Immune and Inflammatory Proteins in Cord Blood as Predictive Biomarkers of Retinopathy of Prematurity in Preterm Infants

Abstract

PURPOSE. To determine whether elevated levels of immune/inflammatory proteins in cord blood, alone or in combination with conventional clinical parameters, can predict the occurrence and progression of retinopathy of prematurity (ROP) in preterm infants. METHODS. This was a retrospective cohort study of 110 premature singleton infants who were born at 32.0 weeks. Cord plasma at birth was assayed for interleukin-6, C3a, C5a, matrix metalloproteinase-2 (MMP-2), MMP-9, tissue inhibitor of metalloproteinase-1, macrophage colony-stimulating factor, endostatin, a proliferation-inducing ligand, insulin-like growth factor-binding protein-1 (IGFBP-1), IGFBP-2, and calcium-binding protein A8/A9 complex levels. The primary outcome measures were the occurrence of any stage ROP, severe ROP (>stage 3), and vision-threatening type 1 ROP requiring laser treatment. RESULTS. ROP was diagnosed in 30 of 110 infants (27.3%), including 14 (12.7%) with severe ROP. Laser treatment was performed on 7 infants (6.4%). Multiple logistic regression analyses indicated that elevated levels of cord plasma IL-6 were significantly associated with severe ROP, whereas elevated levels of cord plasma C5a were significantly associated with ROP laser treatments. However, none of the proteins measured in the cord plasma were associated with ROP occurrence. Using a stepwise regression procedure, we developed a combined prediction model, which included high cord plasma IL-6 levels and low birth weight for severe ROP (area under the curve [AUC], 0.840), and high cord plasma C5a levels and low birth weight for laser treatment (AUC, 0.884). CONCLUSIONS. Elevated levels of cord plasma IL-6 and C5a could be used as independent markers to predict severe ROP and laser treatment, respectively, with combined models predicting ROP progression with good accuracy.

Inflammatory and Angiogenic Mediators in Amniotic Fluid Are Associated With the Development of Retinopathy of Prematurity in Preterm Infants

“…Previous studies, including ours, also noted (i) elevated cord plasma levels of IL-6, C3a, and C5a, and (ii) events in the intrauterine environment that trigger spontaneous preterm delivery are significantly associated with an increased risk of ROP progression. 13 , 32 , 33 Taken together, these findings suggest that pathophysiologic events that predispose preterm neonates to ROP begin before delivery and that therapeutic strategies to decrease the risk of ROP may need to be implemented during pregnancy (e.g., specific treatment with antibiotics, anti-inflammatory drugs, and/or antiangiogenic drugs). Additionally, our findings strongly support the theory of Lee and Dammann 34 regarding the important etiological role of antenatal factors, especially prenatal and perinatal infection/inflammation, in ROP.…”

“…Similar to the current findings in AF, our recent study using cord blood samples at birth, showed that elevated levels of cord plasma IL-6 were significantly associated with severe ROP. 13 Furthermore, previous studies using postnatal blood have demonstrated that inflammatory proteins are significantly elevated in the peripheral blood obtained in the postnatal period of preterm infants with ROP. 6 – 9 , 11 , 12 Therefore, these findings show that in utero to postnatal systemic inflammation is linked to ROP occurrence and progression, and highlight the importance of inflammation in the pathogenesis of ROP.…”

“… 4 , 5 The literature suggests that elevated levels of inflammatory factors and growth factors (insulin-like growth factor [IGF]-1, matrix metalloproteinase [MMP], placenta growth factor, and angiopoietins) in blood obtained later in postnatal life are associated with ROP development. 6 – 12 Furthermore, using cord blood sampled at birth, we have recently shown that elevated cord plasma levels of IL-6 and C5a were independently associated with severe ROP and laser treatment, 13 thereby suggesting that elevated levels of inflammatory and angiogenic proteins in the postnatal blood of infants with ROP may reflect ongoing prenatal or perinatal inflammatory response and its associated mediators, leading to subsequent unfavorable visual outcomes for ROP. In fact, in the context of severe neonatal morbidities, such as bronchopulmonary dysplasia (BPD), periventricular leukomalacia (PVL), cerebral palsy, and hearing impairment, significant associations of elevated cytokine levels in the postnatal and cord bloods, as well as in amniotic fluid (AF), with each of these outcomes have been already reported in very preterm infants.…”

Current evidence and outcomes for retinopathy of prematurity prevention: insight into novel maternal and placental contributions

“…Perinatal inflammation [105][106][107] and nutritional deficiencies [108][109][110] are postulated to render the developing retina more susceptible to ROP pathogenesis. Nutritional deficiencies in polyunsaturated fatty acids (PUFAs), inositol, vitamins A, E, and D supplied in human breast milk (BM) are known to increase inflammation and oxidative stress and therefore these processes are likely inter-related.…”

Cluster Analysis of Early Postnatal Biochemical Markers May Predict Development of Retinopathy of Prematurity

“…However, other vascular and inflammatory proteins as well as growth factors, angiogenetic proteins, and neurotrophins have also been suggested to be associated with ROP. [6][7][8][9][10][11] This multitude of ROP-associated factors demonstrates that numerous signaling pathways may be involved in the development of ROP and that maybe not a single biomarker but a combination of biomarkers should be investigated.…”