Effect of Enteral Lipid Supplement on Severe Retinopathy of Prematurity
Authors: Ann Hellström, Anders K. Nilsson, Dirk Wackernagel, Aldina Pivodic, Mireille Vanpee, Ulrika Sjöbom, Gunnel Hellgren, Boubou Hallberg, Magnus Domellöf, Susanna Klevebro, William Hellström, Mats Andersson, Anna-My Lund, Chatarina Löfqvist, Anders Elfvin, Karin Sävman, Ingrid Hansen-Pupp, Anna-Lena Hård, Lois E. H. Smith, David Ley
Journal: JAMA Pediatrics (2021)

<h3>Importance</h3> Lack of arachidonic acid (AA) and docosahexaenoic acid (DHA) after extremely preterm birth may contribute to preterm morbidity, including retinopathy of prematurity (ROP). <h3>Objective</h3> To determine whether enteral supplementation with fatty acids from birth to 40 weeks’ postmenstrual age reduces ROP in extremely preterm infants. <h3>Design, Setting, and Participants</h3> The Mega Donna Mega trial, a randomized clinical trial, was a multicenter study performed at 3 university hospitals in Sweden from December 15, 2016, to December 15, 2019. The screening pediatric ophthalmologists were masked to patient groupings. A total of 209 infants born at less than 28 weeks’ gestation were tested for eligibility, and 206 infants were included. Efficacy analyses were performed on as-randomized groups on the intention-to-treat population and on the per-protocol population using as-treated groups. Statistical analyses were performed from February to April 2020. <h3>Interventions</h3> Infants received either supplementation with an enteral oil providing AA (100 mg/kg/d) and DHA (50 mg/kg/d) (AA:DHA group) or no supplementation within 3 days after birth until 40 weeks’ postmenstrual age. <h3>Main Outcomes and Measures</h3> The primary outcome was severe ROP (stage 3 and/or type 1). The secondary outcomes were AA and DHA serum levels and rates of other complications of preterm birth. <h3>Results</h3> A total of 101 infants (58 boys [57.4%]; mean [SD] gestational age, 25.5 [1.5] weeks) were included in the AA:DHA group, and 105 infants (59 boys [56.2%]; mean [SD] gestational age, 25.5 [1.4] weeks) were included in the control group. Treatment with AA and DHA reduced severe ROP compared with the standard of care (16 of 101 [15.8%] in the AA:DHA group vs 35 of 105 [33.3%] in the control group; adjusted relative risk, 0.50 [95% CI, 0.28-0.91];<i>P</i> = .02). The AA:DHA group had significantly higher fractions of AA and DHA in serum phospholipids compared with controls (overall mean difference in AA:DHA group, 0.82 mol% [95% CI, 0.46-1.18 mol%];<i>P</i> &lt; .001; overall mean difference in control group, 0.13 mol% [95% CI, 0.01-0.24 mol%];<i>P</i> = .03). There were no significant differences between the AA:DHA group and the control group in the rates of bronchopulmonary dysplasia (48 of 101 [47.5%] vs 48 of 105 [45.7%]) and of any grade of intraventricular hemorrhage (43 of 101 [42.6%] vs 42 of 105 [40.0%]). In the AA:DHA group and control group, respectively, sepsis occurred in 42 of 101 infants (41.6%) and 53 of 105 infants (50.5%), serious adverse events occurred in 26 of 101 infants (25.7%) and 26 of 105 infants (24.8%), and 16 of 101 infants (15.8%) and 13 of 106 infants (12.3%) died. <h3>Conclusions and Relevance</h3> This study found that, compared with standard of care, enteral AA:DHA supplementation lowered the risk of severe ROP by 50% and showed overall higher serum levels of both AA and DHA. Enteral lipid supplementation with AA:DHA is a novel preventive strategy to decrease severe ROP in extremely preterm infants. <h3>Trial Registration</h3> ClinicalTrials.gov Identifier:NCT03201588