Occurring in 6%–10% of infants admitted to neonatal intensive care units (NICUs), necrotizing enterocolitis (NEC) poses a serious threat of complications, such as overwhelming inflammation, multiple orange failure and intestine injury. In up to 40% of cases, the condition can prove fatal. However, early diagnosis and treatment can help prevent serious complications and mortality. A study by researchers at CHOC, part of Rady Children’s Health, demonstrated that a type of white blood cell can serve as a biomarker to help confirm a diagnosis of NEC.
In a separate study, the CHOC Small Baby Unit (SBU) multidisciplinary team used probiotics to prevent NEC, reducing the unit’s already low rate to less than 1%. Preventing NEC obviates the need for treatment, potentially including surgery, and eliminates the risk of associated complications.
Novel diagnostic tool
Currently, a dearth of diagnostic tools makes early identification of NEC challenging.
“As NEC is associated with high risks for morbidity and death, timely diagnosis is crucial,” says Dr. Michel Mikhael, medical director of the CHOC SBU and associate professor of pediatrics at UC Irvine. “It is equally important to rule out NEC when the diagnosis is unclear to avoid unnecessarily exposing infants to antibiotics as part of treatment.”
Clinicians categorize NEC according to Bell’s criteria, which classifies the condition as Stage 1 (suspected), Stage 2 (definite) or Stage 3 (advanced). Stage 1 NEC doesn’t always progress and may resemble other conditions, such as sepsis. In the first study, CHOC physician-scientists, including Dr. Mikhael, investigated whether measuring the number of monocytes in infants’ blood could help differentiate Stage 2 or 3 NEC from Stage 1 or other conditions.
The CHOC team studied absolute monocyte count trends in 130 preterm infants over 72 hours after each was suspected to have NEC. The white blood cell count declined in patients with Stage 2 or 3 NEC, whereas those with possible (Stage 1) or no NEC experienced an increase. The team found that an increase in the absolute monocyte count of 24% or less could differentiate those with Stage 2 or 3 NEC from those with Stage 1 or another condition. Their findings appeared in the Journal of Perinatology.
Investigating probiotics’ preventive potential
In 2021, despite a consistently low NEC rate relative to regional and published benchmarks, the CHOC SBU saw several fatal cases. This experience galvanized the unit’s team to enhance its NEC care practices.
“Upon reviewing the literature and discussing as a team, we determined there was enough published evidence to support the effectiveness of probiotics supplementation in NEC prevention,” Dr. Mikhael says. “We hypothesized that implementing probiotics in our practice using quality improvement frameworks would prevent NEC without any potential side effects.”
The team developed a probiotics administration protocol that prioritized safety and preventing therapy-related complications, such as cross-infection and probiotics-associated sepsis. The team selected a product containing Bifidobacteria, including Bifidobacterium infantis, and Streptococcus thermophilus bacteria, a combination previously studied in randomized controlled trials that has been shown to reduce NEC with no adverse effects, according to Dr. Mikhael.
An impressive decrease, then a regulatory roadblock
Dr. Mikhael and his colleagues followed recommendations from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition to plan how they would store, mix and administer the probiotic product. From May 2022 to October 2023, the team administered more than 4,000 doses to infants born before 32 weeks’ gestation or who weighed less than 1,500 grams at birth. During that period, the SBU’s NEC rate decreased from 4.6% to 0.6%, with zero deaths or cases of probiotics-related sepsis. The Journal of Perinatology published the results in November 2025.
According to Dr. Mikhael, experts hypothesize that probiotics promote the growth of healthy bacteria in the intestines of preterm infants, thereby enhancing immunity, reducing inflammation and achieving a better balance between beneficial and harmful bacteria. The probiotic protocol was a great success, but after 17 months, the SBU team was forced to halt it.
“In September 2023, the Food and Drug Administration (FDA) put a regulatory ban on all probiotics use in preterm infants,” Dr. Mikhael says. “The ban was in response to the death of a preterm infant from probiotics-associated sepsis related to a product that hadn’t been as extensively studied as the one we used. After the ban, our NEC rate rose to 3.8%.”
Hoping for regulatory reconsideration
As more data supporting the safety and effectiveness of probiotics in preventing NEC accumulates, Dr. Mikhael hopes regulators will take notice.
“We published our results to increase awareness on this topic and address the FDA’s decision,” Dr. Mikhael says. “Other centers will publish their experiences soon, with similar results. We have communicated our results to the FDA and patient advocacy groups, and we hope that as more data arrives from other centers, the FDA will reconsider its decision. The CHOC SBU team is proud to be the first to publish our work on this matter.”
Dr. Mikhael believes clinicians can do more to prevent complications, allowing vulnerable infants to once again benefit from probiotics.
“There is a need to identify patient-specific risk factors and standardize formulation, preparation and administration practices to avoid potential probiotics-related sepsis,” he says. “By taking these steps, clinicians could resume providing an intervention with compelling evidence of benefit in tens of thousands of preterm infants.”
Learn about CHOC’s neonatal services, ranked among the nation’s best by U.S. News & World Report and featuring three NICUs, including a Level 4 unit.
