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Probiotic Administration in Preterm Infants: Scientific Statement

/in ISAPP Science Blog /by KC

Board of Directors, International Scientific Association for Probiotics and Prebiotics

in collaboration with

Dr. Geoffrey Preidis MD PhD, Pediatric Gastroenterology, Hepatology & Nutrition

Prof. Andi L Shane MD MPH MSc, Pediatric Infectious Diseases

A recent report of a fatality in an extremely premature infant recipient of a probiotic product has resulted in a warning letter from the United States Food & Drug Administration (FDA) to healthcare practitioners about probiotic supplementation in preterm infants and a warning letter to the probiotic product manufacturer.

Publicly available information suggests that this fatality was the direct consequence of bacteremia resulting from ingestion of the probiotic organism Bifidobacterium longum subsp. infantis delivered in medium chain triglyceride oil. This situation differs from case reports of adverse events that resulted from extrinsic probiotic product contamination (1, 2). This is an important distinction, as the potential risks and mitigation strategies differ between etiologies. As complete details of this most recent fatality have not been released, specific factors that may have contributed to the adverse outcome are unknown. However, it is worth considering the context of this case report within the broader literature available on probiotic use in this population, including the wealth of data available on sepsis incidence.

Evidence from systematic reviews

Premature infants, especially those of <32 weeks gestation and with a birth weight <1500 g, are a vulnerable population at significant risk of morbidity and mortality.  Necrotizing enterocolitis (NEC) is highly prevalent (5-10% incidence) among very preterm infants, with mortality rates of 20-30% and high morbidity among survivors, including short gut syndrome, parenteral nutrition-associated liver disease, and neurocognitive delay.

A large body of literature exists on the use of probiotics in hospitalized preterm infants, with particular focus on the prevention of NEC. At least 85 randomised clinical trials (RCTs) (3) have been conducted to evaluate the use of probiotics in preterm infants for the prevention of diseases associated with prematurity, and a number of systematic reviews with meta-analyses have analysed these data in recent years. Most RCTs conducted in the neonatal intensive care unit (NICU) designate sepsis as one of the main outcome measures.

The most recent meta-analysis was published online October 2 in JAMA Pediatrics (3). This study included 106 trials on probiotic, prebiotic, synbiotic and lactoferrin interventions for either preterm infants <37 weeks and/or those with low birth weight (<2500 g). Administration of probiotics containing multiple strains were found to be most effective in the reduction of all-cause mortality (31% reduction), with a 62% decrease in incidence of severe NEC compared to placebo (moderate and high certainty evidence). Single strain probiotics combined with lactoferrin provided greatest efficacy in the reduction of late-onset sepsis incidence (67% risk reduction with moderate certainty evidence). It was noted that none of the included studies reported cases of probiotic-induced sepsis.

Other authors including groups from the Cochrane Collaboration, American Gastroenterological Association (AGA) and the European Society for Paediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) have found similar results, and studies can be reviewed here:

Probiotics to prevent necrotising enterocolitis in very preterm or very low birth weight infants – Sharif, S – 2023 | Cochrane Library

Probiotics Reduce Mortality and Morbidity in Preterm, Low-Birth-Weight Infants: A Systematic Review and Network Meta-analysis of Randomized Trials – Gastroenterology (gastrojournal.org)

Probiotics for Preterm Infants: A Strain-Specific Systematic… : Journal of Pediatric Gastroenterology and Nutrition (lww.com)

No meta-analysis has attributed increased risk of sepsis to probiotic use in preterm infants – rather, in many cases a protective effect (or a trend toward protection) was reported. However, it is important to acknowledge the real but rare risk of probiotic-induced bacteremia in this population. In a recent review of case reports of probiotic-associated invasive infections in children, probiotic-induced bacteremia in premature infants were found to have resolved in most cases with use of effective antimicrobial therapy (4).

With data collected on over 10,000 preterm infants, substantial benefits demonstrated and a low level of risk identified, promise to improve outcomes in preterm infants who receive a probiotic product currently exists. Based on the evidence currently available, hospitals and NICUs across the globe have already adopted practices relating to probiotic use in preterm infants, some with significant health impacts (5, 6).

Risk benefit analysis and considerations for healthcare implementation

Further work needs to be done to support probiotic administration in the NICU. Collaborative efforts include recommendations for practical steps to improve probiotic product quality assurance specifically for NICU use, published in July 2023 in JAMA Pediatrics (7).

It is important to note that few (or possibly no) effective interventions are without an adverse event profile, and probiotics are no exception. Even food has a safety standard of reasonable certainty and on a regular basis, individuals suffer fatal foodborne infections. When considering the clinical indications for any intervention for an individual patient or a population of individuals, a thorough comparison of all available data on both the potential risks and the potential benefits is warranted.

The American Gastroenterological Association (8) and other major societies (including ESPGHAN and the World Gastroenterology Organisation) (9, 10) endorse probiotic products for the prevention of NEC among preterm low birth weight infants. The societies’ guidelines agree that the recommendation to use probiotics is conditional. Conditional recommendations are sensitive to patients’ values and preferences, and to the guideline panel’s perception of risk-benefit balance.  However, the recent FDA letter does not acknowledge these recommendations and further, recommends against probiotic use in preterm infants despite the robust efficacy data. With interventions such as probiotic administration, ideally shared clinical decision-making with patient and clinician would ensue. Regulatory warnings inform the risk-benefit calculation but typically do not invalidate a clinical recommendation.

Summary

  • Probiotic administration to preterm infants has been demonstrated to significantly reduce the risk of NEC, sepsis and death in large systematic reviews with meta-analyses.
  • Meta-analyses have not identified significant adverse events or safety concerns, although rare case reports have documented sepsis attributed to probiotics.
  • Stringent manufacturing standards are recommended for probiotics in vulnerable populations such as preterm infants.
  • Standardized comprehensive safety reporting across probiotic intervention studies is needed, along with funding for the conduct of long term studies.
  • The risks and benefits of probiotic administration should be considered in both the specific population and individual patients, with regulatory frameworks to enable implementation.
  • More information about this fatality should be immediately released so healthcare professionals and researchers can learn from this experience and continue to provide optimal evidence-based patient care.

To inquire about expert academic physicians available for media comment, please contact ISAPP’s Executive Director, Marla Cunningham, at marla@nullisappscience.org

See also:

NEC Society: Statement on FDA Warning of Probiotics in Preterm Infants

References

(1) Vallabhaneni S, Walker TA, Lockhart SR, et al. Notes from the field: Fatal gastrointestinal mucormycosis in a premature infant associated with a contaminated dietary supplement–Connecticut, 2014. MMWR Morb Mortal Wkly Rep. 2015;64(6):155-156.

(2) Bizzarro MJ, Peaper DR, Morotti RA, Paci G, Rychalsky M, Boyce JM. Gastrointestinal Zygomycosis in a Preterm Neonate Associated With Contaminated Probiotics. Pediatr Infect Dis J. 2021;40(4):365-367.

(3) Wang Y, Florez ID, Morgan RL, et al. Probiotics, Prebiotics, Lactoferrin, and Combination Products for Prevention of Mortality and Morbidity in Preterm Infants: A Systematic Review and Network Meta-Analysis. JAMA Pediatr. 2023 Oct 2:e233849.

(4) D’Agostin M, Squillaci D, Lazzerini M, et al. Invasive Infections Associated with the Use of Probiotics in Children: A Systematic Review. Children (Basel). 2021 Oct 16;8(10):924.

(5)  Rath CP, Athalye-Jape G, Nathan E, et al. Benefits of routine probiotic supplementation in preterm infants. Acta Paediatr. 2023 Jul 28.

(6) Bui A, Johnson E, Epshteyn M, Schumann C, Schwendeman C. Utilization of a High Potency Probiotic Product for Prevention of Necrotizing Enterocolitis in Preterm Infants at a Level IV NICU. The Journal of Pediatric Pharmacology and Therapeutics 2023;28(5):473–475.

(7)  Shane AL, Preidis GA. Probiotics in the Neonatal Intensive Care Unit-A Framework for Optimizing Product Standards. JAMA Pediatr. 2023 Sep 1;177(9):879-880.

(8) Su GL, Ko CW, Bercik P, et al. AGA Clinical Practice Guidelines on the Role of Probiotics in the Management of Gastrointestinal Disorders. Gastroenterology. 2020 Aug;159(2):697-705.

(9) WGO Practice Guideline: Probiotics and Prebiotics. Available from: https://www.worldgastroenterology.org/guidelines/probiotics-and-prebiotics

(10) van den Akker CHP, van Goudoever JB, Shamir R, et al. Probiotics and Preterm Infants: 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. J Pediatr Gastroenterol Nutr. 2020 May;70(5):664-680.

Lactobacillus bacteremia in critically ill patients does not raise questions about safety for general consumers

/in ISAPP Science Blog /by KC

By Dan Merenstein MD, Professor of Family Medicine, Georgetown University Medical Center, Washington DC, USA; Eamonn Quigley MD, Professor of Medicine, Houston Methodist Hospital and Weill Cornell Medical College, Texas USA; Gregory Gloor PhD, Professor of Biochemistry, Schulich School of Medicine and Dentistry, The University of Western Ontario, Canada; Hania Szajewska MD, Professor of Paediatrics, The Medical University of Warsaw, Poland;  and Mary Ellen Sanders PhD, Executive Science Officer, ISAPP, Colorado, USA.

A recent Nature Medicine paper reported blood cultures positive for L. rhamnosus GG in six critically ill patients at Children’s Hospital in Boston.

About this study

Patients (aged 1, 2, 4, 12, 19 and 19 years) with L. rhamnosus-associated bacteremia suffered from different chronic conditions (mitochondrial disorder, cerebral palsy, congenital heart disease, cystic fibrosis) and were located either in the ICU (cardiac or medical/surgical ICU) or ICP (intermediate care program) at the hospital at the time of bacteremia. The bacteremia was discovered during routine blood culture screens. Clinical presentations were not described in detail; however, none had endocarditis or died from the bacteremia, although one did get a central line infection. Two of the six cases of bacteremia in probiotic-consuming patients were determined by attending physicians to be transient or due to contaminants, and were not treated. The other four cases were treated with antibiotics. A further 516 patients dosed with the same probiotic did not develop bacteremia.

The researchers examined the blood isolates and using whole genome sequencing were able to confirm that the Lactobacillus isolated from the blood of these patients was genetically identical – with the exception of a few SNPs – to L. rhamnosus GG present in the probiotic product. This is the preferred approach to confirming the source of blood culture isolates.

Important questions arising from critical review of this paper

  1. Was the study appropriately controlled?

The authors report a seemingly high rate (1.1%) of Lactobacillus bacteremia among the 522 L. rhamnosus-consuming patients compared with 0.009%, the rate of Lactobacillus bacteremia among 21,652 patients who did not receive probiotics.  However, the paper does not justify the legitimacy of comparing these two groups to each other. Indeed, other underlying factors could contribute to the different rates of bacteremia, as these were not matched cohorts. It is important to recognize the limitations of the retrospective design used here, which limits the ability to match controls, and to control for cofounders such as underlying illness, severity of clinical illness and co-therapies (including antibiotics).

  1. What is the mechanism of transmission of the probiotic to the patients’ blood?

Most of the patients had a central line venous catheter. The paper reported that probiotics were mostly administered via tube feeding. If a probiotic is able to readily translocate the gut barrier in such patients, this would be a safety concern. But if the observed bacteremia was due to contamination of a central line, this may say more about hospital procedures than safety of the probiotic. Indeed, 16 years ago, central line contamination leading to fungemia was reported. In a 2005 paper, 92% of cases of fungemia associated with Saccharomyces cerevisiae var boulardii administration had an IV catheter. Based on such reports, handling dried probiotics in a hospital environment with critically ill patients should be done with caution. However, with proper administration procedures, certain probiotics are medically recommended in this setting.

  1. What was the clinical impact of administration of L. rhamnosus GG?

Important clinical parameters such as all-cause mortality (the outcome of greatest importance), length of hospital stay, abscesses, required medications, and others were not reported (although central line infection was reported) for the patients studied. The clinical context of this study would be more easily understood if information on the indications driving probiotic administration was provided. The authors question the risk/benefit of probiotic administration to ICU patients in a children’s hospital yet focus solely on risk and do not measure benefit. This suggests an underlying assumption by the authors that when it comes to probiotics, any risk is too much. Did the patients given L. rhamnosus GG suffer negative clinical outcomes more often than age and condition-matched controls? If so, then giving this probiotic to these patients cannot be recommended. But if not, then even though risk of bacteremia may be higher, if the patients given the probiotic fared better than matched patients, then the probiotic should be considered a reasonable option.

Lastly, the finding of a rate of Lactobacillus bacteremia of 1.1% needs to be viewed in the context of a 20% rate of nosocomial infections in the ICU (here and here).

Lessons regarding probiotic safety

Two main issues are raised by this study. The first is whether the evidence suggests opportunistic pathogenic properties of L. rhamnosus GG or rather that procedures used to administer probiotics in the ICU environment resulted in contamination, which caused bacteremia. No conclusions can be made from this study regarding this. The second is the importance of placing the results of this study into a clinical framework. The study implies risk from probiotic administration, even though the study was not powered for clinical outcomes and could not place any perceived increased risk into the context of any achieved benefit. Further, reporting rates of Lactobacillus bacteremia between cohorts unmatched for important characteristics except for probiotic use does not inform on relative risk.

Importantly for the broader situation of probiotic use, the ICU population is not reflective of the general population, so this study does not allow us to draw conclusions about safety of L. rhamnosus GG use in non-ICU patients.

We recognize the value of careful tracking of potential probiotic-associated infections and appreciate the application of bacterial genomic sequencing to identify the probiotic in the blood. Used more widely, this approach could resolve many purported claims of probiotic bacteremia.

This paper serves as an important reminder that use of probiotics in critically ill patients must be carefully considered and practice must align with learnings from the past, including the risk of central line contamination with probiotics. In addition, this paper highlights the importance of knowing the exact strain (including its antibiotic resistance profile and preferentially also its genome sequence), so that in the rare case of bacteremia, appropriate antibiotics can be administered.

See related article: Hill, C. Balancing the risks and rewards of live biotherapeutics. Nat Rev Gastroenterol Hepatol (2019)

See here for an additional related open-access publication: Probiotic use in at-risk populations. Sanders et al. 2014.