A review of the enhanced CJD surveillance feasibility study in the elderly in Scotland, UK.

BACKGROUND: Variant Creutzfeldt - Jakob disease (vCJD) arose from dietary contamination with bovine-spongiform-encephalopathy (BSE). Because of concerns that vCJD-cases might be missed in the elderly, a feasibility study of enhanced CJD surveillance on the elderly was begun in 2016. Recruitment was lower than predicted. We describe a review of the challenges encountered in that study: identification, referral, and recruitment, and the effects of actions based on the results of that review. METHODS: Review was conducted in 2017. Study data for all eligible cases identified and referred from one participating service (Anne Rowling clinic (ARC)) was curated and anonymised in a bespoke database. A questionnaire was sent out to all the clinicians in medicine of the elderly, psychiatry of old age and neurology (including ARC) specialties in NHS Lothian, exploring possible reasons for low recruitment. RESULTS: Sixty-eight cases were referred from the ARC (March 2016-September 2017): 25% were recruited. Most cases had been referred because of diagnostic uncertainty. No difference was seen between those recruited and the non-recruited, apart from age and referrer. Twelve of 60 participating clinicians completed the questionnaire: only 4 had identified eligible cases. High workload, time constraints, forgetting to refer, unfamiliarity with the eligibility criteria, and the rarity of eligible cases, were some of the reasons given. Suggestions as to how to improve referral of eligible cases included: regular email reminders, feedback to referrers, improving awareness of the study, visible presence of the study team, and integration of the study with other research oriented services. These results were used to increase recruitment but without success. CONCLUSION: Recruitment was lower than predicted. Actions taken following a review at 21 months did not lead to significant improvement; recruitment remained low, with many families/patients declining to take part (75%). In assessing the failure to improve recruitment, two factors need to be considered. Firstly, the initial referral rate was expected to be higher because of existing patients already known to the clinical services, with later referrals being only newly presenting patients. Secondly, the unplanned absence of a dedicated study nurse. Searching digital records/anonymised derivatives to identify eligible patients could be explored.

Enhanced Creutzfeldt-Jakob disease surveillance in the older population: Assessment of a protocol for screening brain tissue donations for prion disease.

Human prion diseases, including Creutzfeldt-Jakob disease (CJD), occur in sporadic, genetic, and acquired forms. Variant Creutzfeldt-Jakob disease (vCJD) first reported in 1996 in the United Kingdom (UK), resulted from contamination of food with bovine spongiform encephalopathy. There is a concern that UK national surveillance mechanisms might miss some CJD cases (including vCJD), particularly in the older population where other neurodegenerative disorders are more prevalent. We developed a highly sensitive protocol for analysing autopsy brain tissue for the misfolded prion protein (PrPSc ) associated with prion disease, which could be used to screen for prion disease in the elderly. Brain tissue samples from 331 donors to the Edinburgh Brain and Tissue Bank (EBTB), from 2005 to 2022, were analysed, using immunohistochemical analysis on fixed tissue, and five biochemical tests on frozen specimens from six brain regions, based on different principles for detecting PrPSc . An algorithm was established for classifying the biochemical results. To test the effectiveness of the protocol, several neuropathologically confirmed prion disease controls, including vCJD, were included and blinded in the study cohort. On unblinding, all the positive control cases had been correctly identified. No other cases tested positive; our analysis uncovered no overlooked prion disease cases. Our algorithm for classifying cases was effective for handling anomalous biochemical results. An overall analysis suggested that a reduced biochemical protocol employing only three of the five tests on only two brain tissue regions gave sufficient sensitivity and specificity. We conclude that this protocol may be useful as a UK-wide screening programme for human prion disease in selected brains from autopsies in the elderly. Further improvements to the protocol were suggested by enhancements of the in vitro conversion assays made during the course of this study.

A clinicopathological study of selected cognitive impairment cases in Lothian, Scotland: enhanced CJD surveillance in the 65 + population group.

BACKGROUND: Variant Creutzfeldt-Jakob Disease (vCJD) is primarily associated with dietary exposure to bovine-spongiform-encephalopathy. Cases may be missed in the elderly population where dementia is common with less frequent referral to specialist neurological services. This study's twin aims were to determine the feasibility of a method to detect possible missed cases in the elderly population and to identify any such cases. METHODS: A multi-site study was set-up in Lothian in 2016, to determine the feasibility of enhanced CJD-surveillance in the 65 + population-group, and undertake a clinicopathological investigation of patients with features of 'atypical' dementia. RESULTS: Thirty patients are included; 63% male, 37% female. They were referred because of at least one neurological feature regarded as 'atypical' (for the common dementing illnesses): cerebellar ataxia, rapid progression, or somato-sensory features. Mean-age at symptom-onset (66 years, range 53-82 years), the time between onset-of-symptoms and referral to the study (7 years, range 1-13 years), and duration-of-illness from onset-of-symptoms until death or the censor-date (9.5 years, range 1.1-17.4 years) were determined. By the censor-date, 9 cases were alive and 21 had died. Neuropathological investigations were performed on 10 cases, confirming: Alzheimer's disease only (2 cases), mixed Alzheimer's disease with Lewy bodies (2 cases), mixed Alzheimer's disease with amyloid angiopathy (1 case), moderate non-amyloid small vessel angiopathy (1 case), a non-specific neurodegenerative disorder (1 case), Parkinson's disease with Lewy body dementia (1 case), and Lewy body dementia (2 cases). No prion disease cases of any type were detected. CONCLUSION: The surveillance approach used was well received by the local clinicians and patients, though there were challenges in recruiting sufficient cases; far fewer than expected were identified, referred, and recruited. Further research is required to determine how such difficulties might be overcome. No missed cases of vCJD were found. However, there remains uncertainty whether this is because missed cases are very uncommon or because the study had insufficient power to detect them.

Patient and GP experiences of pathways to diagnosis of a second primary cancer: a qualitative study.

BACKGROUND: More people are surviving a first primary cancer and experiencing a second, different cancer. However, little is known about the diagnostic journeys of patients with second primary cancer (SPC). This study explores the views of patients and general practitioners (GPs) on their experiences of pathways to diagnosis of SPC, including the influence of a previous diagnosis of cancer on symptom appraisal, help-seeking and referral decisions. METHODS: Qualitative interviews with patients with a SPC diagnosis and case-linked GP interviews in a Scottish primary care setting. In-depth face to face or telephone interviews were conducted, underpinned by a social constructionist approach. Interviews were transcribed and Braun and Clarke's thematic analysis undertaken. Three analysts from the research team read transcripts and developed the coding framework using QSR NVivo version 10, with input from a fourth researcher. Themes were developed from refined codes and interpreted in the context of existing literature and theory. RESULTS: Interviews were conducted with 23 patients (aged 43-84 years) with a SPC diagnosis, and 7 GPs. Five patient themes were identified: Awareness of SPC, symptom appraisal and help-seeking, pathways to diagnosis, navigating the healthcare system, and impact of SPC. GPs interviews identified: experience and knowledge of SPC and referrals and decision-making. CONCLUSIONS: Insights into the pathway to diagnosis of SPC highlights the need for increased awareness of and vigilance for SPC among patients and healthcare providers (HCPs), and emotional support to manage the psychosocial burden.

Study protocol for enhanced CJD surveillance in the 65+ years population group in Scotland: an observational neuropathological screening study of banked brain tissue donations for evidence of prion disease.

INTRODUCTION: Creutzfeldt-Jakob disease (CJD) is a human prion disease that occurs in sporadic, genetic and acquired forms. Variant CJD (vCJD) is an acquired form first identified in 1996 in the UK. To date, 178 cases of vCJD have been reported in the UK, most of which have been associated with dietary exposure to the bovine spongiform encephalopathy agent. Most vCJD cases have a young age of onset, with a median age at death of 28 years. In the UK, suspected cases of vCJD are reported to the UK National Creutzfeldt-Jakob Disease Research & Surveillance Unit (NCJDRSU). There is, however, a concern that the national surveillance system might be missing some cases of vCJD or other forms of human prion disease, particularly in the older population, perhaps because of atypical clinical presentation. This study aims to establish whether there is unrecognised prion disease in people aged 65 years and above in the Scottish population by screening banked brain tissue donated to the Edinburgh Brain Bank (EBB). METHODS: Neuropathological screening of prospective and retrospective brain tissue samples is performed. This involves histopathological and immunohistochemical analysis and prion protein biochemical analysis. During the study, descriptive statistics are used to describe the study population, including the demographics and clinical, pathological and referral characteristics. Controlling for confounders, univariate and multivariate analyses will be used to compare select characteristics of newly identified suspect cases with previously confirmed cases referred to the NCJDRSU. ETHICS AND DISSEMINATION: Brain tissue donations to EBB are made voluntarily by the relatives of patients, with consent for use in research. The EBB has ethical approval to provide tissue samples to research projects (REC reference 16/ES/0084). The findings of this study will be disseminated in meetings, conferences, workshops and as peer-reviewed publications. TRIAL REGISTRATION NUMBERS: 10/S1402/69 and 10/S1402/70.

The burden of obesity in women of reproductive age and in pregnancy in a middle-income setting: A population based study from Jamaica.

INTRODUCTION: Obesity is rising globally and is associated with increased risk of adverse pregnancy outcomes. This study aims to investigate overweight and obesity and its consequences among Jamaican women of reproductive age, particularly development of diabetes, hypertension and the risk of maternal death. MATERIALS AND METHODS: A national lifestyle survey (2007/8) of 1371 women of reproductive age provided data on the prevalence of high BMI, associated risk factors and co-morbidities. A national maternal mortality surveillance database (1998-2012) of 798 maternal deaths was used to investigate maternal deaths in obese women. Chi-squared and Fisher exact tests were used. RESULTS: High BMI (> = 25kg/m2) occurred in 63% of women aged between 15 and 49 years. It was associated with increasing age, high gravidity and parity, and full time employment (p<0.001). Of those with high BMI, 5.5% were diabetic, 19.3% hypertensive and 2.8% were both diabetic and hypertensive. Obesity was recorded in 10.5% of maternal deaths, with higher proportions of deaths due to hypertension in pregnancy (27.5%), circulatory/ cardiovascular disorders (13.0%), and diabetes (4.3%) compared to 21.9%, 6.9% and 2.6% respectively in non-obese women. CONCLUSIONS: This is one of a few studies from a middle-income setting to explore maternal burden of obesity during pregnancy, which contributes to improving the knowledge base, identifying the gaps in information and increasing awareness of the growing problem of maternal overweight and obesity. While survey diagnostic conditions require cautious interpretation of findings, it is clear that obesity and related medical conditions present a substantial public health problem for emerging LMICs like Jamaica. There is an urgent need for global consensus on routine measures of the burden and risk factors associated with obesity and development of culturally appropriate interventions.

Pathways to diagnosis of a second primary cancer: protocol for a mixed-methods systematic review.

INTRODUCTION: As cancer survivors continue to live longer, the incidence of second primary cancers (SPCs) will also rise. Relatively little is understood about the diagnostic pathway for SPCs, how people appraise, interpret symptoms and seek help for a second different cancer and the experiences (including challenges) of healthcare providers relating to SPCs. This study aims to systematically appraise and synthesise the literature on the pathways to diagnosis of an SPC and the associated patient and healthcare provider experiences. METHODS: The approach taken includes systematic searches of published and unpublished literature without any date or language restrictions. MEDLINE, Embase, CAB Abstracts, MEDLINE In-Process and non-indexed citations, PsycINFO, Epub Ahead of Print, In-Process and other non-indexed citations, Ovid MEDLINE Daily, CINAHL, ASSIA, Sociological Abstracts, Web of Science, PROSPERO and grey literature will be searched to identify observational, systematic reviews, mixed methods and qualitative studies of interest. Titles, abstracts and full texts will be screened against the inclusion-exclusion criteria by at least two reviewers independently. Relevant outcomes of interest and study and population characteristics will be extracted. Synthesis will be used guided by the Pathways to Treatment model and the Olesen model of time intervals. ETHICS AND DISSEMINATION: Ethical approval is not required. This systematic review will provide a deeper understanding of the complex and heterogeneous diagnostic pathways of SPCs, while identifying common themes across the diagnostic interval, routes to diagnosis and patient and healthcare provider experiences. These findings will help provide a nuanced picture of the diagnostic pathway for SPCs that may inform policy and consistent practice. In particular, approaches to early diagnosis for an SPC; including the timing and reasons behind the decision by the patient to seek care,the challenges faced by healthcare providers, and in the development of future interventions to reduce the delay in patient time-to-presentation. PROSPERO REGISTRATION NUMBER: CRD42016051692.

A systematic review of implementation strategies to deliver guidelines on obstetric care practice in low- and middle-income countries.

BACKGROUND: Healthcare measures to prevent maternal deaths are well known. However, effective implementation of this knowledge to change practice remains a challenge. OBJECTIVES: To assess whether strategies to promote the use of guidelines can improve obstetric practices in low- and middle-income countries (LMICs). SEARCH STRATEGY: Electronic databases were searched up to February 7, 2014, using relevant terms for implementation strategies (e.g. "audit," "education," "reminder"), and maternal mortality. SELECTION CRITERIA: Randomized and non-randomized studies of implementation strategies targeting healthcare professionals within the formal health services in LMICs were included. DATA COLLECTION AND ANALYSIS: Cochrane methodological guidance was followed. Because of heterogeneity in the interventions, a narrative synthesis was completed. MAIN RESULTS: Nine studies met the inclusion criteria. Moderate-to-low-quality evidence was found to show improvement in the areas of doctor-patient communication (one study), analgesic provision (one study), the management of emergencies (two studies) and maternal and late neonatal mortality (one study each). Intervention effects were not consistent across studies. CONCLUSIONS: Implementation strategies targeting health professionals could lead to improvement in obstetric care in LMICs. Future research should explore what feature of an intervention is effective in one context and how this could be translated into another context. PROSPERO: CRD42014010310.

Barriers and enablers to guideline implementation strategies to improve obstetric care practice in low- and middle-income countries: a systematic review of qualitative evidence.

BACKGROUND: Maternal mortality remains a major international health problem in low- and middle-income countries (LMIC), and most could have been prevented by quality improvement interventions already demonstrated to be effective, such as clinical guideline implementation strategies. The aim of this systematic review was to synthesise qualitative evidence on guideline implementation strategies to improve obstetric care practice in LMIC in order to identify barriers and enablers to their successful implementation. METHODS: We searched MEDLINE and CINAHL databases for articles reporting research findings on barriers and enablers to guideline implementation strategies in obstetric care practice in LMIC. We conducted a "best fit" framework synthesis of the included studies. We used an organisational "stages of change" model as our a priori framework for the synthesis. RESULTS: Nine studies were included: all were based in Sub-Saharan Africa and in hospital health care facilities. The majority of studies (seven) evaluated one particular guideline implementation strategy: clinical audit and feedback (both criterion-based audit and maternal death reviews), and a minority (two) evaluated educational interventions. A range of barriers and enablers to successful guideline implementation was identified. A key finding of the framework synthesis was that "high" and "low" intrinsic health care professional motivation are overall enablers and barriers, respectively, of successful guideline implementation. We developed a modified "stages of change" model to take account of these findings. CONCLUSION: We have identified a number of quality improvement processes that are amenable to change at limited or no additional cost, although some identified barriers may be difficult to address without increased resources. We note the pathways to implementation may be complex and require further research to develop our understanding of individual and organisational behaviours and motivation in LMIC settings. TRIAL REGISTRATION: PROSPERO CRD42015016062.

Maternal death and obstetric care audits in Nigeria: a systematic review of barriers and enabling factors in the provision of emergency care.

BACKGROUND: Maternal death reviews and obstetric audits identify causes and circumstances related to occurrence of a maternal death or serious complication and inform improvements in quality of care. Given Nigeria's high maternal mortality, the lessons learned from past experiences can provide a good evidence base for informed decision making. We aimed to synthesise findings from maternal death reviews and other obstetric audits conducted in Nigeria through a systematic review, seeking to identify common barriers and enabling factors related to the provision of emergency obstetric care. METHODS: We searched for maternal death reviews and obstetric care audits reported in the published literature from 2000-2014. A 'best-fit' framework approach was used to extract data using a structured data extraction form. The articles that met the inclusion criteria were assessed using a nine point quality score. RESULTS: Of the 1,841 abstracts and titles at initial screening, 329 full text articles were reviewed and 43 papers fulfilled the inclusion criteria. Four types of barriers were reported related to: transport and referral; health workers; availability of services; and organisational factors. Three elements stand out in Nigeria as contributing to maternal mortality: delays in Caesarean section, unavailability of magnesium sulphate and lack of safe blood transfusion services. CONCLUSIONS: Obstetric care reviews and audits are useful activities to undertake and should be promoted by improving the processes used to conduct them, as well as extending their implementation to rural and basic level health facilities and to the community. Urgent areas for quality improvement in obstetric care, even in tertiary and teaching hospitals should focus on organisational factors to reduce delays in conducting Caesarean section and making blood and magnesium sulphate available for all who need these interventions.

Using 'appreciative inquiry' in India to improve infection control practices in maternity care: a qualitative study.

BACKGROUND: Infections acquired during childbirth are a common cause of maternal and perinatal mortality and morbidity. Changing provider behaviour and organisational settings within the health system is key to reducing the spread of infection. OBJECTIVE: To explore the opinions of health personnel on health system factors related to infection control and their perceptions of change in a sample of hospital maternity units. DESIGN: An organisational change process called 'appreciative inquiry' (AI) was introduced in three maternity units of hospitals in Gujarat, India. AI is a change process that builds on recognition of positive actions, behaviours, and attitudes. In-depth interviews were conducted with health personnel to elicit information on the environment within which they work, including physical and organisational factors, motivation, awareness, practices, perceptions of their role, and other health system factors related to infection control activities. Data were obtained from three hospitals which implemented AI and another three not involved in the intervention. RESULTS: Challenges which emerged included management processes (e.g. decision-making and problem-solving modalities), human resource shortages, and physical infrastructure (e.g. space, water, and electricity supplies). AI was perceived as having a positive influence on infection control practices. Respondents also said that management processes improved although some hospitals had already undergone an accreditation process which could have influenced the changes described. Participants reported that team relationships had been strengthened due to AI. CONCLUSION: Technical knowledge is often emphasised in health care settings and less attention is paid to factors such as team relationships, leadership, and problem solving. AI can contribute to improving infection control by catalysing and creating forums for team building, shared decision making and problem solving in an enabling environment.

The effectiveness of community-based loan funds for transport during obstetric emergencies in developing countries: a systematic review.

OBJECTIVE: Scarcity and costs of transport have been implicated as key barriers to accessing care when obstetric emergencies occur in community settings. Community-based loans have been used to increase utilization of health facilities and potentially reduce maternal mortality by providing funding at community level to provide emergency transport. This review aimed to provide evidence of the effect of community-based loan funds on utilization of health facilities and reduction of maternal mortality in developing countries. METHODS: Electronic databases of published literature and websites were searched for relevant literature using a pre-defined set of search terms, inclusion and exclusion criteria. Screening of titles, abstracts and full-text articles were done by at least two reviewers independently. Quality assessment was carried out on the selected papers. Data related to deliveries and obstetric complications attended at facilities, maternal deaths and live births were extracted to measure and compare the effects of community-based loan funds using odds ratios (ORs) and reductions in maternal mortality ratio. Forest plots are presented where possible. RESULTS: The results of the review show that groups where community-based loan funds were implemented (alongside other interventions) generally recorded increases in utilization of health facilities for deliveries, with ORs of 3.5 (0.97-15.48) and 3.55 (1.56-8.05); and an increase in utilization of emergency obstetric care with ORs of 2.22 (0.51-10.38) and 3.37 (1.78-6.37). Intervention groups also experienced a positive effect on met need for complications and a reduction in maternal mortality. CONCLUSION: There is some evidence to suggest that community-based loan funds as part of a multifaceted intervention have positive effects. Conclusions are limited by challenges of study design and bias. Further studies which strengthen the evidence of the effects of loan funds, and mechanism for their functionality, are recommended.

The burden of diabetes mellitus during pregnancy in low- and middle-income countries: a systematic review.

BACKGROUND: Little is known about the burden of diabetes mellitus (DM) in pregnancy in low- and middle-income countries despite high prevalence and mortality rates being observed in these countries. OBJECTIVE: To investigate the prevalence and geographical patterns of DM in pregnancy up to 1 year post-delivery in low- and middle-income countries. SEARCH STRATEGY: Medline, Embase, Cochrane (Central), Cinahl and CAB databases were searched with no date restrictions. SELECTION CRITERIA: Articles assessing the prevalence of gestational diabetes mellitus (GDM), and types 1 and 2 DM were sought. DATA COLLECTION AND ANALYSIS: Articles were independently screened by at least two reviewers. Forest plots were used to present prevalence rates and linear trends calculated by linear regression where appropriate. MAIN RESULTS: A total of 45 articles were included. The prevalence of GDM varied. Diagnosis was made by the American Diabetes Association criteria (1.50-15.5%), the Australian Diabetes in Pregnancy Society criteria (20.8%), the Diabetes in Pregnancy Study Group India criteria (13.4%), the European Association for the Study of Diabetes criteria (1.6%), the International Association of Diabetes and Pregnancy Study Groups criteria (8.9-20.4%), the National Diabetes Data Group criteria (0.56-6.30%) and the World Health Organization criteria (0.4-24.3%). Vietnam, India and Cuba had the highest prevalence rates. Types 1 and 2 DM were less often reported. Reports of maternal mortality due to DM were not found. No geographical patterns of the prevalence of GDM could be confirmed but data from Africa is particularly limited. CONCLUSION: Existing published data are insufficient to build a clear picture of the burden and distribution of DM in pregnancy in low- and middle-income countries. Consensus on a common diagnostic criterion for GDM is needed. Type 1 and 2 DM in pregnancy and postpartum DM are other neglected areas.

The effect of surveillance and appreciative inquiry on puerperal infections: a longitudinal cohort study in India.

OBJECTIVE: To evaluate the effects of an intervention comprising surveillance and an organisational change called Appreciative Inquiry on puerperal infections in hospitals in Gujarat state, India. METHODS: This longitudinal cohort study with a control group was conducted over 16 months between 2010 and 2012. Women who delivered in six hospitals were followed-up. After a five month pre-intervention period, the intervention was introduced in three hospitals. Monthly incidence of puerperal infection was recorded throughout the study in all six hospitals. A chi-square test and logistic regression were used to examine for associations, trends and interactions between the intervention and control groups. FINDINGS: Of the 8,124 women followed up, puerperal infections were reported in 319 women (3.9%) over the course of the study. Puerperal sepsis/genital tract infections and urinary tract infections were the two most common puerperal infections. At the end of the study, infection incidence in the control group halved from 7.4% to 3.5%. Levels in the intervention group reduced proportionately even more, from 4.3% to 1.7%. A chi-square test for trend confirmed the reduction of infection in the intervention and control groups (p<0.0001) but the trends were not statistically different from one another. There was an overall reduction of infection by month (OR = 0.94 95% CI 0.91-0.97). Risk factors like delivery type, complications or delivery attendant showed no association with infection. CONCLUSION: Interruption of resource flows in the health system occurred during the intervention phase, which may have affected the findings. The incidence of infection fell in both control and intervention groups during the course of the study. It is not clear if appreciative inquiry contributed to the reductions observed. A number of practical and methodological limitations were faced. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN03513186.

Incidence of adverse outcomes associated with gestational diabetes mellitus in low- and middle-income countries.

BACKGROUND: The contribution of medical conditions such as diabetes mellitus to maternal and neonatal ill-health in low- and middle-income countries is not well documented. OBJECTIVES: To ascertain the incidence of adverse outcomes associated with gestational diabetes mellitus (GDM) in these countries. SEARCH STRATEGY: Electronic databases were searched between 1990 and 2011. SELECTION CRITERIA: Observational, experimental, and quasi-experimental studies reporting adverse outcomes associated with GDM in mothers and their infants in low- and middle-income countries were included. DATA COLLECTION AND ANALYSIS: Titles and abstracts were screened, and full-text articles were independently assessed by at least 2 reviewers. Characteristics of studies were tabulated and quality assessment performed. Median and interquartile range (IQR) were computed for each adverse outcome. MAIN RESULTS: 25 articles were included from an initial 1282 citations. High median incidences of cesarean (43.8%; IQR, 34.9%-65.9%), neonatal jaundice (17.1%; IQR, 8.5%-22.9%), and macrosomia (17.0%; IQR, 8.3%-32.5%) were reported in women with GDM. CONCLUSIONS: The high incidence of some complications of GDM is a concern and may indicate poorer care for women with GDM in low-resource settings. The wide IQRs found indicate uncertainty about the burden of GDM in these settings.

The effectiveness of emergency obstetric referral interventions in developing country settings: a systematic review.

BACKGROUND: Pregnancy complications can be unpredictable and many women in developing countries cannot access health facilities where life-saving care is available. This study assesses the effects of referral interventions that enable pregnant women to reach health facilities during an emergency, after the decision to seek care is made. METHODS AND FINDINGS: Selected bibliographic databases were searched with no date or language restrictions. Randomised controlled trials and quasi experimental study designs with a comparison group were included. Outcomes of interest included maternal and neonatal mortality and other intermediate measures such as service utilisation. Two reviewers independently selected, appraised, and extracted articles using predefined fields. Forest plots, tables, and qualitative summaries of study quality, size, and direction of effect were used for analysis. Nineteen studies were included. In South Asian settings, four studies of organisational interventions in communities that generated funds for transport reduced neonatal deaths, with the largest effect seen in India (odds ratio 0·48 95% CI 0·34-0·68). Three quasi experimental studies from sub-Saharan Africa reported reductions in stillbirths with maternity waiting home interventions, with one statistically significant result (OR 0.56 95% CI 0.32-0.96). Effects of interventions on maternal mortality were unclear. Referral interventions usually improved utilisation of health services but the opposite effect was also documented. The effects of multiple interventions in the studies could not be disentangled. Explanatory mechanisms through which the interventions worked could not be ascertained. CONCLUSIONS: Community mobilisation interventions may reduce neonatal mortality but the contribution of referral components cannot be ascertained. The reduction in stillbirth rates resulting from maternity waiting homes needs further study. Referral interventions can have unexpected adverse effects. To inform the implementation of effective referral interventions, improved monitoring and evaluation practices are necessary, along with studies that develop better understanding of how interventions work.