Efficacy and safety of chlorhexidine cleansing in reducing bacterial skin colonisation of hospitalised low birthweight neonates:a pilot trial (NeoCHG)

This is a pilot study to work out the best way to apply an antiseptic called chlorhexidine to the skin of low birth weight newborn babies who are admitted to hospital. We want to do this because these babies have bacteria living on their skin, just like older children and adults, but in very small babies these bacteria can more easily get into the blood and make them seriously unwell. This study will work out the best strength of the antiseptic, as well as how often it should be applied, and whether or not it should be combined with a skin softener (called emollient), that could be tested in a larger study in the future. This future study would aim to reduce deaths in these newborns, but at the moment we don't know what type of skin cleansing would have the best chance of doing this. So in this pilot study, we will look at how much the different methods reduce counts of bacteria on the skin. We will also look at the newborns skin every day to make sure it is safe.

The antiseptic chlorhexidine has been shown to reduce the risk of dying from infection when it is applied to the umbilical cord in newborns at home in regions with high rates of newborn deaths. However it is still uncertain whether applying chlorhexidine to the body could reduce the risk of infection and death in newborns who are in hospital and also at high risk of infection due to other factors such as low birth weight. In addition, skin softeners, which are often in the form of oils such as sunflower oil, have been shown in some studies to reduce infections, although a recent review was inconclusive. The effect of combining both skin softeners and an antiseptic may have additional undiscovered benefits but has not been adequately tested, therefore this study will also assess this combination.

The trial will be conducted in 2 hospitals, one in Bangladesh, and the other in South Africa. Chlorhexidine wipes will be applied to the skin of the body of newborn babies, starting at from 2 days of age and either daily (Monday-Friday) or three times a week (Monday, Wednesday and Friday) thereafter. In addition, half of each group will receive a skin softener as well. Swabs will be taken from various areas of the skin of the newborns, and we will count the number of bacteria growing from these swabs. In addition, we will monitor the skin of the newborns closely for any signs of reaction to the chlorhexidine. In this way, the study will provide information on the balance between how good the different methods are at reducing bacterial counts, whilst remaining safe. The best concentration and frequency of application, with or without skin softener, will then be chosen to be tested in the larger trial in the future. The larger trial would be able to test whether applying chlorhexidine to the skin of hospitalised low birth weight newborns reduces their risk of getting serious infections, and whether this improves their survival.

This is a pilot randomised study, with a factorial design, comparing the efficacy and safety of varying regimens of skin application of chlorhexidine wipes to low birth weight hospitalised neonates. Comparison will be made between different concentrations of chlorhexidine, and different frequencies of application, as well as addition or omission of emollient, and against a control group. Efficacy will primarily be measured as reduction of total and pathogen specific bacterial colony forming units (CFUs) on a pooled skin swab of the cervical skin folds, umbilicus, nose and groin, as well as a separate peri-rectal swab. Safety, which is the other co-primary outcome, will be based on a modified newborn skin score which assesses skin condition. Other secondary end points will include the change in proportions of bacterial species in different groups, as well as other adverse events such as hypothermia, and skin reactions requiring discontinuation of chlorhexidine.
Chlorhexidine will be applied to the skin of low birth weight neonates (1-2kg) from day 2 of life onwards (sparing the face), and in varying concentrations (0.5%, 1% and 2%), either daily (Monday-Friday) or three times a week (Monday, Wednesday, Friday), and with or without emollient application. Skin swabs will be collected at regular intervals, before chlorhexidine application, and then after 3, 7, and 14 days (or on discharge if earlier). The factorial design, including a control group, enables efficient comparison of frequency, concentration, and emollient in one trial. This will then inform the choice of a regimen to be taken forward into a future trial of chlorhexidine skin application as part of a bundle of interventions aiming to reduce neonatal sepsis and all-cause mortality.

This pilot study will provide valuable information on the use of chlorhexidine and emollients in low birth weight neonates. Primarily, the findings will provide data on efficacy (in terms of reduction in bacterial load) and safety of different concentrations of chlorhexidine, at varying frequencies of application, and with or without emollient, in low birth weight neonates. These are important research questions which have not previously been addressed in this group of neonates. Ultimately, this research aims to choose a regimen which will be tested in a much larger future trial assessing the effectiveness of a larger bundle of interventions, of which chlorhexidine skin cleansing will be a key component, in reducing hospital acquired neonatal sepsis and mortality. However, the results of the pilot will be also of significant benefit to clinicians and researchers in neonatology, microbiology, and dermatology. Providing more data on the safety of chlorhexidine in a low birth weight group of neonates, and the modifying effect of emollients, will be important for clinical practice and guideline development, as well as informing future research studies.

The main intended beneficiaries are neonates themselves. If this intervention in a larger trial was found to be of benefit, even modest reductions in neonatal sepsis would be important given the significant burden of neonatal sepsis globally[1]. As facility deliveries increase globally, preventing hospital acquired infections, which are particularly prevalent in low birth weight neonates in low and middle income countries, will be increasingly important for reducing morbidity and mortality[2]. Preventing hospital acquired infections would improve survival of neonates, and contribute to achieving Sustainable Development Goal (SDG) targets for neonatal mortality, but also reduce long term disability, which often occurs after early neonatal infections, improving the opportunity for low birth weight neonates to thrive. Avoiding preventable long term disability would also have important positive future benefits for the neonates themselves, but also their mothers and families. In particular, improved neonatal survival and child health is also associated with greater women's empowerment, education and workforce participation, with subsequent positive socio-economic effects.

Given the low cost and widespread availability of chlorhexidine and emollients, if they were shown to be of benefit in reducing hospital acquired infections, their use could also represent significant economic savings for hospitals and health systems. Reducing hospital acquired infections may in the short term reduce length of stay, consumption of antibiotics and the intensity of human resource requirements. In the long term, reducing hospital acquired infections may also reduce antimicrobial resistance, which would have significant health and economic benefits, by ensuring available treatments remain effective, and by reducing the requirement for expensive reserve antibiotics.

In summary this pilot will have positive immediate academic impact, and will facilitate further research into prevention of hospital acquired neonatal sepsis, which could have wide ranging benefits from neonatal survival and child development, to wider social and economic development.

1. Seale AC, Blencowe H, Manu AA, et al. Estimates of possible severe bacterial infection in neonates in sub-Saharan Africa, south Asia, and Latin America for 2012: a systematic review and meta-analysis. The Lancet Infectious diseases 2014; 14(8): 731-41.
2. Zaidi AKM, Huskins WC, Thaver D, Bhutta ZA, Abbas Z, Goldmann DA. Hospital-acquired neonatal infections in developing countries. The Lancet 2005; 365(9465): 1175-88.