Association of Hospital Adoption of Probiotics With Outcomes Among Neonates With Very Low Birth Weight

Abstract

ImportanceFor neonates with very low birth weight (VLBW), randomized clinical trials (RCTs) indicate that probiotic treatment decreases the risk of necrotizing enterocolitis (NEC), with smaller decreases in the risk of sepsis and death. There is little evidence on the rate of probiotic adoption in US neonatal intensive care units (NICUs) and whether the benefits seen in trials have materialized in practice.ObjectiveTo estimate changes in probiotic use among neonates with VLBW and to test whether neonates with VLBW treated at NICUs adopting routine probiotic use experience better outcomes compared with neonates treated at nonadopting NICUs.Design, Setting, and ParticipantsThis cohort study used Vermont Oxford Network data on neonates with VLBW in US NICUs from January 1, 2012, to December 31, 2019. Data were analyzed from January 2022 through February 2023.ExposureProbiotics adoption vs nonadoption. Adopting NICUs were defined as those that currently or previously treated at least 20% of neonates with VLBW with probiotics.Main OutcomesThe primary outcomes were rates of NEC, in-hospital mortality, and sepsis, defined as bacterial or fungal infection occurring after day 3 from birth. A difference-in-differences analysis compared changes in VLBW infant outcomes between adopting and nonadopting NICUs before and after hospital-level adoption of probiotics. Additional analyses used the proportion of neonates treated with probiotics in each neonate’s birth NICU and year.ResultsThe analysis included 307 905 neonates with VLBW (mean [SD] gestational age, 28.4 [2.9] weeks; 50.0% male) at 807 US hospitals. The rate of probiotic treatment of neonates with VLBW rose from 1572 of 38 296 neonates (4.1%) in 2012 to 4788 of 37 910 (12.6%) in 2019. Only 123 of 745 NICUs (16.5%) adopted probiotics by 2019, with 4591 of 6017 neonates with VLBW (76.3%) receiving probiotics in 2019 at adopting NICUs. Incidence of NEC declined by 18% at adopting NICUs (odds ratio [OR], 0.82; 95% CI, 0.70-0.95; P = .10) compared with nonadopting NICUs. Probiotic adoption was not associated with a significant reduction in sepsis (OR, 1.11; 95% CI, 0.98-1.25; P = .09) or mortality (OR, 0.93; 95% CI, 0.80-1.08; P = .33).Conclusion and RelevanceIn this cohort study, adoption of routine use of probiotics increased slowly in US NICUs and was associated with lower NEC risk but not with sepsis or mortality among neonates with VLBW. The findings for probiotic adoption and NEC, sepsis, and mortality were smaller than would have been predicted by the totality of RCT evidence but are consistent with a meta-analysis restricted to studies at low risk of bias.

Reevaluating the FDA's warning against the use of probiotics in preterm neonates: A societal statement by ESPGHAN and EFCNI

“…In fact, there are few therapies in neonatal medicine that have been studied as extensively as probiotics. More than 55,000 preterm infants studied in over 60 RCTs and 30 high‐quality nonrandomized studies, including trials from the United States, have received prophylactic probiotics 12–15 . Meta‐analyses show that the risk of severe NEC can be reduced by 30%–50% when appropriate probiotic strains are used.…”

Prioritizing Research to Reduce Mortality for Infants and the Broader US Population

“…When a large-scale analysis of patient outcomes in a clinical setting such as the study by Agha and colleagues does not confirm the full span of findings observed in more controlled environments with smaller samples, it is appropriate to ask questions such as the following: Did the NICUs in VON implement the intervention as it had been conducted in earlier randomized clinical trials? Did patients in clinical settings differ in key aspects from patients enrolled in the preceding trials?…”

“…An especially salient point of the study by Agha and colleagues is that they focused on an intervention designed to reduce mortality. To reverse the latest declines in life expectancy in the US, more research must be conducted with population-level mortality as the primary outcome.…”

“…Patterns of mortality often spur researchers, health care workers, and public health practitioners to action. The study by Agha et al offers a welcome focus on potential mortality benefit for infants born at very low birth weight (VLBW) (<1500 g). As a group, infants have a higher mortality rate than older children, adolescents, and adults younger than age 55 years in the US—a reminder of the vulnerability of the youngest young—and the mortality risk for infants with VLBW is several times higher than for infants of normal birth weight.…”