Incidence of necrotising enterocolitis before and after introducing routine prophylactic Lactobacillus and Bifidobacterium probiotics

Abstract

Objective: To compare rates of necrotising enterocolitis (NEC), late-onset sepsis, and mortality in 5-year epochs before and after implementation of routine daily multistrain probiotics administration in high-risk neonates.

Design: Single-centre retrospective observational study over the 10-year period from 1 January 2008 to 31 December 2017.

Setting: Level 3 neonatal intensive care unit (NICU) of the Norfolk and Norwich University Hospital, UK.

Patients: Preterm neonates at high risk of NEC: admitted to NICU within 3 days of birth at <32 weeks' gestation or at 32-36 weeks' gestation and of birth weight <1500 g.

Intervention: Prior to 1 January 2013 probiotics were not used. Thereafter, dual-species Lactobacillus acidophilus and Bifidobacterium bifidum combination probiotics were routinely administered daily to high-risk neonates; from April 2016 triple-species probiotics (L. acidophilus, B. bifidum, and B. longum subspecies infantis) were used.

Main outcome measures: Incidence of NEC (modified Bell's stage 2a or greater), late-onset sepsis, and mortality.

Results: Rates of NEC fell from 7.5% (35/469 neonates) in the pre-implementation epoch to 3.1% (16/513 neonates) in the routine probiotics epoch (adjusted sub-hazard ratio=0.44, 95% CI 0.23 to 0.85, p=0.014). The more than halving of NEC rates after probiotics introduction was independent of any measured covariates, including breast milk feeding rates. Cases of late-onset sepsis fell from 106/469 (22.6%) to 59/513 (11.5%) (p<0.0001), and there was no episode of sepsis due to Lactobacillus or Bifidobacterium. All-cause mortality also fell in the routine probiotics epoch, from 67/469 (14.3%) to 47/513 (9.2%), although this was not statistically significant after multivariable adjustment (adjusted sub-hazard ratio=0.74, 95% CI 0.49 to 1.12, p=0.155).

Conclusions: Administration of multispecies Lactobacillus and Bifidobacterium probiotics has been associated with a significantly decreased risk of NEC and late-onset sepsis in our neonatal unit, and no safety issues. Our data are consistent with routine use of Lactobacillus and Bifidobacterium combination probiotics having a beneficial effect on NEC prevention in very preterm neonates.

Keywords: Late-onset sepsis; microbiota; necrotizing enterocolitis; preterm; very low birth weight.

Figure 1

The cumulative incidence of necrotising enterocolitis (NEC) from date of birth stratified by epoch. Risk table shows the number of cases still at risk with each passing week from birth, as well as the cumulative numbers of those diagnosed with NEC, who died without a diagnosis of NEC, or who were discharged home without a diagnosis of NEC. One NEC case was censored in this time-to-event analysis, a baby born in the month before 1 January 2013 who developed NEC after that date, leaving 34 cases in the pre-probiotics epoch and 16 cases in the routine probiotics epoch included.

Figure 2

(A) Cumulative incidence of necrotising enterocolitis (NEC) stratified by gestational age at birth and by epoch. (B) Cumulative incidence of NEC stratified by gestational age at birth and by milk type for those who initiated enteral feeds. There was no case of NEC among those fed donor breast milk exclusively and so this group is not shown. (C) Cumulative incidence of mortality up to 200 days after birth, stratified by epoch and gestational age.

Figure 3

The rate of necrotising enterocolitis (NEC) in each year (solid bars with error bars), and linear trends estimated within each era (lines with error bands). Each estimate is shown with a 95% bootstrapped confidence interval.