Methods: Nonconcurrent retrospective analysis of 2 cohorts of 483 very low birth weight (VLBW) infants not exposed and exposed to Binfantis EVC001 probiotic at Oregon Health & Science University from 2014 to 2020
The cumulative incidence of NEC diagnoses decreased from 11.0% (n = 301) in the no EVC001 (unexposed) cohort to 2.7% (n = 182) in the EVC001 (exposed) cohort (P < .01); this was a 73% risk reduction of NEC
NEC-associated mortality decreased from 2.7% in the no EVC001 cohort to 0% in the EVC001 cohort (P = .03)
There was a lack of adverse events (including probiotic sepsis)
Key points from editorial:
“The first cohort study showing a significant decrease in necrotizing enterocolitis (NEC) with the routine administration of probiotic dietary supplements [was] more than 20 years ago”
“The most recent Cochrane Database systematic review 2 included 56 randomized or quasi-randomized trials in which 10 812 infants participated. Meta-analysis found evidence for decreased risk of NEC (Risk ratio [RR] 0.54)”
Both the AGA and ESPGHAN have recommended routine probiotics administration to preterm infants. However, the AAP recommends “against routine probiotic administration citing ‘the lack of FDA-regulated pharmaceutical-grade products in the United States, conflicting data on safety and efficacy, and potential for harm in a highly vulnerable population.’”
“Recognizing that many neonatologists have opted to adopt routine probiotic administration to infants born preterm, the recent American Academy of Pediatrics statement6 recommends that an informed consent process for utilizing probiotics. Dr. Underwood counters: “there is no mention of a need to discuss these risks and benefits by those well-informed clinicians who may not believe that the data support administering probiotics. Inclusion of parents in decision-making in the NICU improves parent satisfaction and infant outcomes.”
My take: It is hard to understand that, despite 20 years of research showing probiotics can reduce mortality and morbidity in premature infants, we have not been able to manufacture a consistent, reliable high-quality probiotic capable of meeting FDA standards.
Methods: This study used the NEOMUNE-NeoNutriNet cohort of VLBW infants from 13 neonatal intensive care units (NICUs) in 5 continents (n = 2831). NEC incidence was compared between infants who received early antibiotics and those who did not.
The incidence of NEC was 9.0% in the group of infants who did not receive early antibiotics (first 72 hrs) (n = 269), compared with 3.9% in those who did receive early antibiotics (n = 2562)
This type of study is inherently difficult due to measured and unmeasured confounders. In a related commentary, Joseph Cantey (Early Antibiotic Therapy and Adverse Outcomes in Preterm Infants: Time for a Trial!, https://doi.org/10.1016/j.jpeds.2020.07.046) notes that some previous studies have shown an association of antibiotics with increased risk of NEC, presumably due to a selection bias (eg. sicker patients getting antibiotics). Fortunately a randomized prospective trial is underway, the NICU Antibiotics and Outcomes (NANO, NCT03997266). This should help determine more carefully the risks and benefits of antibiotics in this vulnerable population.
My take: We have a lot to learn about modulating the premature infant’s microbiome to prevent necrotizing enterocolitis.
Moderate-severe neurodevelopmental impairment was present in 77% of children with extreme prematurity and with short bowel syndrome compared to 44% with extreme prematurity without necrotizing enterocolitis, spontaneous intestinal perforation or short bowel syndrome.
One of the authors, Ira Adams-Chapman, recently passed away (link to obituary: Ira Adams-Chapman, 1965-2020). She and I were residents together in Cincinnati. She was a terrific person.
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.
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.
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+.
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.
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 ,Pediatr Infect Dis J. 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.
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.
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.
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.
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.
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.