Clinical effects of multi-strain probiotics in extremely preterm infants: a multicenter pre-post implementation study in the Netherlands

Probiotics may reduce the risk of necrotizing enterocolitis (NEC), late-onset sepsis (LOS), and mortality in preterm infants. However, their efficacy in extremely preterm infants (gestational age < 28 weeks) is still regularly questioned due to limited data and safety concerns. In Dutch Neonatal Intensive Care Units (NICUs), a three-strain probiotic product (ProPrems®; Bifidobacterium infantis Bb-02, Bifidobacterium lactis BB-12, and Streptococcus thermophilus TH-4) was implemented as standard of care from 2021 onwards. This study evaluates the clinical effects of these probiotics in extremely preterm infants. Pre- and postimplementation cohorts of extremely preterm infants from 6 Dutch NICUs (2018-2023) were compared. Clinical data from the first 29 days of life were collected. Incidence of NEC (modified Bell's stage ≥ IIA), LOS, and mortality were compared with logistic regression; growth velocity with linear regression; and time to full enteral feeds (tFEF) with survival analyses. In total, 481 extremely preterm infants (212 pre-, 269 post-implementation) were included. After implementation, the adjusted odds ratio was 0.49 (0.25-0.99; p = 0.049) for NEC; 0.87 (0.59-1.28; p = 0.49) for LOS; and 0.67 (0.35-1.27; p = 0.22) for all-cause mortality. Furthermore, tFEF decreased by 2 days (p < 0.001) and probiotic use was associated with an increase in growth velocity of 1.8 g/kg/day (p < 0.001). One infant (0.4%) developed probiotic-associated sepsis.

This multicenter pre-postimplementation study showed that multi-strain probiotic administration was associated with lower NEC incidence, shorter tFEF, and greater growth velocity in extremely preterm infants during the first four weeks of life. Probiotic-associated sepsis was rare. These results support continued use of probiotics in this vulnerable population.

• Certain probiotic strains effectively reduce incidence of necrotizing enterocolitis (NEC) in preterm infants, but the efficacy and safety for extremely preterm infants (GA < 28 weeks) remain under debate.

• This study shows that a multi-strain probiotic supplement was associated with lower NEC incidence, shorter time to full enteral feeds, and greater early postnatal growth in a Dutch multicenter cohort of extremely preterm infants. • The incidence of probiotic-associated sepsis in extremely preterm infants was very low in our cohort with just 1 case (0.4%), consistent with the rare occurrence reported previously.