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

Abstract:

Question  Does enteral fatty acid supplementation with arachidonic acid (AA) and docosahexaenoic acid (DHA) from birth to 40 weeks’ postmenstrual age reduce severe retinopathy of prematurity (ROP) in extremely preterm infants?

Findings  This randomized clinical trial found that enteral AA and DHA supplementation lowered the risk of severe ROP by 50%. In addition, the group that received enteral AA and DHA supplementation showed higher serum levels of both AA and DHA compared with controls.

Meaning  Supplementing the diet of the most immature infants born at less than 27 weeks’ gestational age with an enteral lipid solution with AA:DHA had no significant adverse effects and seems to be a promising intervention to prevent sight-threatening ROP and thereby reduce visual impartment and blindness.

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 27 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

Extremely preterm infants have a high incidence of neonatal morbidities, including retinopathy of prematurity (ROP), a neurovascular disease with initial suppression of retinal blood vessel growth followed by pathologic neovascularization that can cause blindness.¹ Treatment of severe ROP aims to cause regression of pathologic neovascularization and prevent retinal detachment by reducing the action of vascular endothelial growth factor (VEGF). Laser therapy is performed under general anesthesia and destroys the hypoxic VEGF-producing peripheral retina. Anti-VEGF therapy comprises intraocular injections, often repeated, of antibodies against VEGF. These substances enter the circulation, and concerns have been raised about their effects on growing tissues. Retinopathy of prematurity correlates with reduced brain volumes and poor psychomotor development.²

Infants born extremely preterm miss the third-trimester transfer from the mother of the ω-6 long chain polyunsaturated fatty acid (LCPUFA) arachidonic acid (AA) and the ω-3 LCPUFA docosahexaenoic acid (DHA). Arachidonic acid and DHA are critical constituents of the retina and the brain, and deficiencies are associated with vascular complications of preterm birth.^3,4 The AA lipid fraction is 2-fold higher in fetal blood than maternal blood throughout gestation, while the DHA lipid fraction is similar to the maternal fraction until approximately 30 weeks’ gestational age (GA), then increases concomitant with rapid brain growth.⁵ The lipid emulsions currently used in parenteral nutrition contain insufficient or no AA and DHA. Breast milk does not provide enough AA and DHA to fulfill the early requirements of extremely preterm infants.^6,7 Thus, extremely preterm infants accumulate AA and DHA deficits during hospitalization.^8,9

Several studies suggest that low ω-3 LCPUFAs are associated with ROP risk. Increased intake of ω-3 protected against pathologic neovascularization in mouse oxygen-induced retinopathy.^10,11 The DHA oxidation product 4-hydroxy-docosahexaenoic acid inhibited pathologic neovascularization independently of its anti-inflammatory effects.¹² Decreased frequency of any ROP or treatment for ROP was reported with the use of fish oil–based parenteral lipid solutions rich in ω-3.^13-15 However, parenteral nutrition with 15% fish oil vs an olive oil–based lipid solution substantially reduced AA serum levels and AA to DHA ratios.¹⁶ A lower AA serum fraction was associated with increased frequency of severe ROP.¹⁷

A few studies have been performed using enteral DHA supplementation given early after birth to preterm infants. A reduction in stage 3 ROP was found in infants with a birth weight of 1000 to 1500 g who received enteral DHA for 14 days.¹⁸ Collins et al¹⁹ reported no benefit and possibly increased risk of bronchopulmonary dysplasia (BPD) with DHA supplementation from the first enteral feeding to 36 weeks’ postmenstrual age (PMA) or hospital discharge in 1273 infants with a GA less than 29 weeks; no effect on ROP was reported.

The primary aim of this trial was to study the frequency of severe (stage 3 and/or type 1) ROP with or without AA and DHA supplementation. Secondary aims were to investigate the effects of AA and DHA supplementation on serum phospholipid fatty acid composition and the rates of other complications of prematurity. This study adds to current knowledge by studying the effects of an enteral lipid supplement containing both AA and DHA given to extremely preterm infants stratified into GA-based groups.

Supplementing the diets of the most immature infants born at less than 27 weeks’ GA with an enteral lipid solution with AA to DHA ratio of 2:1 had no significant adverse effects and seems to be a promising intervention to prevent sight-threate