Probiotics in review

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Like almost every other human entering a pharmacy in the ten last years, I was offered some probiotics when I collected a prescription recently. On my walk back to the car I mused about the evidence behind the shop-assistant’s attempted up-sale. I reminded myself of the use of probiotics to prevent necrotising enterocolitis, and was starting to think of some other indications. Some days later, this review by Hania Szajewska in the Archives of Disease in Childhood popped up; here’s a precis of an excellent paper:

Szajewska, H.What are the indications for using probiotics in children? Arch Dis Child. Published Online First: 7 September 2015

Probiotics are “live microorganisms that, when administered in adequate amounts, confer a health benefit on that host.” The most common strains used therapeutically are the lactobacillus strains L. reamnosus GG (LGG) and L. reuteri DSM 17938 as well as bifidobacterium and saccharomyces. There are also some novel probiotics in development.

Probiotic preparations differ to standard medications as the dose, viability and even agent (organism) are harder to control. There is significant industry influence and, in my opinion, therapeutic development has likely suffered at the expense of populist marketing. Research into probiotics is strain specific; with that comes the challenges of extrapolating the findings to any over-the-counter product. Specifically, probiotics are not regulated as drugs, hence significant concerns exist with respect to labelling and quality.

In this paper, Szajewska reviews the evidence for a number of paediatric indications for probiotics. I’ve simplified and summarised the findings here;

What do we think works?

Necrotising enterocolitis – Multiple RCTs & a Cochrane review, mostly using L. reuteri DSM 17938 show a reduction in NEC in preterm infants. Additionally, there was a reduced time to full feeds, reduced admission length and reduced rates of late-onset sepsis.

Antibiotic associated diarrhoea – Szajewska references her own meta analysis – albeit primarily an adult population – which identified a NNT of 13 for antibiotic associated diarrhoea; the database is predominantly adults. Most effective probiotic agents for this indication are saccharomyces boulardii and LGG.

Infantile colicL. reuteri DSM 17938 was assessed in 4 RCTs; their combined results showed that the use of reduced crying times in breastfed infants with infantile colic. In one analysis (3 trials), L. reuteri DSM 17938 vs placebo reduced crying times at 21 days of life by an average of 43 minutes/day. Probiotics appear more helpful in breastfed by comparison to formula fed infants.

Functional abdominal pain – A meta analysis of LGG for a range of abdominal pain-related functional gastrointestinal disorders (FGDs) showed that LGG was significantly better than placebo in this population, with a NNT = 7. Szajewska doesn’t appear to have much faith in these results with respect to FGDs as a whole, but notes that patients with Irritable bowel syndrome showed the most benefit (NNT = 4).

Acute gastroenteritis – ESPGHAN (the European Society for Paediatric Gastroenterology, Hepatology & Nutrition) recommend consideration of probiotics (LGG > S. boulardii > L. reuteri DSM 17938) for children with acute gastroenteritis, in addition to hydration therapy.

What might work?

Nosocomial infection – The review considers a number of nosocomial infections, and briefly mentions the importance of rotavirus immunisation, where available. A handful of trials showed that probiotics (LGG) vs placebo had no significant differences for risk of post-admission diarrhoea in children under 2 yo; the results contradict some earlier trials in this area, which showed promise.

Prevention of allergy – This is controversial – two studies published by opposing peak bodies disagree. This includes maternal probiotics to reduce long-term outcomes.

H.Pylori – May improve eradication rate, but limited evidence in children.

IBD – Some evidence for inducing remission of Ulcerative colitis; insufficient evidence in Crohn’s disease. 

What doesn’t work?

Functional constipation – no evidence of benefit; not recommended via ESPGHAN 
Within the review, two positive studies jumped out at me, so I went back to the primary literature for a deeper dive.

Gutierrez-Castrellon, P., et al.

Firstly, I was fascinated by the idea of preventing infections in daycare centres – Szajewska’s overall verdict was that there was not currently sufficient evidence, but that LGG and L. reuteri DSM 17938 may have some effect on community-acquired infections. Particularly, the review describes this study;

Gutierrez-Castrellon, P., Lopez-Velazquez, G., Diaz-Garcia, L. et al. Diarrhea in Preschool Children and Lactobacillus reuteri: A Randomized Controlled Trial. 

P: 336 children born at term aged 6-36 months attending a daycare in Mexico
I: 5 drops L. reuteri DSM 17938 for 12 weeks
C: placebo drops
O: The primary outcome was the number of days with diarrhoea per child, which was defined as days when 3 or more loose or watery stools were passed within a 24-hour period with or without vomiting, both during the intervention and for 12 weeks afterwards.

  • About ¼ of families offered enrolment decline; which means we should question the (?social) acceptability of the intervention in this population.
  • Semi blinded – one of the authors was overseeing the block-randomisation.
  • Interesting exclusion criteria including birth weight < 2500 g, chronic disease, failure to thrive, allergy or atopic disease, recent (previous 4 weeks) exposure to probiotics, prebiotics, or antibiotics, or were participating in other clinical trials.
  • A reasonably well defined list of secondary outcomes.
  • Parents were educated about stool descriptors using the Bristol stool scale, and upon a loose motion had to contact the study centre, and then report for assessment. I wonder if this call-presentation process lent itself to underreporting (in both groups.)
  • All four primary outcomes: Number of diarrhea episodes, Episodes of diarrhea per child, Mean duration of diarrhea episodes and Days with diarrhea per child were significantly better in the treatment arm, both during the intervention and afterwards. With p values ranging from 0.03 to 0.01.

Indrio, F et al.

Secondly, the idea that probiotics could reduce infantile colic seemed immensely appealing; it’s an area that has had a myriad of debunked therapies over the last several millenia. T

Indrio F.,Di Mauro A., Riezzo G., et al..Prophylactic use of a probiotic in the prevention of colic, regurgitation, and functional constipation: a randomized clinical trial. JAMA Pediatr. 2014 Mar;168(3):228-33.

P: 589 term infants aged less than one week, in 9 centres across Italy.
I: 5 drops of L reuteri DSM 17938 (1×10^8 cfu) for 90 days
C: placebo
O: Primary outcomes were daily crying time, regurgitation, and constipation during the first 3 months of life. Cost-benefit analysis of the probiotic supplementation.

  • Infants receiving antibiotics in the first week of life were excluded; (in Australian maternity units, this would account for a significant number.)
  • Trial was independently randomized and double blinded.
  • Around ⅙ patients were lost to follow-up; a significant number were withdrawn from the treatment arm for protocol violations by the investigator.
  • Parents recorded data in a structured diary and sought advice as required via usual channels.
  • At both one and 3 months of life, the infants in the treatment arm cried for significantly shorter periods of time and stooled more frequently. At three months, there were fewer episodes of regurgitation in the treatment arm.
  • Although this is a single study, there are a number along similar lines; Szajewska’ paper mentions 4 in total. The results are most striking in this paper, hence my curiosity.

The organism of the hour, L. reuteri DSM 17938 was first cultured from breast milk of a Peruvian mother; it is patented by BioGaia whom provided the study drug and placebo for both trials above.

Conclusions

There’s a growing body of evidence for the potential benefits of probiotics in a number of paediatric conditions.

There is a bias in this review (and pretty much all of academic medicine) towards positive trials. That being said, I haven’t given the details of every study mentioned; Szajewska’s review does so nicely & I also recommend a read of the primary literature.

Most importantly, communicating with parents about the uncertainties about over-the-counter probiotics with respect to labelling, quality, dose and organism remain central to this discussion.

Key points:

  • Probiotics are “live microorgnaisms that, when administered in adequate amounts, confer a health benefit on that host.”
  • There are many vested interests & popular marketing with issues around labelling and quality in this area.
  • Research is strain specific.
  • Main strains researched are; Lactobacillus reuteri DSM 17938, Lactobacillus reamnosus GG (LGG), Bifidobacterium and Saccharomyces
  • Presently, benefit has been demonstrated in NEC, Antibiotic associated diarrhoea, infantile colic, functional abdominal pain and acute gastroenteritis.

 

References:

Szajewska, H.What are the indications for using probiotics in children? Arch Dis Child archdischild-2015-308656 Published Online First: 7 September 2015

Gutierrez-Castrellon, P., Lopez-Velazquez, G., Diaz-Garcia, L. et al. Diarrhea in Preschool Children and Lactobacillus reuteri: A Randomized Controlled Trial. 

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About 

A Paediatric Trainee based in Queensland, Australia, Henry is passionate about Adolescent Medicine & General Paediatrics, with a strong interest in Medical Education & Clinical Teaching. An admitted nerd & ironman with a penchant for Rubik's Cubes & 'Dad jokes'.

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