Are Probiotics Still Relevant in the NICU?

Are Probiotics Still Relevant in the NICU?

Its hard not to hear about probiotics these days.  They are in our grocery aisles 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.  The first food to have probiotics added to it was a Japanese drink called Yakult download (1)and after that the concept took off with Danone’s Activa drink not being far behind. Medicine has studied the effects of probiotics for all sorts of conditions with a pubmed search for reviews of probiotics in humans coming up with over 1800 results.  The concept is enticing for sure.  Take bacteria which are known to populate healthy intestines and provide them either in food or in capsules to change the bacterial population in patients who for one reason or another have cause to believe their intestinal microbiome has shifted to something undesirable.

Do Probiotics Reduce The Risk of Necrotizing Enterocolitis?

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.  In fact the contamination need not be with bacteria as was found in 2014 when Rhizopus oryzae was found in a commonly used product as was described in the Forbes article here.  What made this case garner widespread media attention was that the infant died and justifiably led people to start asking questions about safety.

How Certain Are We of The Quality of the Products?

As I mentioned in another post on Facebook and Twitter 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. 

An additional challenge (emanating from the lack of rigorous quality control demanded by a product deemed a drug) is the certainty that what you believe you are administering is actually in the product on the label.  I demonstrated above how there can be contaminants but shouldn’t the product actually have at least the bacteria that is on the bottle as well?  The majority of probiotics destined for human consumption are meant to contain lactobacillus and/or bifidobacterium.  The question however is whether they actually do when independent analysis is performed.  Sadly independent studies have confirmed that this may not be the case.  A 2004 study by Szajewska and colleagues found that only 3/5 products tests contained the bacteria that were labelled on the bottle. Similarly Toscano et al in 2013 examined products in the European market to determine quality.  Interestingly a decade later their findings were the same in that 58% of 24 products contained what they claimed.  Clearly just because it says it contains these bacteria on the bottle doesn’t necessarily mean that.

Hard To Argue About Sepsis?

Taking all of this theoretical concern into consideration, one has to acknowledge an additional and very important finding from a recent systematic review.  In a pooled analysis of 25 studies on the use of probiotics the risk of sepsis was reduced in the following manner:
1. risk of any sepsis (25 RCTs; RR 0.83, 95% CI 0.73-0.94; I = 26%)
2. bacterial sepsis (11 RCTs; RR 0.82, 95% CI 0.71-0.95; I = 0%),
3. fungal sepsis (6 RCTs; RR 0.57, 95% CI 0.41-0.78; I = 0%)
4. This beneficial effect remains in very low birth weight infants (<1500 g) (19 RCTs; RR 0.86, 95% CI 0.75-0.97; I = 18%), but not in extremely low birth weight infants (<1000 g) (3 RCTs; RR 0.73, 95% CI 0.45-1.19; I = 53%).
A reduction in sepsis is not anything to take lightly.  Late onset sepsis in the NICU can be very damaging and may predict poorer development at 18 months and beyond.  In this study, despite the aforementioned concerns regarding potential infection with the organism provided no such infections occurred.
Despite all the possible benefits, in the NICU much attention has moved towards donor milk and moreover establishing exclusive human milk diets.  With this changing landscape the beneficial effects of probiotics may decrease over time.  Given that the goal of probiotics is to change the microbiome to one that is closer to a breastfed infant will this still be needed? What we will need for sure is a repeating of trials in units that have high rates of human milk exposure to know for sure.
Whether to use probiotics or not becomes a tough question to answer and would be primarily based on your sense of trust in the quality control of the products at the moment I would think.  The benefits appear to be real but the question is, are you willing to take the risk?
Imagine a world in which we could stop antibiotics after one dose.

Imagine a world in which we could stop antibiotics after one dose.

I came across an article from the BBC about a company in Israel that has developed a kit which can determine the presence of bacteria or virus in the blood of a patient within a two-hour window.  More than that the kit has a point of care device as shown below.

Imagine for a moment the impact of being able to determine the presence or absence of sepsis within a two-hour window.  Infants who have respiratory distress with a plan to assess in four-hours to determine need for antibiotics would never receive a dose.  Other infants who were given one dose of ampicillin and gentamicin at birth would not need any further doses if the test indicated no bacteria or viruses present.  Now you might say what is the harm in providing 48 hours of antibiotics or even 5 days if you are unsure of the presence of sepsis? There probably is little harm in a couple of days but the practice of prolonging antibiotics for fear that a patient has suspected sepsis is quite common in Neonatal circles.  A recent article by Greenwood C et al (http://1.usa.gov/1Ex4qlH) examined stools at 1, 2 and 3 weeks of premature infants exposed to either short 1-4 day or longer 5-7 day courses of antibiotics.  The results were quite striking in that the neonates exposed to the longer duration experienced less bacterial diversity than the other group and a preponderance of Enterobacter. Curiously levels of Lactobacillus and Bifidobacteria were low in all groups which might suggest a role for probiotics or explain why they might have been shown to reduce NEC.  In fact in this study higher rates of NEC, sepsis and death were noted in the group receiving prolonged courses!

I have written other posts in which I have commented on Probiotics so to be clear I am not advocating that we use them routinely but one does have to wonder if it would be worthwhile repopulating the intestine of an infant who legitimately needed a 7 day course for a proven infection.  Perhaps this post will stimulate someone to do that very study.

Aside from the perturbed microbiome leading to NEC, sepsis and death we also now have evidence of many long-term effects from antibiotics.  The one creating the most alarm in press is no doubt the emergence of “superbugs” but more recently evidence has started to mount that repeated courses of antibiotics in infancy may lead to adult obesity (http://bit.ly/18JIIj7) and childhood allergy (http://bit.ly/1LwBmBc).

Getting back to this new technology it would still seem to be in the early stages.  Looking through the company’s website they are allowing people to apply to be an early adopter.  Additionally the links to their publications are really presentations at this time.  A Pubmed search failed to come up with any specific articles regarding these products to I would have to say we are still in this products infancy.  That being said it is certainly exciting to speculate about the impact that this innovation could have especially the point of care device pictured above which would bring the diagnosis to the bedside!  I would encourage you to look at MeMeds website as it has a lot of very good information and if you check in from time to time who knows, you might be the first to hear that the two-hour test for sepsis is ready for use in your unit somewhere.

MeMed

http://www.me-med.com/html5/sbs.py?_id=11045&did=2466&G=2466

Can we build a better breast milk with probiotics?

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.