The Community-Level Interventions for Pre-eclampsia (CLIP) cluster randomised trials in Mozambique, Pakistan, and India: an individual participant-level meta-analysis

To overcome the three delays in triage, transport and treatment that underlie adverse pregnancy outcomes, we aimed to reduce all-cause adverse outcomes with community-level interventions targeting women with pregnancy hypertension in three low-income countries. Methods: In this individual participant-level meta-analysis, we de-identified and pooled data from the Community-Level Interventions for Pre-eclampsia (CLIP) cluster randomised controlled trials in Mozambique, Pakistan, and India, which were run in 2014-17. Consenting pregnant women, aged 12-49 years, were recruited in their homes. Clusters, defined by local administrative units, were randomly assigned (1:1) to intervention or control groups. The control groups continued local standard of care. The intervention comprised community engagement and existing community health worker-led mobile health-supported early detection, initial treatment, and hospital referral of women with hypertension. For this meta-analysis, as for the original studies, the primary outcome was a composite of maternal or perinatal outcome (either maternal, fetal, or neonatal death, or severe morbidity for the mother or baby), assessed by unmasked trial surveillance personnel. For this analysis, we included all consenting participants who were followed up with completed pregnancies at trial end. We analysed the outcome data with multilevel modelling and present data with the summary statistic of adjusted odds ratios (ORs) with 95% CIs (fixed effects for maternal age, parity, maternal education, and random effects for country and cluster). This meta-analysis is registered with PROSPERO, CRD42018102564. Findings: Overall, 44 clusters (69 330 pregnant women) were randomly assigned to intervention (22 clusters [36 008 pregnancies]) or control (22 clusters [33 322 pregnancies]) groups. 32 290 (89·7%) pregnancies in the intervention group and 29 698 (89·1%) in the control group were followed up successfully. Median maternal age of included women was 26 years (IQR 22-30). In the intervention clusters, 6990 group and 16 691 home-based community engagement sessions and 138 347 community health worker-led visits to 20 819 (57·8%) of 36 008 women (of whom 11 095 [53·3%] had a visit every 4 weeks) occurred. Blood pressure and dipstick proteinuria were assessed per protocol. Few women were eligible for methyldopa for severe hypertension (181 [1%] of 20 819) or intramuscular magnesium sulfate for pre-eclampsia (198 [1%]), of whom most accepted treatment (162 [89·5%] of 181 for severe hypertension and 133 [67·2%] of 198 for pre-eclampsia). 1255 (6%) were referred to a comprehensive emergency obstetric care facility, of whom 864 (82%) accepted the referral. The primary outcome was similar in the intervention (7871 [24%] of 32 290 pregnancies) and control clusters (6516 [22%] of 29 698; adjusted OR 1·17, 95% CI 0·90-1·51; p=0·24). No intervention-related serious adverse events occurred, and few adverse effects occurred after in-community...

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.

A population-based, multifaceted strategy to implement antenatal corticosteroid treatment versus standard care for the reduction of neonatal mortality due to preterm birth in low-income and middle-income countries: the ACT cluster-randomised trial.

BACKGROUND: Antenatal corticosteroids for pregnant women at risk of preterm birth are among the most effective hospital-based interventions to reduce neonatal mortality. We aimed to assess the feasibility, effectiveness, and safety of a multifaceted intervention designed to increase the use of antenatal corticosteroids at all levels of health care in low-income and middle-income countries. METHODS: In this 18-month, cluster-randomised trial, we randomly assigned (1:1) rural and semi-urban clusters within six countries (Argentina, Guatemala, India, Kenya, Pakistan, and Zambia) to standard care or a multifaceted intervention including components to improve identification of women at risk of preterm birth and to facilitate appropriate use of antenatal corticosteroids. The primary outcome was 28-day neonatal mortality among infants less than the 5th percentile for birthweight (a proxy for preterm birth) across the clusters. Use of antenatal corticosteroids and suspected maternal infection were additional main outcomes. This trial is registered with ClinicalTrials.gov, number NCT01084096. FINDINGS: The ACT trial took place between October, 2011, and March, 2014 (start dates varied by site). 51 intervention clusters with 47,394 livebirths (2520 [5%] less than 5th percentile for birthweight) and 50 control clusters with 50,743 livebirths (2258 [4%] less than 5th percentile) completed follow-up. 1052 (45%) of 2327 women in intervention clusters who delivered less-than-5th-percentile infants received antenatal corticosteroids, compared with 215 (10%) of 2062 in control clusters (p<0·0001). Among the less-than-5th-percentile infants, 28-day neonatal mortality was 225 per 1000 livebirths for the intervention group and 232 per 1000 livebirths for the control group (relative risk [RR] 0·96, 95% CI 0·87-1·06, p=0·65) and suspected maternal infection was reported in 236 (10%) of 2361 women in the intervention group and 133 (6%) of 2094 in the control group (odds ratio [OR] 1·67, 1·33-2·09, p<0·0001). Among the whole population, 28-day neonatal mortality was 27·4 per 1000 livebirths for the intervention group and 23·9 per 1000 livebirths for the control group (RR 1·12, 1·02-1·22, p=0·0127) and suspected maternal infection was reported in 1207 (3%) of 48,219 women in the intervention group and 867 (2%) of 51,523 in the control group (OR 1·45, 1·33-1·58, p<0·0001). INTERPRETATION: Despite increased use of antenatal corticosteroids in low-birthweight infants in the intervention groups, neonatal mortality did not decrease in this group, and increased in the population overall. For every 1000 women exposed to this strategy, an excess of 3·5 neonatal deaths occurred, and the risk of maternal infection seems to have been increased. FUNDING: Eunice Kennedy Shriver National Institute of Child Health and Human Development.