Economic and cost-effectiveness analysis of the community-level interventions for pre-eclampsia (CLIP) trials in India, Pakistan and Mozambique

Background: The Community-Level Interventions for Pre-eclampsia (CLIP) trials (NCT01911494) in India, Pakistan and Mozambique (February 2014-2017) involved community engagement and task sharing with community health workers for triage and initial treatment of pregnancy hypertension. Maternal and perinatal mortality was less frequent among women who received ≥8 CLIP contacts. The aim of this analysis was to assess the incremental costs and cost-effectiveness of the CLIP intervention overall in comparison to standard of care, and by PIERS (Pre-eclampsia Integrated Estimate of RiSk) On the Move (POM) mobile health application visit frequency.Methods: Included were all women enrolled in the three CLIP trials who had delivered with known outcomes by trial end. According to the number of POM-guided home contacts received (0, 1-3, 4-7, ≥8), costs were collected from annual budgets and spending receipts, with inclusion of family opportunity costs in Pakistan. A decision tree model was built to determine the cost-effectiveness of the intervention (vs usual care), based on the primary clinical endpoint of years of life lost (YLL) for mothers and infants. A probabilistic sensitivity analysis was used to assess uncertainty in the cost and clinical outcomes.Results: The incremental per pregnancy cost of the intervention was US$12.66 (India), US$11.51 (Pakistan) and US$13.26 (Mozambique). As implemented, the intervention was not cost-effective due largely to minimal differences in YLL between arms. However, among women who received ≥8 CLIP contacts (four in Pakistan), the probability of health system and family (Pakistan) cost-effectiveness was ≥80% (all countries).Conclusion: The intervention was likely to be cost-effective for women receiving ≥8 contacts in Mozambique and India, and ≥4 in Pakistan, supporting WHO guidance on antenatal contact frequency.Trial registration number: NCT01911494

Planned delivery or expectant management for late preterm pre-eclampsia in low-income and middle-income countries (CRADLE-4): a multicentre, open-label, randomised controlled trial

Background: Pre-eclampsia is a leading cause of maternal and perinatal mortality. Evidence regarding interventions in a low-income or middle-income setting is scarce. We aimed to evaluate whether planned delivery between 34+ 0 and 36+ 6 weeks’ gestation can reduce maternal mortality and morbidity without increasing perinatal complications in India and Zambia. / Methods: In this parallel-group, multicentre, open-label, randomised controlled trial, we compared planned delivery versus expectant management in women with pre-eclampsia from 34+ 0 to 36+ 6 weeks’ gestation. Participants were recruited from nine hospitals and referral facilities in India and Zambia and randomly assigned to planned delivery or expectant management in a 1:1 ratio by a secure web-based randomisation facility hosted by MedSciNet. Randomisation was stratified by centre and minimised by parity, single-fetus pregnancy or multi-fetal pregnancy, and gestational age. The primary maternal outcome was a composite of maternal mortality or morbidity with a superiority hypothesis. The primary perinatal outcome was a composite of one or more of: stillbirth, neonatal death, or neonatal unit admission of more than 48 h with a non-inferiority hypothesis (margin of 10% difference). Analyses were by intention to treat, with an additional per-protocol analysis for the perinatal outcome. The trial was prospectively registered with ISRCTN, 10672137. The trial is closed to recruitment and all follow-up has been completed. / Findings: Between Dec 19, 2019, and March 31, 2022, 565 women were enrolled. 284 women (282 women and 301 babies analysed) were allocated to planned delivery and 281 women (280 women and 300 babies analysed) were allocated to expectant management. The incidence of the primary maternal outcome was not significantly different in the planned delivery group (154 [55%]) compared with the expectant management group (168 [60%]; adjusted risk ratio [RR] 0·91, 95% CI 0·79 to 1·05). The incidence of the primary perinatal outcome by intention to treat was non-inferior in the planned delivery group (58 [19%]) compared with the expectant management group (67 [22%]; adjusted risk difference –3·39%, 90% CI –8·67 to 1·90; non-inferiority p<0·0001). The results from the per-protocol analysis were similar. There was a significant reduction in severe maternal hypertension (adjusted RR 0·83, 95% CI 0·70 to 0·99) and stillbirth (0·25, 0·07 to 0·87) associated with planned delivery. There were 12 serious adverse events in the planned delivery group and 21 in the expectant management group. / Interpretation: Clinicians can safely offer planned delivery to women with late preterm pre-eclampsia, in a low-income or middle-income country. Planned delivery reduces stillbirth, with no increase in neonatal unit admissions or neonatal morbidity and reduces the risk of severe maternal hypertension. Planned delivery from 34 weeks’ gestation should therefore be considered as an intervention to reduce pre-eclampsia associated mortality and morbidity in these settings. / Funding: UK Medical Research Council and Indian Department of Biotechnology

A pre-post study of a multi-country scale up of resuscitation training of facility birth attendants: does Helping Babies Breathe training save lives?

Background: Whether facility-based implementation of Helping Babies Breathe (HBB) reduces neonatal mortality at a population level in low and middle income countries (LMIC) has not been studied. Therefore, we evaluated HBB implementation in this context where our study team has ongoing prospective outcome data on all pregnancies regardless of place of delivery. Methods: We compared outcomes of birth cohorts in three sites in India and Kenya pre-post implementation of a facility-based intervention, using a prospective, population-based registry in 52 geographic clusters. Our hypothesis was that HBB implementation would result in a 20 % decrease in the perinatal mortality rate (PMR) among births ≥1500 g. Results: We enrolled 70,704 births during two 12-month study periods. Births within each site did not differ prepost intervention, except for an increased proportion ofbirths; however, a post-hoc analysis stratified by birthweight documented improvement insurvival. Conclusions: Rapid scale up of HBB training of facility birth attendants in three diverse sites in India and Kenya was not associated with consistent improvements in mortality among all neonates ≥1500 g; however, differential improvements inpopulation, data collection, and ongoing quality monitoring activities. Trial registration: The study was registered at ClinicalTrials.gov: NCT0168101

Causes and circumstances of maternal death:a secondary analysis of the Community-Level Interventions for (CLIP) trials cohort

BACKGROUND: Incomplete vital registration systems mean that causes of death during pregnancy and childbirth are poorly understood in low-income and middle-income countries. To inform global efforts to reduce maternal mortality, we compared physician review and computerised analysis of verbal autopsies (interpreting verbal autopsies [InterVA] software), to understand their agreement on maternal cause of death and circumstances of mortality categories (COMCATs) in the Community-Level Interventions for Pre-eclampsia (CLIP) cluster randomised trials. METHODS: The CLIP trials took place in India, Pakistan, and Mozambique, enrolling pregnant women aged 12–49 years between Nov 1, 2014, and Feb 28, 2017. 69 330 pregnant women were enrolled in 44 clusters (36 008 in the 22 intervention clusters and 33 322 in the 22 control clusters). In this secondary analysis of maternal deaths in CLIP, we included women who died in any of the 22 intervention clusters or 22 control clusters. Trained staff administered the WHO 2012 verbal autopsy after maternal deaths. Two physicians (and a third for consensus, if needed) reviewed trial surveillance data and verbal autopsies, and, in intervention clusters, community health worker-led visit data. They determined cause of death according to the WHO International Classification of Diseases-Maternal Mortality (ICD-MM). Verbal autopsies were also analysed by InterVA computer models (versions 4 and 5) to generate cause of death. COMCAT analysis was provided by InterVA-5 and, in India, by physician review of Maternal Newborn Health Registry data. Causes of death and COMCATs assigned by physician review, Inter-VA-4, and InterVA-5 were compared, with agreement assessed with Cohen's κ coefficient. FINDINGS: Of 61 988 pregnancies with successful follow-up in the CLIP trials, 143 maternal deaths were reported (16 deaths in India, 105 in Pakistan, and 22 in Mozambique). The maternal death rate was 231 (95% CI 193–268) per 100 000 identified pregnancies. Most deaths were attributed to direct maternal causes (rather than indirect or undetermined causes as per ICD-MM classification), with fair to good agreement between physician review and InterVA-4 (κ=0·56 [95% CI 0·43–0·66]) or InterVA-5 (κ=0·44 [0·30–0·57]), and InterVA-4 and InterVA-5 (κ=0·72 [0·60–0·84]). The top three causes of death were the same by physician review, InterVA-4, and InterVA-5 (ICD-MM categories obstetric haemorrhage, non-obstetric complications, and hypertensive disorders); however, attribution of individual patient deaths to obstetric haemorrhage varied more between methods (physician review, 38 [27%] deaths; InterVA-4, 69 [48%] deaths; and InterVA-5, 82 [57%] deaths), than did attribution to non-obstetric causes (physician review, 39 [27%] deaths; InterVA-4, 37 [26%] deaths; and InterVA-5, 28 [20%] deaths) or hypertensive disorders (physician review, 23 [16%] deaths; InterVA-4, 25 [17%] deaths; and InterVA-5, 24 [17%] deaths). Agreement for all nine ICD-MM categories was fair for physician review versus InterVA-4 (κ=0·48 [0·38–0·58]), poor for physician review versus InterVA-5 (κ=0·36 [0·27–0·46]), and good for InterVA-4 versus InterVA-5 (κ=0·69 [0·59–0·79]). The most commonly assigned COMCATs by InterVA-5 were emergencies (68 [48%] of 143 deaths) and health systems (62 [43%] deaths), and by physician review (India only) were health systems (seven [44%] of 16 deaths) and inevitability (five [31%] deaths); agreement between InterVA-5 and physician review (India data only) was poor (κ=0·04 [0·00–0·15]). INTERPRETATION: Our findings indicate that InterVA-5 is less accurate than InterVA-4 at ascertaining causes and circumstances of maternal death, when compared with physician review. Our results suggest a need to improve the next iteration of InterVA, and for researchers and clinicians to preferentially use InterVA-4 when recording maternal deaths. FUNDING: University of British Columbia (grantee of the Bill & Melinda Gates Foundation)

Planned early delivery for late preterm pre-eclampsia in a low- and middle-income setting: a feasibility study

Background: Pre-eclampsia is a leading cause of maternal and perinatal mortality and morbidity globally. Planned delivery between 34+0 and 36+6 weeks may reduce adverse pregnancy outcomes but is yet to be evaluated in a low and middle-income setting. Prior to designing a randomised controlled trial to evaluate this in India and Zambia, we carried out a 6-month feasibility study in order to better understand the proposed trial environment and guide development of our intervention. Methods: We used mixed methods to understand the disease burden and current management of pre-eclampsia at our proposed trial sites and explore the acceptability of the intervention. We undertook a case notes review of women with pre-eclampsia who delivered at the proposed trial sites over a 3-month period, alongside facilitating focus group discussions with women and partners and conducting semi-structured interviews with healthcare providers. Descriptive statistics were used to analyse audit data. A thematic framework analysis was used for qualitative data. Results: Case notes data (n = 326) showed that in our settings, 19.5% (n = 44) of women with pre-eclampsia delivering beyond 34 weeks experienced an adverse outcome. In women delivering between 34+0 and 36+6 weeks, there were similar numbers of antenatal stillbirths [n = 3 (3.3%)] and neonatal deaths [n = 3 (3.4%)]; median infant birthweight was 2.2 kg and 1.9 kg in Zambia and India respectively. Lived experience of women and healthcare providers was an important facilitator to the proposed intervention, highlighting the serious consequences of pre-eclampsia. A preference for spontaneous labour and limited neonatal resources were identified as potential barriers. Conclusions: This study demonstrated a clear need to evaluate the intervention and highlighted several challenges relating to trial context that enabled us to adapt our protocol and design an acceptable intervention. Our study demonstrates the importance of assessing feasibility when developing complex interventions, particularly in a low-resource setting. Additionally, it provides a unique insight into the management of pre-eclampsia at our trial settings and an understanding of the knowledge, attitudes and beliefs underpinning the acceptability of planned early delivery

Safe infant feeding in healthcare facilities: Assessment of infection prevention and control conditions and behaviors in India, Malawi, and Tanzania

Infants need to receive care in environments that limit their exposure to pathogens. Inadequate water, sanitation, and hygiene (WASH) environments and suboptimal infection prevention and control practices in healthcare settings contribute to the burden of healthcare-associated infections, which are particularly high in low-income settings. Specific research is needed to understand infant feeding preparation in healthcare settings, a task involving multiple behaviors that can introduce pathogens and negatively impact health. To understand feeding preparation practices and potential risks, and to inform strategies for improvement, we assessed facility WASH environments and observed infant feeding preparation practices across 12 facilities in India, Malawi, and Tanzania serving newborn infants. Research was embedded within the Low Birthweight Infant Feeding Exploration (LIFE) observational cohort study, which documented feeding practices and growth patterns to inform feeding interventions. We assessed WASH-related environments and feeding policies of all 12 facilities involved in the LIFE study. Additionally, we used a guidance-informed tool to carry out 27 feeding preparation observations across 9 facilities, enabling assessment of 270 total behaviors. All facilities had ‘improved’ water and sanitation services. Only 50% had written procedures for preparing expressed breastmilk; 50% had written procedures for cleaning, drying, and storage of infant feeding implements; and 33% had written procedures for preparing infant formula. Among 270 behaviors assessed across the 27 feeding preparation observations, 46 (17.0%) practices were carried out sub-optimally, including preparers not handwashing prior to preparation, and cleaning, drying, and storing of feeding implements in ways that do not effectively prevent contamination. While further research is needed to improve assessment tools and to identify specific microbial risks of the suboptimal behaviors identified, the evidence generated is sufficient to justify investment in developing guidance and programing to strengthen infant feeding preparation practices to ensure optimal newborn health