The scientific debate on the use of probiotics in preterm infants: Does it save or risk infants’ lives?

The death of a preterm infant associated with bacteria in the probiotic prevention-treatment of NEC (necrotizing enterocolitis) caused a stir. As a result, the United States Food and Drug Administration (FDA) published a warning advising against the administration of probiotics in preterm and low birth weight infants. In a reply, the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) now takes the side of long-standing research findings and criticises the FDA. The risk-benefit analysis continues to show that probiotics save the lives of 30-50% of affected newborns and that suspending treatment would cost many more lives than it could save. In addition, ESPGHAN advocates for the active role of parents in making this treatment decision.

Necrotizing enterocolitis (NEC) is an inflammatory intestinal disease that affects preterm and low birth weight infants. While around 5-7% of preterm neonates become infected with NEC, 400 infants die from this disease every year in the USA alone. This makes NEC one of the leading causes of infant morbidity and mortality.

To date, a widely used prevention method for NEC is the use of certain probiotics in infants at risk of developing a NEC. The more preterm or the lower the birthweight of a newborn, the higher the risk for infection with NEC. Consequently, the mortality risk is highest for very low birth weight infants, with a mortality rate of 30-50%, making them the most in need of prevention. Probiotics therefore aim to protect and save the most vulnerable preterm infants. (More information on NEC is available here).

The FDA warns against the use of probiotics in preterm neonates

In September 2023, the United States Food and Drug Administration (FDA) released a warning against the routine use of probiotics in preterm newborns. It reported a case where a preterm neonate developed sepsis due to bacteria contained in the probiotics and subsequently died.

Following this incident, the FDA warned against the use of probiotics in preterm infants, particularly those with a low birth weight of <1,000g. Instead, the FDA called for establishing pharmaceutical-grade probiotic drugs, as the probiotic is not yet an FDA-regulated and reviewed pharmaceutical.

Strong criticism is levelled at the FDA’s position

The FDA’s warning sparked a new discussion on the topic of NEC prevention. The European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) responded together with EFCNI in a position statement refuting the FDA’s arguments.

They acknowledge the tragic death of the preterm newborn, whilst recognising that this isolated case does not prove causality. Too many details are missing to prove that the probiotics lead to the infant’s death.

Furthermore, the use of probiotics is a well-researched area of interest. A total of 90 randomised controlled trials and high-quality studies have tested the use of probiotics in more than 55,000 preterm infants and draw a consistent picture. While none of these studies reported a single incidence of sepsis, the risk of severe NEC was reduced by 30-50% with the appropriate use of probiotics.

Weighing up the risk-benefit ratio speaks in favour of probiotics

ESPGHAN agrees with the FDA in its safety concerns regarding the unregulated probiotic market. However, they do not see the solution in classifying probiotics as pharmaceuticals, which would not address the root problem. In addition, waiting for pharmaceutical-grade probiotics will drive up costs and take time, actively costing lives that cannot be protected in the meantime. In its 2020 position paper, ESPGHAN offers specific recommendations for a few efficacy-based probiotic strains, in line with the recommendations of other organisations such as the American Gastroenterological Association and the World Health Organization.

After all, the decision should always be made in cooperation with the newborn’s parents. If the parents are given background information about the risks and benefits of the treatment, they can actively participate in the decision-making process and are able to weigh the risks and benefits for their child. Overall, although caution is required, the very favourable risk-benefit ratio justifies the use of well-identified and efficacy-based probiotic strains, in consultation with parents, to prevent NEC in very preterm infants and save the most vulnerable lives.

Paper available at: https://onlinelibrary.wiley.com/doi/10.1002/jpn3.12204

Ful list of authors: Chris van den Akker, Nicholas Embleton, Alexandre Lapillonne, Walter Mihatsch, Silva Salvatore, Roberto Canani, Ener Dinleyici, Magnus Domellöf, Alfredo Guarino, Pedro Gutiérrez‐Castrellón, Iva Hojsak, Flavia Indrio, Alexis Mosca, Rok Orel, Johannes van Goudoever, Zvi Weizman, Silke Mader, Luc Zimmermann, Raanan Shamir, Yvan Vandenplas, Hania Szajewska

DOI: https://doi.org/10.1002/jpn3.12204

Learn more about NEC here: https://newborn-health-standards.org/standards/standards-english/medical-care-clinical-practice/diagnosis-and-management-of-necrotising-enterocolitis-nec/