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Randomized Controlled Trial
. 2021 Apr 1;175(4):359-367.
doi: 10.1001/jamapediatrics.2020.5653.

Effect of Enteral Lipid Supplement on Severe Retinopathy of Prematurity: A Randomized Clinical Trial

Ann Hellström  1 , Anders K Nilsson  1 , Dirk Wackernagel  2 , Aldina Pivodic  1 , Mireille Vanpee  3 , Ulrika Sjöbom  1   4 , Gunnel Hellgren  1   5 , Boubou Hallberg  6 , Magnus Domellöf  7 , Susanna Klevebro  1   8 , William Hellström  9 , Mats Andersson  1 , Anna-My Lund  10 , Chatarina Löfqvist  1   4 , Anders Elfvin  9   10 , Karin Sävman  9   10 , Ingrid Hansen-Pupp  11 , Anna-Lena Hård  1 , Lois E H Smith  12 , David Ley  11
Affiliations
Randomized Controlled Trial

Effect of Enteral Lipid Supplement on Severe Retinopathy of Prematurity: A Randomized Clinical Trial

Ann Hellström et al. JAMA Pediatr. .

Abstract

Importance: Lack of arachidonic acid (AA) and docosahexaenoic acid (DHA) after extremely preterm birth may contribute to preterm morbidity, including retinopathy of prematurity (ROP).

Objective: To determine whether enteral supplementation with fatty acids from birth to 40 weeks' postmenstrual age reduces ROP in extremely preterm infants.

Design, setting, and participants: 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.

Interventions: 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.

Main outcomes and measures: 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.

Results: 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]; P = .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%]; P < .001; overall mean difference in control group, 0.13 mol% [95% CI, 0.01-0.24 mol%]; P = .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.

Conclusions and relevance: 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.

Trial registration: ClinicalTrials.gov Identifier: NCT03201588.

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Conflict of interest statement

Conflict of Interest Disclosures: Drs A. Hellström and Hansen-Pupp reported receiving grants from the Swedish Medical Research Council during the conduct of the study. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Flow Diagram of 209 Eligible Infants for Inclusion in the Arachidonic Acid (AA) and Docosahexaenoic Acid (DHA) Enteral Supplementation Randomized Multicenter Trial
ITT indicates intention-to-treat; IVH, intraventricular hemorrhage; MRI, magnetic resonance imaging; PP, per-protocol; and ROP, retinopathy of prematurity.
Figure 2.
Figure 2.. Cumulative Incidence Functions for Severe Retinopathy of Prematurity (ROP) (Intention-to-Treat [ITT] Population)
Relative risks (RRs) with 95% CI from Poisson regression and subdistribution hazard ratios (HRs) with 95% CI from the survival analyses handling death as a competing risk, for the ITT and per-protocol (PP) population are presented. AA indicates arachidonic acid; and DHA, docosahexaenoic acid.
Figure 3.
Figure 3.. Longitudinal Postnatal Molar Ratio of Serum Arachidonic Acid (AA) and Docosahexaenoic Acid (DHA) of Total Fatty Acids in the AA:DHA and Control Groups (Intent-to-Treat Population)
PMA indicates postmenstrual age.
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