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:

Rehabilitation for Short Bowel Syndrome

As noted in several blog posts, there have been some important advances in the care of short bowel syndrome (SBS)/intestinal failure (IF) patients which have resulted in improved outcomes.  A recent review of 28 children with ≤20 cm of small bowel has been published (J Pediatr 2013; 163: 1361-6, editorial 1243) and provides tangible evidence of these changes.

This retrospective study reviewed the charts of these children managed at Omaha’s intestinal rehabilitation program.  7 patients had NEC, 6 intestinal atresia, 6 had gastroschisis, 3 omphalocele, 5 had malrotation, and 1 patient had vascular disease.

Key results:

  • 27 survived (96%)
  • 14 (50%) had at least one lengthening procedure; in this cohort, bowel lengthening was not associated with a greater rate of adaptation than native bowel.
  • 13/27 (48%) achieved parenteral nutrition independence (“nutritional autonomy”) with their native bowel.
  • Predictors of “successfully rehabilitated” patients: intact colon and ileocecal valve
  • All patients had improvements in lowering PN requirements, total bilirubin, and growth z-scores.
  • Serum transaminase levels did not improve in the nonrehabilitated patients

The main medical treatments at IRP include use of agents for control of bacterial overgrowth, reducing gastric acid production, lipid minimization, promotility and antimotility agents (eg. loperamide), and ethanol locks.  The editorial comments on the “poor results” for surgical intervention, “particularly among those with ultra-short bowel.” This may be due to ‘marginal motility, ischemia, severe wall thickening, or due to adhesions.’

With regard to ethanol locks, the editorial supports them but states, “the main factor in prevention [of line infections] has been maintaining a consistent and strict protocol for catheter care.”

Previous related blog entries:

One More Day Syndrome & Necrotizing Enterocolitis

In many situations, the advice is to wait one more day and then decide/act; however, sometimes one more day winds up being a week, a month, or longer.  A recent editorial indicates that there is enough evidence now for probiotic usage in neonates to prevent necrotizing enterocolitis (NEC).  The authors state that to continue “with the standard of care, in which no new products are provided…is ethically unacceptable” (JAMA Pediatrics 2013; 167: 885-6).  Thanks to Ben Gold for this reference.

Key arguments:

  • A 2011 Cochrane review identified 16 eligible trials with 2842 premature infants (<2500 g, <37 weeks).  Probiotics reduced the incidence of NEC with a relative risk of 0.35 and mortality with a relative risk of 0.40.  Despite the typically cautious recommendations from Cochrane reviews, the authors state “updated review of available evidence supports a change in practice.”
  • While the American Academy of Pediatrics in 2010 noted there is some evidence to support probiotic usage and called for more studies, there are no studies currently being conducted in the U.S.
  • The authors note that the “FDA Center for Biologic Evaluation and Research is committed to policies that effectively prohibit probiotic efficacy trials.” Under current policies, the authors state these “studies will not be conducted in a US setting for the next 20 to 30 years.”
  • Other countries , like Australia, allow use of probiotic with parental consent.
  • The authors propose that probiotic efficacy be studied in a comparative effectiveness design.

Bottomline: Current regulations have stymied the use of probiotic trials for NEC.  What will it take for regulatory agencies to relent and allow this promising research?

Related blog posts:

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) and specific medical management interventions should be confirmed by prescribing physician.  Application of the information in a particular situation remains the professional responsibility of the practitioner.

How Histamine-2 Receptor Blockers May Cause Problems for Preemies

Previously, this blog has noted an association between ranitidine usage and necrotizing enterocolitis (NEC) (see below).  Now, another study provides insight into a potential mechanism (JPGN 2013; 56: 397-400).

This study examined the fecal microbiota in 76 premature infants who were enrolled in a case-controlled, cross-sectional study.  25 infants receiving H2-blockers were compared with 51 matched controls.

Results: microbial diversity was lower, relative abundance of Proteobacteria was increased, and Firmicutes was decreased in the stools of infants receiving H2-blockers.

While this study did not specifically examine the effect of H-2 blockers on NEC (no infants in this study had NEC), there are multiple reasons why the findings should be a cause for concern.

  • Gastric acidity acts as a natural defense against bacterial growth and H-2 blockers (as well as proton pump inhibitors) inhibit this defense
  • Previous studies have shown an association between NEC and with diminished microbial diversity/increased Proteobacteria.  Proteobacteria include well-known pathogens like Klebsiella, Shigella, Escherichia coli, and Citrobacter.

Related blog entries:

Green beans for short gut syndrome

A recent article indicates that the addition of green beans may improve diarrhea and reduce dependence on parenteral nutrition (Adding Dietary Green Beans to Formula Resolves the Diarrhea ) (ICAN. DOI: 10.1177/1941406412469403). Thanks to Kipp Ellsworth for pointing out this reference on his twitter feed.

This small retrospective study of 18 infants examined the addition of green beans to the diet of infants with short bowel syndrome (SBS) (1 jar of stage 2 baby food green beans to every 8 ounces of 30 cal formula).  The average gestational age of the patients was 32 weeks (range 23-39 weeks) and the average birth weight was 1938 gram.  Nine patients had NEC, four had gastroschisis, two had Christmas tree defect, and three had other reasons for either SBS or intestinal failure.  The IF group (n=10) was defined as being dependent on parenteral nutrition to meet nutritional needs; the SBS group (n=8), who were more severely affected, was defined as the malabsorptive state that follows a massive resection.

Products that were used:

  • Gerber Natural Select: 3 gm of fiber per 4 ounce
  • Beach-Nut Homestyle: 2 gm of fiber per 4 ounce
  • HyVee Mother Choice: 2 gm of fiber per 4 ounce
  • These products average 32% soluble and 68% insoluble fiber

While the authors note that they use only amino-acid based formulas currently, at the time of the study, 61% were receiving Peptamen Junior.

It is not clear in the manuscript exactly at what age green beans are introduced. However, a previous case study suggested addition of green beans at ~4 months or >44 weeks postconception.  This prior case study indicated that adding stage 2 green beans changed the caloric density of 30 cal formula to 22 cal/ounce (Nutrition in Clinical Practice 2005; 20: 674-77).  In addition, this adds 2 gm/kg/day of fiber.

Results from current study:

  • 9 of 10 IF patients were able to discontinue parenteral nutrition
  • 2 of 8 SBS patients were able to discontinue parenteral nutrition
  • All infants had improvements in stool consistency, typically within 24 hours of dietary change.

While the authors acknowledge the limitations of the study, they hypothesize that the reason for improvement is due to the fiber content of green beans.   Fermentation of dietary fiber produces short chain fatty acids (SCFAs) which in turn have a trophic effect on the mucosa and enhance nutrient absorption.

Studies have shown that adults with IF or SBS have improved stool consistency with the addition of fiber.  However, the authors note that there have been no studies documenting the effectiveness of dietary fiber in the pediatric SBS/IF population.

Whether green beans would outperform other sources of fiber like pectin, guar gum, bananas or benefiber is not clear.

Additional references/links:

Predicting Necrotizing Enterocolitis with Fecal Biomarker

A recent study has shown some promise in detecting necrotizing enterocolitis (NEC) with a fecal biomarker, S100A12 (J Pediatr 2012; 161: 1059-64).

In this prospective study of 145 preterm infants with a birth weight <1500 g, stool samples were collected on alternated days for 4 weeks.  Fecal S100A12 and calprotectin were measured.  Calprotectin in previous studies has been shown to be a poor marker for NEC.

Fecal S100A12, also called calgranulin C, belongs to a novel group of proinflammatory molecules. It is released by activated or damaged cells under conditions of cell stress and indicates phagocyte-specific damage.

18 (12.4%) developed NEC.  Fecal S100A12 levels were elevated in severe NEC and also at 4-10 days beforehand.  The sensitivity, specificity, positive predictive values, and negative predictive values were 70%, 68%. 37%, and 89% respectively.  Thus, there is limited utility of this stool test due to the limited sensitivity/specificity.  There is substantial overlap between control patients and patients who developed NEC.  Furthermore, fecal S100A12 levels are age-dependent.  Generally, they are higher early in life, likely due to increased mucosal permeability.

Calprotectin levels were elevated at the onset of NEC (median 349 mg/kg) and 48 hours before onset (median 83 mg/kg).  The difference at 48 hours prior to onset did not reach statistical significance.

NEC and thickening agents

Last year the FDA issued a warning regarding food thickeners and necrotizing enterocolitis (FDA: Do not feed SimplyThick to premature infants).  More details are now available (J Pediatr 2012; 161: 354-6).

This information was derived from a series of cases of NEC with a common antecedent, the use of SimplyThick.  After excluding infants with multiple episodes of NEC prior to use of this thickening agent, 22 infants met the case definition and were included in the report.

16 infants started SimplyThick >37 weeks post-menstrual age (PMA).  19 infants developed NEC >37 weeks PMA.  14 cases required surgery and 7 patients died.  The number of days of SimplyThick exposure:

  • 9 patients  –1-10 days
  • 7 patients –11-20 days
  • 6 patients –>20 days
  • Median –13 days

Since most cases of NEC occur in the hospital and are associated with extreme prematurity, these cases are unusual & likely causally related to the use of SimplyThick.  Delayed NEC can also occur with congenital heart disease.  Also, NEC often develops shortly after the introduction of enteral feedings; in this series, patients had been receiving enteral feeds for a median of 43 days prior to NEC onset.  As a consequence, 50% of patients were at home when NEC developed.

The authors postulated that an increased production of short-chain fatty acids by breakdown of xanthan gum component was the mechanism for SimplyThick to increase the risk of NEC.

In a brief commentary on the article, Alan Jobe states that “Neonatologists seem determined to treat the poorly defined reflux that frequently occurs in preterm infants with something –preferably drugs that are off-label and have no proven efficacy…Perhaps clinicians should restrain their enthusiasm for other thickeners for the feeding of preterm infants as well.  The proven treatments for reflux in otherwise normal preterm infants are time and patience.”

While Dr. Jobe makes some helpful points, SimplyThick has been used primarily for swallow dysfunction rather than reflux.  Nevertheless, any thickeners as well as reflux medications can increase the risk of NEC and should be used cautiously.

Related posts:

Avoid ranitidine (acid suppression) in neonates

Do medicines work for GERD infants?

Avoid ranitidine (acid suppression) in neonates

More evidence that ranitidine may contribute to necrotizing enterocolitis and fatal outcomes has been published (Pediatrics 2012; 129: e40-45).

In this study (which was reviewed in The Journal of Pediatrics 2012; 161: 168-69), four neonatal intensive care units in Italy performed a multicenter prospective observational study of very low birth weight (VLBW) inants.  There were 274 neonates with gestational ages ranging from 24-32 weeks and birth weights ranging from 401-1500 grams.  The patients receiving ranitidine were similar to the unexposed group in terms of risk factors for infection/NEC, birth weight, gestational age, sex, APGAR scores, PDA, intubation duration, and central vascular access duration.

  • 34 of 91 (37%) exposed to ranitidine developed infections compared with 9.8% of the group not exposed to ranitidine (OR 5.5)
  • Risk of necrotizing enterocolitis (NEC) was 6.6-fold higher among ranitidine-treated neonates
  • Mortality was 9.9% for ranitidine-treated patients compared with 1.6% of control patients
Since gastric acid acts as a defense against ingested pathogens, theoretically inhibition of acid production allows proliferation of these pathogens with subsequent infections and development of necrotizing enterocolitis.  These potential risks and the general lack of benefit of acid suppression in neonates should help guide clinician decision-making.
Another concern with ranitidine has been among acute appendicitis patients (see references below) where it has been associated with an increased likelihood of developing an abscess.

Additional references/previous related blog entries:

Does necrotizing enterocolitis cause neurologic deficits?

Quite possibly (J Pediatr 2012; 160: 409-14).

There have been recent reports that surgery in preterm and even term infants can affect neurodevelopmental outcomes.  This report, which looked at infants born at <30 weeks or birth weight of <1250 g, adds more information in this area.  The surgery group (n=30) had more white matter injury on MRI and lower developmental scores at 2 years than the nonsurgical group (n=178).  Infants requiring bowel surgery had the worst outcomes.  The exact reasons for these outcomes and the significance are unclear, in part due to the small number of infants with bowel surgery.  Potential factors include inflammatory mediators/cytokines, and anesthesia effects.

The article notes that the FDA has issued warnings regarding anesthetic use in neonates and young children.  These agents may cause abnormalities in the developing brain, particularly in the thalamus.

This study has a number of limitations including the lack of preoperative comparative imaging studies.  Nevertheless, despite unresolved issues regarding causality, it is clear that infants who have necrotizing enterocolitis remain at high risk for poor neurodevelopmental outcomes.

Additional references:

  • -Anesth Analg 2007; 104: 509-20.  Anesthetics in neonates and young children.
  • -J Pediatr 2008; 153: 170-5. Adverse neurodevelopmental outcomes in infants with sepsis or NEC.