Necrotising enterocolitis and mortality in preterm infants after introduction of probiotics: a quasi-experimental study

Noor Samuels, Rob van de Graaf, Jasper V Been, Rogier C J de Jonge, Lidwien M Hanff, René M H Wijnen, René F Kornelisse, Irwin K M Reiss, Marijn J Vermeulen, Noor Samuels, Rob van de Graaf, Jasper V Been, Rogier C J de Jonge, Lidwien M Hanff, René M H Wijnen, René F Kornelisse, Irwin K M Reiss, Marijn J Vermeulen

Abstract

Evidence on the clinical effectiveness of probiotics in the prevention of necrotising enterocolitis (NEC) in preterm infants is conflicting and cohort studies lacked adjustment for time trend and feeding type. This study investigated the association between the introduction of routine probiotics (Lactobacillus acidophilus and Bifidobacterium bifidum; Infloran(®)) on the primary outcome 'NEC or death'. Preterm infants (gestational age <32 weeks or birth weight <1500 gram) admitted before (Jan 2008-Sep 2012; n = 1288) and after (Oct 2012-Dec 2014; n = 673) introduction of probiotics were compared. Interrupted time series logistic regression models were adjusted for confounders, effect modification by feeding type, seasonality and underlying temporal trends. Unadjusted and adjusted analyses showed no difference in 'NEC or death' between the two periods. The overall incidence of NEC declined from 7.8% to 5.1% (OR 0.63, 95% CI 0.42-0.93, p = 0.02), which was not statistically significant in the adjusted models. Introduction of probiotics was associated with a reduced adjusted odds for 'NEC or sepsis or death' in exclusively breastmilk-fed infants (OR 0.43, 95% CI 0.21-0.93, p = 0.03) only. We conclude that introduction of probiotics was not associated with a reduction in 'NEC or death' and that type of feeding seems to modify the effects of probiotics.

Figures

Figure 1. Study inclusion flow chart.
Figure 1. Study inclusion flow chart.
BW, birth weight; GA, gestational age at birth; NICU, neonatal intensive care unit.
Figure 2. Quarterly incidence of NEC 2008–2014.
Figure 2. Quarterly incidence of NEC 2008–2014.
The actual incidence, plotted in blue, reflects the observed proportion of infants developing NEC in the studied population, showing seasonality in NEC incidence. Red dotted line indicates moment of introduction of routine probiotics. The predicted incidence, plotted in grey, represents the estimated incidence of NEC by the interrupted time series model, with adjustment for gender, gestational age, birth weight Z-score, mode of delivery, prenatal steroids, (interaction between probiotic introduction and feeding type), type of feeding, seasonality and non-linear time trend.
Figure 3. Adjusted associations between introduction of…
Figure 3. Adjusted associations between introduction of probiotics and each outcome according to feeding type.
Shown are adjusted odds ratios (ORs) of developing the outcomes in the period after versus before introduction of probiotics for each feeding group. For each outcome a multivariable model was run, adjusted for gender, gestational age, birth weight Z-score, mode of delivery, prenatal steroids, the interaction between probiotic introduction and feeding and non-linear time trend. For more detailed output of the models: see Supplementary Table 1. Abbreviations: CI, confidence interval; NEC: necrotising enterocolitis. Definitions: NEC, necrotising enterocolitis ≥ stage 2; Surgical NEC, NEC requiring surgical treatment; Sepsis, defined as blood culture proven late-onset sepsis during NICU admission.

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