The recently-published paper by the European Society for Paediatric Gastroenterology Hepatology and Nutrition examines the effectiveness and safety of numerous probiotic strains to assess their appropriateness and relevance in providing preterm babies with sufficient nutrition.
ESPGHAN, an organization designed to promote the health of children, hopes the paper, published through the scientific journal, Journal of Pediatric Gastroenterology and Nutrition, will act as a guide for the potential use of probiotics in preterm infants.
Presence of probiotics
Probiotics have been identified as a possible therapy for preterm infants to reduce morbidity and mortality. However, to date, only a limited number of different strains have exhibited preliminary potential effectiveness for probiotics use.
The present position paper aims to provide advice and guidance on which specific strains might potentially be used and which should not be for preterm neonates. In the paper, the working group also strives to address safety issues and recommendations relating to probiotic supplementation for preterm infants.
Probiotic use in preterm infants
Approximately 1-2% of all infants are born very preterm or extremely preterm – two months or earlier than their due date. In total, this amounts to 2.4 million babies around the world being born very preterm or extremely preterm, every year. Of these babies, NEC affects approximately 5% and results in a mortality rate of up to 30%, global bioscience company, according to Chr. Hansen.
Ahead of conducting its research, the European Society for Paediatric Gastroenterology Hepatology and Nutrition found that over 10,000 preterm infants have taken part in randomized controlled trials (RCTs) on probiotics throughout the globe. As a result, the researchers saw the potential that probiotics may be able to lower the rates of enterocolitis (NEC), sepsis and mortality.
Babies born preterm have lower immunological capacities and occasional indwelling catheters. It is vital that the probiotic product can provide quality assurance to indicate the safety and relevancy of its application. For example, the probiotics strains should not include transferable antibiotic resistance genes, and equally, local microbiologists must have the ability to routinely detect probiotic sepsis.
The researchers found that answers to clinical questions relating to which strain to use, at what dosage, and how long to supplement probiotics, are currently unavailable. In addition, there is a rising number of commercial items on the market that contain probiotics that sometimes possess “suboptimal quality”, the paper emphasized.
A recent network meta-analysis by the working group determined the relevant probiotic strains that have a high level of efficacy in terms of clinical outcomes for preterm neonates. However, the researchers found the efficacy in lowering mortality and morbidity was identified for only a minority of the strains or combinations studied.
Comprising neonatology, pediatric gastroenterology and nutrition experts, the working group defined a number of core clinical questions:
1. Are probiotics safe enough for administration to preterm infants?
2. Should probiotics be used in preterm infants? If yes, which probiotics (single or combinations) should be used in what dose?
3. Are combinations of species more effective than the use of a single strain to reduce the risk of NEC (stage 2 or 3)?
4. Which dose of a probiotic strain or combination of strains should be administered?
5. What should be the duration of administering probiotics?
6. Is it appropriate to administer other strains than those studied in large well-conducted randomized controlled trials (RCTs)?
Nutritional supplement marketing recommendations
The research paper highlights that typically probiotics are marketed as nutritional supplements rather than drugs. As a result, this market positioning creates an “unregulated market where manufacturers may change product contents and/or the production process without properly addressing these issues”.
Following the ESPGHAN’s calls for more rigorous and strict production controls on probiotics, particularly in premature neonates, the paper relays the specific importance and concern for obtaining product safety and quality due to the insufficient immune response of preterm infants.
Highlighting how commercial and medical labelling on probiotics items “frequently do not match actual contents in terms of species identity and bacterial count, or contained contamination with non-probiotic bacteria”, the research paper states “ensuring correct product identity at strain level is essential”, during both research and clinical implementation. By doing so, product identification at the strain level is consistent from trial results to clinical practice.
Good Manufacturing Practice (cGMP) guidelines are therefore recommended for the application of probiotic products for premature infants. The paper also sets out that manufacturers should provide compliance and analysis certificates that identify purity, viability, at the end of shelf life, antibiotic susceptibility and resistance profiles, at the very minimum.
As safety and quality assurance issues are so prominent, the researchers recommend that if a baby is placed in a newborn intensive care unit (NICU) and probiotics are administered as part of standard care, then parents “must be actively informed”. Face-to-face communication is advised when discussing the potential benefits and risks associated with probiotics, using written materials to consider local context needs.
Key Recommendations for probiotic use in preterm infants
Included in the researchers’ recommendations are a core number of key responses to questions on the use of probiotics for preterm infants.
1. Selection based on safety
Focusing on the use of probiotics, the working group emphasizes that formulators should select a strain (or combination of strains) containing proven effectiveness and an established safety profile.
Safety is paramount and should be the approach adopted instead of choosing to administer multiple strains from different genera.
Probiotic strains that produce D-lactate are also advised against as these contain a possible risk of safety that has not been sufficiently studied in preterm infants and so remains unclear.
2. Dosage and duration
If probiotics are administered, the paper recommends using similar doses as applied in relevant RCTs. These selected probiotic products should also come with formal quality reports that set out the product’s viability until the end of its shelf life.
Available data does not specifically show an optimal start of treatment or total duration. As a result, the paper sets out that individual units should be used to determine the length of the treatment. The total time should be calculated based on the population who will receive the probiotics and their continual risk of diseases such as NEC.
3. Information transparency
When implementing a probiotic product, local microbiologists should be informed. Using standard culture methods, local microbiologists should also confirm the ability to routinely detect probiotic bacteraemia/fungaemia.
The panel states that only the use of strains without any plasmids containing transferable antibiotic resistance genes is crucial for use. The manufacturer should give and confirm the accuracy of this information.
4. Testing strains
In a clinical setting, the researchers state that the use of a single strain or combination of strains should be practice-based resulting from positive well-conducted RCTs. However, in a research setting, it is relevant to test new strains or new combinations of strains.
Source: Journal of Pediatric Gastroenterology and Nutrition
Published online ahead of print, doi: 10.1097/MPG.0000000000002655
“Probiotics and Preterm Infants - A Position Paper by the ESPGHAN Committee on Nutrition and the ESPGHAN Working Group for Probiotics and Prebiotics”
Authors: C.H.P. van den Akker, et al.