• How much more evidence do you need?

    Andi Shane, Girish Deshpande, and Dan Merenstein bring the pain:

    Although our understanding of the physiological mechanisms of NEC [necrotizing enterocolitis] and its risk factors remains incomplete, a common trigger appears to be perturbation in the intestinal microbiota. Probiotic supplementation provides beneficial microorganisms to a microbiologically perturbed gut. Dissenters claim that the heterogeneity of product, dose, and indication in probiotic intervention studies makes it difficult to compare individual study results.

    Probiotics are considered by some to be “alternative medicine”. They’re live bacteria, like you might find in yogurt or dietary supplements. The idea is that if you put in more “good” bacteria, then there’s less room for “bad” bacteria to grow. Stop smirking. There have been studies of their use in preterm infants to prevent NEC:

    [A] Cochrane review by Alfaleh et al published in 2011 identified 16 eligible trials of 2842 preterm infants (<37 weeks’ gestational age or with a birth weight of <2500 g). Although there was variability in subject demographics, in probiotic products used, and in dosing, the review concluded that enteral probiotic supplementation significantly reduced the incidence of NEC (relative risk, 0.35 [95% CI, 0.24-0.52]) and mortality (relative risk, 0.40 [95% CI, 0.27-0.60]). Notably, there was no evidence of sepsis associated with probiotic products in the trials. As readers are aware, Cochrane reviews are very conservative with the wording of their conclusions and data interpretation; however, Alfaleh et al state that their “updated review of available evidence supports a change in practice.” It is difficult to find such a definitive conclusion statement in other contemporaneous Cochrane reviews.

    No joke. Cochrane reviews often hedge like crazy. This is about as positive a result as you get. So how does the medical community in the US respond?

    Owing to the increased use of probiotics in pediatric practice, representatives from the American Academy of Pediatrics conducted a review of probiotic applications, published in 2010, which concluded that “there is some evidence that probiotics prevent necrotizing enterocolitis in very low birth weight infants (birth weight between 1000 and 1500 grams), but more studies are needed.” (p1217) The questions remain: how much more evidence is needed, and of what quality? This cautious way of thinking on the part of the American Academy of Pediatrics has contributed to the failure to improve outcomes for preterm infants over the last 15 to 20 years. The authors of the American Academy of Pediatrics review did not discuss the regulatory roadblocks that have halted clinical trials with probiotics in the United States or the fact that currently no studies are being conducted. A review of the clinical trials registry, ClinicalTrials.gov, in January 2013 yielded 16 registered trials with the terms probiotic and necrotizing enterocolitis; none are being conducted in the United States.

    The piece goes on to attack the FDA for its policies that prevent good research on probiotics from being done here in the US. It also attacks the way that probiotics seem to be held to a standard that traditional medicine is not. Look, I will be the first to slam any practices, traditional or alternative, that make claims that go beyond evidence. I will be the first to mock those that refuse to engage in studies because they think they might find something they don’t like. Neither applies here. This is a problem that needs fixing, now.


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    • I had an old sage tell me during my neonatal fellowship,”The greatest bias in medical research is in choosing WHAT to study. ” Nowadays it seems that if it does not include some expensive drug or procedure it doesn’t get done. Also good studies on newborns are very expensive to do right and often need collaboration between many centers; something that governments are quite good at funding: oh, I forgot between the sequester and the shutdown there is NO money.