Probiotics and prebiotics in extremely preterm infants

Sammanfattning: Background: Extremely preterm (EPT) infants born before gestational week (gw) 28 and with extremely low birth weight (ELBW, <1,000g) are at risk of  gastrointestinal complications such as feeding intolerance and necrotising enterocolitis (NEC). This contributes to suboptimal nutrition and growth restriction, which has been associated with a worse long-time neurodevelopmental outcome. The probiotic bacterium Limosilactobacillus reuteri DSM 17938 has previously been shown to reduce feeding intolerance when given to preterm infants. The effect of this and other probiotics have, however, been insufficiently studied in EPT-ELBW infants. One explanation for the lack of effect in many probiotic prevention studies in ELBW infants may be an extensive treatment with antibiotics.   Exclusive breast milk feeding can prevent NEC, but the protective effect is incomplete. The variable content of prebiotic human milk oligosaccharides (HMO) has been suggested to explain this.  Aims: To evaluate if oral supplementation with L. reuteri in EPT-ELBW infants improves feeding tolerance, growth rates and neurological development; reduces the prevalence of NEC and sepsis, by having effects on intestinal colonisation, and finally whether mother’s milk HMO composition impacts on NEC, sepsis, and growth.    Methods: In total 134 newborn EPT-ELBW infants were randomised to enteral L. reuteri DSM 17938 supplementation or placebo administered from the first three days until gw 35 – 36 in a double-blind trial. Data was collected during intervention and at a standardised follow-up after 2 years. The primary outcome was time to full enteral feeding analysed with an intention to treat analysis. Secondary outcomes were NEC, culture proven sepsis, growth, and neurological development until two years of age. The breast milk content of 15 dominant HMOs in samples from 2 weeks, 4 weeks and in gw 35 – 36 was analysed with high performance anion-ex-change chromatography. L. reuteri-colonisation was determined with quantitative PCR in stool samples at 1, 2, 3 and 4 weeks, at gw 35 – 36 and at 2 years of age.  Results: Median time to full enteral feeding was 15 days in both study groups. Probiotics were associated with an improved cranial growth during the first 28 days (-1.2 SD vs -1.7 SD; p<0.01). L. reuteri colonisation rate was 86-98% during the supplementation. After two years, infants supple-mented with L. reuteri had a better Bayley-III language mean score (score 90 vs 83, p<0.05). Low HMO diversity in the mother´s breast milk was associated with NEC development in the infant.   Conclusion: L. reuteri did not reduce feeding intolerance in EPT-ELBW infants despite a high colonisation rate. The effect of probiotic supplementation on head growth and language development has not previously been reported and may suggest benefits of regulating the gut microbiota on brain development. A difference in HMO composition in breast milk may be an important factor explaining why exclusively breast milk fed EPT-ELBW infants are partially protected against development of NEC. These studies provide knowledge  and guidance for future strategies for feeding and pro-biotic supplementation in EPT-ELBW born children.