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Probiotics in review


Like almost every other human entering a pharmacy in the last ten years, I was offered probiotics when I collected a prescription. On my walk back to the car, I mused about the evidence behind the shop assistants’ 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., 2016. What are the indications for using probiotics in children? Archives of disease in childhood101(4), pp.398-403.

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

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

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

What are probiotics good for?

Necrotising enterocolitis – Multiple RCTs and a Cochrane review, mostly using L. reuteri DSM 17938, show reduced 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 an NNT of 13 for antibiotic-associated diarrhoea; the database is predominantly adults. The 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 an NNT = 7. Szajewska doesn’t appear to have much faith in these results for FGDs 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 probiotics work for?

Nosocomial infection – The review considers several 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 in risk of post-admission diarrhoea in children under two years old; 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.

Helicobacter pylori – May improve the eradication rate, but limited evidence in children.

Inflammatory bowel disease – Some evidence for inducing remission of ulcerative colitis; insufficient evidence in Crohn’s disease. 

What do probiotics not work for?

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.

Firstly, I was fascinated by preventing infections in daycare centres – Szajewska’s overall verdict was that there was insufficient 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. Pediatrics Mar 2014, peds.2013-0652; DOI: 10.1542/peds.2013-0652

P: 336 children born at term aged 6-36 months attending 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, defined as days when three or more loose or watery stools were passed within 24-hours with or without vomiting, both during the intervention and for 12 weeks.

About ¼ of families offered enrolment declined, so 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 four weeks) exposure to probiotics, prebiotics, or antibiotics, or 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 diarrhoea episodes, episodes of diarrhoea per child, mean duration of diarrhoea episodes and days with diarrhoea 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.

Secondly, the idea that probiotics could reduce infantile colic seemed immensely appealing; it’s an area that has had many debunked therapies.

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 three 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.

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 and 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.

The bottom line

Probiotics are “ive microorgnaisms that confer a health benefit on that host when administered in adequate amounts.

There are many vested interests around labelling and quality.

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.



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