The use of probiotics for Necrotising enterocolitis prophylaxis in the very preterm is increasing across Canada. There are apparently, though, centers that will only give them to larger preterm infants, and not to the most immature.
I think that is based on a mis-interpretation of the literature, perhaps re-inforced by a phrase in some systematic reviews, such as the following:
There is insufficient data with regard to the benefits and potential adverse effects in the most at risk infants weighing less than 1000 grams at birth.
The facts are that the birth weight stratum under 1000g is just not reported in most studies. Many studies however restricted their enrolment either to infants of less than 32 weeks, or less than 1500 grams (or both). As one example the Proprems study randomized only infants under 32 weeks and under 1500 grams, and as in many trials of VLBW infants, about half of the babies were less than 1000g (mean bwt was just over 1kg), and the mean gestational age just under 28 weeks. Very similar mean gestational ages and birth weights are found in all the studies that limited themselves to VLBW (<1500 g) babies.
Probiotics have therefore been tested in thousands of ELBW babies, and the lack of reporting of that specific stratum is not a valid reason for denying those infants the clear benefits.
If we do look at the limited data that have been reported for the subgroup of babies less than 1000g then we find the following for the outcome of NEC grade 2 or worse, with the difference in the incidence of NEC being in the direction of a benefit for probiotics, but not statistically significant.
That analysis is overwhelmed of course by the results from the PIPS trial, which was a very high quality trial, but one of the few to show no impact of probiotics. It used a previously untested strain, which might possibly account for the lack of effect. If we eliminate that trial for a moment from this subgroup, we find a reduction among the other trials which is of very similar magnitude to the overall meta-analysis, with an RR of about 0.66, again not quite significant.
It seems inherently unlikely that probiotics would have a substantial impact on infants between 1kg and 1.5 kg, but no impact below 1 kg. And despite the thousands of randomized babies, there were no reports in the RCTs, and a very small number of case reports, of adverse consequences, i.e. bacteremia, with the probiotic organisms.
So lets look at 2 very recent systematic reviews to see what is new.
The first is from a journal I had never heard of before, but it seems to have been done according to PRISMA standards. Sawh SC, et al. Prevention of necrotizing enterocolitis with probiotics: a systematic review and meta-analysis. PeerJ. 2016;4:e2429. These authors updated the searches and found, compared to recent systematic reviews, another 17 articles including an additional 5,000 babies! This is what the outcome of severe NEC looks like now:
A nearly 50% reduction in severe NEC, with very little heterogeneity, and a total of 10,500 babies studied. They performed the meta-analysis using a random effects model, and as you can tell used the Cochrane group’s software, Revman.
The results for all-cause mortality are here:
When they restricted the NEC analysis to just VLBW babies they found this:
about a 50% reduction among the 6,500 VLBW babies studied, and a 26% reduction in mortality.
Time to full feeds was 2 days shorter, and duration of TPN was 4 days shorter with probiotics compared to control.
The other very recent systematic review Thomas JP, et al. Probiotics for the prevention of necrotizing enterocolitis in very-low-birth-weight infants: A meta-analysis and systematic review. Acta Paediatr. 2017 only included data from VLBW infants, only included English language studies and only included those with a Jadad score of 3 or more (which is an evaluation of quality that is widely used). One thing they did differently was to analyze the different genera of probiotics used,
I am not sure how valuable this is in terms of selecting the bacteria to test against each other for the future, as there are probably differences between strains within genera that are important. Thus the Bifidobacterium breve BBG-001 that was used in the Pips trial, which is here referred to as Costeloe 2016, was ineffective, either because of random variation in outcomes between studies (the 95% CI include a possible RR of NEC of 0.67) or perhaps because of an ineffective strain, or a dose that was too low, or maybe because of cross-infection of the controls (37% of whom were colonized with the probiotic at 2 weeks and 49% by 36 weeks PMA). For whatever reason I think future studies should not include a BBG-001 group (unless a much higher dose is tested) and we should forget about saccharomyces.
It looks like the best strains to be tested in future comparative trials would be a combination of a lactobacillus and Bifidobacterium longum ssp infantis.
Across Canada right now there are 2 preparations being used, either Florababy, a mixture of a Lactobacillus rhamnosus and 4 bifidobacteria, and Biogaia, which is Lactobacillus reuteri. At a recent meeting of the Canadian Perinatal Research Meeting a poster was presented with Data from the Canadian Neonatal Network, including only infants under 29 weeks gestational age. It included over 3000 infants, about a quarter of whom received probiotics among the 17 centers that use probiotics at least occasionally. Dr Balpreet Singh from Dalhousie University in Nova Scotia is the first author. He and his c0-authors showed, in this observational study, a reduction in NEC, with an Odds Ratio of 0.7 for NEC, (0.64 after multivariate adjustment) and a reduction in death and the combined outcome of death or NEC also. I won’t say too much more about it, but will probably re-blog about it when fully published. But it is re-assuring that this retrospective cohort among these extremely preterm babies is consistent with the data with moderately preterm and VLBW infants in the randomized trials.
I hope to see an analysis of the impact of the 2 different preparations, which might help to decide which future trials need to be done. Overall, the impact of probiotics seems to be the same whether your baseline incidence is high or low (the relative impact is the same, even if the absolute benefit will of course be greater if you start from a higher baseline), and seems to be equivalent if you have a higher or lower rate of exclusive breast-feeding.
Thanks for this really neat review of the literature. It has helped make us decide to reintroduce probiotics in our unit
The PIPS study had high cross contamination rate of nearly 60%. This probably is the biggest, If you exclude this from meta analysis you would naturally get significant results.
I wonder if there is a possibility of Individual Patient Data Meta Analysis, which might settle the issue for good.
Being a grandma of a 26 week girl. I was interested on feelings concerning antibiotics for bacterial meningitis and the use of probiotics. She is now 32 weeks. Her Drs are hesitant about introducing the probiotics thinking that
They could cause conflict with the antibiotics. Is this the case?
I can’t give you any individual advice, but as a general rule, probiotic organisms are sensitive to the antibiotics we commonly use, so when we give them together probably (and I say this without perfect scientific knowledge being available) antibiotics that are excreted by the liver and enter the bowel will kill the probiotic organisms before they can actually get very far in the gut. Some antibiotics are largely excreted in the urine, and they may be less likely to kill the probiotics.
In my practice we only stop the probiotics when a baby is put “nil by mouth” and we otherwise continue them during antibiotic use, but without proof that they are helpful in this situation..
There are data from older children showing that probiotics reduce the severity and duration of diarrhoea that can be caused by probiotics. That occurs even when the probiotics are given at the same time as the antibiotics, the probiotics that you need for that effect may not be identical to those used to prevent NEC, Lactobacillus rhamnosus and Saccharomyces boulardii seem to be effective to prevent diarrhoes from antibiotics in older children.
We don’t commonly see diarrhoea as a complication of antibiotics in preterm babies, so I am not sure how relevant the older child data are. In summary I would say we don’t know the best approach for sure, and I think either continuing probiotcs during antibiotic treatment, or stopping them to restart just when you are stopping the antibiotics are probably both justifiable.