Tag Archives: necrotizing enterocolitis

Are Shortages of Premature Formulas Likely Due to Necrotizing Enterocolitis Lawsuits?

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DR Shores et al. J Pediatr Gastroenterol Nutr. 2025;81:158–161. Navigating the blame game: Exploring necrotizing enterocolitis, preterm nutrition, and the ramifications of a formula shortage

Key points from this commentary:

  • “Recent lawsuits involving preterm infant formula manufacturers in the United States (Abbott and Mead Johnson) … [a] formula shortage crisis … might ensue if these formulas are pulled from the market”
  • “Breast milk has long been associated with protection against NEC, possibly due to bioactive molecules that maybe protective. However, infants fed exclusively breastmilk can still develop NEC, highlighting a multifactorial etiology. Mother’s own breast milk provides the best protection against NEC and is the ideal primary form of nutrition for preterm infants…pasteurized donor breast milk provides some protection against NEC and should be offered if mother’s own breast milk is not available”
  • “Although preterm formula does not protect against NEC, it is the healthcare standard, assuming all medical comorbidities are taken into consideration for individualized care…preterm infant formulas that are specifically formulated to provide the calories, protein and micro-nutrient needs of preterm infants”
  • “Placing all the blame for the development of NEC on preterm formula manufacturers is not supported by science and is thus unfounded”
  • “For infants without access to mother’s own or donor breast milk, specialized formulas remain critical to their nutrition and survival….Vilifying formula companies risks provoking further shortages of essential specialized formulas, which could directly harm the very babies we all aim to protect”

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National Covid Memorial Wall in London is a visual representation of the UK’s catastrophic loss to Covid-19. There are more than 240,000 individually hand-painted red hearts, each representing a person who died in the UK with Covid-19 as a direct cause of death. Many of the hearts on the Wall have been personalized with individual message

Key Advances in 2024: An Overview from GutsandGrowth (Part 4)

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This year I had the opportunity to give a lecture to our group that reviewed much of the important advances that happened in 2024. Here are some of the slides (if you have any trouble reading the slides, you can search for the original blog post using author name).

End of the Line for Probiotics for Preterm Infants

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9/29/23 FDA: Risk of Invasive Disease in Preterm Infants Given Probiotics Formulated to
Contain Live Bacteria or Yeast

“The FDA cautions that microorganisms contained in probiotics have been reported in the medical literature as causing bacteremia or fungemia, sometimes with a severe clinical course, in very preterm or very low birthweight (VLBW) infants.”

“Moreover, the American Academy of Pediatrics states ‘Given 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, current evidence does not support the routine, universal administration of probiotics to preterm infants, particularly those with a birth weight of <1000 g.’”

“The FDA is also reminding healthcare providers that FDA has not approved any probiotic product for use as a drug or biological product in infants.”

My take: Despite promising studies (over the last 20 years) indicating that probiotics reduce the risk of necrotizing enterocolitis and death, this appears to be the end of the line for the use of probiotics for preemies in the U.S. To change course, there would need to be a pharmaceutical-grade probiotic and proof that it was a reliable high-quality agent meeting FDA standards along with subsequent studies showing this probiotic was effective.

Reference: Poindexter B. Use of probiotics in preterm infants. Pediatrics 2021;147(6):June 2021:e2021051485. https://publications.aap.org/pediatrics/article/147/6/e2021051485/180282/Use-of-Probiotics-in-PretermInfants

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What About the Risk of Not Intervening to Prevent Necrotizing Enterocolitis?

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J Tobias et al. J Pediatr 2022; 244; 64-71. Open Access: Bifidobacterium longum subsp. infantis EVC001 Administration Is Associated with a Significant Reduction in the Incidence of Necrotizing Enterocolitis in Very Low Birth Weight Infants

Editorial: MA Underwood J Pediatr 2022; 64: 14-16. Open Access: Bifidobacterium infantis, Necrotizing Enterocolitis, Death, and the Role of Parents in the Neonatal Intensive Care Unit

Methods: Nonconcurrent retrospective analysis of 2 cohorts of 483 very low birth weight (VLBW) infants not exposed and exposed to B infantis EVC001 probiotic at Oregon Health & Science University from 2014 to 2020

Key findings:

  • 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.”
  • Parent and clinician resource: necsociety.org. 9 Things You Need to Know About Necrotizing Enterocolitis and NEC Facts

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.

Image Only: Pneumatosis Intestinalis in Necrotizing Enterocolitis

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L Tong, Y-T Chang. NEJM 2022; 386: 1070. Pneumatosis Intestinalis in Necrotizing Enterocolitis

This image below is from an 11 day-old born at 39 weeks gestational age. Sadly, he did not survive an emergency operation.

From NEJM Twitter Feed

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Can Necrotizing Enterocolitis Be Prevented with Antibiotics?

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Y Li et al. J Pediatr 2020; 227: 128-134. Early Use of Antibiotics Is Associated with a Lower Incidence of Necrotizing Enterocolitis in Preterm, Very Low Birth Weight Infants: The NEOMUNE-NeoNutriNet Cohort Study

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.

Key finding:

  • 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.

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Case report: NEJM 2020; 383: 25: 2461. Patient who weighed 520 gram at birth (23 week gestation) developed NEC; she recovered and all orally fed at time of discharge.

Neurodevelopment Impairment in the Majority of Extremely Preterm Infants with Short Bowel Syndrome

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Link to article (paywall)/abstract: Neurodevelopmental and Growth Outcomes of Extremely Preterm Infants with Short Bowel Syndrome

Key finding from study:

  • 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.

Probiotics in Preemies: Lifesaving Therapy

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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

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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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Is CMV a Trigger for Necrotizing Enterocolitis?

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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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