Over the last two decades, probiotic research has expanded exponentially and by 2020, >1300 RCTs have investigated the efficacy of probiotics – mainly in treating intestinal diseases (78%).³

Lactobacillus and Bifidobacterium strains have been the most widely studied and are the most commonly prescribed probiotics.⁴

Which diseases or conditions benefit most from probiotic use?

According to the International Scientific Association for Probiotics and Prebiotics (ISAPP), established in 2002, probiotics have proven efficacy in predominantly gastrointestinal diseases (eg antibiotic-associated diarrhoea, Clostridioides difficile infections, ulcerative colitis, irritable bowel syndrome and infantile colic), as well as urogenital (eg bacterial vaginitis and vulvovaginal candidiasis), and skin conditions (eg atopic dermatitis), and upper respiratory tract infections.⁵

Pre-term neonates at risk of NEC

The ISAPP website also showcases studies that found prophylactic probiotic use can reduce the incidence of necrotising enterocolitis (NEC), mortality, and late-onset sepsis (LOS) in pre-term neonates and can reduce NEC stage ≥2 in very low birth weight infants.⁵ For additional reading material see the reference list below.^{6,7,8,9,10,11,12,13,14,15}

Pre-term birth (<37 weeks of gestation) is one of the leading causes of neonatal morbidity and mortality. Annually, more than 15 million (11.1%) pre-term births are reported worldwide.^16,17

Although the aetiology of NEC is still poorly understood, it is theorised that bacterial colonisation of an infant’s gut may be a significant factor. Abnormal gut bacterial colonisation increasingly recognised as central to the pathogenesis of NEC.¹⁸

The clinical presentation of NEC varies. Bell's modified criteria is commonly used to assist clinicians in classifying the severity of the disease. Severe cases (modified Bell's stage ≥2) have combinations of abdominal distension, pneumatosis, portal venous gas and perforation. Morbidity including long- term sequelae and mortality rates (30%-40%) are high. An incidence of over 10% has been reported in neonates <1500g or <32-weeks.^{19,20,21,22,23,24}

A meta-analysis of 29 RCTs, which compared probiotic use with placebo in very low birth weight infants, found a decreased risk (risk ration 0,57) in NEC with probiotic use. Studies from Germany (n=10 890 pre-term neonates) and Canada (n=1631 pre-term neonates) showed similar significant reductions in severe NEC.^8,11,14

Guideline for probiotic use in pre-term neonates at risk of NEC

Cambridge University Hospitals (United Kingdom) routinely administers the first dose of probiotics in all pre-term neonates at risk of NEC as soon as they are ready for enteral feeds.¹⁸

A number of RCTs and observational studies have demonstrated a reduction in NEC following routine use of probiotics in neonates, including those born <1000g, note the authors of the guideline developed for the hospitals. The guideline recommends that probiotics should be offered to neonates at  highest risk of NEC:¹⁸

• All neonates born <32 weeks gestation
• All very low birth weight preterm neonates (32 to 37 weeks gestation and <1500g). However, the authors point out that although some evidence suggests that pre-term neonates >1000g may benefit more from probiotic treatment than those who are less mature, there is little evidence to support withholding supplementation from less mature neonates
• Other babies who are at risk of dysbiosis may benefit from probiotics (eg short gut/gastroschisis). This should be discussed with the infant’s parents, paediatrician, and surgeon before any decision to supplement is made.

When should probiotics be started?

The authors recommend probiotics should be started as soon as the neonate is ready for enteral feeds (ideally on the first post-natal day). If expressed breast milk/colostrum is not available or likely to be delayed, then probiotics should still be administered for any infant, either via nasogastric/orogastric tube or directly into the mouth once they are deemed ready for enteral feeds.¹⁸

How long should probiotics be continued?

Probiotics should be continued until about 34 weeks corrected age for neonates born <32 weeks gestation. Consider continuing liquid probiotic preparations until current supply is used up. Probiotics should be stopped at discharge for neonates <1500g and 32-36 weeks gestation, recommends the guideline.¹⁸

The risks of bacterial translocation and sepsis may be increased when a neonate is critically ill. Probiotics should therefore be stopped, alongside feeds, if a neonate is very unwell, septic or has signs of evolving NEC. They can be recommenced as soon as feeding is re-started.  Neonates transferring between units should continue on probiotic therapy if they still meet the criteria for use.¹⁸

Which probiotic to use?

The authors of the guideline state there is currently insufficient high quality evidence to recommend one probiotic strain over the other.¹⁸

In 2020 the European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN), issued a position paper, which conditionally recommends the use of Lactobacillus or a combination of Bifidobacterium and Streptococcus thermophiles.²⁵

According to Al-Hadidi et al, Lactobacillus reuteri  possesses anti-inflammatory and anti-microbial properties which may play an integral role in intestinal protection against NEC.²⁶ L reuteri produces reuterin, which has been shown to effectively inhibit pathogenic bacterial growth through the induction of oxidative stress. Investigations using an experimental model have demonstrated the ability of our L. reuteribiofilm formulation to significantly reduce the incidence and severity of NEC, decrease NEC-related mortality, stabilise the intestinal mucosal barrier, and down-regulate the production of proinflammatory cytokines.²⁶

ESPGHAN stresses it is important to screen the selected probiotic for bacteraemia/fungaemia before initiating probiotic therapy. Probiotic bacteraemia is extremely rare, but if it does happen, a suitable anti-microbial agent should be prescribed.¹⁸

Conclusions

In summary, some evidence indicates that routine probiotic supplementation was associated with significantly reduced NEC stage ≥2, LOS, mortality, and time to full feeds in pre-term neonates without significant adverse effects. Importantly, routine probiotic supplementation was associated with significant reduction in NEC ≥Stage 2 in extremely low birth weight neonates.²⁷

References

1. Hill C, et al. Expert consensus document. The International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probiotic. Nat Rev Gastroenterol Hepatol, 2014.
2. McFarland LV. From yaks to yogurt: the history, development, and current use of probiotics. Clin Infect Dis, 2015.
3. Dronkers TMG, et al. Global analysis of clinical trials with probiotics. Heliyon, 2020.
4. Fijan S, et al. Health Professionals’ Knowledge of Probiotics: An International Survey. Int J Environ Res Public Health, 2019.
5. International Scientific Association for Probiotics and Prebiotics. https://isappscience.org/for-clinicians/resources/probiotics/#toggle-id-7
6. Meyer MP, et al. Probiotics for Prevention of Severe Necrotizing Enterocolitis: Experience of New Zealand Neonatal Intensive Care Units. Front Paediatrics, 2020.
7. Jacobs SE, et al. ProPrems study group. Probiotic effects on late-onset sepsis in very preterm neonates: a randomized controlled trial. Pediatrics, 2013.
8. Denkel LA, et al. Protective effect of dual-strain probiotics in preterm neonates: a multi-center time series analysis. PLoS ONE, 2016.
9. Olsen R, et al. Prophylactic probiotics for preterm neonates: a systematic review and meta-analysis of observational studies. Neonatology, 2016.
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13. Van den Akker CHP,et al. Probiotics for preterm neonates: a strain-specific systematic review and network meta-analysis. J Pediatr Gastroenterol Nutr, 2018.
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16. Blencowe H, et al. National, regional, and worldwide estimates of preterm birth rates in the year 2010 with time trends since 1990 for selected countries: a systematic analysis and implications. Lancet, 2012.
17. Liu L, et al. Global, regional, and national causes of under-5 mortality in 2000–15: an updated systematic analysis with implications for the sustainable development goals. Lancet, 2016.
18. Radbone L, Clarke P. Clinical Guideline: Routine use of probiotics to prevent necrotising enterocolitis in high risk preterm neonates. https://www.eoeneonatalpccsicnetwork.nhs.uk/wp-content/uploads/2022/09/Probiotic-Guideline.pdf
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22. Kliegman RM, Walsh MC. Neonatal necrotizing enterocolitis: pathogenesis, classification, and spectrum of illness. Curr Probl Pediatr, 1987.
23. Gregory KE, et al. Necrotizing enterocolitis in the premature infant: neonatal nursing assessment, disease pathogenesis, and clinical presentation. Adv Neonatal Care, 2011.
24. Gephart SM, et al. Necrotizing enterocolitis risk: state of the science. Adv Neonatal Care, 2012.

25. Van de Akker, et al. Probiotics and Preterm Neonates: A Position Paper by the European Society for Paediatric Gastroenterology Hepatology and Nutrition Committee on Nutrition and the European Society for Paediatric Gastroenterology Hepatology and Nutrition Working Group for Probiotics and Prebiotics. Journal of Pediatric Gastroenterology and Nutrition, 2020.
26. Al-Hadidi A, et al. Lactobacillus reuteri in Its Biofilm State Improves Protection from Experimental Necrotizing Enterocolitis. Nutrients, 2021.
27. Deshmukh M, Patole S. Prophylactic Probiotic Supplementation for Preterm Neonates-A Systematic Review and Meta-Analysis of Nonrandomized Studies. Adv Nutr, 2021.