Lactobacillus rhamnosus GG Associated with Increased Necrotizing Enterocolitis in Observational Study

A recent retrospective study (AF Kane et al. J Pediatr 2018; 195: 73-9) with 640 VLBW infants found that the probiobiotic, Lactobacillus rhamnosus GG (LGG), was associated with an increased risk of necrotizing enterocolitis (NEC).

LGG supplementation was started at a median age of 6 days at a dose of 2.5 to 5 x 10 to the 9th CFU/day.

Key finding:

  • LGG group had an aOR of 2.10 for developing NEC.  LGG group NEC incidence was 16.8% whereas NEC incidence was 10.2% prior to institution of LGG.

The authors note their findings are in contrast to findings from 38 randomized trials (10,520) which have found that probiotics lowered the risk of NEC.

My take: This study reinforces the need for further studies to identify which factors and probiotic strains are likely to lead to reduced rates of NEC.

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Preterm Infants with Increased Infections Following Acid Suppression Therapy

A recent study (P Manzoni et al. J Pediatr 2018; 193: 62-7) provide more data on the detrimental effects of gastric acid inhibitors (eg. proton pump inhibitors, histamine-2 receptor antagonists).  This study was a secondary analysis using prospectively collected data from 235 preterm very low birth weight infants. Key findings:

  • “After multivariate analysis, exposure to inhibitors of gastric acidity remained significantly and independently associated with LOS [late-onset sepsis] (OR 1.03); each day of inhibitors of gastric acidity exposure conferred an additional 3.7% odds of developing LOS.”
  • Acid suppression therapy was associated with gram-negative (P<.001) and fungal pathogens (P=.001)
  • The study showed an association between acid blockers and with necrotizing enterocolitis, which was mitigated in those who received bovine lactoferrin

My take (borrowed, in part, from authors): This data “confirm, strengthen, and expand on previous reports describing an association between inhibitors of gastric acidity and infections.”  Thus, the risks of these medications is likely greater than the benefits in the majority of preterm infants.

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Bright Angel Trail

When to Check Gastric Residuals in Preterm Infants

A recent study (A Riskin et al. J Pediatr 2017; 189: 128-34) indicates that routine testing of gastric residual volumes is not needed. In this study of preterm infants ≤34 weeks gestation 239 infants were studied prior and 233 studied after dropping routine checks of gastric residuals.

Key findings:

  • Selective evaluation of gastric residuals was associated with achieving full enteral nutrition 1 day earlier
  • The rate of NEC (stage ≥2) was actually lower in the selective evaluation group (1.7% vs 3.3%) compared to the historic control group

Selective checking of gastric residuals was prompted by the following:

  • abdominal distention
  • vomiting or large regurgitation
  • bilious regurgitation or emesis
  • abnormal behaviors: restlessness, somnolence or apathy
  • increased apnea/bradycardia
  • change in vital signs

While checking gastric residuals had been used to determine feeding intolerance and/or development of necrotizing enterocolitis, this study indicates that routine evaluation is not necessary.

My take: This study challenged a common NICU practice and found that routine assessment of gastric residuals is not needed; selective checking of gastric residuals is sufficient.

Vitamin D in Preterm Infants

Vitamin D has garnered a great deal of attention due to concerns that deficiency worsens the outcomes in so many different conditions, including respiratory tract infections, inflammatory bowel disease, diabetes mellitus (type 1), multiple sclerosis, colorectal cancer, schizophrenia, depression, cardiovascular disease, hepatocellular carcinoma and other conditions.  However, evidence of causation is typically inconclusive.

For preterm infants, a study (Onwuneme C, et al. J Pediatr 2015; 166: 1175-80) notes an association between 25-hydroxy vitamin D (25OHD) levels drawn at 24 hours of life and acute respiratory morbidity.

In this study, levels were also drawn at the time of discharge in the 94 preterm infants.  In addition, maternal 25OHD) levels were checked 24 hours after delivery. These preterm infants were either <32 weeks gestation or <1.5 kg.  The study population was predominantly Caucasian.

Key findings:

  • 92% had 25OHD ≤20 ng/mL (=”<20 group”)
  • 64% had 25OHD ≤12 ng/mL (=”<12 group”)
  • Levels of 25OHD ≤12 ng/mL were associated with increased oxygen requirement (P=.008) and greater need for assisted ventilation (P=.013).  The odds of requiring assisted ventilation were approximately 3-fold higher.
  • The authors state that the baseline characteristics for the <12 group were similar to the <20 group.
  • There was statistical difference in the rate of NEC (Bell stage ≥1) based on the 25OHD levels (P=.048)

The authors note in their discussion that they favor supplementation with 400 IU/day which is in agreement with the American Academy of Pediatrics.  Previous ESPGHAN recommendations were 800-1000 IU/day for infants.

The authors note that 25OHD did not affect sepsis outcome.  In addition, antibiotics during labor was virtually identical between the two groups.  However, no data on CRP values were provided.

Bottomline: This study shows an association between 25OHD values and several important neonatal outcomes.  Whether 25OHD is a marker (eg. epiphenomenon) for these outcomes or whether low 25OHD contributes to these outcomes remains unclear.

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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.

Objective

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).

Results

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).

Conclusions

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

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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.