Improving the survival, growth and developmental of low birth weight newborns through better nutrition

Worldwide, deaths in the first month of life already account for nearly half of all child deaths. This proportion is set to rise as survival in older children is improving faster than in newborns. More than 9 in 10 newborn deaths occur in Africa and Asia and more than 8 in 10 of these deaths are in babies with low birthweight. The greatest risk is in very small babies (birthweight less than 1500g) where as many as 700 of every 1000 die. Small babies who survive often have poor longer-term growth and development posing highly significant consequences for families and societies.

Being small at birth is due mainly to being born too early (preterm), not growing well in the womb or a combination of both. Unfortunately, we do not have effective interventions to prevent either of these problems. Therefore, these small babies are a growing challenge especially in poorer countries.

We know that nutrition and growth in early life are critically important for the development of the body organs, including the brain, and being able to fight-off the infections that cause many newborn deaths. Improved nutrition and optimal growth may also prevent diseases that are important in later life in poorer countries such as lung disease. However, achieving optimal nutrition in small babies remains a huge challenge especially as high quality, safe feeding through the veins, that bridges the gap between birth and full oral feeding, is rarely available in low-resource countries. In addition, the structure and function of the gut in preterm babies is immature and advancing oral feeds too quickly may cause life-threatening gut damage. The immature gut not only struggles to cope with milk feeds but also allows gut bacteria to cross into the body and cause infection. Small babies often need nursing in neonatal units (NNUs) for 4-6 weeks or more and this is exactly where their gut can be colonized with dangerous bacteria that are resistant to the available antibiotics.

There has been little research to tell us how best to feed small babies in NNUs in poorer countries. Even basic principles such as when to introduce feeds and how quickly feeds can be increased safely remain unclear. In addition, there are several promising interventions being developed in richer countries that may well be relevant, feasible and affordable in low-resource settings. These include using nutritional supplements of probiotics (safe, "healthy" bacteria) and components in breast milk ("lactoferrin") to prevent gut infections and boost the baby's immunity.

We will establish a core network of 6 NNUs (4 Nigeria/2 Kenya) linking African clinicians and researchers together and with international experts in newborn nutrition, gut health and longer-term lung and brain development. The network will build capacity in those NNUs with limited previous research experience and also engage researchers who are new to working in poorer countries.

Workshops in Nigeria and Kenya will allow the team to document current practices, share experience of practical feeding problems and review possible interventions for testing. Standard international criteria for the diagnosis of common problems (such as infection) will be adapted for use across the network and we will set-up a database to share essential clinical information. We will test novel methods to detect genes that make bacteria resistant to antibiotics and to measure key nutrients in small volume blood samples. We will also store samples for later research. We will ensure that we develop processes that are achievable even with low-resources so that they can be rolled-out to other NNUs to expand the network.

Our goal is to improve survival, growth and development in low birthweight babies through better nutrition. The network and processes that we will establish will enable us to design and implement the large-scale clinical trials that will be needed to advance care in these most vulnerable infants.

We plan to establish a core network of 6 neonatal units (NNUs; 4 Nigeria/2 Kenya) to improve gut health and early nutrition in low birthweight (LBW) infants. LBW results from premature birth, intra-uterine growth retardation or both. Immature gut structure and function in preterm infants compromises nutrition, facilitates sepsis through bacterial translocation and risks necrotising enterocolitis (NEC). Abnormal microbial colonization of the gut occurs during prolonged NNU admission including with anti-microbial resistant bacteria. Improved gut health and early nutrition would likely prevent sepsis and improve brain and other organ development.

A weak evidence base contributes to the variation in practice regarding establishing feeds especially in vLBW infants (<1500g). Nutritional interventions to improve gut health and reduce mortality that have become routine practice in many NNUs in richer countries may be practical, safe and affordable in low-resource settings. An example is probiotics that reduce all-cause mortality in vLBW infants (RR 0.72; 95% CI 0.57-0.92) and prevent NEC stage 2 or greater (0.57; 0.43-0.74).

Our network will evaluate current evidence and document variation in feeding practices, adapt core outcome sets for common diseases, share anonymised clinical data and identify priorities for research. The dataset will collect information about maternal and early life variables as a basis for the assessment of long-term growth, respiratory and neurodevelopmental outcomes. We will pilot test volumetric absorptive microsampling technology combined with QPlex Array for measuring inflammatory markers and micronutrients in small blood samples and high resolution melt based qPCR to describe acquisition of anti-microbial resistance genes in faecal flora. We will also bank samples for future analysis. We will engage other low-resource NNUs and develop processes that can be rolled-out to expand the network as a resource for multicentre clinical trials.

Our research aims to improve survival, growth and development in babies with low birthweight (weighing less than 2500g) in low-resource countries. It was estimated in 2015 that the 2.7 million deaths that occurred in newborns (the first month of life) constituted almost half of all under five deaths. Over 9 in 10 newborn deaths occurred in Africa and Asia and more than 8 in 10 of these deaths are in babies with low birthweight.

Pragmatic and affordable interventions to improve nutrition and gut health in low birthweight babies may prevent deaths, reduce infections and improve growth and development. Improved early life nutrition alongside changes in the bacteria and other microbes that live in the gut may also prevent problems in older life such as lung diseases which are common in poorer countries. The human and material resources to manage the multiple problems associated with low birthweight are often scarce in the countries where most of these births occur. Nutritional interventions may benefit both the 9 million babies born in Africa and Asia with low birthweight due to being born too early ("preterm") and also the over 32 million infants born in low and middle income countries who had poor growth in the womb resulting in low birthweight in many.

We consider that doctors and researchers working in baby units in Nigeria and Kenya that care for small babies will benefit from joining together in a network including valuable learning in early life nutrition across settings with similar resource constraints. Together with the UK experts, we anticipate that engagement in the network and the project workshops will develop the capacity of all network members in clinical care and research. We are especially keen to engage early and mid-career clinicians and researchers and support their development through the project activities and potential subsequent research projects. We expect that our core network of neonatal units will be sustained long-term and progressively increase the capacity of staff in other similar units as the network grows supported by national newborn and child health societies.

To maximise the potential impact of our research, our team comprises researchers from several disciplines, including those interested in the origins of disease in early life, to establish a secure basis for a wide range of future research and maximise the potential benefits to low birthweight infants. Finally, findings in low birthweight infants in Nigeria and Kenya may well inform clinical practice and stimulate future research in vulnerable newborns in high-income countries.