulty with initiating and maintaining respiration OR Depression of tone 
3 
(Possible) 
Abnormal level of alertness or seizures without difficulty with initiating and maintaining respiration nor 
depression of tone 
Reference [Sell, 2017]: Sell E, Munoz FM, Soe A, et al. Neonatal encephalopathy: Case definition & guidelines for 
data collection, analysis, and presentation of maternal immunisation safety data. Vaccine. 2017; 35: 6501-6505. 

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Congenital Microcephaly 
Congenital microcephaly, also referred to as primary microcephaly due to its presence in 
utero or at birth, is a descriptive term for a structural defect in which a fetus or infant’s 
head (cranium) circumference is smaller than expected when compared to other fetuses or 
infants of the same gestational age, sex and ethnic background 
Levels of Diagnostic Certainty (1 highest level to 4 lowest level of certainty 
Postnatally Diagnosed Microcephaly 
Level 
Description 
1 
Live birth, stillbirth, or spontaneous or therapeutic abortion of at least 24 weeks of Gestational Age (GA)~  
AND  
Head Circumference (HC) 2 Standard Deviations (SD) below mean or <3rd percentile according to GA 
and gender, using appropriate standardized reference charts for the population (e.g., WHO growth 
reference charts if GA ≥37 weeks and Intergrowth-21st reference charts for GA 24–36 weeks)  
AND  
Measured between 24–36 hours after birth or end of pregnancy. 
~GA assessed based on certain Last Menstrual Period (LMP) with confirmatory 1st trimester or 2nd 
trimester ultrasound (US) scan, intrauterine insemination (IUI), or embryo transfer date 
2a 
Live birth, stillbirth, or spontaneous or therapeutic abortion of at least 24 weeks of GA~  
AND  
HC 2 SD below mean or <3rd percentile according to GA and gender, using appropriate standardized 
reference charts for the population (e.g., WHO growth reference charts if GA ≥37 weeks and Intergrowth-
21st reference charts for GA 24–36 weeks)  
AND  
Measured 
• 
within the first 24 hours§ 
OR  
• 
>36 hours and up to 6 weeks after birth or end of pregnancy with no apparent post-natal insult 
resulting in microcephaly  
~GA assessed based on certain LMP with confirmatory 1st trimester or 2nd trimester US scan, IUI, or 
embryo transfer date 
§Take into account the variability in this period based on molding of the head 
2b 
Live birth, stillbirth, or spontaneous or therapeutic abortion of at least 24 weeks of GA~  
AND  
HC 2 SD below mean or <3rd percentile according to GA and gender, using appropriate standardized 
reference charts for the population (e.g., WHO growth reference charts if GA ≥37 weeks and Intergrowth-
21st reference charts for GA 24–36 weeks)  
AND  
• 
within the first 24 hours§ 
OR  
• 
>36 hours and up to 6 weeks after birth or end of pregnancy with no apparent post-natal insult 
resulting in microcephaly  
~GA assessed based on uncertain LMP with 2nd trimester US scan 
§Take into account the variability in this period based on molding of the head 

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Postnatally Diagnosed Microcephaly (continued) 
Level 
Description 
3a 
Live birth, stillbirth, or spontaneous or therapeutic abortion of at least 24 weeks of GA~_ 
AND  
HC 2 SD below mean or <3rd percentile according to GA and gender, using appropriate standardized 
reference charts for the population (e.g., WHO growth reference charts if GA P37 weeks and Intergrowth-
21st reference charts for GA 24–36 weeks)  
AND 
Measured up to 6 weeks after birth or end of pregnancy with no apparent post-natal insult resulting in 
microcephaly 
~GA based on LMP without confirmatory 1st or 2nd trimester Ultrasound 
3b 
Live birth, stillbirth, or spontaneous or therapeutic abortion  
AND 
Case meets criteria for microcephaly using a validated algorithm: 1 inpatient diagnosis OR 2 outpatient 
diagnoses 
OR  
1 outpatient diagnosis AND death in first year using the following diagnostic codes ICD-9-CM code 742.1 
or ICD-10-CM code Q02 
4 
Live birth, stillbirth, or spontaneous or therapeutic abortion 
AND  
Diagnosis of congenital microcephaly based on: 
• 
physical inspection without HC measurement  
OR  
• 
ICD-9-CM or ICD-10-CM code that does not meet validated algorithm criteria above.  
Prenatally Diagnosed Microcephaly 
Level 
Description 
1a 
Fetus of at least 24 weeks GA based on certain LMP with confirmatory 1st trimester (<14 weeks) or 2nd 
trimester US scan IUI, or embryo transfer date  
AND  
HC 2 SD below mean or <3rd percentile according to fetal ultrasound (US) examination using appropriate 
standardized reference charts according to GA and gender for the population (e.g. WHO growth 
reference charts if GA ≥37 weeks and Intergrowth-21st reference charts for GA 24–36 weeks)  
AND  
Confirmation of microcephaly (i.e., HC 2 SD below mean or <3rd percentile) by: 
• 
at least one additional US after 24 weeks and at least one week after first US  
OR 
• 
HC measurement with standard tape measure at birth or autopsy  
1b 
Fetus of at least 24 weeks GA based on uncertain LMP with 2nd trimester US  
AND  
HC 2 SD below mean or <3rd percentile according to fetal ultrasound (US) examination using appropriate 
standardized reference charts according to GA and gender for the population (e.g. WHO growth 
reference charts if GA ≥37 weeks and Intergrowth-21st reference charts for GA 24–36 weeks)  
AND  
Confirmation of microcephaly (i.e., HC 2 SD below mean or <3%) by:  
• 
at least one additional US after 24 weeks and at least one week after first US  
OR  
• 
HC measurement with standard tape measure at birth or autopsy 

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Prenatally Diagnosed Microcephaly (continued) 
Level 
Description 
2 
Fetus of at least 24 weeks GA based on certain or uncertain LMP with fundal height and no confirmatory 
1st or 2nd trimester US scan  
AND  
HC 2 SD below mean or <3rd percentile according to fetal US scan using appropriate standardized 
reference charts according to GA and gender for the population (e.g. WHO growth reference charts if GA 
≥37 weeks and Intergrowth-21st reference charts for GA 24–36 weeks) with femur length and abdominal 
circumference concordant with GA assessment 
AND  
Confirmation of microcephaly (i.e., HC 2 SD below mean or <3%) by:  
• 
at least one additional US scan after 24 weeks and at least one week after first US  
OR  
• 
HC measurement with standard tape measure at birth or autopsy  
3a 
Fetus of at least 24 weeks GA based on certain LMP with confirmatory 1st trimester or 2nd trimester US 
scan, uncertain LMP with 2nd trimester US, IUI, or embryo transfer date 
AND  
HC 2 SD below mean or <3rd percentile according to fetal US scan using appropriate standardized 
reference charts according to GA and gender for the population (e.g. WHO growth reference charts if GA 
≥37 weeks and Intergrowth-21st reference charts for GA 24–36 weeks) with femur length and abdominal 
circumference concordant with GA assessment 
AND  
No additional data to confirm microcephaly (i.e., No additional prenatal US scan or confirmation of 
microcephaly with any additional US or by HC measurement at birth or autopsy at birth or autopsy) 
3b 
Fetus of at least 24 weeks GA based on certain or uncertain LMP with fundal height and no confirmatory 
1st or 2nd trimester US  
AND  
HC 2 SD below mean or <3 percentile according to fetal US scan using appropriate standardized 
reference charts according to GA and gender for the population (e.g., WHO growth reference charts if GA 
P37 weeks and Intergrowth-21st reference charts for GA 24–36 weeks) with femur length and abdominal 
circumference concordant with GA assessment 
AND 
No additional data to confirm microcephaly (i.e., No additional prenatal US scan or confirmation of 
microcephaly by HC measurement at birth or autopsy) 
4 
Fetus of at least 24 weeks GA based on certain LMP with confirmatory 1st trimester or 2nd trimester US 
scan, uncertain LMP with 2nd trimester US, IUI, embryo transfer date, or certain or uncertain LMP with 
fundal height and no confirmatory 1st or 2nd trimester US scan 
AND  
HC 2 SD below mean or <3% according to fetal US examination using appropriate standardized 
reference charts according to GA and gender for the population (e.g. WHO growth reference charts if GA 
≥37 weeks and Intergrowth-21st reference charts for GA 24–36 weeks)  
AND  
HC at birth or autopsy is in the normal range using appropriate standardized reference charts according 
to GA and gender for the population, which means that this is NOT a case of prenatally diagnosed 
congenital microcephaly 
Reference [DeSilva, 2017]: DeSilva M, Munoz FM, Sell E, et al. Congenital microcephaly: Case definition & guidelines 
for data collection, analysis, and presentation of safety data after maternal immunisation. Vaccine. 2017;35:6472 – 
6482. 

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Major Congenital anomalies 
Congenital anomalies, also commonly referred to as birth defects, congenital disorders, 
congenital malformations, or congenital abnormalities. Major congenital anomalies are 
events of prenatal origin that a represent at birth, potentially impacting an infant’s health, 
development and/or survival. 
Levels of Diagnostic Certainty (1 highest level to 4 lowest level of certainty 
Major External Structural Defects 
Level 
Description 
1 
Alterations in external anatomy visible:  
• 
at the time of live birth and persistent beyond the immediate peripartum period unless surgically 
repaired  
OR 
• 
in a stillbirth or in the products of conception of a spontaneous or therapeutic abortion  
AND 
Confirmed by documentation of a diagnosis made by a clinician experienced in diagnosing congenital 
anomalies and with the highest level of morphology training for the specific setting 
2 
Alterations in external anatomy visible:  
• 
at the time of live birth and persistent beyond the immediate peripartum period unless surgically 
repaired  
OR 
• 
in a stillbirth or in the products of conception of a spontaneous or therapeutic abortion  
AND 
Confirmed by documentation of a diagnosis made by a clinician with some experience diagnosing 
congenital anomalies 
3 
Alterations in external anatomy visible: 
• 
at the time of live birth and persistent beyond the immediate peripartum period unless surgically 
repaired  
OR  
• 
in a stillbirth or in the products of conception of a spontaneous or therapeutic abortion  
AND 
Confirmed: 
• 
by documentation of a diagnosis made by a trained maternal or child health care provider with at 
least minimal experience diagnosing congenital anomalies  
OR 
• 
For live births, by using individual (ICD-9/ICD-10) codes or as part of an ICD-9/ICD-10 code based 
algorithm, where the outcome (individual code or algorithm) has been validated 
4 
(Insufficient evidence to confirm) 
Alterations in external anatomy visible: 
• 
at the time of live birth and persistent beyond the immediate peripartum period unless surgically 
repaired  
OR 
• 
in a stillbirth or in the products of conception of a spontaneous or therapeutic abortion  
AND  
Confirmed: 
• 
by medical record review  
OR 
• 
in claims data (ICD-9/ICD-10 diagnoses)  

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Internal Structural Defects 
Level 
Description 
1 
Alterations in internal anatomy present at the time of live birth and persistent beyond the immediate 
peripartum period unless surgically repaired 
AND 
Confirmed by definitive imaging study or intraoperative diagnosis  
OR  
Alterations in internal anatomy detected during autopsy for a stillbirth, spontaneous or therapeutic 
abortion confirmed by documentation by a pathologist or other relevant subspecialist  
2 
Alterations in internal anatomy present at the time of live birth and persistent beyond the immediate 
peripartum period unless surgically repaired  
AND 
Confirmed by documentation of a diagnosis made by a clinician experienced in diagnosing congenital 
anomalies and with the highest level of morphology training for the specific setting without definitive 
imaging or intraoperative evaluation 
OR  
For stillbirth, spontaneous or therapeutic abortion, internal structural defect is visible by ultrasound or 
other imaging modality prenatally 
3 
Alterations in internal anatomy present at the time of live birth and persistent beyond the immediate 
peripartum period unless surgically repaired  
AND 
Confirmed: 
• 
by documentation of a diagnosis made by a clinician with some experience diagnosing congenital 
anomalies  
OR 
• 
using individual (ICD-9/ICD-10) codes or as part of an ICD-9/ICD-10 code based algorithm, where 
the outcome (individual code or algorithm) has been validated 
4 
(Insufficient evidence to confirm) 
Alterations in internal anatomy present: 
• 
at the time of live birth and persistent beyond the immediate peripartum period unless surgically 
repaired  
OR 
• 
at time of stillbirth, spontaneous abortion, or induced abortion  
AND 
Confirmed: 
• 
through medical record review, with the medical record demonstrating that the anomaly was 
present at the time of live birth or time of fetal demise, and that the anomaly was diagnosed by a 
trained maternal or child health care provider with minimal experience diagnosing congenital 
anomalies  
OR 
• 
by claims data (ICD-9/ICD-10 diagnoses) 

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Functional Defects 
Level 
Description 
1 
For live births, alterations in functioning of one or more organs or body parts not due to a structural 
defect, present at the time of birth (or propensity to develop alteration present at live birth), and persistent 
beyond the immediate peripartum period, unless treated through gene therapy or stem cell 
transplantation  
OR  
For stillbirths, spontaneous or therapeutic abortions, alterations in functioning of one or more organs or 
body parts, not due to a structural defect  
AND  
Confirmed by definitive diagnostic study 
2 
For live births, alterations in functioning of one or more organs or body parts not due to a structural 
defect, present at livebirth (or propensity to develop alteration present at live birth), and persistent beyond 
the immediate peripartum period, unless treated through gene therapy or stem cell transplantation  
OR  
For stillbirths, spontaneous or therapeutic abortions, alterations in functioning of one or more organs or 
body parts, not due to a structural defect  
AND  
Confirmed by documentation of a diagnosis made by a clinician experienced in diagnosing congenital 
anomalies and with the highest level of training in the diagnosis of functional defects for the specific 
setting 
3 
For live births, alterations in functioning of one or more organs or body parts not due to a structural 
defect, present at livebirth (or propensity to develop alteration present at live birth), and persistent beyond 
the immediate peripartum period, unless treated through gene therapy or stem cell transplantation OR  
For stillbirths, spontaneous or therapeutic abortions, alterations in functioning of one or more organs or 
body parts, not due to a structural defect  
AND 
Confirmed: 
• 
by documentation of a diagnosis made by a clinician with some experience diagnosing functional 
defects  
OR 
• 
using individual (ICD-9/ICD-10) codes or as part of an ICD-9/ICD-10 code based algorithm, where 
the outcome (individual code or algorithm) has been validated 
4 
(Insufficient evidence to confirm) 
For live births, alterations in functioning of one or more organs or body parts not due to a structural 
defect, present at the time of live birth (or propensity to develop alteration present at livebirth), and 
persistent beyond the immediate peripartum period, unless treated through gene therapy or stem cell 
transplantation  
OR 
For stillbirths, spontaneous or therapeutic abortions, alterations in functioning of one or more organs or 
body parts, not due to a structural defect  
AND 
Confirmed: 
• 
through medical record review, with the medical record demonstrating that the anomaly was 
present at the time of live birth or time of fetal demise, and that the anomaly was diagnosed by a 
trained maternal or child healthcare provider who is not a qualified geneticist, neonatologist, 
pathologist, subspecialist, pediatrician, obstetrician, or family medicine practitioner  
OR  
• 
by claims data (ICD-9/ICD-10 diagnoses) 
Reference [DeSilva, 2016]: DeSilva M, Munoz FM, Mcmillan M, et al. Congenital anomalies: Case definition and 
guidelines for data collection, analysis, and presentation of immunization safety data. Vaccine. 2016;34(49):6015-6026.  

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Table 30 
Neonatal Death 
Death of a live born infant regardless of gestational age at birth, within the first 28 
completed days of life 
Levels of Diagnostic Certainty (1 highest level to 4 lowest level of certainty 
Neonatal death in a non-viable live birth 
Level 
Description 
1 
Live born infant  
AND 
• 
Gestational age <22 weeks (GA level of certainty = 1)  
OR 
• 
Birth weight <500 g  
AND 
Death of infant in first 28 days of life  
AND 
Medically-confirmed death 
2 
Live born infant  
AND 
Gestational age/size of newborn assessed as at least one of: 
• 
Gestational age <22 weeks (GA Level of Certainty = 1 OR 2) 
• 
Birth weight <500 g  
AND 
Death of infant in first 28 days of life  
AND 
Medically-confirmed death OR non-medically-confirmed death 
3 
Live born infant  
AND 
Gestational age <5 months according to parent/family member/delivery attendant (GA Level of Certainty 
= 2 OR 3)  
AND 
Death of infant in first 28 days of life  
AND 
Medically-confirmed death OR non-medically-confirmed death 
Neonatal death in an extremely preterm live birth 
Level 
Description 
1 
Live born infant  
AND 
• 
Gestational age ≥22 and <28 weeks (GA Level of Certainty = 1)  
OR 
• 
Birth weight ≥500 g but <1000 g  
AND 
Death of infant in first 28 days of life  
AND 
Medically-confirmed death 
2 
Live born infant  
AND 
Gestational age/size of newborn assesses as one or more of: 
• 
Gestational age ≥22 and <28 weeks (GA Level of Certainty = 1 OR 2)  
• 
Birth weight ≥500 g but <1000 g  
AND 
Death of infant in first 28 days of life  
AND 
Medically-confirmed death OR non-medically-confirmed death 

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Neonatal death in an extremely preterm live birth (continued) 
Level 
Description 
3 
Live born infant  
AND  
Gestational age ≥5 months but <7 months according to neonate’s parent (mother/father)/family 
member/delivery attendant (GA Level of Certainty = 2 OR 3)  
AND 
Death of infant in first 28 days of life  
AND 
Medically-confirmed death OR non-medically-confirmed death 
Neonatal death in a preterm live birth (gestational age ≥28to <37 weeks) 
Level 
Description 
1 
Live born infant  
AND 
• 
Gestational age ≥28 and <37 weeks (Level of Certainty = 1) 
OR 
• 
Birth weight ≥1000 g but <2500 g  
AND 
Death of infant in first 28 days of life  
AND 
Medically-confirmed death 
2 
Live born infant  
AND  
Gestational age/size of newborn assesses as one or more of: 
• 
Gestational age ≥28 and <37 weeks (GA Level of Certainty = 1 OR 2)  
• 
Birth weight ≥1000 g but <2500 g  
AND 
Death of infant in first 28 days of life  
AND 
Medically-confirmed death OR non-medically-confirmed death 
3 
(MAY apply to LMIC- or may be non-viable in LMIC) 
Live born infant  
AND 
Gestational age ≥7 months but <9 months according to parent/family member/delivery attendant (GA 
Level of Certainty = 2 OR 3)  
AND 
Death of infant in first 28 days of life  
AND 
Medically-confirmed death OR non-medically-confirmed death 
Neonatal death in a term live birth 
Level 
Description 
1 
Live born infant AND 
Gestational age ≥37 weeks (GA Level of Certainty = 1) AND 
• 
Birth weight >2500 g  
OR  
• 
Documented intra-uterine growth retardation if ≤2500 g  
AND 
Death of infant in first 28 days of life  
AND 
Medically-confirmed death 

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Neonatal death in a term live birth (continued) 
Level 
Description 
2 
Live born infant  
AND 
Gestational age/size of newborn assesses as one or more of: 
• 
Gestational age ≥37 weeks (GA Level of Certainty = 1 OR 2) 
• 
Birth weight ≥2500 g  
AND 
Death of infant in first 28 days of life  
AND 
Medically-confirmed death OR non-medically-confirmed death which is confirmed by examination by (by 
at least) non-medically-trained attendant (e.g. undertaker, community member) 
3 
(apply to Lower Middle Income Countries) 
Live born infant AND 2. Gestational age ≥9 months according to parent/family member/delivery attendant 
(GA Level of Certainty = 2 OR 3) AND 
3. 
Death of infant in first 28 days of life  
AND 
4. 
Medically-confirmed death OR non-medically-confirmed death 
Reference [Pathirana, 2016]: Pathirana J, Muñoz FM, Abbing-Karahagopian V, et al. Neonatal death: Case definition 
& guidelines for data collection, analysis, and presentation of immunization safety data. Vaccine. 2016;34(49):6027-
6037. 
Table 31 
Neonatal Infections 
Neonatal bacteremia and sepsis (of early or late onset), meningitis, pneumonia and other 
respiratory infections such as bronchiolitis, caused by bacteria, parasites, viruses or fungi. 
Localized eye and ear infections, encephalitis, urinary tract infections and intestinal 
infections were excluded from these guidelines. 
Neonatal invasive blood stream infections: bacterial/fungal/viral 
Level 
Description 
1 
Recognized pathogen identified using a validated method and from a normally sterile site. 
2 
Not meeting Level 1 of evidence  
AND  
Meeting 3 or more of the following criteria: 
Temperature ≥37.5 ◦C or <35.5 ◦C 
Tachycardia or new or more frequent episodes of bradycardia 
New or more frequent episodes of apnea or increased oxygen requirement or increased requirement for 
ventilatory support 
Lethargy or moving only when stimulated or hypotonia or irritability 
Difficulty in feeding or abdominal distention 
Pallor or poor perfusion or hypotension 
Abnormal White Cell Count or I/T ratio >0.2 
Abnormal platelet count  
Increased inflammatory markers (CRP, procalcitonin) 
Metabolic acidosis as defined by a base excess 
3 
Not meeting Level 1 or 2 of evidence  
AND 
Meeting 2 or more of the following criteria: 
Temperature ≥37.5 ◦C or <35.5 ◦C 
Tachypnea or severe chest in drawing or grunting or cyanosis 
Change in level of activity 
History of feeding difficulty 
History of convulsions 

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Bacterial/fungal/viral meningitis 
Level 
Description 
1 
Recognized pathogen identified using a validated method from cerebrospinal fluid (CSF) 
2 
CSF pleocytosis OR positive IgM antibodies to a specific pathogen in the CSF  
AND 
Recognized pathogen identified using a validated method from a normally 
sterile site (other than CSF)  
AND 
Temperature ≥37.5 ◦C or <35.5 ◦C  
AND 
1 or more criteria below: 
History of convulsions 
Lethargy or irritability 
Coma 
Apnea 
Bulging fontanel 
Neck stiffness 
3a 
CSF pleocytosis  
AND 
No pathogen identified using a validated method from a normally sterile site AND 
Temperature ≥37.5 ◦C or <35.5 ◦C  
AND 
3 or more criteria below: 
History of convulsions 
Lethargy or irritability 
Coma 
Apnea 
Bulging fontanel 
Neck stiffness 
3b 
No lumbar puncture done or no sample available  
AND 
Temperature ≥37.5 ◦C or <35.5 ◦C  
AND 
4 or more criteria below: 
History of convulsions 
Lethargy or irritability 
Coma 
Apnea 
Bulging fontanel 
Neck stiffness 

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Respiratory bacterial/fungal/viral infection 
Level 
Description 
1 
New or progressive or persistent infiltrate or shadowing or fluid in the intrapleural cavity or interlobar 
fissure on chest X-ray  
AND 
• 
Recognized virus identified using a validated assay from an upper respiratory sample  
OR 
• 
Recognized pathogen identified using a validated method and from a normally sterile site  
AND  
3 or more criteria below: 
Temperature ≥37.5 ◦C or <35.5 ◦C 
Tachypnea or Nasal flaring or Chest in-drawing or Grunting 
Desaturations or increased oxygen requirements or increased ventilator requirements or oxygen 
saturation <95% 
Apneas 
Increased respiratory secretions or Increased suctioning requirements 
Cough or wheeze or crepitations 
Increased CRP or procalcitonin 
2 
New or progressive or persistent infiltrate or shadowing or fluid in the intrapleural cavity or interlobar 
fissure on chest X-ray  
AND  
4 or more criteria below: 
Temperature ≥37.5 ◦C or <35.5 ◦C 
Tachypnea or Nasal flaring or Chest in-drawing or Grunting 
Desaturations or increased oxygen requirements or increased ventilator requirements or oxygen 
saturation <95% 
Apneas 
Increased respiratory secretions or Increased suctioning requirements 
Cough or wheeze or crepitations 
Increased CRP or procalcitonin 
3 
2 or more criteria below: 
Difficulty in breathing/Tachypnea 
Severe chest in-drawing 
Nasal flaring 
Grunting 
Wheezing 
Stridor 
Fever 
Reference [Vergnano, 2016]: Vergnano S, Buttery J, Cailes B, et al. Neonatal infections: Case definition and 
guidelines for data collection, analysis, and presentation of immunization safety data. Vaccine. 2016;34 (49):6038-
6046. 

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Table 32 
Respiratory Distress in the Neonate 
Constellation of clinical findings that support the presence of breathing difficulty in the 
neonate (0-28 days of life), independent from etiology or severity, and independent from 
the infant’s gestational age or circumstances at the time of delivery. 
Level 
Description 
1 
Newborn 0 to 28 days of life  
AND 
Abnormal respiratory rate: 
Measurement of number of breaths per minute consistent with: 
• 
Tachypnea = respiratory rate of more than 60 breaths per minute OR  
• 
Bradypnea = respiratory rate of less than 30 breaths per minute OR  
• 
Apnea = cessation of respiratory effort (no breaths) for at least 20 seconds 
AND 
Clinical symptoms consistent with labored breathing: 
• 
Nasal flaring (dilatation of alae nasi) OR 
• 
Noisy respirations in the form of expiratory grunting, stridor, or wheeze OR  
• 
Retractions or increased chest in-drawings on respiration (subcostal, intercostal, sternal, 
suprasternal notch) OR 
• 
Central cyanosis (whole body, including lips and tongue) on room air OR  
• 
Low Apgar Score (< 7 points) at 10 min, with respiration score <2  
AND 
Examination and documentation by qualified, trained, health care provider appropriate for the clinical 
setting. 
2 
Newborn 0 to 28 days of life  
AND 
Abnormal respiratory rate: 
Not measured, but reported as “rapid breathing”, “slow breathing”, having periods of “no breathing”, or 
“abnormal breathing”  
AND 
Clinical symptoms consistent with labored breathing: 
• 
Nasal flaring (dilatation of alae nasi) OR 
• 
Noisy respirations in the form of expiratory grunting, stridor, or wheeze OR 
• 
Retractions or increased chest in-drawings on respiration (subcostal, intercostal, sternal, 
suprasternal notch) or seesaw respirations OR 
• 
Central cyanosis (whole body, including lips and tongue) on room air OR 
• 
Low Apgar Score (< 7 points) at 10 min, with respiration score <2 
AND 
• 
No medical record documentation, but reporting through either a non-medical observer (e.g. 
mother, father, community worker) or via standard census mechanisms (e.g. Demographic and 
Health Surveillance System) OR 
• 
Collection of information from medical record review or billing codes. 
3 
No need for a level 3 per working group. 
4 
Not enough information to ascertain case of respiratory distress. 
5 
Not a case of respiratory distress in the neonate. 
Reference [Leigh, 2017]: Leigh R. Sweet, Cheryl Keech, Nicola P. Klein, et al. Respiratory distress in the neonate: 
Case definition & guidelines for data collection, analysis, and presentation of maternal immunization safety data. 
Vaccine. 2017; 35: 6506-6517. 

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Table 33 
Preterm Birth 
Birth in less than 37 gestation-completed weeks (less than 259 days). 
Prematurity and assessment of gestational age  
Level 
Description 
1 
Certain last menstrual period date (LMP) LMP or intrauterine insemination (IUI) date or embryo transfer 
(ET) date with confirmatory 1st trimester scan (≤13 6/7 weeks).  
OR 
1st trimester scan (≤13 6/7 weeks) 
2a 
Certain LMP* with 2nd trimester scan (14 0/7 weeks to 27 6/7weeks). 
Note: If LMP and U/S do not correlate, default to U/S GA assessment. 
OR 
Certain LMP* with 1st trimester physical examination. 
2b 
Uncertain LMP with 2nd trimester scan (14 0/7 weeks to 27 6/7 weeks). 
3a 
Certain LMP with 3rd trimester scan ≥ 28 0/7 weeks  
OR 
Certain LMP with confirmatory 2nd trimester Fundal Height (FH) 
OR 
Certain LMP with birth weight  
OR 
Uncertain LMP with 1st trimester physical examination. 
3b 
Uncertain LMP with FH.  
OR 
Uncertain LMP with newborn physical assessment.  
OR 
Uncertain LMP with Birth weight 
* 
Definitions of LMP, birth weight and physical assessment in referenced article. 
Reference [Quinn, 2016]: Quinn JA, Munoz FM, Gonik B, et al. Preterm birth: Case definition &amp; guidelines for 
data collection, analysis, and presentation of immunization safety data. Vaccine. 2016;34(49):6047-6056. 

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Table 34 
Failure to Thrive 
Failure to Thrive (FTT) can be broadly defined as a faltering of growth from a previously 
established pattern of growth. It is universally established that a diagnosis of failure to 
thrive should be based on anthropometric data. However no consensus exits as to which 
measurements achieve the highest specificity and sensitivity. Weight is generally 
regarded is the indicator of choice, particularly a change in growth velocity, and as such 
has been selected as the standard for this case definition with a weight for age 
deceleration as the primary indicator of failure to thrive. The case definition should be 
applied when there is no clear alternative diagnosis for the reported event to account for 
the combination of symptoms. 
Level 
Description 
1 
Infant age1 determined by a documented birth date 
AND 
Bare weights obtained using an appropriate electronic baby scale 
AND 
At least 2 such weights, measured at least 4 weeks apart 
AND 
Weight for age or weight for length/height falling by two major percentiles (percentile markers 95, 90, 75, 
50, 25, 10, and 5) over time 2,3,4 
2a 
Infant age determined by a documented birth date 
AND 
Weights obtained using a beam balance scale 
AND 
At least 2 weights, measured at least 4 weeks apart 
AND 
Weight for age deceleration through at least 2 centile spaces on 
growth chart 
OR 
Infants with an undocumented birth date, where age is determined 
based on Mothers recall to nearest month 
AND 
Weights obtained using electronic scale 
AND 
At least 2 weights, measured at least 4 weeks apart 
AND 
Weight for age deceleration through at least two major percentiles (percentile markers 95, 90, 75, 50, 25, 
10, and 5) over time  
2b 
Infant age determined by a documented birth date 
AND 
Weights obtained using a spring balance scale 
AND 
At least 2 weights, measured at least 4 weeks apart 
AND 
Weight for age deceleration through at least 2 centile spaces on 
growth chart  
OR  
Weight measured using electronic scale or beam balance scale 
AND 
Length taken using Infantometer 
AND 
Weight for length less than or equal to the 3rd centile on the 
appropriate growth chart 

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Level 
Description 
3a 
Infants with an undocumented birth date, where age is determined 
based on Mothers recall to nearest month 
AND 
Weight obtain using either beam balance or spring balance 
scale 
AND 
At least 2 weights, measured as least 4 weeks apart 
AND 
Weight for age deceleration through at least two major percentiles (percentile markers 95, 90, 75, 50, 25, 
10, and 5) over time  
3b 
Infants with no weight available 
AND 
Physical examination consistent with FTT5 
AND 
MUAC6 indicative of severe wasting 
1This case definition is limited to infants up to 12 months of age. 
2Homan GJ, Failure to Thrive: A Practical Guide. Am Fam Physician. 2016; 94(4):295-9 
3 Weight should be documented on the appropriate growth chart at the time of assessment. A fall through 2 centile 
spaces may be demonstrated at any point in the first 12 months of life, using any two weights as long as they are taken 
at least 4 weeks apart. Details of use of the weight balances allowable under this case definition and use of the 
Infantometer for length assessment are presented in the reference given below. 
4 For infants born at 37 weeks gestation or above, the WHO growth charts should be applied. When using weight for 
age use the growth chart most accurate for the infants age. The birth to 6 months age range should be used where 
data is available for this range only, the birth to 2 years chart should be used where data is available beyond 6 months 
of life. When using weight for length, use the chart for birth to 2 years. For infants born less than 37 completed weeks 
gestation, the Intergrowth charts for postnatal growth standards in preterm infant should be used. All infants should be 
plotted on their respective growth chart using their corrected age. Links to relevant growth charts are presented in the 
reference given below. 
5 Physical examination with signs of Failure to Thrive (must include at least 2 findings, with at least one major finding) 
Major findings: Reduced subcutaneous fat stores; poor muscle mass; loose skin folds; prominent ribs; thin limbs. Other 
less specific signs include: sparse hair; rashes; pallor; miserable; lethargy/fatigue. 
6 Mid Upper Arm Circumference (MUAC): For infants 0–6 months, a MUAC of 6 110 mm is indicative of severe 
wasting. For infants 6–12 months, a MUAC of 6 115 mm is indicative of severe wasting. Instructions on performing 
MUAC are presented in the reference given below. 
Reference [Ross, 2017]: Ross E, Munoz F, Edem B et al. Failure to thrive: case definition and guidelines for data 
collection, analysis, and presentation of maternal immunization safety data. Vaccine. 2017; 35:6483-6491. 
Table 35 
Standard Definitions for Neonatal Events of interest not defined as 
events in GAIA  
Event of Interest 
Definition  
Large for gestational age 
Birth weight > 90% for newborns of same gestational age in same population (>4000g 
at term). 
Macrosomia 
BW >4000 g (8 lb, 13 oz). 

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10.7. 
Appendix 7: Protocol amendment history 
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the TOC. 
Amendment 2 (21 Jun 2023) 
This amendment is considered substantial based on the criteria defined in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union 
because it significantly impacts the scientific value of the study. 
Overall rationale for the Amendment:  
This amendment is being done to include details pertaining to the exclusion criteria for 
women of nonchildbearing potential, the timeframe for the primary and secondary 
objectives and the Phase of the study (Phase 3b). It also includes updated information 
indicating that all the prior studies listed are collectively called as ‘prior RSV MAT 
studies’ for both cohorts, to allow participants from any of the prior RSV MAT studies 
who are pregnant at enrollment to be enrolled in the prospective cohort. It further clarifies 
the method and source of data collection in the retrospective and prospective cohorts. 
Additional updates were made in the objectives and endpoints section, schedule of 
activities, study design section, participant discontinuation/withdrawal from the study 
section, safety section, statistical considerations, and appendix.  
The list of abbreviations and references were updated, additional information from the 
current protocol template were included, and some minor edits were made for clarity 
wherever applicable. Some minor typographical and grammatical corrections were also 
made in this amendment. 
Summary of changes table of previous amendments (Protocol Amendment 1): 
Section # and Name 
Description of Change 
Brief Rationale 
10.5.1. GAIA Gestational 
age assessment form  
Removed highlighted text (bold text) 
in the form and deleted relevant 
footnotes 
To correct an error where GAIA 
gestational age assessment should not be 
an enrollment criterion. 
Section 7.2 Participant 
discontinuation/withdrawal 
from the study 
Section 7.3 Lost to follow-up 
Text in these sections were edited to 
clarify the criteria to consider for 
participant discontinuation, 
withdrawal and lost to follow-up. 
To clarify the criteria for participant 
discontinuation, withdrawal and lost to 
follow-up. 
Table 6 Collection and 
reporting of safety 
information 
Error in column header corrected 
Initial pregnancy contact was incorrectly 
stated as Visit 2. This has been corrected. 
Section 8.4.10 COVID-19 
infection 
Clarification for capture of COVID-19 
related information added 
Clarification for COVID-19 data collection 
added 
Table 13 95% CI on the 
percentage of participants 
with event(s) of interest 
Number of events for sample size of 
650 study participants updated. 
To correct typos in initial calculation. 
Section 8.4.5.1. List of 
AESIs 
Add pathways to preterm birth: 
insufficient cervix to list of pregnancy 
AESIs 
As this study will collect pregnancy data 
before 24 weeks gestation, this pathway to 

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Section # and Name 
Description of Change 
Brief Rationale 
preterm birth will be relevant as an AESI 
for this study. 
Table 17 Antenatal Bleeding 
Table 22 Pathways to 
preterm birth 
Removed references to conditions 
ineligible for this study, add details on 
insufficient cervix. 
To correct errors where specific conditions 
are referenced as ineligible, as absence of 
those conditions are not part of enrollment 
eligibility criteria. 

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11. 
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guidelines for data collection, analysis, and presentation of safety data after maternal 
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Vaccine. 2017;35:6546-6554. 
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Signature Page for  219510 TMF-16123850 v1.0
Signature Page for TMF-16123850 v1.0
Reason for signing: Approved
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Date of signature: 21-Jun-2023 11:42:37 GMT+0000
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