Despite a considerable reduction in child mortality, nearly six million children under the age of five die each year. Millions more are poorly nourished and in many parts of the world, the quality of education remains poor. Children are at risk from multiple violations of their rights, including child labour, early marriage, and sexual exploitation. Research plays a crucial role in helping to close the remaining gaps in child well‐being, yet the global evidence base for interventions to meet these challenges is mostly weak, scattered and often unusable by policymakers and practitioners. This mega‐map encourages the generation and use of rigorous evidence on effective ways to improve child well‐being for policy and programming.The aim of this mega‐map is to identify, map and provide an overview of the existing evidence synthesis on the interventions aimed at improving child well‐being in low‐ and middle‐income countries (LMICs).Campbell evidence and gap maps (EGMs) are based on a review of existing mapping standards  which drew in particular of the approach developed by 3ie . As defined in the Campbell EGM guidance paper; “Mega‐map is a map of evidence synthesis, that is, systematic reviews, and does not include primary studies” . The mega‐map on child well‐being includes studies with participants aged 0–18 years, conducted in LMICs, and published from year 2000 onwards. The search followed strict inclusion criteria for interventions and outcomes in the domains of health, education, social work and welfare, social protection, environmental health, water supply and sanitation (WASH) and governance. Critical appraisal of included systematic reviews was conducted using “A Measurement Tool to Assess Systematic Reviews”‐AMSTAR‐2 rating scale .We identified 333 systematic reviews and 23 EGMs. The number of studies being published has increased year‐on‐year since 2000. However, the distribution of studies across World Bank regions, intervention and outcome categories are uneven. Most systematic reviews examine interventions pertaining to traditional areas of health and education. Systematic reviews in these traditional areas are also the most funded. There is limited evidence in social work and social protection. About 69% (231) of the reviews are assessed to be of low and medium quality. There are evidence gaps with respect to key vulnerable populations, including children with disabilities and those who belong to minority groups.Although an increasing number of systematic reviews addressing child well‐being topics are being published, some clear gaps in the evidence remain in terms of quality of reviews and some interventions and outcome areas. The clear gap is the small number of reviews focusing explicitly on either equity or programmes for disadvantaged groups and those who are discriminated against. There is now a mega‐map that encourages the generation and use of rigorous evidence on effective ways to improve child well‐being for policy and programming.1.1.1This child well‐being mega‐map shows evidence synthesis studies—systematic reviews and evidence and gap maps (EGMs)—that include studies on the effectiveness of interventions to improve child well‐being in LMICs published in English.What is the aim of this mega‐map?This child well‐being mega‐map provides a visual and interactive display of evidence synthesis studies—systematic reviews and evidence and gap maps—on the effectiveness of interventions to improve child well‐being in low‐ and middle‐income countries.The mega‐map provides a visual and interactive display of completed and on‐going studies structured around a framework: a matrix of interventions and outcomes primarily based on the strategic plan of the United Nations Children's Fund UNICEF, . This in1.1.2The mega‐map includes 356 studies that were published from 2000 to 2018, with interventions to improve child well‐being of those aged 18 years and under.Systematic reviews are included if the inclusion criteria in the reviews mentioned studies from LMICs irrespective of whether studies from LMICs were actually identified. Reviews with multiple populations are included in the map if they had an intervention for child well‐being.1.1.3This mega‐map includes 333 systematic reviews and 23 EGMs. Of the included studies, there is substantial evidence in traditional areas: health and nutrition (234) is the most commonly studied intervention, followed by early child development (194). Education (83) and social protection (62) are fairly well‐represented. However, there is limited evidence synthesis in nontraditional areas: social work and welfare (44), environmental health including WASH (41) and governance (13).The most commonly studied outcomes are health (259) and healthy development (215). Very few studies measured economic impact (42) and risk factor reduction (55) of these interventions.In terms of quality, 26% of the reviews were identified to be of low quality.The mega‐map reveals a lack of evidence on vulnerable children: children with disabilities and children in conflict‐affected settings.Systematic reviews were found to be almost equally concentrated across all regions with sub‐Saharan Africa (292) and South Asia (268) having the highest number of reviews. These were closely followed by Latin America and Caribbean (245), East Asia and Pacific (243) and Middle East and North Africa (234).1.1.4Whilst the evidence base is relatively large, it is unevenly distributed across intervention categories. There is a need for more studies which are explicitly focused on programmes for vulnerable children. There are limited systematic reviews focusing on gender and equity issues in child well‐being. Very few studies were identified assessing programme cost of the interventions.It would be useful for global and country partners to work together to achieve consensus on priority areas for evidence synthesis. They should also adopt a coordinated approach to undertaking and updating maps and reviews across priority areas.1.1.5The authors searched for studies published up to December 2018.22.1Well‐being can be defined as the realisation of children's rights and the fulfilment of the opportunity for every child to be all she or he can be in the light of a child's abilities, potential and skills. The degree to which this is achieved can be measured in terms of positive child outcomes, whereas negative outcomes and deprivation point to the neglect of children's rights  categories. This mega‐map provides an overview of all available evidence (systematic reviews and EGMs) till December 2018 on the key outcome domains and interventions aimed at improving child and adolescent well‐being in LMIC countries using an intervention‐outcome framework.2.4The mega‐map was developed in stages:Framework construction:The first step was to decide the scope of the mega‐map. Specifically, it involved identifying the primary dimensions of the map, that is, interventions and outcomes. We started developing the draft framework by reviewing UNICEF strategic plan documents UNICEF, . We alsoSearch Methodology:Step 1: Included a search of relevant systematic reviews and EGMs from the 3ie database. This initial map included 99 studies.Stage 2: A full database search was performed. The search was carried out on (a) Systematic Review databases, such as 3ie and Campbell Collaboration databases (full list is provided in the appendix) (b) Academic databases, such as OVID and Embase. This identified 302 relevant systematic reviews after the full database search.Stage 3: (a) Additional websites were searched for grey literature, including those of bilateral and multilateral organisations, such as ILO and UNDP; websites of J‐PAL and ANU‐Lib. (b) Experts consulted, and (c) screened and coded studies received from key informants. This phase identified additional 54 studies for inclusion.The search of the full academic databases and grey literature yielded 9,086 hits and 356 studies were included in the final map after screening and coding.2.5The primary population of interest for this map is children and adolescents from LMICs . Children irrespective of their sex in the age group of 18 years and under were included in the EGM. The age group is classified based on the age criteria stated as follows: infanthood (<3 years of age), childhood (3–10 years), adolescence (10–18 years). The population subgroup of interest includes: girls, orphans and vulnerable children, children with disabilities, children belonging to ethnic minorities, child sex workers, child brides, isolated children/street children, children with HIV/AIDS, migrants and children affected by conflict and humanitarian crises.Systematic reviews are often global in scope. Systematic reviews were included if the “inclusion criteria” in the reviews was to include studies from LMICs unrelated to the fact that weather studies from LMICs were actually identified through search or included from screening. The screening process for mega‐map did not check whether the reviews included studies from LMICs. Studies with multiple populations are included in the map if they included an intervention for child well‐being.2.6Title and abstract screening and the evidence classification were undertaken by two independent reviewers, and any discrepancies were resolved by a third reviewer. The studies that passed on to full text stage were screened against the eligibility criterias by two independent reviewers and conflicts resolved by a third reviewer.After screening, all studies were coded for a wide array of information and populated into the map. The studies were coded for bibliographic details, the interventions and outcomes and other relevant aspects such as population, region and countries. The coding was again carried out by two independent reviewers and conflicts were reconciled by a third reviewer. Critical appraisal appraisal of all included studies was performed by independent reviewers.2.7The mega‐map includes 333 systematic reviews and 23 EGMs. A main finding from the map is that there is a substantial amount of evidence in the traditional areas such as early childhood development, health and nutrition and education. However, there is uneven distribution of evidence across region, quality of studies and intervention and outcome subcategories.For example, though health and nutrition were the most populated areas of the map, some gaps were identified; management of severe acute malnutrition (8), agricultural intervention/biofortification (13), m‐health intervention for child health (16). In education, there is limited evidence around remedial education, nonformal education and scholarships and systemic intervention. In terms of quality, about 26% (58) of the systematic reviews were identified to be of low quality for health and nutrition. This was found to be similar for early childhood development (30%) and education (22%).Striking gaps in evidence were identified in the nontraditional areas such as social protection and social welfare, with lack of evidence in many areas such as child trafficking, substance abuse prevention, interventions for child abuse, social insurance and labour market insurance. These were not just under‐researched but also under‐funded. The most funded systematic review areas have been health and nutrition and early childhood development over the years. The major funders of such reviews have been the DFID, World Health Organisation (WHO), Bill and Melinda Gates Foundation, National Institute of Health Research (NIHR) and UNICEF.Health and learning outcomes were found to be the most studied as well. Few studies were identified assessing the impact of interventions on risk reduction, safety, equity, and economic outcomes.UNICEF Strategic Goal 1 (Every child survives and thrives) and Goal 2 (Every child learns) are heavily populated. Goal 3 (Every child is protected from violence and exploitation) and Goal 4 (Every child lives in a clean and safe environment) are less populated and there is scant evidence in Goal area 5 (Every child has an equitable chance in life).2.8Although an increasing number of systematic reviews addressing child well‐being topics are being published, there is a need for more studies across some interventions and outcome areas such as social protection and social welfare. The clear gap is the small number of reviews focusing explicitly on either equity or programmes for disadvantaged groups and those who are discriminated against. There is a need for more studies which are explicitly focused on programmes for vulnerable children. There are limited systematic reviews focusing on gender and equity issues in child well‐being. Very few studies were identified assessing programme cost of the interventions.It would be useful for global and country partners to work together to achieve consensus on priority areas for evidence synthesis and to adopt a coordinated approach to undertaking and updating maps and reviews across priority areas.33.13.1.1Child well‐being is a multidimensional and a holistic concept which provides a contextual understanding of a child in different domains such as health, material well‐being, education, conditions of housing and environment, and interpersonal relations . A decent level of child well‐being is underpinned by the UN convention of Rights of the Child which states that “The child, by reason of his physical and mental immaturity, needs special safeguards and care, including appropriate legal protection, before as well as after birth” . But many children around the world still suffer deficiencies in many dimensions of well‐being.3.1.2According to UNICEF's “State of the World's Children” report 2017), there are 2.2 billion people aged under the age of 18 and the majority of these are living in poverty. Evidence from many countries shows that children who grow up in poverty are more likely to experience poor health, fewer opportunities to access good quality education and to be low paid or unemployed in the future .In recognition of the 2030 Agenda for Sustainable Development, children's rights and well‐being are acknowledged as important for long‐term sustainable development of children. Many SDGs are important reference points for the design of national development strategies for child well‐being including: End poverty (SDG1), End hunger, achieve food security and improved nutrition and promote sustainable agriculture (SDG2), health (SDG3), quality education (SDG4), reduce inequality between and within countries (SDG10). Despite this apparent focus on child well‐being and various international organisations working towards a common goal, striking gaps remain in achieving SDG's.Research plays a crucial role in helping to close the remaining gaps in the global evidence base for effective interventions. SDG 17 targets 17.16 and 17.18 emphasise the increased need for investment in generating sound evidence to improve child well‐being intervention strategies. Though child well‐being interventions have been underway for decades; evidence on the effectiveness of these interventions is often scattered, the value is possibly underestimated and inclusion in national strategies and programmes is rare. Failure to effectively implement evidence‐informed interventions represents a key obstacle in the progress of child well‐being in many LMICs towards achieving the SDG's. This is partly due to a weak evidence base that does not give policy makers and programme managers the information needed to make decisions. Both international and national organisations should work together to fill the gaps in evidence and to gain a better understanding of what works and what does not in child well‐being.3.1.51.Early child development2.Health and nutrition3.Education4.Social work and welfare5.Social protection6.Environment health including Water, Sanitation and Hygiene (WASH)7.GovernanceThe included interventions cover all main strategies to improve child well‐being outcomes. The seven intervention categories are:Goal One: Every child survives and thrivesGoal Two: Every child learnsGoal Three: Every child is protected from violence and exploitationGoal Four: Every child lives in a safe and clean environmentGoal Five: Every child has an equitable chance in lifeTable 3.1.6Evidence‐based research and multicountry experiences make a strong rationale for investing in child well‐being programmes. As evidence‐informed policymaking is seen to be of increasing importance, many agencies commission systematic reviews to inform policy, but due to lack of a central global repository, systematic reviews are often duplicated. Furthermore, they sometimes lack in quality to clearly and correctly inform policy and the existing evidence base around child well‐being has major gaps. Evidence maps are an approach to providing an overview of the available evidence, with various approaches adopted to evidence mapping by different agencies over the years . Since this map has such a broad scope—all of child well‐being—we label it as a mega‐map and map only systematic reviews and EGMs.The mega‐map provides an overview of all available evidence syntheses on the key outcome domains and interventions aimed at improving child well‐being in LMICs using an intervention‐outcome framework. It helps to identify areas in which there are good bodies of synthesised knowledge to inform policy, and those areas in which there is little or no evidence synthesis. The map can help inform the identification of priority areas where evidence synthesis is currently lacking, such as rigorous studies of the effectiveness of early marriage interventions, child labour or the status of children in conflict‐affected situations. This will help create a central repository of all the available resources on the effectiveness of child well‐being.UNICEF's Office of Research‐Innocenti, in collaboration with the Campbell Collaboration has published a set of five research briefs based around UNICEF's five strategic goal areas and highlighting the main findings from the mega‐map as well as remaining evidence gaps. As a subsequent step, the two organisations are worked together on an EGM on ending violence against children in LMICs.3.1.71.EGM on social, behaviour and community engagement intervention produced by the WHO and the International Initiative of Impact Evaluation presents the evidence available on social, behavioural and community engagement interventions related to reproductive, maternal, newborn and child health programmes in LMICs WHO, .2.EGM on primary and secondary education by 3ie that presents evidence on interventions designed to improve access to education and learning outcomes for primary and secondary school children in LMICs .3.EGM on Intimate partner Violence highlights important gaps in the rigorous evidence base of intimate partner violence prevention programmes in LMICs  which drew in particular on the approach developed by 3ie  and outcome categories (and subcategories). Secondary dimensions, such as World Bank region, systematic review quality and population target groups were included as filters.5.21.A clearly stated set of objectives with predefined eligibility criteria for studies.2.An explicit, search methodology.3.A systematic search that attempts to identify all studies that would meet the eligibility criteria.4.An assessment of the validity of the findings of the included studies, for example, through an assessment of risk of bias.5.A systematic presentation, and synthesis, of the characteristics and findings of the included studies.The mega‐map includes only systematic reviews and EGMs of effects of interventions. The key characteristics for a review to be included as a “systematic review” are as follows:Relevant ongoing systematic reviews were also included but they were not assessed for quality. We did not include qualitative studies and the search was restricted to English language only.We also included EGMs and it was defined as an approach for systematic presentation of all relevant evidence of a specified kind for a particular sector, subsector or geography. They typically contain systematic reviews and primary studies, but may include only one of these. There are many approaches to evidence mapping  and includes children from LMICsDifferent child age ranges; infants (0–3 years), child (0–10 years), adolescent (10–18 years) were added as filters.Population subgroups of interest include: children in conflict‐affected regions, children with disabilities, children from underrepresented communities (low income and ethnicity) and malnourished children.5.4The framework‐matrix of interventions and outcomes was primarily based on UNICEF's Strategic Plan .1.Early child development2.Health and nutrition3.Education4.Social work and welfare5.Social protection6.Environment health including WASH7.GovernanceThe included interventions cover all main strategies to improve child well‐being outcomes. The seven main intervention categories are as mentioned below. The description for these categories is given in Annex 5.51.Health2.Healthy development3.Learning and development4.Risk factor reduction5.Safety6.Equity7.Economic ImpactThe categories cover seven broad outcomes as mentioned below:5.6Stage 1: included a search of relevant systematic reviews and EGMs from 3ie databases. This initially included 99 studies.Stage 2: this mapped the studies from a full search of databases and included 302 systematic reviewsStage 3: (a) searched additional websites for grey literature, (b) consulted experts, and (c) screened additional submissions received in response to dissemination of the stage 2 map. This led to inclusion of 356 studies.The mega‐map was developed in three stages:The search was as comprehensive as possible, using (but not limited to) relevant bibliographic databases and EGM databases, web‐based search engines, websites of specialist organisations and bibliographies of relevant reviews. Additionally, reference lists of the included reviews were reviewed.5.6.11.International Organisations–UNICEF–DFID (including Research for Development (R4D)–UNFPA Evaluation Database–WHO2.EGM database–3ie Evidence and Gap Map repository–Swedish Agency For Health Technology Assessment and Assessment of Social Services–Collaboration for Environmental Evidence–Global Evidence Mapping Initiative–Evidence based Synthesis Programme (Department of Veteran affairs)–Cochrane–Evidence based policing matrix–EPPI Centre Evaluation Database of Education Research3.Systematic review database–Cochrane–Campbell Collaboration–3ie Systematic Review Database–Research for Development4.Academic databases–World Bank eLibrary (Ebsco)–The National Bureau of Economic Research (NBER)–Social Science Research Network (SSRN)–International Bibliography of Social Sciences (IBSS)–Applied Social Sciences Index and Abstracts (ASSIA)–Embase–PsycINFO–MEDLINE–ERIC5.Grey Literature search/websites–World Health Organisation–World Bank–UNICEF–UNICEF Office of Research—Innocenti–UN Women–UNESCO–United Nations Population Fund–UN Economic and Social Council–CARE–Save the Children–African Development Bank–Young Lives–Association for the Development of Africa–Médians Sans Frontières–Action against Hunger–World for World Organization–Project Concern–One International–World Vision–Department for International Development–World Food Programme–Valid International–Concern Worldwide–Action Aid–Children's Investment Fund Foundation–International Red Cross–WHO ICTRP–Working Group on Early Childhood Development, Division for Social Policy & Development, Child Fund International–GreyNet International–Proquest Dissertations and Theses–Opengrey–Gates Foundation–Clinton Foundation–Abdul Latif Jameel Poverty Action Lab (J‐PAL)–Urban Youth Evidence Synthesis–Innovations for Poverty Action (IPA)–Child and Youth Finance InternationalA sample search is added as Annex 5.7➢Professor Anthony Costello, Director, Department of Maternal, Newborn, Child and Adolescent Health, World Health Organisation➢Dr. Ajay Khera, Deputy Commissioner In‐charge, Child and Adolescent Health, Ministry of Health and Family Welfare, India➢Dr. Julia St. Thomas, Deputy Director Strategic Initiatives, Violence Prevention and Response Unit, International Rescue Committee, UK.➢Dr. Laura Boone, Senior Technical Advisor for Child Protection International Rescue Committee, UK➢Mr. Laurence Chandy, Director of the Office of Global Insight and Policy, UNICEF➢Mr. Yehualashet Mekonen, Programme Manager, The African Child Observatory, African Child Policy ForumThe framework was developed through a consultative process. An advisory board was formed comprising of key experts in the area:In consultation with the expert group, intervention and outcome categories were agreed and used to set the scope of the mega‐map.66.1Developing the scope is one of the critical stages in an EGM. Specifically, we identified intervention and outcomes to map that formed the EGM framework.1.The initial framework‐matrix of interventions and outcomes was developed based on UNICEF's strategic plan .2.We then referred to strategic plan documents from other major funders and implementers on child well‐being programmes including UNESCO, WHO and the World Bank to identify any additional key intervention and outcomes of relevance.3.The proposed framework was revised based on feedback received by advisory board (mentioned above).4.We then pilot‐coded the framework using 30 key systematic reviews from the 3ie database and the framework revised further based on the exercise.5.A mapping workshop was organised in London where key stakeholders and experts in the area were invited to participate. They reviewed the categories in an interactive exercise to fit the identified papers into the suggested categories and the feedback was reviewed.Stages in framework development:1.Early childhood interventions that addressed the period from pregnancy, childbirth and children up to 3 years of age.2.Health and nutrition interventions that addressed issues such as maternal health, timing and spacing of birth, childbirth, nutrition, prevention and treatment of childhood diseases.3.Educational interventions that aimed to address improved learning and achievements and skills development of children from 4 to 18 years of age.4.Social work and welfare interventions that aimed to protect the child from violence and other risk factors.5.Social protection interventions that aimed to provide financial support to mother, children and families to access the basic amenities for survival and living.6.Environmental WASH interventions to ensure that every child lives in a clean and safe environment.7.Governance and advocacy intervention strategies to ensure sustainability.The final framework aimed to provide an overview of existing systematic reviews and EGMs for child well‐being interventions such as:6.1.1Figure 6.2The interventions included cover all main strategies to improve child well‐being outcomes.Table 6.3(1)Population subgroups of interest include: children with disabilities, children in conflict‐affected regions, children from underrepresented communities  and malnourished children.(2)Regions: East Asia and Pacific, Europe and Central Asia, Latin America and Caribbean, Middle East and North Africa, North America, South Asia, Sub‐Saharan Africa and conflict affected regions.(3)Systematic review quality: Based on AMSTAR 2 as High, medium and low Annex .(4)Country classification by Income level: low‐income: <1,005; lower‐middle income: 1,006–3,955, upper‐middle income: 3,956–12,235 .In addition to interventions and outcomes, the following filters were coded in the systematic reviews and mega‐map:77.1We imported the records from academic databases into our data management software EPPI‐Reviewer 4  Population, Intervention, Comparison, Outcomes and Study design (PICOS) in inclusion criteria, (2) ex ante protocol, 3) rationale for included study designs, (4) comprehensive literature search, (5) duplicate screening, (6) duplicate data extraction, (7) list of excluded studies with justification, (8) adequate description of included studies, (9) adequate risk of bias assessment, (10) reported sources of funding, (11) appropriate use of meta‐analysis, (12) risk of bias assessment for meta‐analysis, (13) allowance for risk of bias in discussing findings, (14) analysis of heterogeneity, (15) analysis of publication bias and (16) report conflicts of interest  identified from our search and screening process for this EGM. The number of studies shown in each figure refers to the total number of studies falling under each category presented. Individual studies may be classified under multiple categories. For instance, if a study examines the impacts of multiple interventions, that study would add to the count for each intervention studied in that paper. The sum of studies for each figure may therefore be greater than the number of unique studies associated with that figure.8.1.1As described in the PRISMA diagram Figure , 9,056 rAs a result, a total of 356 records were included in the final map, of which 54 were identified from grey literature and reference checking. Of these, 3338.2Figure 8.38.3.1Figure Health and nutrition was the most reviewed sector, followed by early childhood development.8.3.2Figure 8.3.3The health quadrant of the EGM which maps the studies of the effects of health interventions on health outcomes—is the most heavily populated section of the map Tables  and 4.8.3.4This is a fairly concentrated area of the map with a good amount of evidence in all intervention sub‐categories; early childhood health intervention (93), maternal education and empowerment (78), early childhood education and parenting 69) and early childhood nutritional interventions (65). The main outcomes noted were health impacts (152) and healthy development (132). Limited evidence was identified on learning and development (28), risk factor reduction (220 and economic impact (18) of these interventions. Only one systematic review was identified with an equity focus. About 30% of the reviews were identified to be of low quality  was the most commonly studies outcome, five on safety and five assessed equity as an outcome measure. Four EGMs assessed impact on health and three on learning and development and risk factor reduction each.8.3.5This is the most populated area of the map, but studies were unevenly distributed across intervention subcategories. Systematic reviews were concentrated in; community health interventions including Community Health Workers  and Antenatal care and postnatal care by Traditional Birth Attendants (TBA)/Skilled Birth Attendant (SBA) (108) and nutritional supplementation programme (62).The least populated areas were management of severe acute malnutrition (8), deworming (9), agricultural interventions/bio‐fortification (13), m‐Health interventions for child health (16), prevention and management of childhood malaria (17) and mental health programmes (23).The outcomes covered by systematic reviews mainly fall in two domains, health impact (188) and healthy development (162). About 26 studies were identified assessing the economic impact of these interventions. Only nine studies were identified assessing equity outcomes. Over 100 studies relate to the main outcomes of mortality, morbidity, disability and childhood illness and nutrition. There were fewer studies relating to risk factors notably on childhood injuries, alcohol and substance abuse, handwashing, clean environment, diet and physical activity.In terms of quality, 26% of child health reviews are classified as low‐quality Figure .Thirteen EGMs were identified in the area of health and nutrition, with the majority covering community health interventions including CHWs (7), mental health programmes (5), antenatal care and postnatal care by TBA/SBA (4), mass media campaigns on health education (4). Healthy development (10) is the most common outcome covered, followed by health (7) and economic impacts (6) and five (5) assessing equity.8.3.6The most studied interventions in the education domain were school based‐health interventions (38), pedagogical approaches (36), alternative schooling/nonformal education (27), teacher training (27), decentralization and local community participation (26), teacher incentives (19) and remedial education (16). Limited systematic reviews were identified on school voucher/reduced fees (10) and systemic renewal (6).Learning and development is the most studied outcome (48), followed by health impacts (38) and health development (30). Only six systematic reviews studied the economic impacts of educational interventions. For learning and development outcomes, the largest number of studies relates to cognitive development (50) and learning and achievement (58). Only six reviews had an equity focus.In terms of quality, 22% of educational reviews were identified to be of low quality Figure .School based interventions (nine) and decentralization and local community participation (nine) and teacher training (seven) were the most covered interventions by EGM. Alternative schooling, school sanitation and WASH and teacher incentives and pedagogical approaches were covered by six EGMs each. No EGMs were identified assessing equity component.8.3.7This is a scarcely populated domain in the map. The largest concentration of reviews in this area were on gender‐based violence interventions (21), also termed as violence against children and women, followed closely by interventions on child abuse (13) and child protection services (13). There was a lack of evidence on child trafficking interventions (one) and substance abuse prevention (two). The outcomes covered by systematic review were concentrated in three outcome domains—safety (30), health (13) and healthy development (15). Only three studies measured the economic impact of these interventions. On safety outcomes, violence against children (35) was the most studied outcome. There was limited evidence on child rights (eight) and FGM prevalence (four). Insufficient evidence was found on child labor and child marriage. There considerable lack of reviews in this intervention areas with explicit focus on equity (one).Twenty‐two percent of reviews were identified to be of low quality Figure .Gender‐based violence interventions (six) were the most covered by EGMs, followed by interventions on child abuse (two), child trafficking interventions (two) and child protection services (two). Safety (five) is the most studied outcome in EGMs as well, followed by health (four) and healthy development (five) and equity (three).8.3.8Social assistance intervention (44) is the most concentrated intervention area, followed by social insurance schemes (13). There was lack of evidence on labour market insurance (one).Health (31) and healthy development (34) were the most studied outcomes, followed by learning and development (15) and safety (14). Economic impact was assessed in nine reviews and no reviews were identified on equity component.24% of the reviews were identified to be of low quality in this area Figure .Social assistance (11) was the most covered intervention area followed by social insurance schemes (four) and labour market insurance (four).Healthy development (10), learning and development (eight) and safety (eight) and equity (six) were the most covered outcomes.8.3.9On the interventions, 24 reviews were identified on improved sanitation and water and 21 on hygiene education. There was limited evidence on prevention of environmental tobacco smoke (seven), safe places to play (three), prevention of outdoor and indoor air pollution (one) and traffic calming (one).On the outcomes, health impacts (33) and risk factor reduction (21) was the most commonly studies outcomes, followed by health development (11). Limited evidence was found assessing impact on equity (six), learning and development (two), safety (one), and economic impact (three) and only one review assessing equity.Nine reviews were assessed to be of low quality and 13 medium of quality Figure .Four EGM were identified each on improved sanitation and water and hygiene education and three on safe places to play.On the outcomes, health (four) and healthy development (four) was the most commonly studied outcomes, followed by risk factor reduction (three), safety (three), equity (three) and economic impact (two).8.3.10Governance was the least studied area of the maps with only six reviews on legislations on child rights (six) and four on child protection legislations (four). Safety (seven) was the most studies outcome, followed by health development (five) and impact on health (four). No studies were identified on equity or economic impact.We identified only two EGMs on child protection legislations. These EGMs assessed impact on safety (2), healthy development (2), and one each on health, risk factor reduction and economic impact. One EGM assessed equity outcomes Figure .8.3.11Figure 8.48.4.1There are thirteen systematic reviews in the mega‐map with an explicit equity focus. That is, reviews which either address equity or focus on a disadvantaged group, such as people with disabilities. These are concentrated in health and nutrition (six), and education intervention (five) areas. There is just one study with respect to early child development, and none at all for social protection or rights and governance. The 13 reviews identified as addressing equity report a broad range of outcomes. Most of these outcomes relate to health and education. However, there are also a number related to the UNICEF goal that every child is protected from violence and exploitation, with child abuse and neglect being reported in three of the 13 studies.Approximately half (six out of 13) of the studies are rated as high quality.8.4.2There is a fair amount of evidence assessing the effectiveness of interventions for all age‐groups, though it is highly concentrated for children in the young child (249). There was limited evidence focusing specifically on vulnerable populations such as children with disabilities (12), children in conflict‐affected regions (11) and malnourished children (8). There were limited systematic reviews focusing on gender and equity issues Figure .8.4.3Systematic reviews were found to be almost equally concentrated in all regions with sub‐Saharan Africa (292) and South Asia (268) having the highest number of reviews. These were closely followed by Latin America and Caribbean (245), East Asia and Pacific (243) and Middle East and North Africa (234) Figure .8.4.4Figure Figure 8.4.5Figure 99.1The main finding reported from the mega‐map is that there is good amount of evidence in more traditional areas of study such as health and nutrition, education and early childhood development. However, there is an uneven distribution of evidence across intervention and outcome subcategories. Though health and nutrition were the most populated areas of the map, there were gaps identified in many subintervention areas; management of severe acute malnutrition, agricultural intervention/biofortification, m‐health intervention for child health. In education, there is limited evidence around remedial education, nonformal education and scholarships and systemic intervention. In terms of quality, about 26% of the systematic reviews were identified to be of low quality for health and nutrition. This was found to be similar for early childhood development (30%) and education (22%). In terms of outcomes, health and learning were found to be the most studied as well; limited studies were identified assessing the impact of interventions on risk reduction, safety, equity and economic outcomes.Striking gaps in evidence were identified in nontraditional areas such as social protection and social welfare and Governance with a lack of evidence in many areas such as in prevention of child trafficking, substance abuse, child abuse and in social insurance and labour market insurance. These areas were not just under‐researched but also under funded. The most funded systematic review areas have been health and nutrition and early childhood development over the years. The major funders have been the DFID, WHO, the Bill and Melinda Gates Foundation, NIHR and UNICEF.9.29.2.1–There is a clear gap in reviews which are explicitly focused either on equity or on programmes for disadvantaged groups and those who are discriminated against such as children with disabilities, children belonging to ethnic minorities and low income groups.–Very few reviews were identified that conducted cost‐analysis.–The evidence synthesis which is available is mostly in the areas of health and education. More is needed in those areas. But more still is needed in other areas where there are limited reviews such as governance.Some priority areas and gaps in evidence are listed in Figure . There p9.2.2One major gap is for mental health interventions and mental health outcomes in LMIC's. Mental health has been recognised as a major development challenge for some time , but the evidence is lagging behind. There are studies for early child interventions, which mostly measure effects on psychosocial development rather than mental health problems. Furthermore, an EGM of disability in LMICs , has promoted them based on evidence from developed countries. Impact evaluations of IRC's projects show good results, but reviews are needed to stay abreast of the growing evidence base.Though, there are no absolute gaps in evidence in this domain, there was limited evidence on systemic renewal and on school vouchers/reduced fees. There is no systematic review of delivering education in humanitarian settings and of inclusive education for people with disabilities. More reviews are needed on the impact of education system strengthening. The 3ie education EGM (which is included in the mega‐map) gives a more detailed picture showing low numbers of primary studies for scholarships and user fees, information interventions and remedial education, as well as a lack of studies for many teacher and cognitive outcomes.Social work and welfare in LMICs is an under‐researched area in child well‐being. There is a lack of studies on child trafficking, early marriage, FGM and child labour. There was also limited evidence relating to child abuse and neglect as well as impact of birth registration. As a follow up to this map, UNICEF has commissioned Campbell Collaboration to undertake a map of Violence Against Children (Pundir, Saran, White, Adona, & Subrahmanian, There were no studies identified highlighting the impact of birth registration on child safety and well‐being.Social protection is well covered because of the amount of reviews on conditional cash transfers, but there is a lack of evidence on social insurance and labour market insurance. Micro insurance programmes offer a financially sustainable model of social protection so more understanding of their effectiveness is important to inform policy.Child injuries are an important area for which there are few reviews. There are also no reviews of safe places to play and traffic calming despite the fact that over 90% of traffic fatalities are in developing countries. There is a new ongoing map on road safety, from which preliminary findings show over 90% of evidence comes from North America. So primary studies of traffic safety measures in LMICs are an important gap.There are no or few studies to help identify effective strategies to reduce the exposure of children to indoor and outdoor air pollution, to reduce the risk of accidents including road‐related accidents, or to reduce risk of exposure to toxic materials.9.3The search strategy was systematic but owing to the large scope of the map, there are limitations. Some studies may have been missed, although several steps were taken to reduce this risk. For example, the search was conducted across a wide range of academic databases and the search was validated by an expert; reference and citation checking was undertaken and key donor websites were searched to identify grey literature. However, hand‐searching of literature was not undertaken.Although we used a consultative process that included two roundtable events to develop the framework, experts did not fully agree on all the categories. For example, there were comments that child protection services and interventions for child abuse should be a single category. Similarly, child right interventions were not fully agreed on. We worked based on the definitions we had, which could have led to judgement bias for some studies.1010.1The mega‐map demonstrates major gaps in our understanding, suggesting many practices in the promotion of child well‐being are largely unsupported by evidence.➢There were gaps in reviews with explicit focus on equity however, there may be review of reviews that contain relevant evidence, but mapping that requires diving into the review contents in more detail. A next step could be to produce an equity‐focused version of the mega‐map which allows identification of which reviews present evidence disaggregated for priority groups.➢It would be useful for global and country partners to work together to achieve consensus on priority areas for evidence synthesis and to adopt a coordinated approach to undertaking and updating maps and reviews across priority areas.➢Efforts are also needed to identify optimal study design, key interventions and outcome areas so that a universal evidence base can be built and used.➢There were a few dated systematic reviews that were identified and these need updating. Examples include in the areas of FGM, early marriage and child labour.➢There is a good amount of high‐quality systematic reviews in health and education and this implies that there is a substantial evidence base for governments and international agencies to draw upon for programme and policy design. The map is a starting point in guiding people to the evidence: further analysis and knowledge brokering is required for the evidence to be usable.➢More evidence synthesis are needed to fill an important gap in measuring interventions to meet the needs of vulnerable populations with important considerations including equity, gender, ethnicity, humanitarian settings and income groups.The mega‐map is the first step in identifying priority areas for rigorous systematic reviews and EGMs on child well‐being interventions. Based on the findings, a systematic research prioritisation should now be undertaken. As an immediate development from the mega‐map, UNICEF‐Innocenti and Campbell Collaboration are now working on an EGM on ending violence against children in low and middle income countries (Pundir et al., S. A., A. K., and W. H. contributed to writing and revising this report. The search strategy was developed and piloted by S. A. and validated by E. J. Search was conducted by S. A. S. A will be responsible for updating this EGM.Content expertiseEGM methods expertiseK. A. has experience regarding generation, communication and use of evidence across all of UNICEF's research and policy areas. H. W. has published papers, including systematic reviews and impact evaluations, on various aspects of child well‐being.Information retrieval expertiseA. S. and H. W. have previous experience in systematic review methodology, including search, data collection, theory‐based synthesis. They carried out the various processes required in an EGM, such as search, eligibility screening, quality assessment and coding. J. A. is an experienced screener and helped in screening and coding of included studies.A. S. has training in designing and implementing search strategies and she performed the searches for the mega‐map. The search strategy was validated by John Eyers, an expert with over 15 years' experienceNone.With thanks to financial support from the Bill and Melinda Gates Foundation, the mega‐map and associated research briefs will be updated annually over the lifetime of the UNICEF Strategic Plan 2018–2021, thus making the resource an open‐access, living map.The mega‐map is funded by UNICEF's Office of Research‐Innocenti.Supporting informationClick here for additional data file.


Variations in guidelines may result in differences in treatments and potentially poorer health-related outcomes. We aimed to systematically review and evaluate the quality of national and international guidelines and create an inventory of CPG recommendations on CPP.We searched EMBASE and MEDLINE databases from inception till August 2020 as well as websites of professional organizations and societies. We selected national and international CPGs reporting on the diagnosis and management of female CPP. We included six CPGs. Five researchers independently assessed the quality of included guidelines using the AGREE II tool and extracted recommendations.Two hundred thirty-two recommendations were recorded and grouped into six categories: diagnosis, medical treatment, surgical management, behavioural interventions, complementary/alternative therapies and education/research. Thirty-nine (17.11%) recommendations were comparable including: a comprehensive pain history, a multi-disciplinary approach, attributing muscular dysfunction as a cause of CPP and an assessment of quality of life. Two guidelines acknowledged sexual dysfunction associated with CPP and recommended treatment with pelvic floor exercises and behavioural interventions. All guidelines recommended surgical management; however, there was no consensus regarding adhesiolysis, bilateral salpingo-oophorectomy during hysterectomy, neurectomy and laparoscopic uterosacral nerve ablation. Half of recommendations  were unreferenced or made in absence of good-quality evidence or supported by expert opinion. Based on the AGREE II assessment, two guidelines were graded as high quality and recommended without modifications (EAU and RCOG). Guidelines performed poorly in the “Applicability”, “Editorial Independence” and “Stakeholder Involvement” domains.Majority of guidelines were of moderate quality with significant variation in recommendations and quality of guideline development.The online version contains supplementary material available at 10.1007/s00192-021-04848-1. Chronic pelvic pain (CPP) is a debilitating condition, affecting 15% of women worldwide . CPP is Clinical practice guidelines (CPG) are systematically developed statements using best available research evidence . They aiGuidelines based on poor evidence or those that fail to reflect the needs of women may contribute to the delivery of suboptimal, ineffective or even harmful interventions thereby compromising the quality of care. To date, there has been no evaluation of the methodological quality of national or international guidelines on female CPP. In this systematic review, we aimed to evaluate the methodological quality of CPP guidelines, produce a comprehensive inventory of recommendations and explore the relationships between recommendations and evidence.https://i-chorus.org). This study is part of a wider project for establishing core outcome sets (COS) in CPP. We followed a methodological approach implemented successfully by previous studies by CHORUS working groups appraising the quality of clinical guidelines in various areas of gynaecology . Discrepancies were resolved by discussion with a third author (SKD). In cases where a recommendation supported by multiple sources of evidence of varying quality, we documented the highest quality of evidence.Five researchers  were trained and assessed the quality of guidelines independently using the AGREE II tool. This is a validated instrument consisting of 23 items grouped into six quality domains and two further global rating items: 1) scope and purpose (items 1–3), (2) stakeholder involvement (items 4–6), (3) rigour of development (items 7–14 items), (4) clarity of presentation (items 15–17), (5) applicability (items 18–21) and (6) editorial independence (items 22–23). Each item was rated using a seven-point Likert scale from 1 (strongly disagree) and 7 (strongly agree) . The “St scope anDomain quality scores were calculated by the summation of scores per item and standardized using a prescribed equation . An overThere is no consensus regarding using AGREE II scores to differentiate between high- and low-quality guidelines or recommendation of guidelines. For the purpose of this study, we considered a domain score < 50% as low quality , 10. TheInter-rater reliability of assessments was tested for agreement using the Fleiss’ kappa co-efficient. Scores of ≤ 0 indicated no agreement, 0.01–0.20 indicated poor agreement, 0.21–0.40 indicated fair agreement, 0.41–0.60 indicated moderate agreement, 0.61–0.80 indicated substantial agreement and 0.81–1.0 indicated almost perfect agreement .Descriptive statistics were calculated for all domains . We used tables to map recommendations, the supporting evidence for recommendations and the hierarchy of evidence.There has been no patient involvement as this study is a systematic review of existing research.The electronic literature search yielded 1294 titles and abstracts. We screened 639 titles and abstracts following the exclusion of 655 duplicate records . In four guidelines , stakeholders included various health professionals  and methodological experts in clinical guideline development. The number of stakeholders in these guidelines ranged from 12 to 52. No guideline reported the involvement of women with CPP during the development process or reported their experiences of the recommended interventions. All guidelines developed recommendations applicable to high-income settings. One guideline (ASRM) described consensus development methods including the modified Delphi method. No guidelines provided a detailed search strategy used to identify supporting evidence for recommendations. Four guidelines  described methods to quality assess research evidence (Table Two guidelines were graded as high (EAU and RCOG) and four guidelines were graded as moderate quality . The EAU and RCOG guidelines scored highly with overall mean scores of 69.86% and 62.50% respectively. The remaining four guidelines scored less than 50% overall mean scores including the ACOG (48.06%), ASRM (48.03%), SOGC (47.34%) and ISPOG (31.55%) guidelines  and “Clarity of Presentation”  domains. The ASRM and EAU guidelines achieved the highest scores in the “Scope and Purpose” domain. The ACOG and EAU guidelines achieved the highest scores in the “Clarity of Presentation” domain Table . GuideliThe Fleiss kappa index varied between 0.217 to 0.386 and demonstrated fair agreement between reviewers , medical treatment (72 recommendations), surgical treatment (29 recommendations), behavioural/physical interventions (18 recommendations), alternative treatments (7 recommendations) and education/research (5 recommendations).Overall, 39 recommendations (17.11%) were comparable across guidelines including a comprehensive pain history, multifactorial nature of CPP including attributing muscular causes of CPP, an assessment of quality of life and multi-disciplinary approach. There was significant variation in recommendations regarding hormonal treatment, role of surgical interventions  as well the effectiveness of psychological and physical therapies.Risks of interventions and procedures were reported in five guidelines . The rationale of clinical decision making was discussed in all guidelines,Ninety-seven recommendations regarding diagnosis and investigation of CPP were made across guidelines. Of these, 39 recommendations (40.21%) were comparable across all six guidelines. Included guidelines described the multifactorial nature of CPP including causes such as bladder pain syndrome (BPS), irritable bowel syndrome (IBS) and muscular/myofascial dysfunction. All guidelines attributed CPP to muscular/myofascial causes including trigger points. Urological conditions such as BPS and interstitial cystitis were featured in five guidelines . Three guidelines referred to endometriosis  and four guidelines alluded to nerve damage . IBS was described as a contributing factor by three guidelines .A detailed pain history was recommended by all guidelines; however, only two guidelines suggested a visual analogue scale (VAS) to measure pain intensity (ISPOG and SOGC). All guidelines recommended the evaluation of psychosocial factors including the recognition of concomitant mood disorders and assessment of quality of life. However, no guideline specified which patient-reported outcome measurement instrument to utilize.Investigation of CPP varied among guidelines. The role of imaging such as transvaginal ultrasound to exclude adenomyosis, adnexal masses and endometriosis was recommended by three guidelines . MRI was recommended by the RCOG guideline to diagnose adenomyosis; however, its ability to accurately detect endometriotic deposits was uncertain (ASRM and RCOG). Diagnostic laparoscopy was recommended by five guidelines . However, the RCOG guideline suggested laparoscopy as a second-line investigation if other therapeutic interventions fail. Cystoscopy was recommended by the SOGC guideline only.A multi-disciplinary and multi-speciality approach to pain management was explicitly stated by five guidelines . Furthermore, the ACOG, ISPOG and EAU guidelines also recommended that care of patients with CPP should be undertaken by pain medicine specialists.Seventy-two recommendations were extracted regarding medical treatment of CPP. No recommendations were comparable in this domain. Nineteen recommendations focused on analgesia. Treatments with the highest grade of recommendations (i.e. level of evidence 1a and grade A recommendation) were paracetamol, NSAIDs , gabapentin, antidepressants, topical capsaicin and opioids Table .Simple analgesia including paracetamol and NSAIDs was specifically recommended by two guidelines (EAU and ASRM). The use of anticonvulsants such as pregabalin and gabapentin to treat CPP was described by four guidelines . Pain management with opioids was described by two guidelines (EAU and SOGC). However, only the EAU guideline stated which opioid to use, the preferred route of administration, a detailed consenting process including risks of addiction and dependency as well as plans for monitoring. In comparison, the ACOG guideline did not recommend treatment of CPP using opioids. Adjuvant medications such as tricyclic anti-depressants were suggested by four guidelines .Hormonal treatment was recommended for underlying gynaecological causes such as endometriosis by three guidelines . The use of oral contraceptives as a first-line treatment was stated by two guidelines (ASRM and SOGC). Progestins, Danazol and GnRH analogues were considered as first-line treatments in women with suspected endometriosis by the SOGC guideline. The ASRM guideline considered these as second-line treatments and recommended that an alternative diagnosis should be sought if adequate pain relief was not achieved. The RCOG also recommended hormonal treatment however did not specify which agents. A diagnostic laparoscopy was recommended in instances where pain was refractory to hormonal treatment after 3 to 6 months Table .Disease-specific treatments were described for BPS, chronic anal pain syndrome, irritable bowel syndrome (IBS) and myofascial dysfunction by four guidelines . For suspected IBS, antispasmodics were recommended by one guideline (RCOG). A comprehensive list of BPS treatments including lifestyle modifications, oral medications, neuromodulation, intravesical therapies including trigonal and submucosal injections as well as hydrodistension was detailed by one guideline (EAU). Management of chronic anal pain syndrome using inhaled salbutamol, botulinum toxin A, electrogalvanic stimulation and percutaneous tibial nerve stimulation was described by the EAU guideline Table .This domain consisted of 29 recommendations. However, no recommendations were comparable despite surgical management described by all guidelines. Twenty-four recommendations specifically referred to surgical procedures. The highest grade of recommendations supported hysterectomy for refractory symptoms, hysterectomy with ovarian conservation for endometriosis/adenomyosis and treatment of peritoneal pockets frequently associated with endometriosis and did not support routine adhesiolysis Table . It mustHysterectomy was recommended by three guidelines for refractory and severe symptoms . One guideline advised bilateral salpingo-oophorectomy during hysterectomy to relieve symptoms such as CPP secondary to endometriosis (ASRM). In contrast, the SOGC guideline suggested ovarian conservation was an acceptable option during hysterectomy for adenomyosis/endometriosis. The use of HRT after hysterectomy and bilateral oophorectomy for CPP secondary to endometriosis was described by a single guideline (SOGC).Presacral neurectomy and laparoscopic uterosacral nerve ablation were discussed by two guidelines (ASRM and SOGC). The ASRM guideline did not recommend these in instances of endometriosis-related CPP. However, it did suggest that presacral neurectomy may be beneficial in reducing the severity of dysmenorrhoea. The SOGC guideline stated the role of presacral neurectomy for pain reduction in endometriosis remained unclear Table .There was a difference in recommendations regarding adhesiolysis. Laparoscopic adhesiolysis was supported by the ISPOG guideline; however, the SOGC and ACOG guidelines did not recommend routine laparoscopic adhesiolysis in the context of CPP. The RCOG guideline recognized the benefit of dividing dense vascular adhesions to reduce pelvic pain but did not support adhesiolysis of fine adhesions Table .Three guidelines  recommended surgical treatment of endometriosis using laparoscopic ablation or excision. A single guideline (EAU) described sacral neurostimulation for chronic anal pain syndrome. Transurethral resection of bladder lesions in type 3 BPS was recommended by the EAU guideline. Ablative surgery for BPS was advised by a single guideline as a last resort and by knowledgeable surgeons only (EAU) Table .Eighteen recommendations described behavioural interventions. No recommendations were comparable across guidelines. The highest grade (i.e. level of evidence I and grade A) of recommendations supported psychological interventions combined with medical/surgical, biofeedback treatment in pelvic pain and dyssynergic defecation and biofeedback as an adjunct to muscle exercises in overactive pelvic floor muscles Table .Psychological treatments were recommended by three guidelines . The EAU and ISPOG guidelines recommended integrating psychological interventions with standard medical/surgical treatments for CPP. The EAU guideline specifically referred to the role of psychological treatment in various conditions including PBS, urethral pain syndrome and chronic vulvar pain.The ACOG guideline recommended cognitive behavioural therapy, pelvic floor physiotherapy or sexual therapy alone or in combination to manage myofascial dysfunction and dyspareunia secondary to CPP. Only one guideline (EAU) recommended training pelvic floor muscles to improve quality of life and sexual function. The EAU guideline advocated using behavioural strategies for patients and their partners with sexual dysfunction secondary to CPP.Physiotherapy was recommended by a single guideline (EAU) for BPS and pelvic floor overactivity. Pelvic floor muscle treatment was considered a first-line treatment in CPP by the EAU guideline.Only one guideline (SOGC) reported the use of exercise in the treatment of CPP due to myofascial dysfunction. No further details regarding the type of exercise (aerobic or resistance) were provided Table .Seven recommendations focused on alternative treatments. No recommendations were comparable across guidelines. The highest grade (i.e. level of evidence I and grade A) of recommendations supported treatment of myofascial trigger points by dry needling or pressure Table . There wOne guideline reported limited data supporting the use of alternative therapies to treat CPP including acupuncture, trigger point treatment, reflexology, biofeedback, distension therapy, homoeopathy and Thiele massage (ISPOG). A single guideline (EAU) supported the use of alternative therapies such as TENS to treat CPP. There were no consistent recommendations regarding acupuncture and use was limited to specific clinical scenarios. The EAU guideline did not recommend acupuncture in the treatment of BPS. However, the ACOG guideline supported use of acupuncture in CPP secondary to muscoskeletal aetiology Table .Five recommendations were relevant to education and research. No recommendations were comparable in this domain. One guideline advised incorporating CPP into the curricula of health professionals (SOGC). Two guidelines outlined future research priorities including the role of gene therapy, effectiveness of surgical management and investigating myofascial and sexual dysfunction in CPP (EAU and SOGC).Three guidelines  reported the grading of evidence used to support recommendations. Each guideline used a different grading scale including the Oxford Centre for Evidence-based Medicine Levels of Evidence (EAU), the Scottish Intercollegiate Guidelines Network (SIGN) grading system (RCOG) and the Canadian Task Force on Periodic Health Exam grading (SOGC). Of note, the ACOG guideline evaluated evidence using the US Preventative Services Task Force grading system; however, the level of evidence supporting each recommendation was not reported.The total number of references cited in guidelines ranged from 22 to 644. The number of Cochrane reviews cited by each guideline ranged from 1 to 20. One guideline did not use any Cochrane reviews to support recommendations. The total number of RCTs used per guideline ranged from 6 to 32. Almost half of the recommendations  were unreferenced, made in the absence of good quality evidence or supported by expert opinion.There is significant variation in CPP guideline quality and recommendations. We identified 189 unique recommendations but only 39 recommendations were comparable across 6 guidelines. A lack of consensus was observed in recommendations regarding medical and surgical treatments as well as complementary/alternative therapies. Nearly half of recommendations  were unreferenced, or made in absence of good quality evidence or supported by expert opinion. The quality of guidelines was variable; only two guidelines were assessed as high quality using the AGREE II instrument. Guidelines performed poorly in the “Applicability”, “Editorial Independence” and “Stakeholder Involvement” domains.To our knowledge, this is the first study to systematically appraise the methodological quality and map recommendations of CPP guidelines. We used robust and reproducible methods that have been successfully implemented in previous studies. To improve the scientific rigour of this review, five reviewers trained in using the AGREE II tool assessed guidelines, thereby minimizing possible bias arising from data collection or inherent limitations of the AGREE II tool related to inter-observer variations. Nevertheless, the inter-rater agreement among reviewers was fair.This study has limitations. The AGREE II instrument is used to assess the rigour of guideline development rather than the quality of guideline content. Scoring achieved using the AGREED II tool is not a reflection of applicability or implementation in clinical practice . All revThis systematic review reflects variations in guideline recommendations and the poor quality of guideline development. Similar results were found in studies critically appraising the quality of guidelines including BPS, endometriosis, obstetric perineal lacerations and the use of transvaginal mesh implants in prolapse , 10, 16.Various terminology has been used by authors and organizations to describe clinical practice recommendations. These have included clinical practice guidelines, consensus statements, position statements, practice alerts and hybrid terms such as consensus guidelines. Such terms can be indicative of the level of evidence and strength of recommendations. However, authors have used these terms interchangeably with a lack of consistency and available evidence. This poses a particular problem and possibly a challenge in harmonization of clinical guidance, as encountered in this study, of identifying “true” clinical practice guidelines that are developed using rigorous methodology. The use of inconsistent terminology may mislead clinicians about the level of confidence to place in recommendations and the process by which they were developed. Further consensus initiatives are needed for transparency and clarity regarding the definitions of these terminologies .Guidelines support and provide an evidence base to the clinical decisions made in daily practice. However, we observed that almost half of all recommendations were made despite the absence of good quality evidence. The shortage of primary research supporting the management of women with CPP may prohibit the development of useful guidelines . FurtherDiagnostic and therapeutic guideline recommendations are helpful in standardizing and improving the quality of care. However, they are limited and may not be relevant or apply in every clinical field of practice. CPP is a manifestation resulting from various underlying conditions that may evolve and develop into regional pain disorders. The complex aetiology of CPP and scarcity of available evidence may cause clinicians to resort to their own experience or seek expert opinions. A holistic approach is needed as underlying causes, treatment options and concerns of women with CPP can vary. Additionally, groups/societies publish guidelines for their members rather than a broader audience. The focus and scope of guidelines may be influenced by the clinical/scientific theme, interests or priorities of publishing societies/professional groups. For example, professional bodies for gynaecologists may focus on endometriosis only in women presenting with CPP. This may have contributed to the variability of recommendations for the management of female CPP observed in this study. The inclusion of a multidisciplinary stakeholder committee will help produce concise and collaborative recommendations that prevent duplicate investigations and the recommendation of ineffective treatments. This study indicated that guidelines performed poorly in the Stakeholder Involvement domain reflecting unilateralism in their approach to CPP including a lack of engagement and participation with their target audience, i.e. women with CPP.In this review, all guidelines recommended surgical intervention; however, there was no consensus among guidelines. The lack of consistent recommendations presents difficulty when supporting or refuting the effectiveness of surgical procedures, such as adhesiolysis, to manage female CPP. The benefit of bilateral salpingo-oophorectomy during hysterectomy was also unclear with contradictory advice given in two guidelines. There is a place for hysterectomy in the management of CPP particularly due to endometriosis; however, patient selection is paramount . FurtherIn an era of patient-centred care, it was concerning that no guideline reported including women with CPP in the development process. Views and perceptions of women with CPP can be incorporated to frame the overarching theme of future guidelines as well as ensure the quality and relevance of recommendations. For example, all guidelines discussed the association of sexual abuse and CPP. However, no guideline specifically outlined recommendations pertaining to sexual abuse. Furthermore, no guideline reported women’s experiences to support the use of recommended interventions. These insights are invaluable for policymakers and guideline developers. The identification of barriers and facilitators can influence the successful implementation of interventions. In this review, included guidelines may not have incorporated qualitative research findings because of a lack of primary qualitative studies exploring the experiences of women with CPP , 23.The detrimental impact of CPP on quality of life outcomes has been described and identified as a priority for women with CPP . DespiteThere is an increased prevalence of sexual dysfunction observed in women with CPP compared with those without CPP (69.6% versus 30.4%) . UnderlySimilarly, exercise has been successfully incorporated into multidisciplinary treatment programmes to treat female CPP , 27. AvaOur findings are consistent with other studies that noted the Applicability, Editorial Independence and Stakeholder Involvement domains as areas of improvement for future guideline development , 10, 16.Our findings suggest that guidelines performed poorly in the Stakeholder Involvement domain. Guidelines failed to engage and involve women with CPP in the development process. Most guidelines were unsuccessful at including individuals from relevant professional groups therefore narrowing their scope to managing CPP. For example, only a single guideline included health professionals from various disciplines such as gastroenterology, neurology, pain medicine, urology and psychology. The inclusion of a multidisciplinary guideline development group will help produce concise and collaborative recommendations. Furthermore, in complex conditions such as CPP which may be due to a single or multiple concurrent causes or indeed idiopathic, input from multiple specialities is required. It is vital that clinical pathways are efficient and coordinated. A diagnostic pathway can often be a frustrating and negative experience for women with CPP hindered by delay . GuideliThe Applicability domain refers to the implementation of guideline recommendations. Various factors can influence the successful implementation of guidelines such as the awareness of recommendations, associated costs and resource implications. Development of guidelines without effective and structured implementation strategies may not lead to the expected changes in clinical practice. Identification of barriers and facilitators in advance and incorporating these into the guideline development process can lead to tailored implementation strategies. These can improve adherence and avoid unnecessary investigations and inadequate interventions .Maintaining editorial independence is vital to ensure the reliability and validity of recommendations. Influence or interference from funding bodies or conflicts of interest from members of the guideline development group can introduce bias and undermine the credibility of the guideline development process. Conflicts of interest can be mitigated by guideline developers obtaining and presenting full and transparent disclosures.The majority of guidelines were of moderate quality with significant variation in recommendations and the quality of guideline development. Adoption of standardized guideline development methods will ensure guideline recommendations are relevant, reliable and transferrable to clinical practice.ESM 1(DOCX 34 kb)ESM 2(DOCX 21 kb)ESM 3(DOCX 19 kb)


NRAS-initiated JMML is heterogeneous and adequate management ranges from watchful waiting to allogeneic hematopoietic stem cell transplantation (HSCT). Upfront azacitidine in KRAS patients can achieve long-term remissions without HSCT; if HSCT is required, a less toxic preparative regimen is recommended. Germline CBL patients often experience spontaneous resolution of the leukemia or exhibit stable mixed chimerism after HSCT. JMML driven by PTPN11 or NF1 is often rapidly progressive, requires swift HSCT and may benefit from pretransplant therapy with azacitidine. Because graft-versus-leukemia alloimmunity is central to cure high risk patients, the immunosuppressive regimen should be discontinued early after HSCT.Juvenile myelomonocytic leukemia (JMML) is a rare pediatric leukemia characterized by mutations in five canonical RAS pathway genes. The diagnosis is made by typical clinical and hematological findings associated with a compatible mutation. Although this is sufficient for clinical decision-making in most JMML cases, more in-depth analysis can include DNA methylation class and panel sequencing analysis for secondary mutations.  PTPN11, NRAS, KRAS, NF1, or CBL) [JMML is a pediatric leukemia with shared features of myelodysplastic and myeloproliferative neoplasms, usually manifesting during early childhood with leukocytosis, thrombocytopenia, pronounced monocytosis, splenomegaly, immature precursors on peripheral blood (PB) smear, and bone marrow (BM) blast count below 20% ,2,3. Its or CBL) . For mos or CBL) ,7. Clini or CBL) ,9. In thThe Ras pathway is a sequence of kinases in the cell that serves as a chain of communication between extracellular mitogens and the cell nucleus . ExternaPTPN11, NRAS, KRAS, NF1, or CBL), resulting in net hyperactivation of the Ras-GTP-GDP loop, are present in hematopoietic cells of >90% of children diagnosed with JMML [Genetic mutations in specific Ras pathway components , SOS1, RAF1, KRAS, BRAF, NRAS or other members of the RAS pathway [PTPN11 mutations is not identical in JMML and NS/MPD [Noonan syndrome (NS), the most common rasopathy with an incidence of 1 in 1000–2500 children , bears c pathway ,44,45. C pathway . Althoug pathway . Althougd NS/MPD , there id NS/MPD .SETBP1, JAK3, SH2B3, or ASXL1 genes. Not infrequently, the secondary mutations affect the Ras pathway itself (“Ras double mutants”). In addition, a role for subclonal mutations in the Polycomb Repressive Complex 2 network was highlighted [Systematic exome sequencing studies revealed that JMML is generally characterized by a paucity of somatic mutations in the neoplastic clone when compared to most other types of cancer . Howeverhlighted . Severalhlighted ,49. Furthlighted ,49.RRAS mutations [CCDC88C-FLT3 fusion responsive to sorafenib was described in a pediatric patient with clinical features of JMML and monosomy 7 [ALK [ROS1 [FIP1L1-RARA [HCMOGT-1-PDGFRB [NDEL1-PDGFRB [NUP98-HOXA11 [Less than 10% of JMML cases are negative for the five canonical driver mutations. Rarely, these children harbor germline or somatic activating utations ,50. Recenosomy 7 . Other fy 7 [ALK ,53, ROS1LK [ROS1 ,53, FIP11L1-RARA , HCMOGT-1-PDGFRB , NDEL1-P1-PDGFRB , and NUP8-HOXA11 . Althoug8-HOXA11 ,53.JMML occurs in 1.2 children per million per year, accounting for 2% of pediatric hematopoietic malignancies . One hal9 G/L in all but exceptional cases [The PB smear typically shows mild to pronounced leukocytosis with monocytosis without a significantly increased number of blasts (median 2% myeloblasts) ,64. Immaal cases . Bone maal cases .PTPN11, KRAS, NRAS, and CBL genes, and a meticulous search for features of NF-1 including family history. Genetic analysis of NF1 can be added, but it is laborious, and the interpretation of findings is not always straightforward. On cytogenetics, two-thirds of cases exhibit a normal karyotype. Monosomy 7 is the most frequent aberration [PTPN11 and KRAS mutations, but rarely with NF1, NRAS, or CBL. A traditional hallmark of clonogenic JMML cells is their hypersensitivity to GM-CSF in vitro [The combination of young age, splenomegaly, skin lesions, appearance of myeloid and erythroid precursors in the PB, and/or elevated levels of HbF should prompt the pediatric oncologist to suspect JMML and initiate specific tests. First of all, this involves the molecular analysis of driver mutations in the erration ,53,65, oin vitro ,67. Howein vitro . Similarin vitro . It was in vitro .NRAS and KRAS mutations as in JMML [Bacterial  and vira in JMML , but the in JMML ,76, high in JMML .LIN28B [The genetic subtypes discussed above account for the phenotypic diversity of JMML only incompletely. For example, long-identified prognostic parameters, such as age of the patient, sex, platelet count, or elevated levels of fetal hemoglobin ,40,59, dLIN28B . In addiLIN28B ,82.The first study examining the role DNA methylation changes in a large European series of 127 children with JMML revealed CpG island hypermethylation of a candidate gene set in up to half of the cases . ImportaPTPN11 mutation and older children, both known factors for inferior clinical course, whereas the low-methylation group was enriched for patients with NS/MPD, CBL cases, and young children with somatic NRAS mutations. The group with intermediate hypermethylation was characterized by somatic KRAS mutations and occurrence of monosomy 7 [NF1 or PTPN11 mutations, secondary mutations, LIN28B overexpression and AML-like expression profile [Extending these findings to a genome-wide scope using array-based methods, study groups in Europe , Japan  and Unitnosomy 7 . The Japnosomy 7 . In addi profile . The Nor profile . Interes profile ,88, agai-Level of fetal hemoglobin -PTPN11, NF1, KRAS, NRAS, CBL)Panel sequence analysis of the five primordial Ras pathway genes -Where available, the following additional information will aid in clinical decision-making, though it is not indispensable for adequate management in most cases:-DNA methylation class-SETBP1, JAK3, RRAS, RRAS2, and ASXL1; other targets are rare.Panel sequence analysis of recurrent secondary mutations. The assessment should include With extensive molecular diagnostic work-up of JMML established in major international study groups and large centers around the world, it has become evident that there can no longer be a uniform one-size-fits-all approach for this disorder . The autPTPN11- or NF1-driven JMML. On the other hand, a group of patients exist who are clinically well and have low HbF. Here, spontaneous clinical regression of the disease can occur in the long run without therapy. The search for an unrelated stem cell donor may be deferred in these cases. In between these two ends of the spectrum, the prospective identification of patients who benefit from watchful waiting is the real challenge. Factors suggesting surveillance without therapy include infant age, clinical status, age-appropriate levels of HbF, and low methylation class [The disease course in this group is remarkably heterogeneous. In older children with severe thrombocytopenia, increased HbF and high methylation class, a rapidly progressive course with a considerable risk of recurrence after HSCT is to be expected, likening the disorder to on class ,89,90. HNRAS or KRAS mutation to be detected in a suspected JMML case. Most of these children have additional syndromic features of the rasopathy spectrum [It is very rare for a germline spectrum ,92 or cospectrum . Anecdotspectrum ,95. BecaKRAS-JMML are typically very young, often infants. Concurrent monosomy 7 in the neoplastic clone is often observed (see below). Autoimmune phenomena  should be searched for, and a diagnostic differentiation from RALD [KRAS-driven JMML tends to be aggressive, requiring rapid intervention. In the past, long-term survival without HSCT has not been reported for this group, but the picture is now changing with the introduction of azacitidine. KRAS-mutated JMML responds particularly well to low-dose azacitidine with long-lasting clinical and molecular remissions [2/day on five consecutive days or 75 mg/m2/day on seven consecutive days, repeated every 28 days; due to instability, immediate intravenous or subcutaneous application of the cold reconstituted solution must be observed. Azacitidine has a favorable toxicity profile in children with JMML, mainly including lower-grade cytopenias, gastrointestinal discomfort, and infections [KRAS-mutated JMML with a low risk profile.Children diagnosed with rom RALD ,96,97 shmissions ,99. Regifections ,98. It i2/day, to be adjusted according to clinical course) and/or cytarabine (40 mg/m2/day × 5 days) [2/day × 5 days) and fludarabine (30 mg/m2/day × 5 days) may also be considered [PTPN11 mutation.This is the numerically largest group that also carries the highest risk of rapid progression and early death. As no curative chemotherapy regimen is known, expeditious planning of allogeneic HSCT is mandatory. Within this group, risk factors for an unfavorable course are: age at diagnosis ≥2 years, significantly increased level of HbF, presence of secondary mutations, and/or high methylation class. In these cases, the aim should be to perform HSCT within a period of 3 months after diagnosis (recommendations for implementation see below). Low-dose azacitidine is the preferable option for upfront therapy until HSCT in non-high risk cases, with the goal to achieve a more favorable biological status of the leukemia. In many affected children, this treatment leads to a clinical partial remission or at least sufficient disease control until HSCT ,99,100 H 5 days) . If a pansidered . Howevernsidered . It is nnsidered . Until mPTPN11 cause Noonan syndrome, a condition of the rasopathy spectrum predisposing to a myeloproliferative disorder imitating JMML. For this reason, genetic diagnostics in suspected cases of JMML must always be carried out in both hematopoietic and non-hematopoietic material. Cultivated fibroblasts from a skin biopsy are ideal; hair follicles are less invasive, but more challenging to analyze. An oral mucous membrane swab has a high probability of contamination with hematopoietic cells, even if it is macroscopically not bloody, and should therefore only be scored if the result is negative.Germline mutations in PTPN11 should not just encompass the hotspot exons 3 and 13 because Noonan syndrome mutations may also be found in exons 4 or 8. The spectrum of somatic PTPN11 mutations in nonsyndromic JMML and germline PTPN11 mutations in Noonan-associated MPD overlaps to a great extent but not completely [In cases of suspected JMML in very young patients or with clinical evidence of Noonan syndrome, the diagnostic test for mpletely .The distinction between non-syndromic JMML and Noonan-associated MPD is important, as the latter is usually self-limiting. However, these patients must be monitored carefully, as there can be relevant clinical compromise from cell infiltrates, making it necessary to begin cytoreductive therapy. In individual cases, a clonal development towards a bona fide neoplastic disease is possible ,102,103.NF1 usually confirms the clinical diagnosis in children with JMML/NF-1 [NF1-inactivating heterozygous variation in the germline of the patient that arose de novo (~50% of cases) or was inherited. These lesions are often, but not always, deletions or truncating missense mutations reported as recurrent aberrations in the NF-1 literature. In addition, the neoplastic clone exhibits somatic loss of heterozygosity at the NF1 locus or an independent second NF1 mutation, leading to biallelic NF1 inactivation [NF1 lesion, but driven by an unrelated event, may be present. With careful work-up, however, such dilemmas are rare.If not already recognized in the patient, the syndrome can usually be diagnosed clinically and/or through family history at the time of onset of JMML. In younger children, only café-au-lait spots but not the other typical signs of neurofibromatosis may be present. Six or more café-au-lait spots as stipulated in the NIH criteria are noted in the majority of children, but in exceptional cases there may be none or fewer. Genetic analysis of MML/NF-1 . The typtivation ,104,105.PTPN11 mutation. Consistent with this recommendation, JMML/NF-1 cases almost always have an intermediate or high methylation profile [JMML on the basis of NF-1 manifests more frequently at an older age than the other groups and typically does not involve a drastically reduced platelet count. Some children initially show little clinical impairment. However, long-term survival without HSCT has not yet been observed in this group, so that proceeding to transplant and inception of therapy with azacitidine is advisable as in patients with somatic  profile .CBL mutations in JMML is a heterozygous missense point mutation in CBL exons 8 or 9 in the germline, accompanied by uniparental isodisomy of the 11q chromosome arm as a somatic event in hematopoietic cells, leading to loss of heterozygosity [CBL-JMML have massive organ enlargement and may require splenectomy for symptom relief. Most patients do not require swift HSCT but can be managed with watchful waiting; many of these experience spontaneous resolution of the myeloproliferation. The homozygous CBL-mutant status in hematopoietic cells may persist until adulthood even in the absence of hematologic abnormalities [CBL inactivation in five patients with a clinical course that required HSCT [The typical configuration of zygosity ,36,37. Mmalities . Patientmalities ,36. It ired HSCT , again iNF1 gene in the absence of clinical NF-1 features [ALK, ROS1, or FLT3 [Suspected cases of JMML with negative panel sequencing for all five primordial genes and no clinical evidence of NF-1 are called “quintuple-negative” or “all-negative”. In a third of these cases, in-depth multimodal genetic analysis uncovered a driving role of the features . In othe or FLT3 ,53. SomeKRAS mutations, in contrast to an association between monosomy 7 and PTPN11 or NF1 in the high methylation group, and the absence of monosomy 7 in patients with low methylation pattern [The significance of monosomy 7 for the biology of JMML is unclear, and there seems to be no association with clinical features or relevance for outcome . Interes pattern . The mec pattern . This co pattern .2/d on day 1) [Busulfan-based myeloablative conditioning regimens are commonly chosen and achieve 55–73% OS with a moderate 10–15% rate of transplant-related mortality but significant probability of leukemia relapse in the order of 25–35% ,111,112.n day 1) . In an an day 1) . Matchedn day 1) . Matchedn day 1) ,116,117.n day 1) ,112,118.n day 1) .The North American group noted better post-HSCT outcome of patients with JMML who experienced molecular response to pretransplant chemotherapy , similarBeside the leukemia biology factors discussed above, the way the transplant procedure is handled significantly influences the risk of relapse. It is likely that it is not so much the conditioning regimen but rather the establishment of a graft-versus-leukemia effect that is decisive for the success of allogeneic HSCT in JMML ,110,111.NF1 or somatic PTPN11 mutation, and high DNA methylation define a patient group whose risk of JMML recurrence after HSCT is even higher than 50%, bringing up the question of post-transplant prophylaxis. On the basis of favorable data for other myeloid neoplasms [2/day for five consecutive days, every 28 days) plus donor lymphocyte infusions . However, we emphasize that there are no systematic data for this approach in JMML.Age at diagnosis ≥2 years, eoplasms ,130,131 PTPN11-driven JMML to trametinib [Despite the prominent role of the Ras/MAPK network, attempts to target this complex signal cascade have shown limited therapeutic benefit in JMML ,132. Theametinib . BCL2 inametinib ,135 and ametinib ,137. Witametinib ,139,140.