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National Collaborating Centre for Women's and Children's Health (UK). Multiple Pregnancy: The Management of Twin and Triplet Pregnancies in the Antenatal Period. London: RCOG Press; 2011 Sep. (NICE Clinical Guidelines, No. 129.)

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Multiple Pregnancy: The Management of Twin and Triplet Pregnancies in the Antenatal Period.

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3Guideline development methodology

3.1. Introduction

This guideline was commissioned by NICE and developed in accordance with the process outlined in ‘The guidelines manual’ (see http://www.nice.org.uk/guidelinesmanual). Table 3.1 summarises the key stages of the process.

Table 3.1. Stages in the NICE guideline development process and edition of ‘The guidelines manual’ followed at each stage.

Table 3.1

Stages in the NICE guideline development process and edition of ‘The guidelines manual’ followed at each stage.

Information about the clinical areas covered by the guideline (and those that are excluded) is available in the scope of the guideline (reproduced in Appendix A). The guideline development group (GDG) was guided by NICE not to consider screening for gestational diabetes because ‘Diabetes in pregnancy’ (NICE clinical guideline 63)21 had included a question on ‘which women were at risk of gestational diabetes’ and had not identified multiple pregnancy as a risk factor for gestational diabetes. The GDG recommended to NICE that the review of ‘Diabetes in pregnancy’ (started in March 2011) include specific consideration of multiple pregnancy as a risk factor for gestational diabetes.

All GDG members’ potential and actual conflicts of interest were recorded on declaration forms provided by NICE (summarised in Appendix B). None of the interests declared by GDG members constituted a material conflict of interest that would influence recommendations developed by the GDG.

Organisations with interests in the management of twin and triplet pregnancies in the antenatal period were encouraged to register as stakeholders for the guideline. Registered stakeholders were consulted throughout the guideline development process. A list of registered stakeholder organisations for the guideline is presented in Appendix C.

In accordance with NICE’s Equality Scheme, ethnic and cultural considerations and factors relating to disabilities have been considered by the GDG throughout the development process and specifically addressed in individual recommendations where relevant. Further information is available from: www.nice.org.uk/aboutnice/howwework/NICEEqualityScheme.jsp.

3.2. Developing review questions and protocols and identifying evidence

The GDG formulated review questions based on the scope (see Appendix D) and prepared a protocol for each review question (see Appendix E). These formed the starting point for systematic reviews of relevant evidence. Published evidence was identified by applying systematic search strategies (see Appendix F) to the following databases: Medline (1950 onwards), Embase (1980 onwards), Cumulative Index to Nursing and Allied Health Literature (CINAHL; 1982 onwards) and three Cochrane databases (Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews and the Database of Abstracts of Reviews of Effects). Searches to identify economic studies were undertaken using the above databases, the NHS Economic Evaluation Database (NHS EED) and the Health Technology Assessment (HTA) database. None of the searches was limited by date or language of publication (although publications in languages other than English were not reviewed). Generic and specially developed search filters were used to identify particular study designs, such as randomised controlled trials (RCTs). There was no systematic attempt to search grey literature (conference abstracts, theses or unpublished trials), nor was hand searching of journals not indexed on the databases undertaken.

Towards the end of the guideline development process, the searches were updated and re-executed to include evidence published and indexed in the databases by 1 November 2010.

3.3. Reviewing and synthesising evidence

Evidence relating to clinical effectiveness was reviewed and synthesised according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach (see http://www.gradeworkinggroup.org/index.htm). In the GRADE approach, the quality of the evidence identified for each outcome listed in the review protocol is assessed according to the factors listed below, and an overall quality rating (high, moderate, low or very low) is assigned by combining the ratings for the individual factors.

  • Study design (as an indicator of intrinsic bias; this determines the initial quality rating)
  • Limitations in the design or execution of the study (including concealment of allocation, blinding, loss to follow up; these can reduce the quality rating)
  • Inconsistency of effects across studies (this can reduce the quality rating)
  • Indirectness (the extent to which the available evidence fails to address the specific review question; this can reduce the quality rating)
  • Imprecision (this relates to statistical or clinical significance of reported effects; uncertainty in effects can reduce the quality rating)
  • Other considerations (including large magnitude of effect, evidence of a dose-response relationship, or confounding variables likely to have reduced the magnitude of an effect; these can increase the quality rating in observational studies, provided no downgrading for other features has occurred).

The type of review question determines the highest level of evidence that may be sought. For issues of therapy or treatment, the highest possible evidence level is a well-conducted systematic review or meta-analysis of RCTs, or an individual RCT. In the GRADE approach, a body of evidence based entirely on such studies has an initial quality rating of high, and this may be downgraded to moderate, low or very low if factors listed above are not addressed adequately. For issues of prognosis, the highest possible level of evidence is a controlled observational study (a cohort study or case–control study), and a body of evidence based on such studies would have an initial quality rating of low, which might be downgraded to very low or upgraded to moderate or high, depending on the factors listed above.

For each review question the highest available level of evidence was sought. Where appropriate, for example, if a systematic review, meta-analysis or RCT was identified to answer a question directly, studies of a weaker design were not considered. Where systematic reviews, meta-analyses and RCTs were not identified, other appropriate experimental or observational studies were sought. For diagnostic tests, test evaluation studies examining the performance of the test were used if the accuracy of the test was required, but where an evaluation of the effectiveness of the test in the clinical management of the condition was required, evidence from RCTs or cohort studies was optimal. For studies evaluating the accuracy of a diagnostic test, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and likelihood ratios for positive and negative test results (LR+ and LR, respectively), were calculated or quoted where possible (see Table 3.2). If LR+ is between 5 and 10 it is classified as ‘strong’; if LR+ is more than 10 it is classified as ‘convincing’. If LR is between 0.1 and 0.2 it is classified as ‘strong’; if LR is less than 0.1 it is classified as ‘convincing’.26

Table 3.2. ‘2 × 2’ table for calculation of diagnostic accuracy parameters.

Table 3.2

‘2 × 2’ table for calculation of diagnostic accuracy parameters.

The GRADE system described above covers studies of treatment effectiveness. It is also being used increasingly for studies reporting diagnostic test accuracy measures, which is relevant to several of the review questions in this guideline. For such studies, NICE recommends using the Quality Assessment of Studies of Diagnostic Accuracy (QADAS) methodology checklist to assess the quality of individual studies (see the NICE guidelines manual). A body of evidence based on prospective cohort studies would have an initial quality rating of high, whereas a body of evidence based on retrospective cohort studies or case–control studies would have an initial quality rating of moderate.

Some studies were excluded from the guideline reviews after obtaining copies of the corresponding publications because they did not meet inclusion criteria specified by the GDG (see Appendix G). The characteristics of each included study were summarised in evidence tables for each review question (see Appendix H). Where possible, dichotomous outcomes were presented as relative risks (RRs) or odds ratios (ORs) with 95% confidence intervals (CIs), and continuous outcomes were presented as mean differences (MDs) with 95% CIs or standard deviations (SDs). Absolute effects for dichotomous outcomes were calculated as the estimated relative effect (RR or OR) multiplied by an estimate of baseline risk (for a single study the baseline risk is the risk in the control group): absolute effects for continuous outcomes were estimated directly as the difference between outcomes in the different treatment groups.

The body of evidence identified for each review question (or part of a review question) was presented in the form of a GRADE findings table (evidence profile) summarising the quality of the evidence and the results (summary relative and absolute effect sizes and associated CIs). Where possible, the body of evidence corresponding to each outcome specified in the review protocol was subjected to quantitative meta-analysis. In such cases, summary effect sizes were presented as summary RRs, summary ORs or weighted mean differences (WMDs). Where summary RRs or summary ORs were estimated via meta-analysis the baseline risk was assumed to be the mean baseline risk in the studies included in the meta-analysis. By default, meta-analyses were conducted by fitting fixed effects models, but where unexplained heterogeneity was identified (I-squared statistic greater than 33%) random effects models were used. Where quantitative meta-analysis could not be undertaken (for example, because effect measures reported in the evidence were not accompanied by standard errors or data that would allow standard errors to be calculated), the range of effect sizes reported in the included studies was presented. Forest plots for all meta-analyses conducted for the guideline are presented in Appendix I. GRADE findings are presented in full in Appendix J and abbreviated versions (summary of findings without the individual components of the quality assessment) are presented in this document.

Various approaches may be used to assess imprecision in the GRADE framework. In this guideline, dichotomous outcomes in intervention studies were downgraded in terms of imprecision when the total number of events was less than 300 and continuous outcomes were downgraded when the total sample size was less than 400. These are default thresholds used in GRADE for intervention studies. For diagnostic test accuracy studies, evidence was downgraded in terms of imprecision when the width of the 95% CI for any of sensitivity, specificity, PPV or NPV was 40 percentage points or more, or if no CIs were reported. These thresholds or decision rules have been used in other NICE clinical guidelines (for example ‘Non-invasive ventilation for motor neurone disease’, NICE clinical guideline 105).27

3.4. Incorporating health economics

The aims of the health economic input to the guideline were to inform the GDG of potential economic issues relating to the management of twin and triplet pregnancies in the antenatal period, and to ensure that recommendations represented a cost-effective use of healthcare resources. Health economic evaluations aim to integrate data on benefits (ideally in terms of quality adjusted life years [QALYs]), harms and costs of different care options.

The GDG prioritised a number of review questions where it was thought that economic considerations would be particularly important in formulating recommendations. Systematic searches for published economic evidence were undertaken for these questions. For economic evaluations, no standard system of grading the quality of evidence exists and included papers were assessed using a quality assessment checklist based on good practice in economic evaluation.28 Reviews of the (very limited) relevant published health economic literature are presented alongside the clinical effectiveness reviews.

Health economic considerations were aided by original economic analysis undertaken as part of the development process. For this guideline the areas prioritised for economic analysis were cost effectiveness of:

3.5. Evidence to recommendations

For each review question recommendations for clinical care were derived using, and linked explicitly to, the evidence that supported them. In the first instance, informal consensus methods were used by the GDG to agree short clinical and, where appropriate, cost effectiveness evidence statements which were presented alongside the evidence profiles. Statements summarising the GDG’s interpretation of the evidence and any extrapolation from the evidence used to form recommendations were also prepared to ensure transparency in the decision-making process. The criteria used in moving from evidence to recommendations are summarised as:

  • Relative value placed on the outcomes considered
  • Trade-off between clinical benefits and harms
  • Quality of the evidence
  • Other considerations (including equalities issues)

In areas where no substantial clinical research evidence was identified, the GDG considered other evidence-based guidelines and consensus statements or used its members’ collective experience to identify good practice. The health economics justification in areas of the guideline where the use of NHS resources (interventions or tests) was considered was based on GDG consensus in relation to the likely cost effectiveness implications of the recommendations. The GDG also identified areas where evidence to answer review questions was lacking and used this information to formulate recommendations for future research.

Towards the end of the guideline development process formal consensus methods were used to consider all the clinical care recommendations and research recommendations that had been drafted previously. The GDG identified ten ‘key priorities for implementation’ (key recommendations) and six high-priority research recommendations. The key priorities for implementation were those recommendations thought likely to have the biggest impact on pregnancy care and outcomes in the NHS as a whole; they were selected using a variant of the nominal group technique (see the NICE guidelines manual). The priority research recommendations were selected in a similar way.

3.6. Stakeholder involvement

Registered stakeholder organisations were invited to comment on the draft scope and the draft guideline. Stakeholder organisations were also invited to undertake a prepublication check of the final guideline to identify factual inaccuracies. The GDG carefully considered and responded to all comments received from stakeholder organisations. The comments and responses, which were reviewed independently for NICE by a Guidelines Review Panel, are published on the NICE website.

3.7. Specific considerations for this guideline

For this guideline, the effectiveness of interventions was assessed against the following main outcomes:

  • maternal morbidity during pregnancy and after birth
  • maternal mortality during pregnancy and after birth
  • perinatal morbidity
  • perinatal mortality
  • in utero and postnatal transfer rates for specialist neonatal care
  • maternal satisfaction relating to the provision of antenatal care.

Where the evidence supported it, the GDG made separate recommendations for women with twin and triplet pregnancies, for women with monochorionic and dichorionic twin pregnancies, and for women with monoamniotic and diamniotic twin pregnancies.

Copyright © 2011, National Collaborating Centre for Women’s and Children’s Health.

No part of this publication may be reproduced, stored or transmitted in any form or by any means, without the prior written permission of the publisher or, in the case of reprographic reproduction, in accordance with the terms of licences issued by the Copyright Licensing Agency in the UK [www.cla.co.uk]. Enquiries concerning reproduction outside the terms stated here should be sent to the publisher at the UK address printed on this page.

The use of registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant laws and regulations and therefore for general use.

Bookshelf ID: NBK83099

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