You might think this title is a joke but it is actually quite serious. Volatile organic carbons (VOCs) are what give stool it’s characteristic and often very malodorous scent. These same VOCs though could serve as biomarkers for preemies at risk of NEC. In fact previous research using an artificial nose has suggested as much. In 2015 de Meij TGJ et al published a study looking at VOCs entitled Early detection of necrotizing enterocolitis by fecal volatile organic compounds analysis. They used an electronic nose to try and detect changes in VOCs before the onset of NEC. This study which included a small sample of 13 with NEC compared to 14 without found a different profile of VOCs starting about 2-3 days before diagnosis of NEC. The study was quite small though and may not have made the waves that a larger trial might have.
Along comes the bigger trial
This month the DOVE study was published by Probert C et al “Faecal volatile organic compounds in preterm babies at risk of necrotising enterocolitis: the DOVE study”. The study picks up where this last one left off by looking at a much larger sample of babies. They managed to recruit 1326 babies under the age of 34 weeks of whom 49 developed NEC vs 70 matched controls. Of the 49 with NEC only 32 had sufficient stool samples for analysis since not every infant stooled every day. For the study all babies in these units had each stool sample collected from birth and then frozen until ready for analysis. The samples were then analyzed from 6 days prior to the diagnosis of NEC in the cases vs a day equivalent of 6 days prior in the controls. NEC was defined as stage IIa or greater.
When looking at overall numbers of VOCs between cases and controls there was no difference (35.8 in cases and controls 36.4). When grouping VOCs into 9 different natural groupings (factors) though, some interesting findings emerged.
The five best VOCs for prediction had the following receiver operator curves. Not dramatic curves but acceptable for a relationship overall with NEC.
Each of these factors were found to be associated with different demographics. For example, factor 1 VOCs were correlated to gestational age. Factor 4 contained six correlated VOCs which are associated with formula milk feeds and age. The risk of NEC increases with the value of factor 4, raising the question of whether an elevated level of this factor could predict NEC. Another curious finding was the presence of VOCs in factors 8 that are protective against NEC. One of the VOCs is known to be produced by bifidobacteria and lactobacillus both of which are also associated with less NEC. It makes some sense then that factor 8 would be negatively correlated with NEC.
The results raise some questions for the future like how would units actually use this information? The lead time before NEC that these VOCs were identified were anywhere from about 3-4 days. Could a unit ready device be ready in the near future with point of care technology? It wouldn’t help to find out from an outside lab several days after NEC what the VOC profile was but if it was at your finger tips that might be helpful. The next issue as I see it is what if anything you can do about it. Is there a guarantee that if three to four days prior to NEC you find these VOCs rising as in factor 4 that you can prevent NEC? It is possible that the cascade towards NEC has already started and it is now unavoidable.
In spite of these questions I find it quite interesting that we would be able to utilize these VOCs in such a way. One never knows if in the future an electronic nose will show up in an NICU near you!
Any regular reader of this blog will know that human milk and the benefits derived from its consumption is a frequent topic covered. As the evidence continues to mount it is becoming fairly clear that the greater the consumption of mother’s own milk the better the outcomes appear to be with respect to risks of late onset sepsis or BPD as examples. Moving to an exclusive human milk diet has been advocated by some as being the next step in improving outcomes further. While evidence continues to come suggesting that replacement of fortification with a human based instead of a bovine based fortifier may improve outcomes, the largest studies have been retrospective in nature and therefore prone to the usual error that such papers may have.
What is evident though as the science pursues this topic further is that the risk of necrotizing enterocolitis or NEC is not zero even with a human milk diet. Why is that? It might be that some risks for NEC such as intestinal ischemia or extreme prematurity simply are too much to overcome the protective effect of breastmilk. Perhaps though it could be related to something intrinsic in the breastmilk that differs from one mother to another with some producing more protective milk than others.
Secretors vs Non-secretors
When it comes to the constituents of breastmilk, human milk oligosaccharides or HMOs are known to be secreted into breastmilk differently depending on whether a mother has a secretor gene or not. this has been demonstrated recently in HMOs affecting the microbiome in infants Association of Maternal Secretor Status and Human Milk Oligosaccharides With Milk Microbiota: An Observational Pilot Study. HMOs are capable of a few things such as stimulating growth of beneficial microbes and acting as “receptor decoys” for pathogenic bacteria. Previous rat models have also demonstrated their potential to reduce NEC in rat models. Essentially, mothers who have the secretor gene produce more diverse types of HMOs than mothers who are secretor negative.
What came out of the study were a couple very interesting findings. The first is that when analyzing the HMOs present in breastmilk at 2 weeks and comparing those who developed NEC to those who did not there was one significant difference. Lacto-N-difucohexaose I (LNDH I)had a median level of 0 (IQR 0-213) from the milk of those mothers who had infants affected by NEC. There were no differences observed for any other HMOs.
Also of interest was the greater diversity of HMOs present in the breastmilk samples of mothers whose infants did not develop NEC. This was present at all time points.
How Could This Be Useful?
If a broader array of HMOs is associated with less risk of NEC and the presence of LNDH I carries the same association it opens the door to the next phase of this research. Could provision of LNDH I in particular but moreover a wide array of HMOs to mother’s milk reduce the occurrence of NEC? This will need to be tested of course in well designed randomized trials but this type of fortification could be the next step in what we add to human milk to enhance infant outcomes. Given that it may be difficult to determine in short order whether women have these HMOs already a broad based fortification strategy assuming insufficient amounts of HMOs would be best. A quick search on clinicaltrials.gov shows that there are 101 trials in children looking at HMOs at the moment so more information on this topic is certainly on the way. Could HMOs be the magic bullet to help reduce NEC? Just maybe!
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 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 articlehere.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. http://www.cbc.ca/1.2992414
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?
The picture looks ridiculous. Why does this seem so unnatural yet we feed babies this same product around the world. Granted they don’t drink it from the source as this man is but the liquid is in essence the same. As the saying goes, “Cow’s milk is for baby cows”. When you put it that way it helps put in context the question posed as the title of this post. Should we be surprised that the consumption of a milk meant for another species might have some side effects at a population level if fed to enough infants; especially those with fragile bowel due to prematurity or other high risk condition compromising blood flow to the gut.
The following piece was written by Kari Bonnar with contributions from Sharla Fast both Registered Dieticians in our NICUs. It has been recognized for some time now that the use of donor milk in our highest risk premature infants is associated with less NEC and based on a previous review of the evidence we have been using DBM for the past several years. What this post explores though is the potential for further benefit by taking the next step. That is to ask the question; what additional benefit may be gained by replacing all sources of Cow’s Milk protein in this population. I am delighted to present their review of the literature here as I am sure you will find it as informative and thought provoking as I have.
The health benefits of human milk for all infants, including those born extremely premature, have been increasingly recognized and published.1 The American Academy of Pediatrics policy statement on breastfeeding and the use of human milk recommends that all preterm infants receive human milk including donor human milk if mother’s own milk is unavailable.2 When compared with a diet of preterm formula, premature infants have improved feeding tolerance and a lower incidence of late onset sepsis and necrotizing enterocolitis (NEC) when fed their mothers’ own milk.3 For mothers of extremely premature infants, providing sufficient milk to meet their infant’s needs is a common challenge. Pasteurized donor human milk has been made available to this population in WRHA since 2011 as it has been found to be well tolerated and is also associated with a significantly lower incidence of NEC.4
However, as the sole nutritive substance, human milk does not meet the macronutrient and micronutrient requirements of preterm infants. Multi-nutrient fortifiers are required to provide additional protein, minerals and vitamins to ensure optimal nutrient intake and neurodevelopmental growth.5Prolacta Bioscience has recently launched in Canada with their human milk-based fortifiers, which are gaining popularity due to the ongoing research and success with these products in the United States, Austria, and now Canada.6 It is a new and novel approach that is proving to be most beneficial in reducing neonatal morbidity and mortality rates.7
In infants fed an exclusive human milk diet, Sullivan et al. found a reduction in medical NEC of 50% and surgical NEC of almost 90% compared to a diet containing cow’s milk-based products.7 To date, there is no other intervention that has had such a marked effect on the incidence of NEC.8 Abrams et al. found that for every 10% increase in intake of anything other than an exclusive human milk diet, the risk of NEC increases by 11.8% and the risk of surgical NEC increases by 21%, both with a 95% confidence interval.9
Patel et al. found that for every dose increase of 10ml/kg/day of human milk over the first 28 days post birth, the odds of sepsis decreased by 19%.10 Further to this, they found that overall NICU costs were lowest in very low birth weight (VLBW) infants who received the highest daily dose of human milk. Similarly, Abrams et al. reported that for each 10% increase in the intake of other than exclusive human milk diet, there was an 18% increase in risk for sepsis.9 In addition to predisposing the infant to other morbidities in the preterm population, and subsequent neurodevelopmental disability, sepsis significantly increases NICU costs by 31%. This translates into higher societal and educational costs for VLBW infants who survive sepsis with neurodevelopmental disability.10,11
A reduction in the number of days on total parenteral nutrition (TPN) was found by Cristofalo at al. with the use of an exclusive human milk based diet, in addition to reduction in sepsis and NEC.12 These same findings have been documented by Ghandehari et al. which reflect that an exclusive human milk diet leads to improved feeding tolerance and therefore, a decrease in total TPN days.13 Given that TPN is often the cause of late onset sepsis, the reduction of TPN days is imperative and almost always translates into decreased length of stay.14 Abrams et al. found that duration of TPN was 8 days less in infants receiving a diet containing <10% cow’s milk-based protein versus ≥ 10%, another recognizable dose related finding.9
It is well documented that increased growth leads to a decreased incidence of cerebral palsy and poor neurodevelopmental scores at 18-22 months corrected age, therefore adequate growth (weight, head circumference and length) is crucial in this population.15 The study by Hair et al. followed a standardized feeding protocol with early and rapid advancement of fortification with donor human milk derived fortifier and found that growth standards were being met and resulted in a marked decrease in extrauterine growth restriction.14 Cristofalo et al. study also compared growth rates, which were found to be slightly slower in the human milk fortified versus cow’s milk fortified arm of this study. However, it was mentioned that the small differences could be prevented with further adjustments in fortifier to improve rates of growth, as shown by Hair et al.12, 14 Abrams et al. confirms in their findings that growth rates were similar among human milk-based and cow’s milk-based fortification.9 This is a popular area of ongoing research with many abstracts also showing adequate growth rates with use of human milk-based fortifiers.
In closing, the review of current evidence clearly indicates that a diet of exclusive human milk is associated with lower mortality and morbidity in extremely premature infants without compromising growth and should be considered as an approach to nutritional care for these infants. Further research is needed to fully capture the extent to which using exclusive human milk diets actually reduce overall healthcare costs via improving the short and long term outcomes of extremely premature infants. Research to date only explores the financial impact for the first few years of life; therefore the true costs of these major morbidities are vastly underestimated and underreported. There are many unpublished trials and abstracts that are currently in process that will only strengthen the shift toward exclusive human milk-based diets, ideally making this common practice among Canadian centres in the very near future.
1 American Academy of Pediatrics. Section on Breastfeeding. Breastfeeding and the use of human milk. Pediatrics 2005; 115:496-506
2 American Academy of Pediatrics. Section on Breastfeeding. Breastfeeding and the use of human milk. Pediatrics 2012; 129:3;e827-41
3 Schanler RJ, Shulman RJ, Lau C. Feeding strategies for premature infants: Beneficial outcomes of feeding fortified human milk vs preterm formula. Pediatrics 1999;103:1150-7
4 Boyd CA, Quigley MA, Brocklehurst P, Donor Breast milk versus infant formula for preterm infants: a systematic review and meta-analysis. Arch Dis Child Fetal Neonatal Ed 2007;92:F169-75
5 Agostini C et al. Enteral nutrition supply for preterm infants: commentary from the European society for pediatric gastroenterology, hepatology, and nutrition committee on nutrition. JPGN 2010;50:1:85-91
7 Sillivan S, et al. An Exclusively Human Milk-Based Diet is Associated with a Lower Rate of necrotizing Enterocolitis than a Diet of Human Milk and Bovine Milk-Based Products. J Pediatr 2010:156;562-7
8 Bell EF. Preventing necrotizing enterocolitis: what works and how safe? Pediatrics 2005:115;173-4
9 Abrams SA, Schanler RJ, Lee ML, Rechtman DJ. Greater Mortality and Morbidity in Extremely Preterm Infants fed a diet containing cow milk protein products. Breastfeed Med. 2014:9;1-8
10 Patel AL, Johnson TJ, Engstrom JL, Fogg LF, Jegier BJ et al. Impact of early human milk on sepsis and health-care costs in very low birth weight infants. J Perinatology 2013:33:514-19
11 Ganapathy V, Hay JW, Kim JH. Cost of necrotizing enterocolitis and cost-effectiveness of exclusively human milk-based products in feeding extremely premature infants. Breastfeed Med. 2012:7;29-37
12 Cristofalo EA, Schanler RJ, Blanco CL, Sullivan S, Trawoeger R, et al. Randomized trial of exclusive human milk versus preterm formula diets in extremely premature infants. J Pediatr. 2013;1-4
13 Ghandehari H, Lee ML, Rechtman DJ. An exclusive human milk based diet in extremely premature infants reduces the probability of remaining on total parenteral nutrition: a reanalysis of the data. BMC. 2012:5;188
14 Hair AB, Hawthorne KM, Chetta KE, Abrams, SA. Human milk feeding supports adequate growth in infants ≤1250 grams birth weight. BMC. 2013:6;459
15 Ehrankranz RA, Dusiuk AM, Vohr BR, Wright LL, Wrage LA, et al. Growth in the neonatal intensive care unit influences neurodevelopmental and growth outcomes of extremely low birth weight infants. Pediatrics. 2006.117:4; 1253-61