Association of Retinopathy of Prematurity With Low Levels of Arachidonic Acid

JAMA Ophthalmology

Feb 2018

DOI: 10.1001/jamaophthalmol.2017.6658

Citations:70

Influential Citations:2

Observational Studies (Human)

Enhanced Details

Methods

Design: randomized, open-label, single-site controlled trial conducted at a neonatal intensive care unit in Gothenburg, Sweden. Participants: 90 extremely preterm infants born <28 weeks gestational age enrolled 2013–2015; 78 had known ROP outcomes; 43 male (55%); mean gestational age 25.5 weeks (SD 1.4); mean birth weight 797 g (SD 223).

Intervention

Parenteral lipid emulsions delivered intravenously as part of parenteral nutrition: SMOFlipid (15% fish oil; ω-3 LC-PUFAs) vs Clinoleic (olive oil-based, no fish oil); lipid dose 2–3 g/kg/day; started soon after birth; duration not specified; both groups received enteral nutrition (maternal or donor breast milk with individualized fortification).

Results

Lower postnatal arachidonic acid (AA; 20:4 ω-6) serum fractions during the first month were strongly associated with the development of any ROP and severe ROP. At 32 weeks PMA, AA fraction was lower in infants who developed severe ROP. Logistic models showed predictive value of AA levels combined with gestational age: first-month AA AUC 0.806 for any ROP (sensitivity 95.1%, specificity 41.2%); for severe ROP, AUC 0.886 (sensitivity 90.3%, specificity 70.6%). AA at 32 weeks PMA plus GA at birth predicted differentiation between no ROP and later ROP (AUC 0.825; sensitivity 96.6%, specificity 53.3%), and no ROP vs later severe ROP (AUC 0.894; sensitivity 96.8%, specificity 78.6%). In summary, low postnatal AA is associated with ROP, and evaluating AA in addition to GA may aid prediction; consideration of AA supplementation in extremely preterm infants to reduce ROP risk warrants further study; causality is not established.

Limitations

Small, single-site study; not population-based; absorption of parenteral fatty acids not measured; associations do not prove causality; generalizability may be limited.

Abstract

Importance Mice with oxygen-induced retinopathy fed matched diets except for &ohgr;-3 long-chain polyunsaturated fatty acids (LC-PUFAs) vs &ohgr;-6 LC-PUFAs demonstrate relative antiangiogenic and neuroprotective associations of &ohgr;-3 LC-PUFAs. However, supplementing preterm infants with LC-PUFAs has been inconsistent in reducing major preterm morbidities. However, few studies measured serum lipid levels after supplementation. Objective To examine the associated risk of retinopathy of prematurity (ROP) from the levels of circulating &ohgr;-3 and &ohgr;-6 LC-PUFAs. Design, Setting, and Participants This longitudinal clinical study was a further analysis of serum lipid levels from a randomized controlled trial cohort of 90 infants born at gestational age (GA) less than 28 weeks. From April 4, 2013, to September 22, 2015, cord blood samples, followed by venous blood samples, were obtained at birth and at 1, 7, 14, and 28 days after birth and then at postmenstrual age (PMA) 32, 36, and 40 weeks at the neonatal intensive care unit at Sahlgrenska University Hospital in Göteborg, Sweden. Main Outcomes and Measures Serum phospholipid fatty acids were transmethylated and measured by gas chromatography–mass spectrometry. Mann-Whitney test, logistic regression Spearman rank correlation, and receiver operating characteristic curve analysis were used to compare differences between infants with no ROP and infants who developed ROP. Results Serum levels from 78 infants (43 male [55%]; mean [SD] GA, 25.5 [1.4] weeks) with a known ROP outcome were evaluated. Lower area under the curve (AUC) of arachidonic acid (AA) (20:4 &ohgr;-6) was seen in infants with a later diagnosis of ROP compared with infants with no ROP in the first month of life (mean, 34.05 [95% CI, 32.10-36.00] vs 37.15 [95% CI, 34.85-39.46]; P < .05). In addition, lower levels of AA at 32 weeks’ PMA were seen in infants with later severe ROP compared with in those without ROP (mean, 7.06 [95% CI, 6.60-7.52] vs 8.74 [95% CI, 7.80-9.67]; P < .001). In logistic modeling, low postnatal serum levels of AA and GA at birth identified with a sensitivity greater than 90% of infants who developed ROP. Conclusions and Relevance Low postnatal levels of the &ohgr;-6 LC-PUFAs (AA) are strongly associated with ROP development. Evaluating postnatal AA fraction after birth in addition to GA may be useful for ROP prediction. Trial Registration clinicaltrials.gov Identifier: NCT02760472 show less