Probiotics -Another Positive Study for Prevention of Necrotizing Enterocolitis

The topic of probiotics and necrotizing enterocolitis has been discussed several times on this blog (see some links below).  Here’s an abstract from a recent J Pediatr 2015;166: 545–51.


To test the efficacy of probiotic and prebiotic, alone or combined (synbiotic), on the prevention of necrotizing enterocolitis (NEC) in very low birth weight (VLBW) infants.

Study design

A prospective, randomized, controlled trial was conducted at 5 neonatal intensive care units in Turkey. VLBW infants (n = 400) were assigned to a control group and 3 study groups that were given probiotic (Bifidobacterium lactis), prebiotic (inulin), or synbiotic (Bifidobacterium lactis plus inulin) added to breastmilk or formula for a maximum of 8 weeks before discharge or death. The primary outcome was NEC (Bell stage ≥2).


The rate of NEC was lower in probiotic (2.0%) and synbiotic (4.0%) groups compared with prebiotic (12.0%) and placebo (18.0%) groups (P < .001). The times to reach full enteral feeding were faster (P < .001), the rates of clinical nosocomial sepsis were lower (P = .004), stays in the neonatal intensive care unit were shorter, (P = .002), and mortality rates were lower (P = .003) for infants receiving probiotics, prebiotics, or synbiotic than controls. The use of antenatal steroid (OR 0.5, 95% CI 0.3-0.9) and postnatal probiotic (alone or in synbiotic) (OR 0.5, 95% CI 0.2-0.8) decreased the risk of NEC, and maternal antibiotic exposure increased this risk (OR 1.9, 95% CI 1.1-3.6).


In VLBW infants, probiotic (Bifidobacterium lactis) and synbiotic (Bifidobacterium lactis plus inulin) but not prebiotic (inulin) alone decrease NEC.

Related blog posts:

Current Mortality from Being Born Premature

A recent study (Patel RM et al. NEJM 2015; 372: 331-40) provides prospectively collected data on 6075 deaths among 22,248 live births with gestational ages 22-29 weeks from the U.S NICHD Neonatal Research Network. between 2000 thru 2011:

Key findings:

  • Improved death rate in most recent period of study:  number of deaths per 1000 live births was 275  (2000-2003), 285 (2004-2007), 258 (2008-2011)
  • While there were fewer pulmonary deaths with time, the deaths attributed to necrotizing enterocolitis increased: number of deaths per 1000 live births was 23 (2000-2003), 29 (2004-2007), 30 (2008-2011).  Necrotizing enterocolitis was the leading cause of death between 15-60 days of life (Figure 1).
  • Overall, 40.4% of deaths occurred within 12 hours after birth.  Only 17.3% occurred after 28 days of life.
  • For the entire study period, the rate of death (per thousand) was associated with gestational age: 949 (22 weeks), 730 (23 weeks), 427 (24 weeks), 258 (25 weeks), 157 (26 weeks), 115 (27 weeks), 78 (28 weeks)
  • The authors speculate that the overall reduction in death rate is likely related to more aggressive respiratory care (for bronchopulmonary dysplasia); one marker of this was increased usage of high-frequency ventilation.

Bottomline: While there has been improvement, being born premature is associated with high mortality.

Neonatal Nutrition Lecture -What We Know Right Now

A recent terrific lecture at Northside Hospital’s neonatology conference by Reese Clark highlighted what we know about neonatal nutrition and what we should be striving to achieve.  This blog entry has abbreviated/summarized this presentation. Though not intentional, some important material is likely to have been omitted; in addition, transcription errors are possible as well.

Dr. Clark was willing to share slides from his talk and a related talk on necrotizing enterocolitis:

Here are a couple of key points from his talk regarding postnatal growth and feedings:

  • Every baby needs good nutrition.  While this is an obvious point, a lot of effort is focused on aspects of care needed in only a small number of neonates.
  • New target for weight gain in premature infants should be 20 gm/kg/day.  This growth is associated with better outcomes (Pediatrics 2006; 117: 1253 Ehrenkranz RA).  In this study, which controlled for a large number of variables, those in the top quartile of growth had much lower rates of cerebral palsy and neurologic impairments.  These improvements were also significant when comparing those in the top quartile to those in the 2nd and 3rd quartiles who were not sicker than those in the top quartile.
  • Most premature neonates are not achieving adequate growth with z-scores for weight and height lower at discharge from the NICU than their z-scores at birth. That is, despite advances in enteral and parenteral nutrition, premature neonates are falling behind while in the NICU. (Clark RH, et al. Pediatrics 2003; 111: 986)
  • Recognizing the supremacy of human milk has been the most important advance and has lead to much lower rates of necrotizing enterocolitis.  There is now a great case for exclusive human milk (J Pediatr 2013; 163: 1592-95; BMC Res Notes 2013; 6: 459)
  • With parenteral nutrition, higher amounts of amino acid have been associated with less issues with hyperglycemia. (Pediatrics 2007; 120: 12: 86-96; Pediatrics 2013; 163: 1278-82)
  • Insulin for hyperglycemia has been associated with poorer outcomes.
  • Does carnitine help with lipid metabolism? No one really knows –no randomized trials.
  • Continuous NG feeds are not associated with fewer signs/symptoms (e.g.. apnea, bradycardia, arching) than NG bolus feeds.
  • Acid suppression in neonates is not effective and potentially harmful
  • We need to use the best growth curves for premature infants: Fenton and Olsen growth charts

Since there are not going to be any trials randomizing neonates into groups assigned to poor growth, we will not know with certainty the impact of good nutrition on long-term outcomes.  Issues with reverse causation and selection bias make it difficult to know whether those with poor growth had other factors besides their nutritional plan which contributed to their outcomes.

Bottomline: We need to continue to optimize nutrition in premature infants; this includes using human milk and preventing necrotizing enterocolitis (which includes avoid acid blockers).  Our goal should be to have infants leave the NICU better nourished than when they arrived.

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.


How Proton Pump Inhibitors Can Cause Infections

In yesterday’s blog, the editorial on “Acid-reducing agents in infants and children: friend or foe?” also commented on an additional study (JAMA Pediatr. 2014. doi: 10.1001/jamapediatrics.2014.696) which addresses the issue of how proton pump inhibitors (PPIs) may contribute to an increased risk of infections.  It is well-known that use of PPIs (and to a lesser extent histamine-2 receptor antagonists) contribute to a significant increased risk of community-acquired pneumonias and gastrointestinal infections (probably including necrotizing enterocolitis in infants).

In this study, (from the editorial) “acid suppression was associated with a positive gastric culture (P =.003) and increased median concentration of gastric bacteria (P<.001). Full-column nonacid reflux was associated with higher concentrations of bacteria in the lung.”

In this era of pioneering microbiome research, it is not surprising that chronic changes in gastric acid production could cause these results.  This is something to consider when calculating risks and benefits, particularly in situations where the benefits are quite minimal.

Here’s the abstract:

Importance  The use of acid suppression has been associated with an increased risk of upper and lower respiratory tract infections in the outpatient setting but the mechanism behind this increased risk is unknown. We hypothesize that this infection risk results from gastric bacterial overgrowth with subsequent seeding of the lungs.

Objectives  To determine if acid-suppression use results in gastric bacterial overgrowth, if there are changes in lung microflora associated with the use of acid suppression, and if changes in lung microflora are related to full-column nonacid gastroesophageal reflux.

Design, Setting, and Participants  A 5-year prospective cohort study at a tertiary care center where children ages 1 to 18 years were undergoing bronchoscopy and endoscopy for the evaluation of chronic cough. Acid-suppression use was assessed through questionnaires with confirmation using an electronic medical record review.

Main Outcomes and Measures  Our primary outcome was to compare differences in concentration and prevalence of gastric and lung bacteria between patients who were and were not receiving acid-suppression therapy. We compared medians using the Wilcoxon signed rank test and determined prevalence ratios using asymptotic standard errors and 95% confidence intervals. We determined correlations between continuous variables using Pearson correlation coefficients and compared categorical variables using the Fisher exact test.

Results  Forty-six percent of patients taking acid-suppression medication had gastric bacterial growth compared with 18% of untreated patients (P = .003). Staphylococcus (prevalence ratio, 12.75 [95% CI, 1.72-94.36]), Streptococcus (prevalence ratio, 6.91 [95% CI, 1.64-29.02]), Veillonella (prevalence ratio, 9.56 [95% CI, 1.26-72.67]), Dermabacter (prevalence ratio, 4.78 [95% CI, 1.09-21.02]), and Rothia (prevalence ratio, 6.38 [95% CI, 1.50-27.02]) were found more commonly in the gastric fluid of treated patients. The median bacterial concentration was higher in treated patients than in untreated patients (P = .001). There was no difference in the prevalence (P > .23) of different bacterial genera or the median concentration of total bacteria (P = .85) in the lungs between treated and untreated patients. There were significant positive correlations between proximal nonacid reflux burden and lung concentrations of Bacillus (r = 0.47, P = .005), Dermabacter (r = 0.37, P = .008), Lactobacillus (r = 0.45, P = .001), Peptostreptococcus (r = 0.37,P = .008), and Capnocytophagia (r = 0.37, P = .008).

Conclusions and Relevance  Acid-suppression use results in gastric bacterial overgrowth of genera including Staphylococcus and Streptococcus. Full-column nonacid reflux is associated with greater concentrations of bacteria in the lung. Additional studies are needed to determine if acid suppression–related microflora changes predict clinical infection risk; these results suggest that acid suppression use may need to be limited in patients at risk for infections.

Related blog posts:

Probiotics for NEC -More Work is Needed (part 2)

For very low birth weight (VLBW) premature infants, there is even more evidence that probiotics are effective (The Journal of Pediatrics Volume 165, Issue 2 , Pages 285-289.e1, August 2014 -thanks to Kipp Ellsworth for abstract link).

Abstract ():

Study design

Within the observational period (September 1, 2010, until December 31, 2012, n = 5351 infants) study centers were categorized into 3 groups based on their choice of Lactobacillus acidophilus/Bifidobacterium infantis use: (1) no prophylactic use (12 centers); (2 a/b) change of strategy nonuser to user during observational period (13 centers); and (3) use before start of observation (21 centers). 


The use of probiotics was associated with a reduced risk for necrotizing enterocolitis surgery (group 1 vs group 3: 4.2 vs 2.6%,P = .028; change of strategy: 6.2 vs 4.0%, P < .001), any abdominal surgery, and hospital mortality. Infants treated with probiotics had improved weight gain/day, and probiotics had no effect on the risk of blood-culture confirmed sepsis. In a multivariable logistic regression analysis, probiotics were protective for necrotizing enterocolitis surgery (OR 0.58, 95% CI 0.37-0.91; P = .017), any abdominal surgery (OR 0.7, 95% CI 0.51-0.95; P = .02), and the combined outcome abdominal surgery and/or death (OR 0.43; 95% CI 0.33-0.56; P < .001).

Probiotics For NEC -More Work is Needed (part 1)

From Kipp Ellsworth’s Twitter Feed:

The Time for a Confirmatory NEC Probiotic Prevention Trial in ELBW Infants is Now. Editorial in J Peds  (The Journal of Pediatrics
Volume 165, Issue 2 , Pages 389-394, August 2014)

This editorial reviews previous studies and recommends implementing a Probiotic Trial in North America. Here’s an excerpt:

An adequately powered double-blinded placebo-controlled trial replicating a previous effective NEC prevention study in VLBW infants was published (the ProPrem trial)…the study revealed a significant reduction of NEC: from 4.4%-2.0% but no effect on mortality (4.9% vs 5.1%)…A closer look at the results of the ProPrem study, however, reveals that the probiotic supplementation did not have any effect on NEC in the ELBW (<1000 g) infants, which is consistent with two small previous studies reporting data on these infants separately.3642 Thus, there is currently no compelling evidence for recommending prophylactic probiotics to prevent NEC in infants with a birth weight <1000 g. Especially important is the lack of safety information in these most immature and highly vulnerable babies…Probiotics appear promising for use as prevention strategy for NEC, but there is still insufficient data for general recommendation of the use of probiotics in the ELBW infant. We argue, therefore, that now is the time to conduct in the North American setting, a high quality confirmative NEC prevention trial using probiotics in at-risk ELBW infants.”

Related blog post:

You Still Need the Data

A recent study (J Pediatr 2014; 165: 23-9) confirmed the obvious: “early empiric antibiotic use in preterm infants is associated with lower bacterial diversity.”  That being said, you still need the data and the specific changes are of importance.

This study examined the stools from 74 preterm infants (≤32 weeks gestational age) and determined how the microbiota changed in relation to no antibiotics (18% of cohort), brief antibiotics (1-4 days) (64% of cohort), or ‘intensive’ antibiotics (5-7 days) (18% of cohort).  Empiric antibiotics consisted of ampicillin and gentamicin.  Stools were analyzed with the 16s ribosomal DNA community profiling.

The key findings are graphically shown in Figure 1 with pie charts showing the relative abundance of 10 bacterial genera at week 1, week 2, and week 3 in each of the three groups.

  • Those who received 5-7 days of antibiotics had the most changes in their microbiota with increased Enterobacter and lower bacterial diversity in the second and third weeks of life.
  • In those who received no empiric antibiotics there was increasing bacterial diversity noted sequentially.  These changes were not seen in either of the antibiotic groups. However, the group with brief antibiotic exposure returned to their baseline diversity by week 3.
  • Infants receiving early antibiotics experienced more cases of necrotizing enterocolitis, sepsis and death than those who were not exposed to antibiotics (this was not proven to be casually-related).

Take-home message: This study proves that antibiotics change the microbiome in neonates and that neonates exposed to antibiotics may have complications as a result.  Better biomarkers (with rapid turn around time) would allow more careful selection of which neonates need empiric antibiotics.

Related blog posts:

Looking Beyond the Headline for Ultra-Short Bowel Syndrome

A quick glance at a recent study (JPGN 2014; 58: 438-42) suggests a favorable outlook for patients with ultra-short bowel syndrome (U-SBS). U-SBS has been defined as having a residual small bowel length <10 cm distal to the ligament of Treitz.  A more cynical definition by a colleague years ago was that U-SBS was when patients can fart and burp at the same time.

Looking at the details:  This study enrolled 11 patients into a prospective Italian database since 2000 and examined their outcomes.  Inclusion criteria included U-SBS diagnosed in the neonatal period (<28 days) and necessitating home parenteral nutrition at discharge.

The demographics note that these patients were bigger at birth and less premature than typical series of patients with SBS:

  • Only one of the patients had necrotizing enterocolitis as the sole underlying disease and six patients had volvulus.
  • All but two had ≥50% of their colons, with five having their entire colon.
  • All but one of these patients had gestational age ≥32 weeks and only two  patients had documented birth weight less than 2300 gm.

The authors note that these patients currently receive SMOFlipid as outpatients and Omegaven as inpatients.  All patients receive some enteral feedings.  Loperamide is used selectively.


  • Inpatient hospital care ranged from 23 to 104 days/year, but had improved during the last year of followup.
  • With >5 years of followup, 2 of the 11 patients had died.  One of these patients had severe intestinal failure associated liver disease (IFALD) despite use of Omegaven.
  • One patient underwent isolated intestinal transplantation.
  • No children in this series underwent a bowel-lengthening…”given the shortness of the residual small bowel, the gain of length after any procedure will not significantly improve absorption.”

Given their results, the authors note that despite recommendations for early referral for intestinal transplantation in patients with U-SBS, this may not result in a survival benefit.  They note a study by Pironi et al (Gut 2011; 60: 17-25) that showed that among 80 intestinal transplant candidates, 5-year survival was greater in those who were not transplanted.

Bottomline: This small cohort shows that certain populations of U-SBS may do well clinically for a long time with medical management. Caution should be used in extrapolating these results to SBS patients with different demographics.

Therapeutic Inertia in U.S Neonatal Units (vis-a-vis Probiotics)

“More than 90% of very low birth weight (VLBW) infants receive substandard care” could be the headline of a recent article/editorial (J Pediatr 2014; 164: 980-5 & 959-60).  Instead they are titled: “Cohort Study of Probiotics in a North American Neonatal Intensive Care Unit” and “Probiotic Supplementation in Preterm Infants: It is Time to Change Practice.”

In the article introduction, the authors state: “In 2011, faced with overwhelming evidence that probiotics could decrease NEC in preterm infants, and because there were no significant risks described in the extensive literature, we decided to introduce probiotics as routine care for the prevention of NEC.”

Methods: Prospective cohort study of infants at a single center NICU.  Examined rates of necrotizing enterocolitis (NEC) and death for 17 months before and after introduction of a probiotic (FloraBABY).  This probiotic (0.5 g) was mixed with water and administered just before milk once a day.  It was started at the first feeding and continued until the infant reached 34 weeks postmenstrual age.

Key findings:

  • Probiotics reduced NEC from 9.8% to 5.4% (OR for NEC 0.51)
  • Probiotics reduced combined outcome for NEC or death from 17% to 10.5% (OR 0.56).  Reduction in death by itself did not meet statistical significance.

Why, in 2012, were probiotics only used in 8-9% of VLBW?

Potential profits for probiotics are small which has limited studies of specific strains.  The probiotic, FloraBABY, in this study cost 11 cents per day in amount used; however, since the probiotic came in a tub, the actual cost was $12.79 for a 60-g tub for each patient.  Thus, manufacturers are unlikely to support studies to garner FDA approval.

Yet, there have been 22 randomized controlled trials published which “showed substantial benefits of probiotics and no adverse events.” A recently completed ProPrems trial (Jacob S et al, presented at 2013 PAS Annual Meeting) used a probiotic called ABC Dophilus Probiotic Powder for Infants.  This trial showed “a significant, >50%, reduction in NEC despite an incidence in their control patients of only 4.4%” and despite the fact that >95% of infants received breast milk.

“Good quality control and confirmation of the contents of the preparation are essential…There seems to be no further reason to delay the introduction of this evidence-based therapy in the NICU.”  The adoption of probiotics could avoid 2500 cases of NEC every year in North America.

The editorial notes that the evidence for probiotics is much better than many other therapies used in NICUs.  They note that some have argued that “the evidence that probiotics reduce mortality rates is as conclusive as that for surfactant for respiratory distress syndrome.”  A recent Cochrane review of 17 trials and >4900 VLBW infants showed that the RR of severe NEC for probiotics versus control was 0.41.

If people really understood this issue, there would be outrage over this issue.  In the U.S., there was recently extensive coverage over inaction about a faulty ignition switch which has been linked to at least 13 deaths.  The potential reduction in NEC and deaths with probiotics is likely much greater.

While the editorial recommends involving parent representative groups, I recommend discussing this issue with your neonatology colleagues along with your “quality care” team to find out what they are going to do about it.  Given the enormous costs in most NICUs, it is likely that each unit could self-fund a quality project (with consented patients) to provide probiotics to this vulnerable population.

Bottomline: Probiotics have excellent evidence as prophylaxis for NEC in VLBW infants.  Physicians need to advocate for their usage to “avoid years of therapeutic inertia.”

Related blog post: One More Day Syndrome & Necrotizing Enterocolitis …

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications/diets (along with potential adverse effects) should be confirmed by prescribing physician/nutritionist.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

The Genius of Breastmilk

While there has been a lot of talk about how breastmilk improves IQ/development (see links below), there are many other reasons why breastmilk is amazing.  For example, breastmilk reduces the risk of necrotizing enterocolitis (NEC).  A recent study on this effect: J Pediatr 2013; 163: 1592-5.

In this multicenter randomized controlled trial involving 7 NICUs, the authors studied extremely premature infants whose mothers did not provide their breastmilk.  Infants were fed either a cows-milk based preterm formula (COW, n=24) or pasteurized donor human milk (HUM, n=29). Birth weight and gestational age were similar in both groups, approximately 990 g and 27.5 weeks respectively.


  • HUM patients had fewer days of parenteral nutrition: 27 vs. 36, P=.04
  • HUM patients had fewer bouts of NEC: 1 (3%) vs. 5 (21%), P=.08; surgical NEC occurred 4 times in COW group compared with 0 in HUM patients (P=.04)

Take-home message: The data from this study are in line with recent American Academy of Pediatrics policy statement that recommends the following: “premature infants should receive only human milk from their mother and that, if it is not available, pasteurized donor human milk should be used.”

Another relevant study: J Pediatr 2010; 156: 562-7.

Related blog posts: