Probiotics in Preemies: Lifesaving Therapy

Lots of studies have indicated that probiotics may be beneficial in premature newborns; the problem is that there are currently no FDA-approved probiotics for preterm infants. The use of probiotics as a non-regulated FDA product leads to the potential risk of contamination due to inconsistent quality control as well as variability in the strains and concentrations.  The risks are not inconsequential as there has been a report of 29-week infant who died from mucormycosis due to probiotic contamination with mold.

Despite the potential problems with probiotics in this population, their usage is increasing as described in a recent multicenter retrospective cohort study (KD Gray et al. J Pediatr 2020; 222: 59-64) which took place between 1997-2016 with 78,076 infants (23-29 weeks gestational age) in 289 NICUs.

Key findings

  • 3626 (4.6%) received probiotics
  • Probiotic use increased over the study period (>10% in 2015 & 2016)
  • By matching 2178 infants who received probiotics with 33,807 without probiotics, the authors determined that those received probiotics had a decrease likelihood of necrotizing enterocolitis (OR 0.62) and death (OR 0.52).  The authors observed an increase in Candida infection (OR 2.23); though, this is an infrequent infection and the absolute difference in risk was <1%
  • Limitations: “similar to many previous studies, there was great variation in probiotic products and organisms, as well as a lack of dosing information, which made it unclear which product, organism, or dose might be most effective.”  Also, other contributing factors like consumption of breastmilk and antibiotic exposure are not detailed in this report.

My take: Probiotics could be life-saving for premature infants. It would be nice if we could find out which strains work and which ones do not as well as to assure safe manufacturing processes.

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Updated Outcome Data for Necrotizing Enterocolitis

A recent systematic review (IH Jones, NJ Hall. J Pediatr 2020; 220: 86-92) provides contemporary outcomes for infants with necrotizing enterocolitis (NEC). The authors analyzed from 38 articles (from 1375 abstracts); the authors excluded data from developing countries. This review included 21,349 infants with any stage of NEC and 7540 with Bell stage 2a+.

Key findings:

  • Overall mortality was 23.5% in all neonates with confirmed NEC (Bell stage 2a+), 34.5% for infants who underwent surgery
  • Mortality rates were higher for extremely low birthweight infants (<1000 g) at 40.5%; the rate was 50.9% for surgical NEC in this cohort
  • Neurodevelopmental disability was reported in only 4 studies and ranged between 24.8% and 61.1% (n=1209)
  • Intestinal failure was reported with an incidence of 15.2% to 35.0% (n=1370)

A limitation with this study is the lack of agreement on definitions/diagnosis for necrotizing enterocolitis and intestinal failure.

My take: This study shows that NEC still carries a high mortality.

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Sandy Springs

Is CMV a Trigger for Necrotizing Enterocolitis?

Previously, it has been recognized that increased rates of necrotizing enterocolitis (NEC) have been associated with viral outbreaks (eg. rotavirus, norovirus) (J Pediatr Surg. 2004;39:453–7 , 2010l;29: 644-7.).

A more recent study (S Panesso-Gomez et al. J Pediatr 2019; 214: 34-40) examines the association between cytomegalovirus (CMV) and NEC.

Key Findings:

  • In this retrospective cohort (2000-2016) with paraffin-embedded samples, the authors detected CMV by PCR or immunohistochemistry (IHC) in 7 (4%) of 178 infants with either NEC (n=143) or spontaneous intestinal perforation (n=35).
  • PCR was more sensitive and was positive in all 7 detected cases whereas IHC identified CMV in 4 of the cases.

One of the limitations of the study was the lack of a control group, though previous reports have found congenital CMV in 0.4% of preterm infants with very low birth weight (<1500 g) and in 0.5-1% of all liver births.

My take: This study shows an association between the presence of CMV and NEC; hence, CMV may be one of many factors which increase susceptibility to NEC.

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Yonah Mountain

Plasma miR-1290 -Specific Biomarker for Necrotizing Enterocolitis

Briefly noted: P Cheung, et al. J Pediatr 2019; 205: 83-90.  This study showed that a plasma biomarker for necrotizing enterocolitis (NEC), miR-1290, was very useful in a cohort of 301 neonates.

  • Of 20 infants with miR-1290 > 650 copies/microliter, 15 were diagnosed with NEC.
  • In those with intermediate values (220-650 copies/microliter) adding CRP (>1.58 mg/dL) allowed for a sensitivity of 0.83, specificity of 0.96, a positive predictive value of 0.75, and a negative predictive value of 0.98.
  • The authors state that 7 of 36 infants had NEC diagnosed earlier by 8-32 hrs based on the availability of miR-1290 testing.

My take: Biomarkers are helping us identify serious diseases more quickly and changing how we practice.  Hopefully, work in this area will help us identify NEC sooner and improve outcomes.

Below is a visual abstract indicating that transfusion for platelet count less than 25 K was associated with a lower rate of death/major bleeding that a platelet count threshold of 50 K.

Visual abstract indicates that most preterm infants do not need platelet transfusions as long as the platelet count is >25 K.

The Impact of Maternal Antibiotics on Necrotizing Enterocolitis and Death in Neonates

A recent study (BD Reed et al. J Pediatr 2018; 197: 97-103) showed that prenatal antibiotic exposure was associated with lower rates of necrotizing enterocolitis (NEC) or death.

In this secondary analysis of a progressive study with 580 infants (<32 weeks) that were cared for in Level III neonatal intensive care units, the authors examined the outcomes of the neonates in relation to whether their mothers had prenatal antibiotics within 72 hours of delivery.

Key findings:

  • Two-thirds of mothers received antibiotics w/in 72 hrs of birth, mainly ampicillin (37%) and azithormycin (26.4%).  Most (~60%) of the mothers who received antibiotics received more than 1 antibiotic.
  • In this cohort, NEC occurred in 7.5%, late onset sepsis (LOS) in 11.1%, and death in 9.6%.  The combined outcome of any of these events occurred in 21.3% of study infants.
  • Prenatal antibiotics were associated with a reduced risk of NEC (OR 0.28, CI 0.14-0.56), reduced risk of death (OR 0.29, CI 0.14-0.60) but not LOS (OR 1.59, CI 0.84-2.99).  Thus, the first two outcomes were within the confidence limits but not LOS.

The authors indicate that their initial hypothesis was that maternal antimicrobials (w/in 72 hours of birth) would increase the risk of NEC but in fact provided a 3-fold protection and reduced the risk of death.  The effects presumably would be mediated by changes in the infant microbiome related to infant’s exposure to microbial environment at birth and/or transplacental passage of antibiotics.  The authors note that their study did not consider mothers to be in the exposure to antibiotics group if their only exposure was antibiotics at the time of cesarean section due to limited time to effect neonate.  They did review this group and noted that if they were included in the exposure group that it would not have significantly changed the findings.

My take: This  intriguing finding that NEC and death occurred less often in infant’s whose mothers received antibiotics prior to delivery needs further study as does the long-term effect.


Point-of-Care Calprotectin Values in Preterm Infants at Risk for Necrotizing Enterocolitis

It doesn’t look like calprotectin measurement in newborns is going to be terribly useful for detecting necrotizing enterocolitis.  A recent study (W Nakayuenyongsuk et al. J Pediatr 2018; 196: 98-103) showed a great deal of variability in the calprotectin values in their cohort of 62 infants.


  • All infants had a birth weight of <1500 g
  • Stools collected daily (first stool of the day) either for 30 days or postmenstrual age of 32 weeks (whichever was longer)

Results: Calprotectin Values in microgram/gram

  • 1st week of life: All patients: Mean 637 +/- 638, Median 273
  • 2nd week of life: All patients: Mean 349 +/- 414, Median 180
  • 3rd week of life: All patients: Mean 486 +/- 470, Median 316
  • 4th week of life: All patients: Mean 488 +/- 385, Median 412
  • 5th week of life: All patients: Mean 358 +/- 339, Median 226
  • 6th week of life: All patients: Mean 370 +/- 334, Median 295
  • 7th week of life: All patients: Mean 240 +/- 191, Median 184
  • 8th week of life: All patients: Mean 445 +/- 110, Median 466

The highest subset scores for calprotectin was noted in the 1st week of life among preterm infants with gestational age >30 weeks.  In this group, the mean value was 799 +/- 651 and the median value was 718.

There were only two patients who developed necrotizing enterocolitis, both of whom did have an early rise in calprotectin

My take: This data shows elevated and highly variable calprotectin values in the neonatal period.  There was also a trend towards higher values among those with postnatal age >30 weeks.

Related blog post: Fecal calprotectin values in first years of life



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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