Shock index thresholds to predict adverse outcomes in maternal hemorrhage and sepsis: A prospective cohort study.

INTRODUCTION: Shock index (SI) is a predictor of hemodynamic compromise in obstetric patients. The SI threshold for action is not well understood. We aimed to evaluate SI thresholds as predictors of outcomes in obstetric patients. MATERIAL AND METHODS: We undertook a prospective cohort study at three South African hospitals of women with postpartum hemorrhage (n = 283) or maternal sepsis (n = 126). The "first" and "worst" SI following diagnosis were recorded. SI was compared with conventional vital signs as predictors of outcomes. The performance of SI <.9, SI .9-1.69 and SI ≥1.7 to predict outcomes (maternal death; Critical Care Unit admission; major procedure; hysterectomy) and hemorrhage-specific outcomes (lowest hemoglobin <70 g/l; blood transfusion ≥4 IU) were evaluated. RESULTS: "First" SI was one of two best performing vital signs for every outcome in postpartum hemorrhage and sepsis. In hemorrhage, risk of all outcomes increased with increasing "first" SI; for blood transfusion ≥4 IU odds ratio was 4.24 (95% confidence interval 1.25-14.36) for SI ≥1.7 vs SI .9-1.69. In sepsis, risk of all outcomes increased with increasing "worst" SI. Sensitivity, specificity, positive and negative predictive values of "first" SI <.9 vs SI ≥.9 for maternal death were 100.0%, 55.2%, 4.6% and 100.0%, respectively, in hemorrhage and 80.0%, 50.4%, 12.3% and 96.7%, respectively, in sepsis. CONCLUSIONS: The shock index was a consistent predictor of outcomes compared with conventional vital signs in postpartum hemorrhage and sepsis. SI <.9 performed well as a rule-out test and SI .9-1.69 and SI ≥1.7 indicated increased risk of all outcomes in both cohorts. These thresholds may alert to the need for urgent intervention and prevent maternal deaths.

Exploring the effect of implementation and context on a stepped-wedge randomised controlled trial of a vital sign triage device in routine maternity care in low-resource settings.

BACKGROUND: Interventions aimed at reducing maternal mortality are increasingly complex. Understanding how complex interventions are delivered, to whom, and how they work is key in ensuring their rapid scale-up. We delivered a vital signs triage intervention into routine maternity care in eight low- and middle-income countries with the aim of reducing a composite outcome of morbidity and mortality. This was a pragmatic, hybrid effectiveness-implementation stepped-wedge randomised controlled trial. In this study, we present the results of the mixed-methods process evaluation. The aim was to describe implementation and local context and integrate results to determine whether differences in the effect of the intervention across sites could be explained. METHODS: The duration and content of implementation, uptake of the intervention and its impact on clinical management were recorded. These were integrated with interviews (n = 36) and focus groups (n = 19) at 3 months and 6-9 months after implementation. In order to determine the effect of implementation on effectiveness, measures were ranked and averaged across implementation domains to create a composite implementation strength score and then correlated with the primary outcome. RESULTS: Overall, 61.1% (n = 2747) of health care providers were trained in the intervention (range 16.5% to 89.2%) over a mean of 10.8 days. Uptake and acceptability of the intervention was good. All clusters demonstrated improved availability of vital signs equipment. There was an increase in the proportion of women having their blood pressure measured in pregnancy following the intervention (79.2% vs. 97.6%; OR 1.30 (1.29-1.31)) and no significant change in referral rates (3.7% vs. 4.4% OR 0.89; (0.39-2.05)). Availability of resources and acceptable, effective referral systems influenced health care provider interaction with the intervention. There was no correlation between process measures within or between domains, or between the composite score and the primary outcome. CONCLUSIONS: This process evaluation has successfully described the quantity and quality of implementation. Variation in implementation and context did not explain differences in the effectiveness of the intervention on maternal mortality and morbidity. We suggest future trials should prioritise in-depth evaluation of local context and clinical pathways. TRIAL REGISTRATION: Trial registration: ISRCTN41244132 . Registered on 2 Feb 2016.

Incidence of eclampsia and related complications across 10 low- and middle-resource geographical regions: Secondary analysis of a cluster randomised controlled trial.

BACKGROUND: In 2015, approximately 42,000 women died as a result of hypertensive disorders of pregnancy worldwide; over 99% of these deaths occurred in low- and middle-income countries. The aim of this paper is to describe the incidence and characteristics of eclampsia and related complications from hypertensive disorders of pregnancy across 10 low- and middle-income geographical regions in 8 countries, in relation to magnesium sulfate availability. METHODS AND FINDINGS: This is a secondary analysis of a stepped-wedge cluster randomised controlled trial undertaken in sub-Saharan Africa, India, and Haiti. This trial implemented a novel vital sign device and training package in routine maternity care with the aim of reducing a composite outcome of maternal mortality and morbidity. Institutional-level consent was obtained, and all women presenting for maternity care were eligible for inclusion. Data on eclampsia, stroke, admission to intensive care with a hypertensive disorder of pregnancy, and maternal death from a hypertensive disorder of pregnancy were prospectively collected from routine data sources and active case finding, together with data on perinatal outcomes in women with these outcomes. In 536,233 deliveries between 1 April 2016 and 30 November 2017, there were 2,692 women with eclampsia (0.5%). In total 6.9% (n = 186; 3.47/10,000 deliveries) of women with eclampsia died, and a further 51 died from other complications of hypertensive disorders of pregnancy (0.95/10,000). After planned adjustments, the implementation of the CRADLE intervention was not associated with any significant change in the rates of eclampsia, stroke, or maternal death or intensive care admission with a hypertensive disorder of pregnancy. Nearly 1 in 5 (17.9%) women with eclampsia, stroke, or a hypertensive disorder of pregnancy causing intensive care admission or maternal death experienced a stillbirth or neonatal death. A third of eclampsia cases (33.2%; n = 894) occurred in women under 20 years of age, 60.0% in women aged 20-34 years (n = 1,616), and 6.8% (n = 182) in women aged 35 years or over. Rates of eclampsia varied approximately 7-fold between sites (range 19.6/10,000 in Zambia Centre 1 to 142.0/10,000 in Sierra Leone). Over half (55.1%) of first eclamptic fits occurred in a health-care facility, with the remainder in the community. Place of first fit varied substantially between sites (from 5.9% in the central referral facility in Sierra Leone to 85% in Uganda Centre 2). On average, magnesium sulfate was available in 74.7% of facilities (range 25% in Haiti to 100% in Sierra Leone and Zimbabwe). There was no detectable association between magnesium sulfate availability and the rate of eclampsia across sites (p = 0.12). This analysis may have been influenced by the selection of predominantly urban and peri-urban settings, and by collection of only monthly data on availability of magnesium sulfate, and is limited by the lack of demographic data in the population of women delivering in the trial areas. CONCLUSIONS: The large variation in eclampsia and maternal and neonatal fatality from hypertensive disorders of pregnancy between countries emphasises that inequality and inequity persist in healthcare for women with hypertensive disorders of pregnancy. Alongside the growing interest in improving community detection and health education for these disorders, efforts to improve quality of care within healthcare facilities are key. Strategies to prevent eclampsia should be informed by local data. TRIAL REGISTRATION: ISRCTN: 41244132.

Effect of a novel vital sign device on maternal mortality and morbidity in low-resource settings: a pragmatic, stepped-wedge, cluster-randomised controlled trial.

BACKGROUND: In 2015, an estimated 303 000 women died in pregnancy and childbirth. Obstetric haemorrhage, sepsis, and hypertensive disorders of pregnancy account for more than 50% of maternal deaths worldwide. There are effective treatments for these pregnancy complications, but they require early detection by measurement of vital signs and timely administration to save lives. The primary aim of this trial was to determine whether implementation of the CRADLE Vital Sign Alert and an education package into community and facility maternity care in low-resource settings could reduce a composite of all-cause maternal mortality or major morbidity (eclampsia and hysterectomy). METHODS: We did a pragmatic, stepped-wedge, cluster-randomised controlled trial in ten clusters across Africa, India, and Haiti, introducing the device into routine maternity care. Each cluster contained at least one secondary or tertiary hospital and their main referral facilities. Clusters crossed over from existing routine care to the CRADLE intervention in one of nine steps at 2-monthly intervals, with CRADLE devices replacing existing equipment at the randomly allocated timepoint. A computer-generated randomly allocated sequence determined the order in which the clusters received the intervention. Because of the nature of the intervention, this trial was not masked. Data were gathered monthly, with 20 time periods of 1 month. The primary composite outcome was at least one of eclampsia, emergency hysterectomy, and maternal death. This study is registered with the ISRCTN registry, number ISRCTN41244132. FINDINGS: Between April 1, 2016, and Nov 30, 2017, among 536 223 deliveries, the primary outcome occurred in 4067 women, with 998 maternal deaths, 2692 eclampsia cases, and 681 hysterectomies. There was an 8% decrease in the primary outcome from 79·4 per 10 000 deliveries pre-intervention to 72·8 per 10 000 deliveries post-intervention (odds ratio [OR] 0·92, 95% CI 0·86-0·97; p=0·0056). After planned adjustments for variation in event rates between and within clusters over time, the unexpected degree of variability meant we were unable to judge the benefit or harms of the intervention (OR 1·22, 95% CI 0·73-2·06; p=0·45). INTERPRETATION: There was an absolute 8% reduction in primary outcome during the trial, with no change in resources or staffing, but this reduction could not be directly attributed to the intervention due to variability. We encountered unanticipated methodological challenges with this trial design, which can provide valuable learning for future research and inform the trial design of future international stepped-wedge trials. FUNDING: Newton Fund Global Research Programme: UK Medical Research Council; Department of Biotechnology, Ministry of Science & Technology, Government of India; and UK Department of International Development.

Development and evaluation of a novel Vital Signs Alert device for use in pregnancy in low-resource settings.

OBJECTIVES: Haemorrhage, hypertension, sepsis and abortion complications (often from haemorrhage or sepsis) contribute to 60% of all maternal deaths. Each is associated with vital signs (blood pressure (BP) and pulse) abnormalities, and the majority of deaths are preventable through simple and timely intervention. This paper presents the development and evaluation of the CRADLE Vital Signs Alert (VSA), an accurate, low-cost and easy-to-use device measuring BP and pulse with an integrated traffic light early warning system. The VSA was designed to be used by all cadres of healthcare providers for pregnant women in low-resource settings with the aim to prevent avoidable maternal mortality and morbidity. METHODS: The development and the mixed-methods clinical evaluation of the VSA are described. RESULTS: Preliminary fieldwork identified that introduction of BP devices to rural clinics improved antenatal surveillance of BP in pregnant women. The aesthetics of the integrated traffic light system were developed through iterative qualitative evaluation. The traffic lights trigger according to evidence-based vital sign thresholds in hypertension and haemodynamic compromise from haemorrhage and sepsis. The VSA can be reliably used as an auscultatory device, as well as its primary semiautomated function, and is suitable as a self-monitor used by pregnant women. CONCLUSION: The VSA is an accurate device incorporating an evidence-based traffic light early warning system. It is designed to ensure suitability for healthcare providers with limited training and may improve care for women in pregnancy, childbirth and in the postnatal period.

Maternal and perinatal adverse outcomes in women with pre-eclampsia cared for at facility-level in South Africa: a prospective cohort study.

BACKGROUND: Hypertensive disorders of pregnancy contribute to 14% of all maternal deaths, the majority of which occur in low- and middle-income countries. The aim of the study was to describe the maternal and perinatal clinical outcomes of women with pre-eclampsia living in middle- and low-income countries. METHODS: The study was a prospective observational study of women with pre-eclampsia (n = 1547, 42 twin pregnancies) at three South African tertiary facilities. Using stepwise logistic regression model area under the receiver operating characteristic curve (AUROC) values, the association between maternal baseline and admission characteristics and risk of adverse outcomes was evaluated. Main outcome measures were eclampsia, kidney injury and perinatal death. RESULTS: In 1547 women with pre-eclampsia, 16 (1%) died, 147 (9.5%) had eclampsia, four (0.3%) had a stroke and 272 (17.6%) had kidney injury. Of the 1589 births, there were 332 (21.0%) perinatal deaths; of these, 281 (84.5%) were stillbirths. Of 1308 live births, 913 (70.0%) delivered <37 completed weeks and 544 (41.7%) delivered <34 weeks' gestation. Young maternal age (AUROC = 0.76, 95% confidence interval (CI) = 0.71-0.80) and low Body Mass Index BMI (AUROC 0.65, 95% CI = 0.59-0.69) were significant predictors of eclampsia. Highest systolic blood pressure had the strongest association with kidney injury, (AUROC = 0.64, 95% CI = 0.60-0.68). Early gestation at admission was most strongly associated with perinatal death (AUROC = 0.81, 95% CI = 0.77-0.84). CONCLUSIONS: The incidence of pre-eclampsia complications, perinatal death and preterm delivery in women referred to tertiary care in South Africa was much higher than reported in other low- and middle-income studies and despite access to tertiary care interventions. Teenage mothers and those with low BMI were at highest risk of eclampsia. This information could be used to inform guidelines, the research agenda and policy.

Evaluation of a novel vital sign device to reduce maternal mortality and morbidity in low-resource settings: a mixed method feasibility study for the CRADLE-3 trial.

BACKGROUND: The CRADLE-3 trial is a stepped-wedge randomised controlled trial aiming to reduce maternal mortality and morbidity by implementing a novel vital sign device (CRADLE Vital Sign Alert) and training package into routine maternity care in 10 low-income sites. The MRC Guidance on complex interventions proposes that interventions and implementation strategies be shaped by early phase piloting and development work. We present the findings of a three-month mixed-methodology feasibility study for this trial, describe how this was informed by the MRC guidance and the study design was refined. METHODS: The fidelity, dose, feasibility and acceptability of implementation and training materials were assessed in three representative non-trial sites (Zimbabwe, Ethiopia, India) using multiple-choice questionnaires, evaluation of clinical management (action log), healthcare provider (HCP) semi-structured interviews and focus groups 4-10 weeks after implementation. Simultaneously, the 10 sites included in the main trial (eight countries) collected primary outcome data to inform the power calculation and randomisation allocation and assess the feasibility of data collection. RESULTS: The package was implemented with high fidelity (85% of HCP trained, n = 204). The questionnaires indicated a good understanding of device use with 75% of participants scoring > 75% (n = 97; 90% of those distributed). Action logs were inconsistently completed but indicated that the majority of HCP responded appropriately to abnormal results. From 18 HCP interviews and two focus groups it was widely reported that the intervention improved capacity to make clinical decisions, escalate care and make appropriate referrals. Nine of the ten main trial sites achieved ethical approval for pilot data collection. Intensive care was an inconsistent marker of morbidity and stroke an infrequent outcome and therefore they were removed from the main trial composite outcome. Tools and methods of data collection were optimized and event rates used to inform randomisation. CONCLUSIONS: This feasibility study demonstrates that the components of the intervention were acceptable, methods of implementing were successful and the main trial design would be feasible. Qualitative work identified key moderators that informed the main trial process evaluation. Changes to the training package, implementation strategy, study design and processes were identified to refine the implementation in the main trial. TRIAL REGISTRATION: ISRCTN41244132 ; Registered 24/11/2015.

Evaluation of a novel device for the management of high blood pressure and shock in pregnancy in low-resource settings: study protocol for a stepped-wedge cluster-randomised controlled trial (CRADLE-3 trial).

BACKGROUND: Obstetric haemorrhage, sepsis and pregnancy hypertension account for more than 50% of maternal deaths worldwide. Early detection and effective management of these conditions relies on vital signs. The Microlife® CRADLE Vital Sign Alert (VSA) is an easy-to-use, accurate device that measures blood pressure and pulse. It incorporates a traffic-light early warning system that alerts all levels of healthcare provider to the need for escalation of care in women with obstetric haemorrhage, sepsis or pregnancy hypertension, thereby aiding early recognition of haemodynamic instability and preventing maternal mortality and morbidity. The aim of the trial was to determine whether implementation of the CRADLE intervention (the Microlife® CRADLE VSA device and CRADLE training package) into routine maternity care in place of existing equipment will reduce a composite outcome of maternal mortality and morbidity in low- and middle-income country populations. METHODS: The CRADLE-3 trial was a stepped-wedge cluster-randomised controlled trial of the CRADLE intervention compared to routine maternity care. Each cluster crossed from routine maternity care to the intervention at 2-monthly intervals over the course of 20 months (April 2016 to November 2017). All women identified as pregnant or within 6 weeks postpartum, presenting for maternity care in cluster catchment areas were eligible to participate. Primary outcome data (composite of maternal death, eclampsia and emergency hysterectomy per 10,000 deliveries) were collected at 10 clusters (Gokak, Belgaum, India; Harare, Zimbabwe; Ndola, Zambia; Lusaka, Zambia; Free Town, Sierra Leone; Mbale, Uganda; Kampala, Uganda; Cap Haitien, Haiti; South West, Malawi; Addis Ababa, Ethiopia). This trial was informed by the Medical Research Council guidance for complex interventions. A process evaluation was undertaken to evaluate implementation in each site and a cost-effectiveness evaluation will be undertaken. DISCUSSION: All aspects of this protocol have been evaluated in a feasibility study, with subsequent optimisation of the intervention. This trial will demonstrate the potential impact of the CRADLE intervention on reducing maternal mortality and morbidity in low-resource settings. It is anticipated that the relatively low cost of the intervention and ease of integration into existing health systems will be of significant interest to local, national and international health policy-makers. TRIAL REGISTRATION: ISCRTN41244132. Registered on 2 February 2016. Prospective protocol modifications have been recorded and were communicated to the Ethics Committees and Trials Committees. The adapted Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) Checklist and the SPIRIT Checklist are attached as Additional file 1.

Early warning system hypertension thresholds to predict adverse outcomes in pre-eclampsia: A prospective cohort study.

OBJECTIVES: To evaluate the association between blood pressure (BP) measurements and adverse outcomes in women with pre-eclampsia. STUDY DESIGN: A prospective cohort study of women with pre-eclampsia admitted to three South African tertiary facilities. BP was measured using the CRADLE Vital Signs Alert (VSA), incorporated with a traffic light early warning system; green: systolic BP <140 mmHg and diastolic BP <90 mmHg, yellow: systolic BP 140-159 and/or diastolic BP 90-109 mmHg (but neither is above the upper threshold), red: systolic BP ≥160 mmHg and/or diastolic BP ≥110 mmHg. MAIN OUTCOME MEASURES: Maternal: death, eclampsia, stroke, kidney injury; process measures: magnesium sulfate use, Critical Care Unit (CCU) admission; perinatal: stillbirth, neonatal death, preterm delivery. RESULTS: Of 1547 women with pre-eclampsia (including 42 twin pregnancies), 33.0% of women triggered a red light on admission and 78.6% at their highest BP. Severe hypertension and adverse outcomes were common across yellow and red categories. Comparing admission red to yellow lights, there was a significant increase in kidney injury (OR 1.74, CI 1.31-2.33, trend test p = .003), magnesium sulfate use (OR 3.40, CI 2.24-5.18, p < .001) and CCU admission (OR 1.50, CI 1.18-1.91, p < .001), but not for maternal death, eclampsia, extended perinatal death or preterm delivery. CONCLUSION: The CRADLE VSA, with integrated traffic light early warning system, can identify women who are hypertensive, at increased risk of severe pre-eclampsia complications and in need of escalation of care. Women who triggered a red light were at increased risk of kidney injury, magnesium sulfate use and CCU admission.

Hybrid vitronectin-mimicking polycaprolactone scaffolds for human retinal progenitor cell differentiation and transplantation.

Many advances have been made in an attempt to treat retinal degenerative diseases, such as age-related macular degeneration and retinitis pigmentosa. The irreversible loss of photoreceptors is common to both, and currently no restorative clinical treatment exists. It has been shown that retinal progenitor and photoreceptor precursor cell transplantation can rescue the retinal structure and function. Importantly, retinal progenitor cells can be collected from the developing neural retina with further expansion and additional modification in vitro, and the delivery into the degenerative host can be performed as a single-cell suspension injection or as a complex graft transplantation. Previously, we have described several polymer scaffolds for culture and transplantation of retinal progenitor cells of both mouse and human origin. This tissue engineering strategy increases donor cell survival and integration. We have also shown that biodegradable poly(ɛ-caprolactone) induces mature photoreceptor differentiation from human retinal progenitor cells. However, poor adhesive properties limit its use, and therefore it requires additional surface modification. The aim of this work was to study vitronectin-mimicking oligopeptides (Synthemax II-SC) poly(ɛ-caprolactone) films and their effects on human retinal progenitor cell adhesion, proliferation, and differentiation. Here, we show that the incorporation of vitronectin-mimicking oligopeptide into poly(ɛ-caprolactone) leads to dose-dependent increases in cell adhesion; the optimum dose identified as 30 µg/ml. Inhibition of human retinal progenitor cells proliferation was seen on poly(ɛ-caprolactone) and was maintained with the hybrid scaffold. This has been shown to be beneficial for driving cell differentiation. Additionally, we observed equal expression of Nrl, rhodopsin, recoverin, and rod outer membrane 1 after differentiation on the hybrid scaffold as compared to the standard fibronectin coating of poly(ɛ-caprolactone). After transplantation into rd1 retina degenerative mice, human retinal progenitor cells were able to migrate to the outer nuclear layer and survive for three weeks. We conclude that Synthemax II-SC can be incorporated into poly(ɛ-caprolactone) to create a hybrid chemically defined scaffold for clinical application.