Proteomic Profile in Retinopathy of Prematurity: A Secondary Analysis of the Mega Donna Mega Randomized Clinical Trial.

109 of 538 analyzed protein profiles during the first month of life were associated with severe ROP.

• A total of 177 extremely preterm infants were included (mean [SD] GA, 25.6 [1.4] weeks; 100 male [56.5%]).
• 50 of 177 infants (28.2%) developed severe ROP (stage ≥3 and/or treated).
• Proteomics covered 538 analytes using targeted Olink Proximity Extension Assay.
• Proteins associated with severe ROP were related to immune response, apoptotic processes, blood coagulation, and lipid metabolism.
• Analysis used mixed models for repeated measures, adjusted for GA, study center, and AA/DHA supplementation, and tested for interaction between severe ROP and postnatal age.

The most pronounced association with severe ROP was a fast rise in fibroblast growth factor 21 (FGF-21) during the first postnatal days.

• FGF-21 showed a β = 0.68 (95% CI, 0.39–0.97; Q = .002) for the interaction between severe ROP and postnatal age.
• FGF-21 is described as a metabolic stress-induced hormone.
• The rise in FGF-21 occurred specifically during the first postnatal days.
• This was identified as the most pronounced proteomic association with severe ROP among all 538 analyzed proteins.

Tissue plasminogen activator (tPA) also showed a strong association with severe ROP during the first postnatal days.

• tPA showed a β = 0.21 (95% CI, 0.13–0.29; Q < .001) for the interaction with postnatal age.
• tPA was identified as the second most pronounced proteomic association with severe ROP.
• tPA is related to blood coagulation pathways.

The increase in serum FGF-21 level in the first week of life was associated with multiple markers of clinical severity.

• Higher FGF-21 rise was associated with lower gestational age.
• Higher FGF-21 rise was associated with lower birth weight.
• Higher FGF-21 rise was associated with low enteral energy intake.
• Higher FGF-21 rise was associated with more days receiving mechanical ventilation.

No association was observed between AA/DHA supplementation and the serum proteome.

• The MDM trial assigned half of the infants to enteral lipid supplementation with AA/DHA (100/50 mg/kg per day) from birth to term equivalent age.
• The other half received standard nutrition without AA/DHA supplementation.
• The trial was double-masked.
• Proteomic analyses were adjusted for AA/DHA supplementation status, and no supplementation effect on the proteome was detected.

The study population consisted of extremely preterm infants born before 28 weeks of gestational age enrolled at 3 university hospitals in Sweden from 2016 to 2019.

• This was an exploratory, post hoc analysis of serum proteome profiles from the Mega Donna Mega (MDM) randomized clinical trial (ClinicalTrials.gov Identifier: NCT03201588).
• Mean (SD) gestational age was 25.6 (1.4) weeks.
• 100 of 177 infants (56.5%) were male.
• Data were analyzed from January to March 2025.