Guideline Status

This Is The Current Release Of The Guideline.

This guideline updates a previous version: Royal

College of Obstetricians and Gynaecologists (RCOG).
Jakarta, 31 October 2017
 Methodology

• Methods Used to Collect/Select the Evidence

• Searches of Electronic Databases

• Description of Methods Used to Collect/Select the

Evidence
The Cochrane Library and Cochrane Register
of Controlled Trials

• Were searched for relevant randomised controlled trials,

systematic reviews, and meta-analyses.
• A search of Medline from was also carried out.
• The date of the last search was.
• In addition, relevant conference proceedings and
abstracts were searched.
 The databases were searched

• Using the relevant Medical Subject Heading

(MeSH) terms including all sub-headings.

• This was combined with a keyword search using

'human', 'female', 'pregnancy', 'abortion',
'miscarriage', 'habitual', 'recurrent', 'randomised
controlled trials' and 'meta-analysis'.
 Source Documents

• Number of Source Documents

• Not stated
• Methods Used to Assess the Quality and Strength
of the Evidence
• Weighting According to a Rating Scheme (Scheme
Given)
• Rating Scheme for the Strength of the Evidence
 Classification of Evidence Levels
• 1++ High-quality meta-analyses, systematic reviews of
randomised controlled trials or randomised controlled trials
with a very low risk of bias

• 1+ Well-conducted meta-analyses, systematic reviews of

randomised controlled trials or randomised controlled trials
with a low risk of bias

• 1– Meta-analyses, systematic reviews of randomised controlled

trials or randomised controlled trials with a high risk of bias

• 2++ High-quality systematic reviews of case–control or cohort

studies or high-quality case–control or cohort studies with a
very low risk of confounding, bias or chance and a high
probability that the relationship is causal
 Classification of Evidence Levels Con’t

• 2+ Well-conducted case–control or cohort studies with

a low risk of confounding, bias or chance and a
moderate probability that the relationship is causal

• 2– Case–control or cohort studies with a high risk of

confounding, bias or chance and a significant risk that
the relationship is not causal

• 3 Non-analytical studies, e.g., case reports, case series

• 4 Expert opinion
 Methods Used

• Methods Used to Analyze the Evidence

• Review of Published Meta-Analyses

Systematic Review

• Description of the Methods Used to Analyze the

Evidence
 Methods Used to Formulate the
Recommendations

• Expert Consensus

• Informal Consensus

• Description of Methods Used to Formulate the

Recommendations
 Grades of Recommendations
• A - At least one meta-analysis, systematic review or
randomised controlled trial rated as 1++, and directly
applicable to the target population; or
A systematic review of randomised controlled trials or a
body of evidence consisting principally of studies rated as
1+, directly applicable to the target population and
demonstrating overall consistency of results.

• B - A body of evidence including studies rated as 2++

directly applicable to the target population, and
demonstrating overall consistency of results; or
Extrapolated evidence from studies rated as 1++ or 1+
 Grades of Recommendations Con’t

• C - A body of evidence including studies rated as 2+ directly

applicable to the target population and demonstrating
overall consistency of results; or
Extrapolated evidence from studies rated as 2++

• D - Evidence level 3 or 4; or
Extrapolated evidence from studies rated as 2+
 Major Recommendations

• In addition to these evidence-based

recommendations, the guideline development
group also identifies points of best clinical practice
in the original guideline document.

• Classification of evidence levels (1++ to 4) and

grades of recommendations (A-D) are defined at
the end of the "Major Recommendations" field.
 Methodology Checklist 1: Systematic Reviews and Meta-analyses
SIGN gratefully acknowledges the permission received from the authors of the AMSTAR tool to base this checklist
SIGN on their work: Shea BJ, Grimshaw JM, Wells GA, Boers M, Andersson N, Hamel C,. et al. Development of AMSTAR:
a measurement tool to assess the methodological quality of systematic reviews. BMC Medical Research
Methodology 2007, 7:10 doi:10.1186/1471-2288-7-10. Available from http://www.biomedcentral.com/1471-2288/7/10
[cited 10 Sep 2012]

Study identification (Include author, title, year of publication, journal title, pages)

Guideline topic: Key Question No:

Before completing this checklist, consider:

1. Is the paper a systematic review or meta-analysis? IF NO reject. IF YES continue.
2. Is the paper relevant to key question? Analyse using PICO (Patient or Population Intervention
Comparison Outcome). IF NO reject. IF YES complete the checklist.

Checklist completed by:

Section 1: Internal validity

In a well conducted systematic review: Does this study do it?

1.1 The study addresses a clearly defined research

question.i
Yes □ No □
Can’t say □
1.2 At least two people should select studies and Yes □ No □
extract data.ii
Can’t say □
1.3 A comprehensive literature search is carried Yes □ No □
out.iii
Can’t say □ Does not apply □
1.4 The authors clearly state if or how they limited Yes □ No □
their review by publication type.iv

1.5 The included and excluded studies are listed.v Yes □ No □

1.6 The characteristics of the included studies are Yes □ No □

provided.vi

1.7 The scientific quality of the included studies is Yes □ No □

assessed and documented.vii
 Notes on Methodology Checklist 1: Systematic Reviews and Meta-analyses
The top part of the form identifies the study and links it to the particular guideline and key question to which it relates. It includes a couple of reminders of
factors you should consider before deciding whether it is worth progressing to a full appraisal of the paper concerned.

Section 1 This section makes a series of statements about aspects of the systematic review process that affect the internal validity of the review and
asks you to assess how well the review addresses each issue. The objective is to assess how well the authors have dealt with the risk of
bias in their methods.
{Note that the “Response” column is for guidance only. You may opt for a different rating depending on how information is presented in any
given review.}
Statement 1.1 The study addresses a clearly defined research question

Why is this important? When does this Response:

statement
apply?
Before work starts on a systematic review, the Always applies.
research question to be answered should be
clearly stated along with the criteria to be
used to decide which studies will be included
in or excluded from the review.
Yes. Where the research question is clearly stated. Reference to a
protocol, ethics approval, or pre-determined/a priori published
research objectives may meet this criterion.
No. If the authors state the question they wish to address but provide
no information on how they went about selecting individual studies.
Can’t say. Where the information is not clearly explained. eg the
authors indicate that they had criteria for including or excluding
studies but fail to state what the specific criteria were, or fail to specify
the question clearly.
 Methodology Checklist 2: Controlled Trials
SIGN

Study identification (Include author, title, year of publication, journal title, pages)

Guideline topic: Key Question No: Reviewer:

Before completing this checklist, consider:

1. Is the paper a randomised controlled trial or a controlled clinical trial? If in doubt, check the
study design algorithm available from SIGN and make sure you have the correct checklist. If it is a
controlled clinical trial questions 1.2, 1.3, and 1.4 are not relevant, and the study cannot be rated
higher than 1+

2. Is the paper relevant to key question? Analyse using PICO (Patient or Population Intervention
Comparison Outcome). IF NO REJECT (give reason below). IF YES complete the checklist.

Reason for rejection: 1. Paper not relevant to key question  2. Other reason  (please specify):

SECTION 1: INTERNAL VALIDITY

In a well conducted RCT study… Does this study do it?

i
1.1 The study addresses an appropriate and clearly focused question. Yes  No 
Can’t say 
ii
1.2 The assignment of subjects to treatment groups is randomised. Yes  No 
Can’t say 
iii
1.3 An adequate concealment method is used. Yes  No 
Can’t say 
1.4 Subjects and investigators are kept ‘blind’ about treatment Yes  No 
iv
allocation. Can’t say 
1.5 The treatment and control groups are similar at the start of the Yes  No 
v
trial. Can’t say □
1.6 The only difference between groups is the treatment under Yes  No 
vi
investigation. Can’t say 
1.7 All relevant outcomes are measured in a standard, valid and Yes  No 
vii
reliable way. Can’t say 
1.8 What percentage of the individuals or clusters recruited into each
treatment arm of the study dropped out before the study was
viii
completed?
1.9 All the subjects are analysed in the groups to which they were Yes  No 
ix
randomly allocated (often referred to as intention to treat analysis). Can’t say  Does not
apply 
1.10 Where the study is carried out at more than one site, results are Yes  No 
x
comparable for all sites. Can’t say  Does not
apply 
 Notes on Methodology Checklist 2: Controlled Trials
The top part of the form identifies the study and links it to the particular guideline and key question to which it relates. It
includes reminders of factors you should consider before deciding whether it is worth progressing to a full appraisal of the
paper concerned.

Section 1 This section makes a series of statements about aspects of the systematic review process that affect the internal validity of the
review and asks you to assess how well the review addresses each issue. The objective is to assess how well the authors have
dealt with the risk of bias in their methods.
If you would like more information on randomised controlled trials, their characteristics and weaknesses then please refer to
Greenhalgh T. How to read a paper: the basics of evidence-based medicine. 3rd edition. Oxford: Blackwell;2006. Section 3.3
Page 44.
Note that the “Response” column is for guidance only. You may opt for a different rating depending on how information is
presented in any given review.}

Statement 1.1 The study addresses an appropriate and clearly focused question
What does this statement mean? When does this Response:
statement apply?

Unless a clear and well defined question is Always applies
specified, it will be difficult to assess how
well the study has met its objectives or how
relevant it is to the question you are trying to
answer on the basis of its conclusions.
Yes - if elements of the research question are present in
the text. {Note that this does not have to be exactly in the
PICO format, but all the elements must be present}.
No if there is no clear question in the text.
Can’t say - if you think there is insufficient detail to allow
an assessment to be made.
 Methodology Checklist 3: Cohort studies
SIGN

Study identification (Include author, title, year of publication, journal title, pages)

Guideline topic: Key Question No: Reviewer:

Before completing this checklist, consider:

1. Is the paper really a cohort study? If in doubt, check the study design algorithm available from SIGN and make
sure you have the correct checklist.

2. Is the paper relevant to key question? Analyse using PICO (Patient or Population Intervention Comparison
Outcome). IF NO REJECT (give reason below). IF YES complete the checklist..

Reason for rejection: 1. Paper not relevant to key question □ 2. Other reason □ (please specify):

Please note that a retrospective study (ie a database or chart study) cannot be rated higher than +.

SECTION 1: INTERNAL VALIDITY

In a well conducted cohort study: Does this study do it?

i
1.1 The study addresses an appropriate and clearly focused question. Yes □ No □

Can’t say □

SELECTION OF SUBJECTS
1.2 The two groups being studied are selected from source populations that are
ii
Yes □ No □
comparable in all respects other than the factor under investigation.
Can’t say □ Does not
apply □

1.3 The study indicates how many of the people asked to take part did so, in each of
iii
Yes □ No □
the groups being studied.
Does not
apply □

1.4 The likelihood that some eligible subjects might have the outcome at the time of
iv
Yes □ No □
enrolment is assessed and taken into account in the analysis.
Can’t say □ Does not
apply □

1.5 What percentage of individuals or clusters recruited into each arm of the study
v
dropped out before the study was completed.

1.6 Comparison is made between full participants and those lost to follow up, by
vi
Yes □ No □
exposure status.
Can’t say □ Does not
apply □
 Notes on Methodology Checklist 3: Cohort Studies
The studies covered by this checklist are designed to answer questions of the type “What are the effects of this exposure?”, It relates to studies
that compare a group of people with a particular exposure with another group who either have not had the exposure, or have a different level of
exposure. Cohort studies may be prospective (where the exposure is defined and subjects selected before outcomes occur), or retrospective
(where exposure is assessed after the outcome is known, usually by the examination of medical records).

Section 1 Section 1 identifies the study, the reviewer, the guideline for which the paper is being considered as evidence, and the key
question(s) it is expected to address. The reviewer is asked to consider a series of aspects of cohort study design and to
make a judgement as to how well the current study meets this criterion. Each relates to an aspect of methodology that
research has shown to be likely to influence the conclusions of a study.
Because of the potential complexity and subtleties of the design of this type of study, there are comparatively few criteria
that automatically rule out use of a study as evidence. It is more a matter of increasing confidence in the strength of
association between exposure and outcome by identifying how many aspects of good study design are present, and how
well they have been tackled. A study that fails to address or report on more than one or two of the questions addressed
below should almost certainly be rejected.
If you would like more information on cohort studies, their characteristics and weaknesses then please refer to Greenhalgh
T. How to read a paper: the basics of evidence-based medicine. 3rd edition. Oxford: Blackwell;2006. Section 3.4 Page 49.
Retrospective studies or single cohort studies are generally regarded as a weaker design, and should not receive
a rating higher than “+”.
Definitions for terms marked with a * can be found in the Cochrane Handbook.
{Note that the “Response” column is for guidance only. You may opt for a different rating depending on how information is
presented in any given review.}

Statement 1.1 The study addresses an appropriate and clearly focused question
What does this statement mean? When does this Response:
statement apply?

Unless a clear and well defined Always applies Yes - if elements of the research question are present
question is specified in the report of in the text.
the review, it will be difficult to
 Methodology Checklist 4: Case-control studies
SIGN

Study identification (Include author, title, year of publication, journal title, pages)

Guideline topic: Key Question No: Reviewer:

Before completing this checklist, consider:

1. Is the paper really a case-control study? If in doubt, check the study design algorithm available from SIGN and
make sure you have the correct checklist.

2. Is the paper relevant to key question? Analyse using PICO (Patient or Population Intervention Comparison
Outcome). IF NO REJECT (give reason below). IF YES complete the checklist.

Reason for rejection: Reason for rejection: 1. Paper not relevant to key question □ 2. Other reason □ (please
specify):

SECTION 1: INTERNAL VALIDITY

In an well conducted case control study: Does this study do
it?
i
1.1 The study addresses an appropriate and clearly focused question. Yes  No 

Can’t say

SELECTION OF SUBJECTS
ii
1.2 The cases and controls are taken from comparable populations. Yes  No 

Can’t say

iii
1.3 The same exclusion criteria are used for both cases and controls. Yes  No 

Can’t say

iv
1.4 What percentage of each group (cases and controls) participated in the study? Cases:

Controls:

1.5 Comparison is made between participants and non-participants to establish their Yes  No 
v
similarities or differences.
Can’t say

vi
1.6 Cases are clearly defined and differentiated from controls. Yes  No 

Can’t say

 Notes on Methodology Checklist 4: Case Control Studies
The studies covered by this checklist are designed to answer questions of the type “What are the factors that caused this event?”, and involve
comparison of individuals with an outcome with other individuals from the same population who do not have the outcome. These studies start
after the outcome of an event, and can be used to assess multiple causes of a single event. They are generally used to assess the causes of
a new problem, but may also be useful for the evaluation of population based interventions such as screening.

Section 1 SECTION 1 identifies the study, the reviewer, the guideline for which the paper is being considered as evidence, and the
key question(s) it is expected to address. The reviewer is asked to consider a series of aspects of cohort study design
and to make a judgement as to how well the current study meets this criterion. Each relates to an aspect of methodology
that research has shown makes a significant difference to the conclusions of a study.
Case-control studies need to be very carefully designed, and the complexity of their design is often not appreciated by
investigators, leading to many poor quality studies being conducted. The questions in this checklist are designed to
identify the main features that should be present in a well designed study. There are few criteria that should, alone and
unsupported, lead to rejection of a study. However, a study that fails to address or report on more than one or two of the
questions addressed below should almost certainly be rejected.
If you would like more information on case-control studies, their characteristics and weaknesses then please refer to
Greenhalgh T. How to read a paper: the basics of evidence-based medicine. 3rd edition. Oxford: Blackwell;2006. Section
3.5 Page 50.
Definitions for terms marked with a * below can be found in the Cochrane Handbook.
{Note that the “Response” column is for guidance only. You may opt for a different rating depending on how information is
presented in any given review.}

Statement 1.1 The study addresses an appropriate and clearly focused question
What does this statement mean? When does this statement Response:
apply?
Unless a clear and well defined question Always applies YES - if elements of the research question
is specified in the report of the review, it are present in the text.
will be difficult to assess how well it has
NO if there is no clear questioning the text.
met its objectives or how relevant it is to
 Methodology Checklist 5: Studies of Diagnostic Accuracy
SIGN
This checklist is based on the work of the QUADAS2 team at Bristol Univeristy
(http://www.bris.ac.uk/quadas/).

Study identification (Include author, title, reference, year of publication)

Guideline topic: Key Question No:

Before completing this checklist, consider:

1. Is the paper really a study of diagnostic accuracy? It should be comparing a specific diagnostic test
against another, and not a general paper or comment on diagnosis.
2. Is the paper relevant to key question? Analyse using PICO (Patient or Population Intervention
Comparison Outcome). IF NO REJECT (give reason below). IF YES complete the checklist..
Reason for rejection: Reason for rejection: 1. Paper not relevant to key question □ 2. Other reason □
(please specify):

Checklist completed by:

All the questions in the following sections have associated footnotes providing short explanations behind
each of the questions. Users who want more detailed explanations should consult the QUADAS-2:
Background Document.

DOMAIN 1 – PATIENT SELECTION

Risk of bias

In a well conducted diagnostic study… Is that true in this study?

1.1 A consecutive sequence or random selection of Yes  Can’t say 

patients is enrolled.i No 

1.2 Case – control methods are not used.ii Yes  Can’t say 
No 
iii
1.3 Inappropriate exclusions are avoided. Yes  Can’t say 
No 

Applicability

1.4 The included patients and settings match the Yes  Can’t say 
key question.iv No 

DOMAIN 2 – INDEX TEST

Risk of bias
In a well conducted diagnostic study… Is that true in this study?

2.1 The index test results interpreted without Yes  Can’t say 
knowledge of the results of the reference
No 
standard.v

2.2 If a threshold is used, it is pre-specified.vi Yes  Can’t say 

No 
 Methodology Checklist 6: Economic Evaluations
SIGN This checklist is based on the BMJ requirements for authors submitting economic studies for publication in that journal.
Drummond M, Jefferson TO. Guidelines for authors and peer reviewers of economic submissions to the BMJ. BMJ
1996:313;275
Study identification (Include author, title, year of publication, journal title, pages)

Guideline topic: Key Question No: Reviewer:

Before completing this checklist, consider:

1. Is the paper an economic study (ie assessing the cost effectiveness of something), or is it just a study
of costs? REJECT IF THE LATTER IS TRUE.
2. Is the paper relevant to the key question? Analyse using PICO (Patient or Population Intervention
Comparison Outcome). IF NO REJECT (give reason below). IF YES complete the checklist.
Reason for rejection: 1. Not an economic study  2. Paper not relevant to key question □
3. Other reason □ (please specify):

SECTION 1: INTERNAL VALIDITY

In a well conducted economic study... Does this study do it?

1.1 The study addresses an appropriate and clearly focused question Yes  No 
Can’t say 
1.2 The economic importance of the question is clear Yes  No 
Can’t say 
1.3 The choice of study design is justified Yes  No 
Can’t say 
1.4 All costs that are relevant from the viewpoint of the study are Yes  No 
included and are measured and valued appropriately

1.5 The outcome measures used to answer the study question are Yes  No 
relevant to that purpose and are measured and valued appropriately
Can’t say  Not applicable

1.6 If discounting of future costs and outcomes is necessary, it been Yes  No 
performed correctly
Can’t say  Not applicable

1.7 Assumptions are made explicit and a sensitivity analysis performed Yes  No 
Can’t say 
1.8 The decision rule is made explicit and comparisons are made on the Yes  No 
basis of incremental costs and outcomes.

1.9 The results provide information of relevance to policy makers Yes  No 

SECTION 2: OVERALL ASSESSMENT OF THE STUDY

2.1 How well was the study conducted? High quality (++)
Acceptable (+)
Unacceptable – reject 0
 Notes on Methodology Checklist 6: Economic Evaluations

The top part of the form identifies the study and links it to the particular guideline and key question to which it relates. It includes reminders of
factors you should consider before deciding whether it is worth progressing to a full appraisal of the paper concerned.

Section 1 Section 1 identifies the study and asks a series of questions aimed at establishing the internal validity of the study under
review - i.e. making sure that it has been carried out carefully, and that the results are likely to be reliable and useful. Each
question covers an aspect of study design that is known to make a significant difference to the conclusions of a study.
Note that the “Response” column is for guidance only. You may opt for a different rating depending on how information is
presented in any given review.}

Statement 1.1 The study addresses an appropriate and clearly focused question

What does this statement mean? When does this Response:

statement apply?
As with clinical evaluations, a clearly defined question Always applies Yes - if elements of the research
is essential to allow the user to assess how well the question are present in the text. {Note
study has met its objectives or how relevant it is to the that this does not have to be exactly in
guideline recommendation to which the results might the PICO format, but all the elements
be applied. For an economic evaluation, the question must be present}.
should contain information on the alternatives under
comparison, the viewpoint, and (ideally) the form of No if there is no clear question in the
economic evaluation being used and the resulting text.
decision rule. Can’t say - if you think there is
insufficient detail to allow an assessment
to be made.
 Considered judgement

Key question:

A: Quality of evidence
1. How reliable are the studies in the body of evidence? (see SIGN 50, section 5.3.1, 5.3.4)
If there is insufficient evidence to answer the key question go to section 9.
Comment here on any issues concerning the quantity of evidence available on Evidence level
this topic and its methodological quality. Please include citations and evidence
levels.

2. Are the studies consistent in their conclusions? (see SIGN 50, section 5.3.2)
Comment here on the degree of consistency demonstrated by the evidence. Where there are
conflicting results, indicate how the group formed a judgement as to the overall direction of the
evidence.

3. Are the studies relevant to our target population? (see SIGN 50, section 5.3.3)
For example, do the studies:
 include similar target populations, interventions, comparators or outcomes to the key
question under consideration?
 report on any comorbidities relevant to the target population?
 use indirect (surrogate) outcomes
 use indirect rather than direct comparison of outcomes

4. Are there concerns about publication bias? (see SIGN 50, section 5.3.5)
Comment here on concerns about all studies coming from the same research group, funded by
industry etc

B: Evidence to recommendations
5. Balancing benefits and harms (see SIGN 50, section 6.2.2, 6.2.3)
Comment here on the potential clinical impact of the intervention/action – eg magnitude of effect;
balance of risk and benefit.
What benefit will the proposed intervention/action have?
Describe the benefits. Highlight specific outcomes if appropriate.

What harm might the proposed intervention/action do?

Describe the benefits. Highlight specific outcomes if appropriate.