Higher Docosahexaenoic Acid Serum Levels associated with less severe ROP in Preterm Infants

Extremely preterm birth cuts off the supply of the ω-6 long-chain polyunsaturated fatty acid (LC-PUFA) arachidonic acid (AA; 20:4 ω-6) and the ω-3 docosahexaenoic acid (DHA; 22:6 ω-3) from the mother. These fatty acids are structural and functional cell membrane components that are involved in energy metabolism, growth, immune defense, inflammation, vascularization, and vascular tone. They are specifically important to the eye, vascular endothelium, and brain. With the current neonatal care, extremely preterm infants accumulate substantial deficits in AA and DHA, which could be factors in neonatal morbidities, including ROP.

Ann Hellström and team hypothesized that higher mean daily DHA and AA levels were associated with less severe ROP. Specifically this cohort study aimed to assess whether ROP severity is associated with serum levels of LC-PUFA, especially DHA and AA and their interaction, during the first 28 postnatal days.

The cohort study analyzed the Mega Donna Mega study, a randomized clinical trial that provided enteral fatty acid supplementation at 3 neonatal intensive care units in Sweden. Infants included in this cohort study were born at a gestational age of less than 28 weeks between December 20, 2016, and August 6, 2019. Severity of ROP was classified as no ROP, mild or moderate ROP (stage 1-2), or severe ROP (stage 3 and type 1). Serum phospholipid fatty acids were measured through gas chromatography–mass spectrometry. Areas under the curve were used to calculate mean daily levels of fatty acids during postnatal days 1 to 28. Blood samples were obtained at the postnatal ages of 1, 3, 7, 14, and 28 days.

A total of 175 infants were included in analysis. Of these infants, 99 were boys (56.6%); the median (IQR) gestational age was 25 weeks 5 days (24 weeks 3 days to 26 weeks 6 days), and the median (IQR) birth weight was 785 (650-945) grams.

A higher DHA proportion was seen in infants with no ROP compared with those with mild or moderate ROP or severe ROP (OR per 0.5–molar percentage increase]; gestational age– and birth weight–adjusted OR, 0.66).

The corresponding adjusted OR for AA levels per 1–molar percentage increase was 0.83 (95% CI, 0.66-1.05). The association between DHA levels and ROP severity appeared only in infants with sufficient AA levels, suggesting that a mean daily minimum level of 7.8 to 8.3 molar percentage of AA was necessary for a detectable association between DHA level and less severe ROP.

In this cohort, higher mean daily serum levels of DHA, but not significantly higher levels of AA, during the first 28 postnatal days were associated with less severe ROP. These findings suggested that a minimum mean daily AA serum level of 7.8 to 8.3 molar percentage was required to achieve the association between higher DHA level and less severe ROP.

Oxidative stress from deranged oxygenation, mechanical ventilation, parenteral nutrition, sepsis, blood transfusions, and other factors are crucially involved in ROP development. Both AA and DHA are highly unsaturated fatty acids and prone to peroxidation. However, proper membrane inclusion of these LC-PUFAs could promote membrane integrity and prevent oxidative stress damage. Greater availability of AA and DHA may increase membranes' integrity in the central nervous system and vasculature.

High levels of the ω-3 DHA and eicosapentaenoic acid can suppress AA levels. Accordingly, supplementation with ω-3 fatty acids from fish oil in preterm infants can decrease AA serum levels.

Given the importance of AA in growth and development, especially of the central nervous system, providing AA supplementation to the extremely preterm newborn is likely needed to compensate for maternal supply loss. However, it is essential to balance AA and DHA or eicosapentaenoic acid levels to favor the physiological incorporation of these fatty acids.

This cohort study found that higher serum DHA levels during the first 28 postnatal days were associated with less severe ROP even after adjustment for known risk factors, but there was no association for AA levels. The association between higher DHA level and less severe ROP appeared to emerge with sufficiently high AA levels. Therefore, further studies of nutrition strategies are needed to identify LC-PUFA associations that may prevent ROP and possibly other morbidities

Source: JAMA Network Open. 2021;4(10):e2128771.

doi:10.1001/jamanetworkopen.2021.28771