Operationalising kangaroo Mother care before stabilisation amongst low birth Weight Neonates in Africa (OMWaNA): protocol for a randomised controlled trial to examine mortality impact in Uganda

The primary objective of the OMWaNA trial is to determine the effect of KMC initiated before stabilisation on mortality within seven days relative to standard care among neonates weighing ≤ 2000 g. Secondary objectives include:

This is a four-centre, open-label, individually randomised, superiority trial with two parallel groups: an intervention arm allocated to receive KMC and a control arm allocated to receive standard care. Treatment allocation is random in a 1:1 ratio between groups.

The host institution for the trial is the Medical Research Council/Uganda Virus Research Institute (MRC/UVRI) and London School of Hygiene & Tropical Medicine (LSHTM) Uganda Research Unit in Entebbe. The trial is being undertaken in collaboration with Makerere University and LSHTM. The trial is being conducted at four Ugandan government hospitals: Entebbe, Jinja and Masaka Regional Referral Hospitals and Iganga District Hospital (Fig. 1).

Uganda has a population of 42.9 million and is ranked 162/189 on the Human Development Index (2017) [31]. The population is predominately rural (76%) and the poverty incidence is 27% nationally [32]. Poverty rates vary considerably, with the highest rates occurring in rural areas where subsistence farming is the primary source of income. The Busoga sub-region, where Jinja and Iganga are located, has the third highest incidence of poverty in the country (42.1%), while the Wakiso sub-region, where Entebbe is located, has the second lowest (7.5%) [32].

In Uganda, the neonatal mortality rate is estimated at 19.9 per 1000 live births, with a resultant 32,296 deaths in 2018 [1]. Complications of prematurity are responsible for 27% of neonatal deaths [33], as compared to 35% globally [1]. An estimated 107,921 (7%) Ugandan babies were born preterm in 2014 [5].

Characteristics of the four trial hospitals are shown in Table 1. Each hospital has a neonatal special care unit, which accepts referrals from their respective region/district. The level of equipment in these government facilities differs, but all have: bag-mask resuscitation; incubators and/or overhead radiant heaters for thermal support; intravenous (IV) fluids, nasogastric tubes and syringes for feeding support; oxygen supply (concentrators or cylinders) and nasal prongs for respiratory support; IV and oral antibiotics; phototherapy for jaundice; aminophylline for prematurity-associated apnoea; and phenobarbital for seizures. Pulse oximetry and improvised bubble continuous positive airway pressure (CPAP) ventilation are available at some of the trial hospitals. Invasive ventilation and surfactant are unavailable at all sites. Standard care at the four sites involves provision of intermittent KMC to neonates weighing ≤ 2000 g once stable, in line with current WHO guidelines.

The trial will include admitted neonates weighing ≤ 2000 g for whom the indication for KMC is ‘uncertain’ according to WHO guidelines concerning clinical stability [10]. Eligibility criteria are listed below.

Inclusion criteria:

Exclusion criteria:

The schedule of procedures for the OMWaNA trial is outlined in Fig. 2.

Figure 3 describes the flow of participants from the time of screening through follow-up at 28–30 days.

All admitted neonates weighing ≤ 2000 g at the four trial hospitals will be screened for eligibility by a study nurse or medical officer (Fig. 3a, ‘Screening for eligibility’). Eligibility will be assessed as soon as possible after admission and once the baby is aged ≥ 1 h to allow for transition immediately after birth. This is in recognition of the large physiological changes that take place following delivery and that the stability of a newborn aged < 1 h may change rapidly and not accurately reflect their subsequent clinical trajectory. Trained study staff will ascertain chronological age and relevant pregnancy details by examining source documents and/or conducting a standardised maternal interview. Weight will be measured using the Seca™ 384 electronic weighing scale. A focused examination will be conducted to assess for the presence of major congenital malformations, severe jaundice and seizures.

Neonates for whom KMC is indicated per WHO guidelines (i.e. are considered ‘stable’) will be excluded and receive KMC as part of standard care (Fig. 3a, ‘Stable to receive KMC’). Neonates for whom the indication for KMC is ‘uncertain’ per WHO guidelines (i.e. are ‘prior to stability’) will be further assessed. For those neonates who are found to meet eligibility criteria (Fig. 3a, ‘Screening for eligibility’), a trained member of the study staff will monitor HR and SpO₂ using a Masimo Rad-8© pulse oximeter for 10 min and measure respiratory rate manually by counting breaths for 1 min. Those found to meet the criteria for ‘life-threatening instability’ (Fig. 3a, ‘Too unstable’), or who have seizures or jaundice requiring treatment, will not be eligible for immediate recruitment and will enter a cycle of reassessment every 3 h. All will continue to receive clinically indicated treatments and cardiorespiratory monitoring at the discretion of the on-duty paediatrician, medical officer or nurse. If, during any reassessment within the first 48 h, a neonate is found to have improved and no longer meets exclusion criteria, recruitment may proceed. Neonates who continue to have life-threatening instability or meet other exclusion criteria by 48 h will be permanently excluded.

Written informed consent will be sought from the parents of all participants for the following: neonatal inclusion in the study; collection of sociodemographic and clinical data; and randomisation to a study arm. Consent will also be obtained for the possibility that the caregiver will provide continuous skin-to-skin contact, if randomised to that arm. Additionally, consent will be obtained for the collection of household socioeconomic and cost data, as well as data on infant–caregiver attachment and women’s wellbeing. Study medical officers or nurses will request informed consent. The preferred person to provide informed consent for neonatal involvement is the mother. If a mother is unavailable or too ill to provide consent, consent can be obtained from the father. Once the mother is available and feeling well enough, the informed consent process will be repeated to confirm her consent for her baby’s continued participation. An impartial and literate witness will be used during consent for non-literate parents, as per International Council for Harmonisation-Good Clinical Practice (GCP) guidance.

Study staff will be trained in infection prevention and standard operating procedures (SOP) will detail infection control measures for the use of study equipment to avoid contamination between participants. Axillary temperature will be measured with a digital thermometer in degrees Celsius; three measurements will be taken to enable calculation of the mean value. Respiratory rate will be measured manually by counting breaths for 1 min. Blood glucose will be measured with a capillary sample using the study glucometer. Head circumference (HC) will be measured and a physical examination will be conducted. Baseline clinical and anthropometric data will be collected as soon as possible after enrolment, with the exception of gestational age and crown-foot length, which may be delayed to within 48 h of enrolment. Gestational age will be estimated using Ballard score [34], last menstrual period and foot length [35]. Length will be measured using the Seca™ 210 neonatal measuring mat.

Socioeconomic data, including household details, will be collected within 48 h of enrolment using standardised parent interviews. The Women’s Capabilities Index (WCI) questionnaire will also be administered to mothers during this timeframe. Study staff will also inform families that, over the coming month, they will be asked about their expenditures and the activities of members of their household in order to evaluate the economic impact of KMC relative to standard care.

Treatment allocation is random in a 1:1 ratio between groups using permuted blocks of varying block sizes. The allocation sequence was computer-generated centrally at MRC/UVRI by an independent statistician, stratified by birthweight (< 1000, 1000–1499 or ≥ 1500 g) and recruitment site. The random allocation sequence is uploaded onto the REDCap (Research Electronic Data Capture, Nashville, TN, USA) platform [36] and accessed using a computer with Internet access at each site. The randomisation server and research database are hosted at the MRC/UVRI and LSHTM Unit data centre. This precludes any possibility of study staff viewing the allocation sequence. Allocation is revealed only after the study medical officer or nurse has entered all required screening data into REDCap. The mother is the unit of randomisation; twin and triplet participants will be allocated to the same arm. Each site has one spare computer in case of breakdown or theft; if both fail, the site will revert to random allocation using telephone as the back-up option. Given the nature of the KMC intervention, blinding parents/caregivers is not possible. Process and outcome data will be anonymised and all analyses will be blinded. Analyses will be unblinded for the Data and Safety Monitoring Board (DSMB) at their request.

Neonates in the intervention group will receive KMC initiated as soon as possible after randomisation. Neonates will be naked except for hat and diaper, and will be secured to the exposed chest of the caregiver using a KMC wrap (Fig. 4a). The caregiver is seated or lying on a bed, while the neonate receives any clinically indicated therapies (e.g. IV fluids, antibiotics, oxygen). Caregivers will be encouraged to provide KMC as close to continuously as possible, aiming for at least 18 h per day. If the primary caregiver is unavailable, another family member (e.g. father, grandmother) or close friend (helper) will be encouraged to provide KMC. If a family member or helper is not available to continue KMC, the neonate will be placed into an incubator or under a radiant heater until the caregiver returns. KMC will continue to be encouraged until discharge and at home after discharge, as per WHO guidelines. KMC is commonly practiced until the baby is 2500 g or resists the KMC position, which is often at 4–10 weeks after birth.

Neonates who meet any of the criteria for stopping KMC (Fig. 3d, ‘Criteria for stopping KMC’) will be temporarily withdrawn from the intervention and cared for in an overhead heater or incubator at the discretion of the on-duty paediatrician. KMC may be restarted once all of the following criteria are met: (1) no longer meet any of the stopping criteria; (2) no apnoea requiring bag-mask ventilation for 24 h; (3) not on phototherapy; (4) no seizures for 24 h; (5) no abdominal distension; (6) caregiver available and willing to do KMC; (7) no healthcare worker concerns about clinical condition.

Neonates in the control group will be cared for in an incubator (Fig. 4b) or under a radiant heater. Caregivers are able to touch, hold and feed their baby, but may not provide any skin-to-skin contact until the neonate meets WHO criteria for KMC, i.e. are considered ‘stable’. Neonates will be considered stable when the following criteria have been met for a continuous period of ≥ 24 h: (1) breathing spontaneously with SpO₂ > 90% in room air; (2) no need for supplemental oxygen or CPAP; (3) respiratory rate 40–< 60 breaths/min; (4) no apnoea; (5) HR 80–< 180 beats/min; (6) axillary temperature 36.0–37.4 °C; and (7) no need for IV fluids. These criteria are consistent with those being used in the WHO-led Immediate KMC (I-KMC) trial [37]. Once stable, neonates can transition to routine (intermittent) KMC with the caregiver in line with standard care at the trial sites. As in the intervention arm, neonates in the control arm who meet any of the criteria for stopping KMC (Fig. 3d, ‘Criteria for stopping KMC) will be cared for in an overhead heater or incubator until restart criteria are met.

Participant flow around the study sites is illustrated in Fig. 5, using Entebbe Hospital as an example. All neonates are initially stabilised and assessed at a radiant heater. While clinically ‘unstable’, neonates allocated to KMC are cared for in a study bed and those allocated to standard care are cared for in an incubator or radiant heater. Participants in both arms are transferred to the KMC step-down unit once they meet stability criteria.

Substantial expansion of neonatal care capacity and infrastructure at all trial sites has been embedded within the OMWaNA trial. This includes enlargement of the KMC areas within the neonatal units to ensure that all neonates, whether in KMC or not, can be cared for safely. Additional infrastructure improvements include sinks to provide an optimal environment for infection control, bathrooms/toilets for mothers/caregivers and office space for clinical staff. One study medical officer and 4–5 study nurses have been recruited to join the clinical teams at each site. Further, each site will be provided with the following supplies and equipment: six Masimo Rad-8© oximeters with neonatal sensors; one oxygen concentrator; two thermometers; one glucometer with blood glucose testing strips; one neonatal ventilation bag and mask; one Seca™ 384 neonatal weighing scale; one Seca™ 210 neonatal measuring mat; 2–3 paediatric stethoscopes; and a minimum of four adjustable beds. In addition, KMC wraps will be provided to support practice in each unit.

At the time of discharge, all caregivers will be provided with an illustrated handout on neonatal danger signs and instructed to contact the site study team or seek medical help if their baby becomes unwell. Caregivers of babies in both arms will be encouraged to continue KMC at home. All participants will be given an appointment to attend the follow-up clinic at the respective study site on days 28–30. At this visit, cranial ultrasound (Entebbe and Jinja Hospitals only) and anthropometry will be performed, feeding practices and outcomes (alive, dead, readmitted) will be documented, and the WCI and Maternal Infant Responsiveness Instrument (MIRI) questionnaires will be administered to mothers.

If participants are discharged before day 7, additional follow-up will be arranged according to study site. If participants do not attend the follow-up visit, a telephone call will be made the same day to ascertain outcome and feeding practices and to arrange follow-up, either in the clinic or at the families’ home, as soon as possible. Routine follow-up beyond the planned study follow-ups will be provided by the study staff according to standard practice and based upon the clinical need of the baby.

Adverse events (AE) are medical events or laboratory findings, which result in a change in clinical management after randomisation and until 28 days after birth. A serious adverse event (SAE) is defined as an event that results in death, is life-threatening, requires hospitalisation or prolongation of hospitalisation, results in persistent or significant disability, or requires intervention to prevent permanent impairment or damage [38]. Study medical officers and nurses will inform the site paediatrician about any SAE occurrence within 24 h. SAEs will be followed up by the paediatrician until their resolution or stabilisation, or until causality is determined to be unrelated to the trial intervention. If a serious but unexpected AE occurs, which might be related to the trial intervention, a SAE report will be submitted to the Research Ethics Committees (REC) at UVRI and LSHTM within 48 h of the investigators becoming aware of the event, with a follow-up report provided within a further five working days. This expedited reporting will be limited to those outcomes not already listed as primary or secondary outcomes, yet which might reasonably occur as a consequence of the trial intervention. All SAEs will be reported to the Sponsor and RECs as part of their respective annual progress and safety report.

The DSMB will oversee the overall integrity of the study, its safety and its continued relevance and ability to answer the primary objective. DSMB members include a perinatal epidemiologist/statistician (chair), a South African neonatologist and a neonatal bioethicist. The DSMB will receive a summary of SAEs after one month of recruitment, then move to every three or six months; the DSMB will decide the frequency following the first report. An interim analysis will be performed on the primary outcome when approximately half of neonates have been randomised. An independent statistician will perform the interim analysis, blinded to treatment allocation and report to the DSMB. Analyses will be unblinded at the request of the DSMB. In light of these data and other evidence from relevant studies, the DSMB will inform the Trial Steering Committee (TSC) if in their view: it is evident that no clear outcome will be obtained with the current trial design; they have a major ethical or safety concern; or it is evident that the intervention is clearly superior and continuing the trial would be unethical to those in the control arm. The TSC will make the final decision on study continuation.

The study will be monitored by the Reciprocal Monitoring Scheme of the East African Consortium for Clinical Research in collaboration with the Research Compliance and Quality Assurance section of the MRC/UVRI and LSHTM Unit. Dedicated study monitors, independent of the study team, will oversee progress and ensure the trial is conducted and data are handled in accordance with the protocol, SOPs and applicable ethical and regulatory requirements. In addition, the UVRI REC will conduct initial site visits with neonatal specialists from the Uganda Paediatrics Association and the Ugandan Ministry of Health Newborn Steering Committee. The trial may be subject to audit by LSHTM under their remit as Sponsor, the Study Coordination Centre and other regulatory bodies to ensure adherence to GCP.

The primary outcome is all-cause early neonatal mortality (within seven days). Estimates suggest that three-quarters of neonatal deaths occur in the first week of life [2].

Secondary outcomes are as listed below.

Understanding the hypothesised causal pathways for clinical effects of the intervention (objective 3) will be achieved by measurement of the following process outcomes, which are categorised as providing very early (within 24 h), early (within 72 h) or late clinical impact.

Trial data will be electronically entered into trial-specific case report forms on tablets using an offline, mobile REDCap application, with inbuilt ranges and consistency checks. Data from tablets will be synchronised once daily over a secure connection with the web-based REDCap database, hosted at the MRC/UVRI and LSHTM Unit data centre. Cardiorespiratory data from Masimo Rad-8© oximeters will be downloaded using Stowood Visi-Download™ software, captured in CSV files, securely transmitted to MRC/UVRI, analysed with PROFOX™ software and reconciled with the trial database. Cranial ultrasound images will be stored in OsiriX Dicom™ software and interpreted blind to allocation and clinical details. Logs linking parent/caregiver names and residence location will be stored separately on password-protected computers, with a hard copy stored in locked cabinets in secure rooms at all sites.

All data will be stored in institutional servers at the MRC/UVRI and LSHTM Unit during the study. Data from the web-based REDCap database will be downloaded and stored on institutional servers at LSHTM in London for access by the PIs and independent statistician for analysis and preparation of reports for the DSMB, respectively. These secure, password-protected servers are only accessible within the LSHTM network and activity is fully audited, recording both login details and file system access. Access will be limited to essential research personnel.

Assuming a control mortality rate of 25% across the four recruitment sites, 1750 neonates (875 per arm) would enable us to detect a relative difference between arms of 22.4% (5.6% absolute difference) with 80% power and a significance level of 5%. If the control mortality rate were in fact as low as 18%, we would still be able to detect a relative difference of 27% (absolute difference of 4.8%). We plan to recruit 2188 neonates (1094 per arm) in order to allow for 10% withdrawal due to clinical deteriorations and consent withdrawal, and 10% dilution due to non-compliance and loss to follow-up. This sample size would enable us to detect absolute reductions of 6.3% and 5.4% from control rates of 25% and 18%, respectively, with 90% power.

The process evaluation is being conducted to strengthen understanding of KMC initiation before stabilisation on neonatal health outcomes, considering both intended (beneficial) and unintended (negative) clinical effects. Changes in neonatal care between hospitals and from before the trial will also be assessed. This evaluation will be conducted in accordance with the MRC guidance on process evaluation of complex interventions [46], and will integrate quantitative and qualitative data. Quantitative outputs will include data related to causal pathways for clinical effects, neonatal admissions data, and health system- and facility-level survey data. Quantitative data will be summarised using descriptive statistics. Qualitative data will be collected though in-depth interviews, focus group discussions and workshops with parents/caregivers, healthcare providers and other key stakeholders to identify experiences of KMC and explore facilitators and barriers to inform uptake and sustainability. These data will be analysed using a thematic content approach. An iterative methodology will be used with data collected at several time points and then used to inform later explorations. Intervention reporting will follow the template for intervention description and replication (TIDieR) [47], which will ensure a shared understanding of all activities related to the trial intervention and, if shown to be effective, how these relate to any proposed scale-up activities. In addition, the TIDieR will facilitate thoughtful consideration regarding the transferability of findings outside a trial setting and to other hospitals in Uganda and elsewhere.

The incremental cost, cost-effectiveness, budget impact and equity of KMC for neonates before stabilisation relative to standard care will be examined from both an aggregated and a disaggregated societal perspective (provider and household combined), in accordance with the reference case [48]. Effects of the intervention on neonatal health and maternal wellbeing will be assessed. Both financial costs, which reflect actual monies paid, and economic costs, which reflect the full value of resources used, will be examined. Multiple data sources will be triangulated to arrive at best estimates. Where possible, resource use and unit costs will be collected and presented separately, although some costs, such as out-of-pocket payments for transport, do not permit this. Household costs will be collected through surveys amongst a sample of caregivers at the time of discharge and during follow-up visits. Costs to providers will be collected prospectively and retrospectively using project accounts, key informant interviews, facility audits, direct observations and time-use surveys. As necessary, secondary data on costs of treating subsequent conditions may be supplemented with limited primary data collection in the trial hospitals. Costs and effects will be modelled using a lifetime time horizon.

Obtaining timely informed consent for this RCT may be challenging given the involvement of sick neonates [51, 52], the fact that KMC needs to be started as soon as possible after birth and the fact that some women may be too ill, especially within the first 24 h, to provide consent or participate. In addition, some of these women may not be literate. Parental stress is compounded by the fact that complications may be unexpected, especially in low-resource settings, where knowledge of preterm birth is generally low. To help address these issues, the OMWaNA trial utilises the continuous consent approach [53], which involves providing information at multiple time points both before and after recruitment. Studies have found that the validity of consent improves when discussion continues after recruitment [53]. This approach has three main elements:

Audit data from the feasibility study at Jinja Hospital suggest that ~ 400 eligible neonates are admitted annually [14]. Preliminary data suggest that ~ 500 eligible neonates each are admitted to Iganga and Entebbe Hospitals per year and ~ 800 eligible neonates are admitted to Masaka Hospital per year. Thus, a total population of ~ 4400 eligible neonates is expected over the 24-month recruitment period, which means a recruitment rate of ~ 50% will be required to achieve the target sample of 2188. The feasibility study findings suggest that this is realistic and achievable [14]. The trial timeline includes a three-month buffer period in the event that recruitment is delayed or slower than expected. Further, training of study staff emphasised the importance of timely reporting and responsiveness to recruitment issues.

Among neonates in the control group, non-adherence with allocation (e.g. parents demanding early KMC) is a potential issue; however, this has not been reported in other trials [11]. Adherence in both arms, particularly the KMC arm, could be affected by parents witnessing a death (e.g. in the KMC position). Some babies will die regardless of the trial arm to which they are randomised. Preterm neonates can die quickly, even in settings with intensive care, and such deaths are a recognised impediment to KMC [54]. Stigma regarding preterm birth is common in Uganda, but has not impeded KMC practice for stable babies [55]. Study staff will counsel parents about the potential for mortality at the time of enrolment as well as counsel parents of neonates who die and those who witness a death. In addition, prompt reporting of all SAEs and trial monitoring through regular site visits will further facilitate timely identification of and responsiveness to any compliance issues, should they arise.

Adherence to the target duration of KMC (≥ 18 h/day) may be challenging [56]. Among five RCTs that promoted continuous KMC, three reported durations of ≥ 20 h/day [18, 57, 58] and two did not report duration [15, 59]. Among 16 RCTs evaluating intermittent KMC in stable neonates, one reported mean/median duration of 17 h/day, five reported 10–14 h/day and nine reported < 10 h/day [60]. The OMWaNA trial will employ a comprehensive approach to improve adherence. An illustrated KMC handout will be provided to caregivers at the time of enrolment. Study staff will counsel mothers about the benefits of KMC throughout the hospital stay, including the time of discharge. Studies have noted the importance of staff training and counselling for KMC [61, 62], and a related RCT demonstrated the efficacy of peer-counselling in promoting breastfeeding among hospitalised preterm neonates [63]. We will establish KMC peer-counselling programmes at each site, enlisting mothers who practiced KMC as participants when they return for follow-up. Peer counselling will address many maternal concerns and may help facilitate longer durations of KMC. We will also engage hospital administrators about KMC guidelines. Adjustable beds and KMC wraps will be provided, as these have been shown to improve adherence [56]. Lack of privacy and inadequate space for beds and equipment were identified as significant barriers to KMC practice in the feasibility study [14]. Provision of increased space within the four neonatal units may facilitate caregiver privacy as well as help improve clinical providers’ ability to safely care for at-risk neonates. Despite these measures, this is a pragmatic trial and some non-adherence is inevitable. The effect of non-adherence might be to dilute the size of the effect of KMC (assuming it ‘works’) and this has been factored into the sample size calculations. Biannual neonatal quality of care surveys, including progress monitoring of KMC provision/services, will be conducted at the four sites as part of the process evaluation.

Over the six months preceding the start of the trial, the study team has made extensive efforts to expand neonatal care capacity at the four hospitals. Improvements include increased space and water supply in the neonatal units, office space for clinical staff, bathrooms/toilets for caregivers, adjustable beds for KMC, and various equipment and supplies. Despite these efforts, context-related resource constraints are inevitable. In government facilities, such as the four trial hospitals, supply/medication shortages are common and repair of malfunctioning equipment (e.g. incubators, oxygen concentrators) is often protracted. Triannual (every four months) surveys of staffing, equipment, supply and medication availability, and infrastructure across the sites are included in the process evaluation. In addition to the supplies and equipment provided before trial commencement, the budget includes a small allowance to help cover the cost of necessary commodities for each participating neonate.

Electrical power is required for incubators, radiant warmers, oxygen concentrators and phototherapy. Lack of access to reliable electricity is a problem in many LMICs, including Uganda, where a 2007 national survey showed that only 19% of government hospitals had reliable electricity (during working hours) or a backup generator with fuel [64]. In 2014, a study at Jinja Hospital recorded 120 episodes of power failure (mean of 13 times/week), with a median duration of 30 min each, over a 64-day period [65]. The four trial hospitals have reliable power supply, with occasional brief power outages (e.g. when back-up generators run out of fuel). Daily communication between staff at the MRC/UVRI and LSHTM Unit and the sites will facilitate timely identification and resolution of any significant power outages impacting patient care. Frequency and duration of power outages will be recorded by site staff.