Low serum sphingosine-1-phospate and its chaperone ApoM associate with retinopathy of prematurity

Retinopathy of prematurity (ROP) is a neurovascular retinal disease affecting extremely preterm infants (<28 weeks’ gestational age), and links between early lipid metabolism and ROP are unclear. We investigated whether the lipid mediator sphingosine-1-phosphate (S1P) and its carrier apolipoprotein M (ApoM) are associated with ROP and parenteral nutrition in preterm infants. In this multicenter cohort, extremely preterm infants were grouped by ROP outcome: no ROP (n=72) or any ROP (n=105). Serum was collected at birth and longitudinally to postnatal day 100. S1P was quantified by LC-MS/MS and ApoM by proximity extension assay. Associations between first month mean parenteral fluid intake, S1P, ApoM, and ROP were analyzed using logistic regression; log-normal linear regression was applied to continuous outcomes, adjusting for gestational age and LCPUFA supplementation. Results showed that serum S1P and ApoM were positively correlated (r=0.53, 95% CI 0.50–0.56). Higher first-month parenteral fluid intake was associated with lower S1P and ApoM (per 50 mL/kg/day, geometric mean ratio [GMR] 0.84, 95% CI 0.79–0.88 for S1P; 0.97, 95% CI 0.96–0.98 for ApoM; both p<0.001). Higher mean S1P in the first month was associated with reduced odds of any ROP (per 0.1 μmol/L, adjusted odds ratio 0.84, 95% CI 0.71–0.99, p=0.037). Mean ApoM was associated with ROP only in unadjusted analyses. In conclusion, low S1P and ApoM levels were linked to high parenteral fluid exposure and ROP development, suggesting that infants with high parenteral nutrition requirements may be particularly vulnerable to S1P/ApoM depletion, supporting this pathway as a potential therapeutic target.