A feasibility and pilot trial of enteral probiotic administration in preterm infants admitted to a neonatal unit in Nigeria

Lead Research Organisation: University of Ibadan
Department Name: Surgery & Medicine

Abstract

Globally in 2017, amongst the 5.4 million children who died under the age of 5 years, almost 1 in 2 of these deaths (46%) occurred in the first month of life. Worldwide, 20 million newborns (up to 1 in 5 of all births) are low birth weight (LBW; weighing <2,500g) resulting from prematurity (being born too early) and/or poor growth in the womb. 80% of neonatal deaths occur in these small infants and long-term impairments are common amongst survivors. The greatest burden of preterm births and newborn deaths occur in low and middle-income countries and over one third of newborn deaths occur in sub-Saharan Africa (sSA). These high rates of death, and disability, including long-term impaired learning, amongst preterm and low birthweight (LBW) infants present a major challenge to families and health services in low and middle-income countries.

The most vulnerable newborns are nursed in neonatal units which are able to provide only a limited range of interventions. We have established a network of 7 neonatal units in Nigeria and Kenya. Each of these units typically admit between several hundreds to over one thousand babies each year. They are able to support feeding (e.g. using naso-gastric tubes), treat infections and also practice Kangaroo Mother Care where once babies are stable they are placed skin-to-skin usually with their mothers. More advanced levels of care are not available and access to laboratory investigations and Xrays is limited.

About 1 in 4 (25%) of babies born before 36 weeks of pregnancy and admitted to these units die. Major causes of death are complications of prematurity and infections. In addition, advanced methods of feeding, such as feeding through the veins, are not available, and establishing and progressing feeds safely in small babies is difficult. This is important because babies who are feeding well can usually be discharged from the unit which reduces their risk of infection and reduces healthcare costs and the workload for staff.

We propose to evaluate whether giving a daily oral supplement of probiotics (live bacteria that have health benefits) would benefit these vulnerable babies. Probiotics have been given to many thousands of highly vulnerable preterm infants in research studies done in high-income countries and some poorer countries but they have not been adequately tested in sub-Saharan Africa. There is convincing evidence form this research that probiotics reduce deaths from all causes, prevent infections and also speed-up tolerance of oral feeds without causing harmful effects.

Before we can design large research study of probiotics for preterm babies in neonatal units in sub-Saharan Africa, we need to do some preparatory work. In this study, we plan to test the feasibility and likely effectiveness of giving a probiotic in one large neonatal unit in Ibadan, Nigeria. We will also develop the necessary process for undertaking high-quality research even in a low-resource setting. This initial study will be done over 22 months. We plan to invite the parents of 100 babies born before 36 weeks of pregnancy to join the study. The babies would be allocated randomly to receive either the daily probiotic or a matched placebo (inactive preparation) during their stay on the unit. We would monitor the babies closely and record important events such as episodes of infection diagnosed using optimal laboratory procedures provided through the trial.

The main question to be addressed by this initial study is whether it is possible to undertake a much larger study in this setting to reliably assess the potential benefits of probiotics for these highly vulnerable babies.

Technical Summary

Our proposal is based on a fixed effects meta-analysis of 23 RCTs of preterm infants in 10 LMICs (n=4,783; Deshpande 2017). Probiotics reduced all cause mortality (RR 0.73 [95% CI 0.59 to 0.90]; P=0.003), necrotising enterocolitis (RR 0.46 [0.34 to 0.61]; P<0.00001), late-onset sepsis (RR 0.80 [0.71 to 0.91]; P=0.0009) and time to full enteral feeds (-1.95 days; [-3.44 to -0.45]; P<0.00001). No adverse effects were ascribed to probiotics in the systematic review and there are only limited case reports of adverse effects in preterm/VLBW infants. Based on global clinical trial evidence, probiotic administration has becoming routine in many neonatal units in industrialised countries.

The meta-analysis included only two studies in Africa (Egypt and South Africa) and neither may be representative of other neonatal units in the sub-continent. Probiotics effects likely differ according to host characteristics, exposure to environmental microbes and nosocomial pathogens, antibiotic use and feeding practices. There is an urgent need to test this intervention in low-resource settings with the highest rates of neonatal mortality.

For selection of probiotic for neonates, network meta-analysis advises the inclusion of Lactobacilli and Bifidobacterium spp. to simulate the gut flora in the healthy, breast-fed infant and use of multistrain preparations that have greater beneficial effects including the prevention of NEC. For this initial study, we have selected a product that contains three probiotic strains (L acidophilus, B infantis, B bifidum) suspended in oil, manufactured in South Africa and with a long shelf life at room temperature. This probiotic is used extensively in highly vulnerable infants in neonatal practice in the UK and no significant safety concerns have arisen.

This proposal aims to ultimately address the evidence gap regarding the potential health benefits of probiotics in preterm/VLBW infants in a low resource setting in sSA.

Planned Impact

This project will have multiple impacts:
1) we will strengthen collaborations between UK experts and experienced clinicians in LMICs, helping to develop research expertise and become independent researchers as well as inspiring future clinical researchers
2) provide key information to inform the design of a definitive multi-centre trial of probiotics to reduce neonatal mortality in LMIC settings using mixed-methods - the knowledge gained will be directly relevant to other similar nutritional and non-nutritional interventions on neonatal units
3) provide high quality scientific data on the impact of probiotics on disease and health in a high risk patient group including key clinical morbidities and microbiomic data relevant to infection control and use of antibiotics.

We would expect the newborns participating in the trial to benefit from the greater clinical evaluation required to document study endpoints including access to laboratory investigations (bacterial culture) and abdominal Xrays if required.

Publications

10 25 50