Can we build a better breast milk with probiotics?

Its hard not to hear about probiotics these days.  They are in our grocery stores as supplements to yoghurt and other foods and can be purchased in health food stores or at your local pharmacy.  They appear to be everywhere as word spreads about the importance of your microbiome in maintaining good overall health.

It didn’t take long for clinician scientists to turn their attention to the neonate who is at risk of necrotizing enterocolits (NEC).  It has been known for some time that formula feeding versus breast milk plays a role in the development of NEC as premature infants fed formula repeatedly were found across studies to have a higher incidence of NEC.  The evidence is so strong in fact that the Cochrane review on the subject states Enteral supplementation of probiotics prevents severe NEC and all cause mortality in preterm infants. Our updated review of available evidence strongly supports a change in practice.   If you have read such reviews you know that they rarely come out this strong in their support of something! Furthermore, infants fed formula may have a different preponderance of more pathogenic bacteria in the colon and less lactobacillus and bifidobacterium species.  The idea behind providing probiotics to neonates would therefore be to repopulate the intestine of these vulnerable infants with good bacteria and potentially reduce the incidence of a devastating condition like NEC.

If only it were that easy though

The issue of using Probiotics in preterm infants is a contentious one to say the least.  While the evidence appears to indicate an overall benefit in terms of reducing rates of NEC there remain concerns regarding the safety of providing bacteria to this population even though the bacteria are thought to be beneficial.  The people who urge caution in the use of probiotics say so due to a few reports of sepsis after the introduction of probiotics with the organism that the patient was provided or with a different species that was could be traced to a contaminated product.  As noted in an article on CBC recently these products fall under the category of a nutritional product rather than a medication with Health Canada and therefore are not subject to the same rigorous quality control standards as other comparable medications would be.

Others while recognizing the potential for contamination and sepsis would argue that the risk is low compared to the benefit provided to the infants overall and therefore claim benefits outweigh risks.

Manipulating Breastmilk in a Double Bling RCT

Given the above concerns regarding administration of these products to neonates I was excited to see the randomized double blinded study by  Benor S et al; Probiotic supplementation in mothers of very low birth weight infants. This study enrolled mother and infant pairs within 72 hours after birth to commence on maternal treatment with Lactobacillus acidodphilus and Bifidobatera lactis  versus placebo until discharge.   The rationale for giving probiotics to lactating mothers was based on a previous study showing less atopic dermatitis in the offspring of mothers who took such treatment while breastfeeding and in a study of breast milk demonstrating lower levels of the inflammatory cytokine transforming growth factor beta (TNF-B).  Less inflammation might equate to less NEC.

The primary outcome was Bell Stage II NEC and the investigators required 90 mothers in each arm to show a difference in the incidence of NEC based on previous work in their centre.  All included pairs needed to be providing >50% EBM in order to minimize any effect from formula.  The overall incidence of NEC at the completion of the study was 27% in the placebo group vs 12% probiotic group and for NEC II 18% vs 4% in those treated with probiotics.  The rates of NEC were quite high compared to what we typically see and the authors noted that even for their site (for uncertain reasons) there was a higher rate than they expected.  Neither of the rates of NEC were statistically different (both reached p=0.15 levels) but there was a significant issue with this study.

The total recruitment was 25 in the probiotic and 33 in the control arm.  This was a far cry from the estimated 90 needed per side.  The reason for this goes back to the start of this blog entry.  The study needed to be stopped due to poor enrolment.  Why so low? The majority of mothers approached for this study did not want to risk not getting probiotics so they opted to simply take them due to the perceived health benefits that as adults they already believe exist.  Sadly I think this problem would resurface in many places if the study was replicated.  This loss of equipoise by the families will make obtaining consent for such studies very difficult and we may not get a satisfactory answer.

Interestingly the authors of this study also measured TNF-B and found a strong trend towards lower levels in the breast milk of the probiotic supplemented group matching the trend towards less NEC.

I sincerely hope that another study such as this can be done without such issues in recruitment as the strategy would address the issue of not providing the bacteria directly to the neonate while still potentially reaping the benefits of less NEC.  For now we will have to wait and see.

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