OMWaNA Operationalising kangaroo Mother care before stabilisation among low birth Weight Neonates in Africa: RCT to examine mortality impact in Uganda

Globally, there are 2.6 million neonatal deaths each year (defined as death during the first 28 days) and over 80% of these deaths occur in babies who are born small, due to being born too soon (preterm), being too small for their gestational age, or both. Preterm birth complications are the most common cause of death for children under age five worldwide, and yet there has been much slower progress in reducing these deaths compared to child deaths from malaria or HIV. Three-quarters of deaths due to prematurity occur in sub-Saharan Africa and south Asia, where there is limited availability of neonatal intensive care and most hospitals lack basic equipment. In Uganda alone, an estimated 45,000 newborn deaths occur annually, at least a quarter of which are directly due to complications of prematurity.

Kangaroo Mother Care (KMC) involves placing the baby skin-to-skin with a caregiver, usually the mother, promoting warmth and breastfeeding and also empowering the mother, increasing maternal confidence to improve bonding with the baby. KMC has been found to reduce deaths by 40% for newborns weighing less than 2000g, but these trials included only babies that were considered to be stable. WHO guidelines recommend KMC for babies weighing 2000g or less at birth, starting as soon as they are 'stable,' i.e., not on any other medical treatments. However, the majority of deaths occur in babies before they have stabilised, with complications like breathing difficulties, soon after birth and in settings without neonatal intensive care. The only randomised controlled trial of KMC on survival amongst babies before stabilisation reported a 43% mortality reduction compared to standard care (incubators). Importantly, this trial excluded over half of eligible babies and had other design problems. Hence, there is currently not enough evidence to recommend KMC for small babies before stabilisation who could benefit the most. A well-designed trial is needed to assess the impact of KMC started before stabilisation on mortality compared to incubator care.

The Operationalising kangaroo Mother care before stabilisation among low birth Weight Neonates in Africa (OMWaNA) trial is a partnership of the Medical Research Council Uganda, Makerere University, and the London School of Hygiene and Tropical Medicine. Omwana means 'child' in Uganda's national language. The aim of this trial is to determine the impact of KMC, started before stabilisation, on mortality (at 7 and 28 days) compared to incubator care in a group of babies weighing 2000g or less. In the trial, 2188 babies who are not yet stable will be assigned by chance to receive either KMC or incubator care. The trial will take place in four "typical" hospitals without intensive care (Jinja, Masaka, Iganga, Entebbe). Incubators are the standard method of keeping small and preterm babies warm in Ugandan hospitals, often with several newborns sharing. The trial will also compare the overall costs of KMC and incubator care, considering both costs to hospitals and costs to families. With parents and hospital staff, we will evaluate issues that support or discourage starting KMC before stabilisation. In addition, we will measure quality of life among women caring for small babies in Uganda with a new survey tool.

The Ugandan Government committed to meeting an ambitious global goal for newborn survival and has given high priority to addressing newborn deaths. The National Newborn Steering Committee has recommended increased scale-up of KMC in health facilities. Key stakeholders will be engaged throughout the trial including the Uganda Ministry of Health, Uganda Paediatric Association, UNICEF (headquarters and country), WHO, and the International KMC Network. The findings of this trial will help inform wider use of KMC in Uganda and around the world, especially in settings where most babies die, and where neonatal intensive care is not available.

Globally, there are 2.6 million neonatal deaths annually. Over 80% of these occur in neonates who are small at birth. Kangaroo Mother Care (KMC) involves placing a preterm/low birthweight neonate skin-to-skin with a caregiver. A Cochrane review reported 40% mortality reduction with KMC in stable neonates. The WHO recommends KMC for routine care of newborns 2000g or less, initiated when clinically stable; yet, estimates suggest at least 75% of neonatal deaths occur before stabilisation in settings without intensive care. The only RCT of KMC before stabilisation (Ethiopia, 123 neonates) reported major mortality impact (RR 0.57) but had design challenges.

The Operationalising kangaroo Mother care before stabilisation among low birth Weight Neonates in Africa (OMWaNA) trial is a partnership of MRC/UVRI, LSHTM and Makerere University. The trial will be conducted in four Ugandan hospitals without intensive care (Jinja, Masaka, Iganga, Entebbe). We will undertake an individually randomised, controlled, superiority trial with two parallel groups to determine the effect of KMC initiated before stabilisation on mortality at 7 and 28 days relative to incubator care among 2188 neonates 2000g or less. Secondary outcomes include length of stay, weight gain, and underlying mechanisms by which KMC may influence mortality (e.g., temperature instability, apnoea, oxygen desaturation, intraventricular haemorrhage).

The economic evaluation will estimate the incremental costs and cost-effectiveness of KMC relative to incubator care from the provider, household, and societal perspectives, and model the total cost of scaling up KMC nationally. We will also utilise a novel tool to assess women's well-being, qualitatively explore enablers and barriers to implementation, and conduct a process evaluation of KMC initiation before stabilisation. Key stakeholders engaged include the Ugandan Ministry of Health, Uganda Paediatric Association, UNICEF, WHO, and the International KMC Network.

The OMWaNA trial findings have potential for major impact on newborn survival and child health. Preterm birth is the leading cause of both neonatal and under-five child deaths, and over 80% of neonatal deaths occur in those who are small at birth. Estimates suggest at least 75% of neonatal deaths occur before stabilisation in settings without intensive care. If KMC is shown to be effective in reducing mortality in this population, for example by ~25% as applied in our sample size, then the number of lives saved could be 3-fold the number of child deaths due to HIV. Alternatively, if KMC is found not to be effective, it would highlight the need for more investment in technological innovations for newborn care in low-resource settings. The trial includes an economic evaluation, which will inform health system decision-making as well as capture broader benefits of KMC relative to incubator care among mothers using a novel women's well-being score. Qualitative evaluations throughout the trial will consider barriers and facilitators, which are key for wider uptake and sustainability.

Even at this early stage, key stakeholders are involved and enthusiastic, notably:

1) National level: Uganda's Ministry of Health, particularly the Newborn Steering Committee, and Uganda Paediatric Association (UPA) have demonstrated an active interest in the trial, with the latter represented on the Trial Steering Committee (TSC). Findings from the economic and qualitative aims will impact on current programmatic questions for implementation and sustainability. Estimation of the incremental cost-effectiveness of KMC relative to incubator care will inform running costs at facilities as well as district programme planning. [Letter of support: UPA]

2) International level: UNICEF and the International Kangaroo Mother Care Network have been involved in trial design and both are represented on the TSC. The Kangaroo Acceleration Partnership in which Prof Lawn (PI) and Dr Morgan (Co-PI) are engaged is also involved. The WHO guideline for preterm care highlighted key gaps in evidence regarding KMC before stabilisation, including clear criteria for stability and optimal timing and duration to improve health outcomes. Prof Lawn sits on this WHO review committee; thus, trial results will allow this influential guideline to be updated with robust evidence. [Letters of support: UNICEF, International Kangaroo Mother Care Network, TSC Chair]

3) Clinical care: Standardised KMC and other clinical care guidelines, plus the training tools developed and refined during the trial, may have an important impact on promoting provider competency and improving facility-based care of small, sick newborns in low-resource settings in collaboration with the UN's Every Newborn Action Plan. [Letter of support: UNICEF]

4) Future science and understanding pathways of effect: A further impact would be greater scientific understanding of physiological mechanisms by which KMC may influence mortality, including improved thermal control and autonomic stability, reduced apnoea, and decreased intraventricular haemorrhage. Such an understanding could inform how to reduce long-term disability risk as well as innovations for more targeted delivery of the intervention, with wider implications for neonatal care. [Letter of support: TSC Chair]

5) Local clinical and research capacity: Newborn clinical research capacity will be strengthened at MRC/UVRI and the four hospitals, facilitating further trials. Study paediatricians and medical officers will receive training in clinical trial methods and implementation, and will benefit from authorship, short courses, PhDs, and other opportunities. [Letters of support: MRC/UVRI, Hospital Directors, UPA]