Enteral long-chain polyunsaturated fatty acids and necrotizing enterocolitis: A systematic review and meta-analysis.

BACKGROUND: Preterm infants are at risk of long-chain polyunsaturated fatty acid (LCPUFA) deficiency. Recent studies on high-dose DHA; n-3 LCPUFA in preterm infants suggested potential positive effects on cognitive outcomes but raised concerns about some increased neonatal morbidities. These studies and recent recommendations for DHA supplementation generated controversy owing to the lack of balance between DHA and arachidonic acid (ARA; n-6 LCPUFA). OBJECTIVES: To identify the effect of enteral supplementation of DHA, with and without ARA, on necrotizing enterocolitis (NEC) in very preterm infants. METHODS: A systematic review of randomized and controlled trials compared enteral LCPUFAs with placebo or no supplementation in very preterm infants. We searched PubMed, Ovid-MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and CINHAL databases from inception to July 2022. Data were extracted in duplicate using a structured proforma. A meta-analysis and metaregression with random-effects models were used. The interventions evaluated were DHA alone vs. that combined with ARA, source of DHA, dose, and supplement delivery methods. Methodological qualities and risk of bias were assessed using the Cochrane risk-of-bias tool. RESULTS: Fifteen randomized clinical trials (RCTs) included 3963 very preterm infants with 217 cases of NEC. Supplementation with DHA alone increased NEC (2620 infants; RR: 1.56; 95% CI: 1.02, 2.39) with no evidence of heterogeneity (I2 = 0.0%, P = 0.46). Multiple metaregression revealed significant reduction in NEC when ARA was supplemented with DHA (aRR 0.42; 95% CI: 0.21, 0.88). The source of DHA, dose, and feeding type revealed no associations with NEC. Two RCTs supplemented high-dose DHA to lactating mothers. There was a significant increase in risk of NEC with this approach (1148 infants; RR: 1.92; 95% CI: 1.02, 3.61) with no evidence of heterogeneity (I2 = 0.0, P = 0.81). CONCLUSIONS: Supplementation with DHA alone may increase risk of NEC. Concurrent supplementation with ARA needs to be considered when adding DHA to preterm infants' diet.

The Role of Dietary Fats in the Development and Prevention of Necrotizing Enterocolitis.

Necrotizing enterocolitis (NEC) is a significant cause of mortality and morbidity in preterm infants. The pathogenesis of NEC is not completely understood; however, intestinal immaturity and excessive immunoreactivity of intestinal mucosa to intraluminal microbes and nutrients appear to have critical roles. Dietary fats are not only the main source of energy for preterm infants, but also exert potent effects on intestinal development, intestinal microbial colonization, immune function, and inflammatory response. Preterm infants have a relatively low capacity to digest and absorb triglyceride fat. Fat may thereby accumulate in the ileum and contribute to the development of NEC by inducing oxidative stress and inflammation. Some fat components, such as long-chain polyunsaturated fatty acids (LC-PUFAs), also exert immunomodulatory roles during the early postnatal period when the immune system is rapidly developing. LC-PUFAs may have the ability to modulate the inflammatory process of NEC, particularly when the balance between n3 and n6 LC-PUFAs derivatives is maintained. Supplementation with n3 LC-PUFAs alone may have limited effect on NEC prevention. In this review, we describe how various fatty acids play different roles in the pathogenesis of NEC in preterm infants.