Over the last 20 years, rates of cannabis use among pregnant people have increased significantly, making cannabis the most commonly used illegal substance in the antenatal period. THC, the active ingredient in cannabis, crosses the placental barrier and binds to endocannabinoid receptors on fetal organs. However, because definitive data on the risks of prenatal cannabis use remain limited, many clinicians do not counsel patients on this topic. This study provides an updated assessment of the association between prenatal cannabis use and pregnancy, fetal, and neonatal outcomes, adjusting for tobacco use and other confounders. The authors updated their previous systematic review and meta-analysis to include cohort or case-control studies published between November 2021 and April 2024 in MEDLINE, CINAHI, PsycInfo, Global Health, and the Cochrane Database of Systematic Reviews. Studies were included if they compared cannabis use versus no or less use during pregnancy and adjusted for confounders. Two independent researchers assessed each study for eligibility, risk of bias, and certainty-of-evidence ratings. Primary outcomes were preterm birth (PTB), small for gestational age (SGA), low birth weight (LBW), and perinatal morbidity. The results were analyzed to determine effect sizes and adjusted odds ratios, incorporating frequency of cannabis use when possible. Fifty-one publications were included, 8 of which were new additions since the prior analysis, yielding a total sample of 21,146,938 patients. Among the 20 studies evaluating LBW (N=1,763,753), cannabis use was associated with higher odds of LBW (OR, 1.75; 95% CI, 1.41-2.18). In 5 studies reporting dosage, heavy users had an even greater risk (OR, 2.36; 95% CI, 1.50-3.7). Twenty studies evaluated PTB (N=20,938,125), showing increased risk among cannabis users (OR, 1.52; 95% CI, 1.26-1.83), with a stronger association among heavy users (OR, 1.95; 95% CI, 1.40-2.73). Six studies assessed perinatal mortality (N=16,868,920), finding elevated odds among users (OR, 1.29; 95% CI, 1.07-1.55), though this association was not significant in analyses restricted to heavy use, leading to a low certainty-of-evidence rating. Four studies evaluated SGA (N=4,520,474) and reported increased odds among cannabis users (OR, 1.57; 95% CI, 1.36-1.81), with similar findings in heavy-use analyses (OR, 1.63; 95% CI, 1.35-1.96). Overall, the findings suggest with moderate certainty that prenatal cannabis use increases the risk of LBW, PTB, and SGA, and with low certainty that it increases perinatal mortality. The addition of recent studies expanded the sample size and supported a dose-dependent association, strengthening confidence in the results. The strengths of the review include its clinically relevant outcomes, strict exclusion criteria, and adjustment for key confounders such as tobacco. The limitations included heterogeneity between studies and gaps in collected data.

Background:Opioids are prescribed for the management of chronic non-cancer pain, but they have important limitations and evidence does not support long-term use. People taking opioids therefore need support to reduce or stop use. Objectives:The research aimed to inform better practice, pathways and service design to support people to reduce or stop their use of opioids and address inequalities. Our objectives were to evaluate evidence on: effectiveness, safety (including adverse effects, adverse event) and acceptability of interventions to reduce opioid use barriers and facilitators to effective intervention inequalities in access to, acceptability of and benefiting from interventions. Methods:We undertook four systematic reviews of published evidence on effectiveness; safety and acceptability; barriers and facilitators and inequalities. Searches included databases [MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, PsycInfo® (American Psychological Association, Washington, DC, USA)], trial registries (EU-CTR, International Standard Randomised Controlled Trial Number, Australian New Zealand Clinical Trials Register, ClinicalTrials.gov), websites (National Institute for Health and Care Research - be part of research, National Institute for Health and Care Excellence Evidence Search, Health Management Information Consortium, British Pain Society Members area) and repositories (Google Scholar, CORE.ac.uk) up to September 2022. Records were independently assessed for inclusion using prespecified criteria: (1) adults with chronic non-cancer pain, with (2) prescription opioid use of at least 3 months experiencing an (3) intervention aiming reduce or discontinue the use of opioids. Cochrane Risk-of-Bias tool for randomised controlled trials and the appropriate Critical Appraisal Skills Programme tool were used for cohort, case-control and qualitative studies. For the reviews of effectiveness and safety, data were synthesised and presented using tables and narrative synthesis. Meta-analysis was not appropriate. The barriers and facilitators review used thematic synthesis. Results:A total of 44 studies (reported across 52 papers) were included in at least 1 of the reviews: 27 studies were included in the effectiveness, 7 in safety and 16 in the barriers and facilitators reviews. All but two studies provided evidence for the inequalities review. The characteristics of the included studies were heterogeneous with different intervention approaches examined. Fifteen studies reported effects on pain. There was no difference in pain severity between intervention and control groups across seven of eight comparative studies. All but two studies reported change in opioid use. The proportion of patients who ceased opioid use varied across studies and some studies reported evidence of later relapse. Other outcomes, including anxiety and depression and sleep quality, were examined across the included studies but there was no clear pattern of effect. No adverse event studies reported serious adverse event and no participants reportedly withdrew due to adverse event. Few studies examined intervention acceptability. Barriers and facilitators:Eight barriers and eight facilitators were identified. They highlight the complex nature of the tapering process with the potential for multiple interdependent, behavioural, structural and contextual barriers to arise. Inequalities:Most studies reported on PROGnosis RESearch Strategy partnership-Plus categories, but few considered impact. Our findings suggest males and older patients experience poorer tapering outcomes. Conclusions:Evidence to support any specific opioid tapered reduction intervention is mixed and uncertain. Our findings reinforce that service design and delivery require careful consideration of individual-level factors and highlight the potential to widen inequalities. Stakeholders consulted on the evidence suggest valuing relationships, addressing fear and stigma and upskilling in behaviour change techniques are key. Study registration:This study is registered as PROSPERO CRD42020171135. Funding:This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: NIHR128842) and is published in full in Health Technology Assessment; Vol. 30, No. 27. See the NIHR Funding and Awards website for further award information.

Description: The American College of Physicians' Population Health and Medical Science Committee (PHMSC) developed this best practice advice to inform clinicians about what is currently known about the benefits and harms of cannabis or cannabinoids in the management of chronic noncancer pain and to provide advice for clinicians counseling patients seeking this therapy. Methods: The PHMSC considers areas where evidence is uncertain or emerging or practice does not follow the evidence to provide clinical advice based on a review and assessment of scientific work, including systematic reviews and individual studies. Sources of evidence included a living systematic review on cannabis and cannabinoid treatments for chronic noncancer pain and a series of living systematic reviews and primary studies. Best Practice Advice 1a: Clinicians should counsel patients about the benefits and harms of cannabis or cannabinoids when patients are considering whether to start or continue to use cannabis or cannabinoids to manage their chronic noncancer pain. Best Practice Advice 1b: Clinicians should counsel the following subgroups of patients that the harms of cannabis or cannabinoid use for chronic noncancer pain are likely to outweigh the benefits: young adult and adolescent patients, patients with current or past substance use disorder, patients with serious mental illness, and frail patients and those at risk for falling. Best Practice Advice 2: Clinicians should advise against starting or continuing to use cannabis or cannabinoids to manage chronic noncancer pain in patients who are pregnant or breastfeeding or actively trying to conceive. Best Practice Advice 3: Clinicians should advise patients against the use of inhaled cannabis to manage chronic noncancer pain.

Prenatal cannabis use continues to increase, and cannabis remains the most commonly used illegal substance in pregnancy. Accumulating evidence suggests potential adverse effects on fetal and neonatal outcomes following cannabis use in pregnancy. To update a living systematic review and meta-analysis to provide a timely understanding regarding cannabis use in pregnancy and fetal and neonatal outcomes. The previous review was updated by searching bibliographic databases MEDLINE, CINAHL, PsycInfo, Global Health, and Evidence-Based Medicine Reviews Cochrane Database of Systematic Reviews from November 1, 2021, through April 4, 2024. Cohort or case-control studies comparing pregnancies with and without prenatal cannabis use on prespecified fetal or neonatal outcomes with adjustment for confounders, such as co-use of tobacco products, were included. Two independent reviewers screened studies, with disagreements resolved through discussion. Included studies were extracted by 1 reviewer and confirmed by a second. Risk of bias was assessed with the Newcastle-Ottawa Scale. Random-effects meta-analyses of unadjusted and adjusted odds ratios (ORs) were performed for all primary outcomes. Results were synthesized using the Grading of Recommendations Assessment, Development, and Evaluation approach. Primary outcomes were preterm birth (PTB; <37 weeks of gestation), small for gestational age (SGA), low birth weight (LBW; <2500 g), and perinatal mortality. For this update, 8 new studies with 1 709 998 participants were added, for a total of 51 studies synthesized (N = 21 146 938). From meta-analyses of adjusted effect sizes, moderate-certainty evidence indicated that cannabis use in pregnancy was associated with increased odds of LBW (20 studies; OR, 1.75; 95% CI, 1.41-2.18), PTB (20 studies; OR, 1.52; 95% CI, 1.26-1.83), and SGA (12 studies; OR, 1.57; 95% CI, 1.36-1.81), and low-certainty evidence indicated that it was associated with greater odds of perinatal mortality (6 studies; OR, 1.29; 95% CI, 1.07-1.55). Previously, the evidence was rated as very low or low certainty. Cannabis use in pregnancy was associated with greater odds of PTB, SGA, and LBW even after adjusting for co-use of tobacco products, and confidence in these findings increased from low in the prior review to moderate in the current meta-analysis. The findings of this study may help inform patient counseling and future public health policies.

Importance Prenatal cannabis use continues to increase, and cannabis remains the most commonly used illegal substance in pregnancy. Accumulating evidence suggests potential adverse effects on fetal and neonatal outcomes following cannabis use in pregnancy. Objective To update a living systematic review and meta-analysis to provide a timely understanding regarding cannabis use in pregnancy and fetal and neonatal outcomes. Data Sources The previous review was updated by searching bibliographic databases MEDLINE, CINAHL, PsycInfo, Global Health, and Evidence-Based Medicine Reviews Cochrane Database of Systematic Reviews from November 1, 2021, through April 4, 2024. Study Selection Cohort or case-control studies comparing pregnancies with and without prenatal cannabis use on prespecified fetal or neonatal outcomes with adjustment for confounders, such as co-use of tobacco products, were included. Two independent reviewers screened studies, with disagreements resolved through discussion. Data Extraction and Synthesis Included studies were extracted by 1 reviewer and confirmed by a second. Risk of bias was assessed with the Newcastle-Ottawa Scale. Random-effects meta-analyses of unadjusted and adjusted odds ratios (ORs) were performed for all primary outcomes. Results were synthesized using the Grading of Recommendations Assessment, Development, and Evaluation approach. Main Outcomes and Measures Primary outcomes were preterm birth (PTB; <37 weeks of gestation), small for gestational age (SGA), low birth weight (LBW; <2500 g), and perinatal mortality. Results For this update, 8 new studies with 1 709 998 participants were added, for a total of 51 studies synthesized (N = 21 146 938). From meta-analyses of adjusted effect sizes, moderate-certainty evidence indicated that cannabis use in pregnancy was associated with increased odds of LBW (20 studies; OR, 1.75; 95% CI, 1.41-2.18), PTB (20 studies; OR, 1.52; 95% CI, 1.26-1.83), and SGA (12 studies; OR, 1.57; 95% CI, 1.36-1.81), and low-certainty evidence indicated that it was associated with greater odds of perinatal mortality (6 studies; OR, 1.29; 95% CI, 1.07-1.55). Previously, the evidence was rated as very low or low certainty. Conclusions and Relevance Cannabis use in pregnancy was associated with greater odds of PTB, SGA, and LBW even after adjusting for co-use of tobacco products, and confidence in these findings increased from low in the prior review to moderate in the current meta-analysis. The findings of this study may help inform patient counseling and future public health policies.

To cite: Wieringa S, McGuire H, Wang Q, et al. BMJ EvidenceBased Medicine Epub ahead of print: [please include Day Month Year]. doi:10.1136/ bmjebm-2023-112352 © Author(s) (or their employer(s)) 2023. Reuse permitted under CC BYNC. No commercial reuse. See rights and permissions. Published by BMJ. Introduction Over time, an international consensus on ‘best practice’ for developing a range of guidelines has been reached in many areas. However, there are always new challenges for guideline developers. Sustainability is one of those increasingly important challenges as it is for healthcare professionals, government policymakers, organisational leaders, patients and citizens. Sustainability may nowadays seem to many as meaning a concern for planetary health in view of climate change only. However, historically and conceptually environmental sustainability (living within the planets boundaries) forms a trinity with social equity and economic sustainability, as those with less resources are often most at risk of the consequences of poor planetary health. This broader understanding of sustainability has been adopted most notably in the 17 United Nations Sustainable Developments Goals that include wellbeing, climate action, clean energy, decent work, sustainable growth and reduced inequalities. Through this and other frameworks, healthcare institutions and professional bodies everywhere have committed themselves to provide and train for sustainable healthcare. Initiatives have begun to bloom to include sustainability in guideline development too, but much still has to happen. Sustainability is, for instance, considered in many evidence to decision (EtD) frameworks such as GRADE, but only in the sense of equity and feasibility, not environmental sustainability. In this article, inspired by an international workshop ‘Sustainable Healthcare Guidance’ at the Guidelines International Network meeting, held in Toronto, Canada in September 2022, we argue that three important shifts in guideline development are required.

Objective: To determine whether prenatal cannabis use alone increases the likelihood of fetal and neonatal morbidity and mortality. Study Design: We searched bibliographic databases, such as PubMed, Embase, Scopus, Cochrane reviews, PsycInfo, MEDLINE, Clinicaltrials.gov, and Google Scholar from inception through February 14, 2022. Cohort or case-control studies with prespecified fetal or neonatal outcomes in pregnancies with prenatal cannabis use. Primary outcomes were preterm birth (PTB; <37 weeks of gestation), small-for-gestational-age (SGA), birthweight (grams), and perinatal mortality. Two independent reviewers screened studies. Studies were extracted by one reviewer and confirmed by a second using a predefined template. Risk of bias assessment of studies, using the Newcastle-Ottawa Quality Assessment Scale, and Grading of Recommendations Assessment, Development, and Evaluation for evaluating the certainty of evidence for select outcomes were performed by two independent reviewers with disagreements resolved by a third. Random effects meta-analyses were conducted, using adjusted and unadjusted effect estimates, to compare groups according to prenatal exposure to cannabis use status. Results: Fifty-three studies were included. Except for birthweight, unadjusted and adjusted meta-analyses had similar results. We found very-low- to low-certainty evidence that cannabis use during pregnancy was significantly associated with greater odds of PTB (adjusted odds ratio [aOR], 1.42; 95% confidence interval [CI], 1.19 to 1.69; I2, 93%; p=0.0001), SGA (aOR, 1.76; 95% CI, 1.52 to 2.05; I2, 86%; p<0.0001), and perinatal mortality (aOR, 1.5; 95% CI, 1.39 to 1.62; I2, 0%; p<0.0001), but not significantly different for birthweight (mean difference, -40.69 g; 95% CI, -124.22 to 42.83; I2, 85%; p=0.29). Because of substantial heterogeneity, we also conducted a narrative synthesis and found comparable results to meta-analyses. Conclusion: Prenatal cannabis use was associated with greater odds of PTB, SGA, and perinatal mortality even after accounting for prenatal tobacco use. However, our confidence in these findings is limited. Limitations of most existing studies was the failure to not include timing or quantity of cannabis use. This review can help guide health care providers with counseling, management, and addressing the limited existing safety data. Protocol Registration: PROSPERO CRD42020172343.

IntroductionThe Washington Health Technology Assessment (HTA) program has been guiding coverage decisions in the state since 2007. The Center for Evidence-based Policy works with the program to develop evidence-based HTA reports. In 2020, we presented an HTA on cell-free DNA prenatal screening for chromosomal aneuploidies. In the committee’s discussion, questions around access to screening tests and to prenatal care more generally were raised. We present a case study of how health equities were considered in the development of coverage criteria.MethodsWe conducted an HTA using standard systematic review methodologies. Outcomes focused on test accuracy and the impact of screening. We did not look for evidence on access to prenatal screening tests or people’s experience of prenatal screening. We reviewed the meeting transcript to identify issues of health equity and how they influenced the final decision.ResultsDuring the discussion of the evidence, the committee raised concerns around equitable access to cell-free DNA tests and prenatal screening, including: direct costs to the person; access to the full range of prenatal screening, including ultrasound; and, uptake of prenatal screening. Based on the findings from the evidence report, expert testimony, and public comment, the committee voted to cover cell-free DNA prenatal screening for chromosomal aneuploidies unconditionally.ConclusionsHealth equity is increasingly important in healthcare decision-making. Decision makers should consider how a decision may reduce health inequities and how it may inadvertently increase existing health inequities. Decision makers also need to understand the context within which the decision will be implemented. Consideration of health equity can be addressed in a number of ways, for example through systematic review of equity issues or patient experience or through the use of contextual knowledge from expert and public testimony. Regardless of the method, decision makers should remain transparent in how health equity considerations influenced their final determination.

Background At the start of the COVID-19 pandemic, guidance was needed more than ever to direct frontline healthcare and national containment strategies. Rigorous guidance based on robust research was compromised by the emergence of the pandemic and the urgency of need for guidance. Rather than aiming to "get guidance right", guidance developers needed to "get guidance right now". Aim To examine how guidance developers have responded to the need for credible guidance at the start of the COVID-19 pandemic. Methods An exploratory mixed-methods study was conducted among guidance developers. A web-based survey and follow-up interviews were used to examine the most pertinent challenges in developing COVID-19 guidance, strategies used to address these, and perspectives on the implications of the COVID-19 pandemic on future guidance development. Results The survey was completed by 46 guidance developers. Survey findings showed that conventional methods of guidance development were largely unsuited for COVID-19 guidance, with 80% (n = 37) of respondents resorting to other methods. From the survey and five follow-up interviews, two themes were identified to bolster the credibility of guidance in a setting of extreme uncertainty: (1) strengthening end-user involvement and (2) conjoining evidence review and recommendation formulation. 70% (n = 32) of survey respondents foresaw possible changes in future guidance production, most notably shortening development time, by reconsidering how to balance between rigour and speed for different types of questions. Conclusion "Getting guidance right" and "getting guidance right now" are not opposites, rather uncertainties are always part of guidance development and require guidance developers to balance scientific robustness with usability, acceptability, adequacy and contingency. This crisis points to the need to acknowledge uncertainties of scientific evidence more explicitly and points to mechanisms to live with such uncertainty, thus extending guidance development methods and processes more widely.

To determine whether maternal cannabis use in pregnancy increases the odds of perinatal morbidity and mortality. We conducted a systematic literature search of databases from inception to January, 2021 to identify studies involving perinatal outcomes of offspring prenatally exposed to cannabis through maternal use. We included cohort or case-control studies that met eligibility criteria. Selection and quality rating were conducted by 2 independent reviewers. Data abstraction was confirmed by a second reviewer. Primary outcomes were preterm birth (PTB; < 37 weeks of gestation), birth weight, small-for-gestational-age (SGA; weight < 10th percentile) and perinatal death. We conducted a meta-analysis for the primary outcomes, using unadjusted and adjusted data, where available. Fifty studies (in 72 publications) were included. From unadjusted data, we found that maternal cannabis use in pregnancy was significantly associated with greater odds of PTB (odds ratio [OR] 1.64; 95% confidence interval [CI], 1.43-1.89), low birth weight (mean difference, -135.86 g; 95% CI, -191.93 -79.78g), SGA (OR, 1.92; 95% CI, 1.55-2.38), and perinatal death (OR, 1.85; 95% CI, 1.47-2.32). From estimates adjusted for multiple factors including tobacco use, we found that maternal cannabis use in pregnancy remained significantly associated with greater odds of PTB (OR 1.33; 95% confidence interval [CI], 1.11-1.58) and SGA (OR, 1.71; 95% CI, 1.49-1.98), but was no longer significantly associated with low birth weight (mean difference, -40.69 g; 95% CI, -124.22-42.83). A summary estimate for perinatal death was not calculated due to insufficient data. Our findings suggest that maternal cannabis use in pregnancy is associated with greater odds of PTB and SGA. However, the data were significantly heterogeneous with wide prediction intervals suggestive of uncertainty in associations and their clinical relevance.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

BACKGROUND AND OBJECTIVE:This article explores the need for conceptual advances and practical guidance in the application of the GRADE approach within public health contexts. METHODS:We convened an expert workshop and conducted a scoping review to identify challenges experienced by GRADE users in public health contexts. We developed this concept article through thematic analysis and an iterative process of consultation and discussion conducted with members electronically and at three GRADE Working Group meetings. RESULTS:Five priority issues can pose challenges for public health guideline developers and systematic reviewers when applying GRADE: (1) incorporating the perspectives of diverse stakeholders; (2) selecting and prioritizing health and "nonhealth" outcomes; (3) interpreting outcomes and identifying a threshold for decision-making; (4) assessing certainty of evidence from diverse sources, including nonrandomized studies; and (5) addressing implications for decision makers, including concerns about conditional recommendations. We illustrate these challenges with examples from public health guidelines and systematic reviews, identifying gaps where conceptual advances may facilitate the consistent application or further development of the methodology and provide solutions. CONCLUSION:The GRADE Public Health Group will respond to these challenges with solutions that are coherent with existing guidance and can be consistently implemented across public health decision-making contexts.

Background: Managing polypharmacy is a challenge for healthcare systems globally. It is also a health inequality concern as it can expose some of the most vulnerable in society to unnecessary medications and adverse drug-related events. Care for most patients with multimorbidity and polypharmacy occurs in primary care. Safe deprescribing interventions can reduce exposure to inappropriate polypharmacy. However, these are not fully accepted or routinely implemented. Aim: To identify barriers and facilitators to safe deprescribing interventions for adults with multimorbidity and polypharmacy in primary care. Design & setting: A systematic review of studies published from 2000, examining safe deprescribing interventions for adults with multimorbidity and polypharmacy. Method: A search of electronic databases: MEDLINE, Embase, Cumulative Index of Nursing and Allied Health Literature (CINHAL), Cochrane, and Health Management Information Consortium (HMIC) from inception to 26 Feb 2019, using an agreed search strategy. This was supplemented by handsearching of relevant journals, and screening of reference lists and citations of included studies. Results: In total, 40 studies from 14 countries were identified. Cultural and organisational barriers included: a culture of diagnosing and prescribing; evidence-based guidance focused on single diseases; a lack of evidence-based guidance for the care of older people with multimorbidities; and a lack of shared communication, decision-making systems, tools, and resources. Interpersonal and individual-level barriers included: professional etiquette; fragmented care; prescribers’ and patients’ uncertainties; and gaps in tailored support. Facilitators included: prudent prescribing; greater availability and acceptability of non-pharmacological alternatives; resources; improved communication, collaboration, knowledge, and understanding; patient-centred care; and shared decision-making. Conclusion: A whole systems, patient-centred approach to safe deprescribing interventions is required, involving key decision-makers, healthcare professionals, patients, and carers.

In this chapter we put forward more theoretical proposals for gathering evidence of mechanisms. Specifically, the chapter covers the identification of a number of mechanism hypotheses, formulation of review questions for search, and then how to refine and present the resulting evidence. Key issues include increased precision concerning the nature of the hypothesis being examined, attention to differences between the study population (or populations) and the target population of the evidence assessors, and being alert for masking mechanisms, which are other mechanisms which may mask the action of the mechanism being assessed. An outline example concerning probiotics and dental caries is given. (Databases that may be helpful for some searches can be found online in Appendix A ).

Previous chapters in Part III develop accounts of how to gather and evaluate evidence of claims about mechanisms. This chapter explains how this evaluation can be combined with an evaluation of evidence for relevant correlations in order to produce an overall evaluation of a causal claim. The procedure is broken down to address efficacy, external validity, and then the overall presentation of the claim.

In this chapter, we discuss how to evaluate evidence of mechanisms. This begins with an account of how a mechanistic study provides evidence for features of specific mechanism hypotheses, laying out a three step procedure of evaluating: (1) the methods used, (2) the implementation of the methods, and (3), the stability of the results. The next step is to combine those evaluations to present the quality of evidence of the general mechanistic claim.

Evidence-based guidelines whether national, regional or developed by specialty groups, must search for, and explicitly consider, evidence from sources other than conventional clinical trials and their quantitative data. This need for appraising and including knowledge from a wide variety of sources in guideline development is well recognised.1–3 Although evidence on statistical association—usually from randomised controlled trials (RCTs)—is commonly thought to be the dominant type of knowledge appraised and included, guideline developers frequently use a range of other types of knowledge including the views and experiences of those using and providing health services, understanding of how interventions work (eg, from logic models or realist evaluations), and other information, such as aetiology and the context of care (online supplementary text box 1). ### Supplementary file 1 [SP1.pdf] These different types of knowledge are used and needed in many situations, for example, when evidence from RCTs is not available, impossible to obtain, contradictory or inappropriate. They can also be used in conjunction with knowledge from RCTs to provide context, to assess relevance and to understand bias. Furthermore, explicit (written or spoken) knowledge and the more intricate forms of knowledge like experiential and contextual knowledge can help guideline makers to take an approach consistent with the intentions of early evidence-based medicine (EBM) proponents: namely, that best evidence is not restricted to evidence from RCTs and meta-analyses alone.4 However, how to properly appraise (judge) and include (integrate) different kinds of knowledge remains unclear. Agreed methods are not yet available or are in the early stages of development and the need for and use of different kinds of knowledge is not always explicitly acknowledged, which affects the use of guidelines in practice.5 6 International and cultural differences in guideline production practices may further impede developments in appraising and including a broader range of types of knowledge (online supplementary …

This chapter introduces how to assess evidence of mechanisms, explaining a summary protocol for use of evidence of mechanisms in assessing efficacy, then external validity (developed theoretically in Part III, with tools for implementation offered in Part II). An outline of quality assessment—of a whole body of evidence, rather than individual studies—is given. The chapter finishes with a brief introduction to the ideas developed in Part III: gathering evidence of mechanisms (Chap. 5 ); evaluating evidence of mechanisms (Chap. 6 ); and using evidence of mechanisms to evaluate causal claims (Chap. 7 ).

An important problem in causal inference in medicine involves establishing causal relationships between environmental exposures and negative health outcomes. It is typically not possible to use RCTs to solve this problem, for ethical reasons. The approach outlined in this book is compared to two other prominent approaches: the procedures of the International Agency for Research on Cancer (IARC), and SYRINA, a framework for detecting exposures that affect the endocrine system.

The book offers explicit methods to evaluate the evidence of mechanisms in medicine and develops procedures for searching for evidence of mechanisms, for evaluating evidence of mechanisms, and for combining this evaluation with evidence of association to yield an overall evaluation of effectiveness

This chapter offers a brief summary of mechanisms, as including complex-system mechanisms (a complex arrangement of entities and activities, organised in such a way as to be regularly or predictably responsible for the phenomenon to be explained) and mechanistic processes (a spatio-temporal pathway along which certain features are propagated from the starting point to the end point). The chapter emphasises that EBM+ is concerned with evidence of mechanisms, not mere just-so stories, and summarises some key roles assessing evidence of mechanisms can play, particularly with respect to assessing efficacy and external validity.