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Association of inflammatory and angiogenic biomarkers in maternal plasma with retinopathy of prematurity in preterm infants

Abstract

Objective

To investigate whether various novel inflammatory and angiogenic biomarkers in maternal plasma, alone or in combination with baseline antenatal factors, could predict retinopathy of prematurity (ROP) in preterm infants.

Methods

A retrospective cohort study was conducted on 140 premature singleton neonates born to women with preterm birth (ā‰¤32 weeks) and screened for ROP. Maternal blood obtained at the time of admission was assayed for CRP, endoglin, endostatin, IGFBP-2, IGFBP-3, IL-6, LBP, MMP-8, PlGF, S100A8/A9, TGFBI, and VEGFR-1. The primary outcome measures included severe ROP (stage 3 or higher) and type 1 ROP requiring treatment.

Results

ROP was present in 25.7% (36/140) of the study population, including 20 (14.3%) cases of severe ROP and 14 (10%) with type 1 ROP. Multiple logistic regression analyses revealed significant associations between high concentrations of maternal plasma LBP and severe ROP, and between elevated plasma IL-6 and LBP levels and type 1 ROP (all Pā€‰<ā€‰0.05), while adjusting for confounders (i.e., gestational age [GA] at sampling). Prenatal prediction models for severe ROP and type 1 ROP were developed by combining plasma IL-6 or LBP levels with GA at sampling, which showed good discriminatory power (area under the curve = 0.747 and 0.854, respectively).

Conclusions

IL-6 and LBP in maternal plasma were found to be independently associated with severe ROP and type 1 ROP. Prediction models based on these biomarkers along with GA at sampling may serve as good prenatal indicators for the neonatal risk of ROP progression in women at risk of preterm birth.

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Fig. 1: ROC curve analysis.

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Data availability

The dataset for this study is available from the corresponding author upon reasonable request.

References

  1. Hellstrom A, Smith LE, Dammann O. Retinopathy of prematurity. Lancet 2013;382:1445ā€“57.

    PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  2. Blencowe H, Lawn JE, Vazquez T, Fielder A, Gilbert C. Preterm-associated visual impairment and estimates of retinopathy of prematurity at regional and global levels for 2010. Pediatr Res. 2013;74:35ā€“49.

    PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  3. Hong EH, Shin YU, Bae GH, Choi YJ, Ahn SJ, Sobrin L, et al. Nationwide incidence and treatment pattern of retinopathy of prematurity in South Korea using the 2007-2018 national health insurance claims data. Sci Rep. 2021;11:1451.

    CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  4. Bas AY, Demirel N, Koc E, Ulubas Isik D, Hirfanoglu IM, Tunc T, et al. Incidence, risk factors and severity of retinopathy of prematurity in Turkey (TR-ROP study): a prospective, multicentre study in 69 neonatal intensive care units. Br J Ophthalmol. 2018;102:1711ā€“6.

    PubMedĀ  Google ScholarĀ 

  5. Tavassoli S, Wach R, Haynes R, Markham R, Williams C. Estimate of incidence of ROP requiring treatment in extreme preterms and impact on service-7 year review in tertiary unit. Eye 2019;33:845ā€“9.

    PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  6. Binenbaum G, Ying GS, Quinn GE, Dreiseitl S, Karp K, Roberts RS, et al. A clinical prediction model to stratify retinopathy of prematurity risk using postnatal weight gain. Pediatrics 2011;127:e607ā€“614.

    PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  7. Hartnett ME, Penn JS. Mechanisms and management of retinopathy of prematurity. N Engl J Med. 2012;367:2515ā€“26.

    CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  8. Chen ML, Allred EN, Hecht JL, Onderdonk A, VanderVeen D, Wallace DK, et al. Placenta microbiology and histology and the risk for severe retinopathy of prematurity. Invest Ophthalmol Vis Sci. 2011;52:7052ā€“8.

    PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  9. Hellgren G, Lofqvist C, Hansen-Pupp I, Gram M, Smith LE, Ley D, et al. Increased postnatal concentrations of pro-inflammatory cytokines are associated with reduced IGF-I levels and retinopathy of prematurity. Growth Horm IGF Res. 2018;39:19ā€“24.

    CASĀ  PubMedĀ  Google ScholarĀ 

  10. Holm M, Morken TS, Fichorova RN, VanderVeen DK, Allred EN, Dammann O, et al. Systemic inflammation-associated proteins and retinopathy of prematurity in infants born before the 28th week of gestation. Invest Ophthalmol Vis Sci. 2017;58:6419ā€“28.

    CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  11. Lynch AM, Wagner BD, Mandava N, Palestine AG, Mourani PM, McCourt EA, et al. The relationship of novel plasma proteins in the early neonatal period with retinopathy of prematurity. Invest Ophthalmol Vis Sci. 2016;57:5076ā€“82.

    CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  12. Rivera JC, Holm M, Austeng D, Morken TS, Zhou TE, Beaudry-Richard A, et al. Retinopathy of prematurity: inflammation, choroidal degeneration, and novel promising therapeutic strategies. J Neuroinflammation. 2017;14:165.

    PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  13. Silveira RC, Fortes Filho JB, Procianoy RS. Assessment of the contribution of cytokine plasma levels to detect retinopathy of prematurity in very low birth weight infants. Invest Ophthalmol Vis Sci. 2011;52:1297ā€“301.

    CASĀ  PubMedĀ  Google ScholarĀ 

  14. Sood BG, Madan A, Saha S, Schendel D, Thorsen P, Skogstrand K, et al. Perinatal systemic inflammatory response syndrome and retinopathy of prematurity. Pediatr Res. 2010;67:394ā€“400.

    PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  15. Lofqvist C, Andersson E, Sigurdsson J, Engstrom E, Hard AL, Niklasson A, et al. Longitudinal postnatal weight and insulin-like growth factor I measurements in the prediction of retinopathy of prematurity. Arch Ophthalmol. 2006;124:1711ā€“8.

    PubMedĀ  Google ScholarĀ 

  16. Lofqvist C, Hansen-Pupp I, Andersson E, Holm K, Smith LE, Ley D, et al. Validation of a new retinopathy of prematurity screening method monitoring longitudinal postnatal weight and insulinlike growth factor I. Arch Ophthalmol. 2009;127:622ā€“7.

    PubMedĀ  Google ScholarĀ 

  17. Hutchinson AK, Melia M, Yang MB, VanderVeen DK, Wilson LB, Lambert SR. Clinical models and algorithms for the prediction of retinopathy of prematurity: a report by the american academy of ophthalmology. Ophthalmology 2016;123:804ā€“16.

    PubMedĀ  Google ScholarĀ 

  18. Dammann O, Rivera JC, Chemtob S. The prenatal phase of retinopathy of prematurity. Acta Paediatr. 2021;110:2521ā€“8.

    PubMedĀ  Google ScholarĀ 

  19. Lynch AM, Berning AA, Thevarajah TS, Wagner BD, Post MD, McCourt EA, et al. The role of the maternal and fetal inflammatory response in retinopathy of prematurity. Am J Reprod Immunol. 2018;80:e12986.

    PubMedĀ  Google ScholarĀ 

  20. Lynch AM, Wagner BD, Hodges JK, Thevarajah TS, McCourt EA, Cerda AM, et al. The relationship of the subtypes of preterm birth with retinopathy of prematurity. Am J Obstet Gynecol. 2017;217:354.e351ā€“354.e358.

    Google ScholarĀ 

  21. Woo SJ, Park KH, Jung HJ, Kim S, Choe G, Ahn J, et al. Effects of maternal and placental inflammation on retinopathy of prematurity. Graefes Arch Clin Exp Ophthalmol. 2012;250:915ā€“23.

    PubMedĀ  Google ScholarĀ 

  22. Woo SJ, Park JY, Hong S, Kim YM, Park YH, Lee YE, et al. Inflammatory and angiogenic mediators in amniotic fluid are associated with the development of retinopathy of prematurity in preterm infants. Invest Ophthalmol Vis Sci. 2020;61:42.

    CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  23. Park YJ, Woo SJ, Kim YM, Hong S, Lee YE, Park KH. Immune and inflammatory proteins in cord blood as predictive biomarkers of retinopathy of prematurity in preterm infants. Invest Ophthalmol Vis Sci. 2019;60:3813ā€“20.

    CASĀ  PubMedĀ  Google ScholarĀ 

  24. Goldstein GP, Leonard SA, Kan P, Koo EB, Lee HC, Carmichael SL. Prenatal and postnatal inflammation-related risk factors for retinopathy of prematurity. J Perinatol. 2019;39:964ā€“73.

    CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  25. Chow SS, Craig ME, Jones CA, Hall B, Catteau J, Lloyd AR, et al. Differences in amniotic fluid and maternal serum cytokine levels in early midtrimester women without evidence of infection. Cytokine 2008;44:78ā€“84.

    CASĀ  PubMedĀ  Google ScholarĀ 

  26. Lencki SG, Maciulla MB, Eglinton GS. Maternal and umbilical cord serum interleukin levels in preterm labor with clinical chorioamnionitis. Am J Obstet Gynecol. 1994;170:1345ā€“51.

    CASĀ  PubMedĀ  Google ScholarĀ 

  27. Young BK, Li X, Arslan AA. Parallel maternal and fetal immune activation by bacterial toxins in vitro. J Perinat Med. 2011;40:73ā€“76.

    PubMedĀ  Google ScholarĀ 

  28. Fierson WM, American Academy of Pediatrics Section on O, American Academy of O, American Association for Pediatric O, Strabismus, American Association of Certified O. Screening examination of premature infants for retinopathy of prematurity. Pediatrics 2013;131:189ā€“95.

    PubMedĀ  Google ScholarĀ 

  29. Fierson WM. Screening examination of premature infants for retinopathy of prematurity. Pediatrics 2018;142:e20183061.

    PubMedĀ  Google ScholarĀ 

  30. Early Treatment For Retinopathy Of Prematurity Cooperative Group. Revised indications for the treatment of retinopathy of prematurity: results of the early treatment for retinopathy of prematurity randomized trial. Arch Ophthalmol. 2003;121:1684ā€“94.

    Google ScholarĀ 

  31. Early Treatment for Retinopathy of Prematurity Cooperative G, Good WV, Hardy RJ, Dobson V, Palmer EA, Phelps DL, et al. Final visual acuity results in the early treatment for retinopathy of prematurity study. Arch Ophthalmol 2010;128:663ā€“71.

    Google ScholarĀ 

  32. Mintz-Hittner HA, Kennedy KA, Chuang AZ. Efficacy of intravitreal bevacizumab for stage 3+ retinopathy of prematurity. N Engl J Med. 2011;364:603ā€“15.

    CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  33. Stahl A, Lepore D, Fielder A, Fleck B, Reynolds JD, Chiang MF, et al. Ranibizumab versus laser therapy for the treatment of very low birthweight infants with retinopathy of prematurity (RAINBOW): an open-label randomised controlled trial. Lancet 2019;394:1551ā€“9.

    CASĀ  PubMedĀ  Google ScholarĀ 

  34. Lee SY, Park KH, Jeong EH, Oh KJ, Ryu A, Kim A. Intra-amniotic infection/inflammation as a risk factor for subsequent ruptured membranes after clinically indicated amniocentesis in preterm labor. J Korean Med Sci. 2013;28:1226ā€“32.

    CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  35. Hartnett ME. Pathophysiology and mechanisms of severe retinopathy of prematurity. Ophthalmology 2015;122:200ā€“10.

    PubMedĀ  Google ScholarĀ 

  36. Woo SJ, Park KH, Lee SY, Ahn SJ, Ahn J, Park KH, et al. The relationship between cord blood cytokine levels and perinatal factors and retinopathy of prematurity: a gestational age-matched case-control study. Invest Ophthalmol Vis Sci. 2013;54:3434ā€“9.

    PubMedĀ  Google ScholarĀ 

  37. Ryu A, Park KH, Oh KJ, Lee SY, Jeong EH, Park JW. Predictive value of combined cervicovaginal cytokines and gestational age at sampling for intra-amniotic infection in preterm premature rupture of membranes. Acta Obstet Gynecol Scand. 2013;92:517ā€“24.

    PubMedĀ  Google ScholarĀ 

  38. Park KH, Cho YK, Lee CM, Choi H, Kim BR, Lee HK. Effect of preeclampsia, magnesium sulfate prophylaxis, and maternal weight on labor induction: a retrospective analysis. Gynecol Obstet Invest. 2006;61:40ā€“44.

    CASĀ  PubMedĀ  Google ScholarĀ 

  39. Gibbs RS, Blanco JD, St Clair PJ, Castaneda YS. Quantitative bacteriology of amniotic fluid from women with clinical intraamniotic infection at term. J Infect Dis. 1982;145:1ā€“8.

    CASĀ  PubMedĀ  Google ScholarĀ 

  40. Park KH, Kim SN, Oh KJ, Lee SY, Jeong EH, Ryu A. Noninvasive prediction of intra-amniotic infection and/or inflammation in preterm premature rupture of membranes. Reprod Sci. 2012;19:658ā€“65.

    CASĀ  PubMedĀ  Google ScholarĀ 

  41. Howards PP. An overview of confounding. Part 2: how to identify it and special situations. Acta Obstet Gynecol Scand. 2018;97:400ā€“6.

    PubMedĀ  Google ScholarĀ 

  42. DeLong ER, DeLong DM, Clarke-Pearson DL. Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach. Biometrics 1988;44:837ā€“45.

    CASĀ  PubMedĀ  Google ScholarĀ 

  43. Wright SD, Ramos RA, Tobias PS, Ulevitch RJ, Mathison JC. CD14, a receptor for complexes of lipopolysaccharide (LPS) and LPS binding protein. Science. 1990;249:1431ā€“3.

    CASĀ  PubMedĀ  Google ScholarĀ 

  44. Muta T, Takeshige K. Essential roles of CD14 and lipopolysaccharide-binding protein for activation of toll-like receptor (TLR)2 as well as TLR4 Reconstitution of TLR2- and TLR4-activation by distinguishable ligands in LPS preparations. Eur J Biochem. 2001;268:4580ā€“9.

    CASĀ  PubMedĀ  Google ScholarĀ 

  45. HernĆ”ndez C, Ortega F, GarcĆ­a-RamĆ­rez M, Villarroel M, Casado J, GarcĆ­a-Pascual L, et al. Lipopolysaccharide-binding protein and soluble CD14 in the vitreous fluid of patients with proliferative diabetic retinopathy. Retina 2010;30:345ā€“52.

    PubMedĀ  Google ScholarĀ 

  46. Chen FC, Sarioglu N, Buscher U, Dudenhausen JW. Lipopolysaccharide binding protein in the early diagnosis of intraamniotic infection of pregnant women with premature rupture of the membranes. J Perinat Med. 2009;37:135ā€“9.

    PubMedĀ  Google ScholarĀ 

  47. Hong S, Park KH, Kim YM, Lee YE, Park Y, Lee JE. A protein microarray analysis of plasma proteins for the prediction of spontaneous preterm delivery in women with preterm labor. Reprod Sci. 2020;27:1187ā€“96.

    CASĀ  PubMedĀ  Google ScholarĀ 

  48. Sorokin Y, Romero R, Mele L, Wapner RJ, Iams JD, Dudley DJ, et al. Maternal serum interleukin-6, C-reactive protein, and matrix metalloproteinase-9 concentrations as risk factors for preterm birth <32 weeks and adverse neonatal outcomes. Am J Perinatol. 2010;27:631ā€“40.

    PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  49. Pfeiffer KA, Reinsberg J, Rahmun A, Schmolling J, Krebs D. Clinical application of maternal serum cytokine determination in premature rupture of membranesā€”interleukin-6, an early predictor of neonatal infection? Acta Obstet Gynecol Scand. 1999;78:774ā€“8.

    CASĀ  PubMedĀ  Google ScholarĀ 

  50. Jones KL, Croen LA, Yoshida CK, Heuer L, Hansen R, Zerbo O, et al. Autism with intellectual disability is associated with increased levels of maternal cytokines and chemokines during gestation. Mol Psychiatry. 2017;22:273ā€“9.

    CASĀ  PubMedĀ  Google ScholarĀ 

  51. Tanaka T, Narazaki M, Kishimoto T. IL-6 in inflammation, immunity, and disease. Cold Spring Harb Perspect Biol. 2014;6:a016295.

    PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  52. Park H, Park KH, Kim YM, Kook SY, Jeon SJ, Yoo HN. Plasma inflammatory and immune proteins as predictors of intra-amniotic infection and spontaneous preterm delivery in women with preterm labor: a retrospective study. BMC Pregnancy Childbirth 2018;18:146.

    PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  53. Mitra S, Aune D, Speer CP, Saugstad OD. Chorioamnionitis as a risk factor for retinopathy of prematurity: a systematic review and meta-analysis. Neonatology 2014;105:189ā€“99.

    PubMedĀ  Google ScholarĀ 

  54. Villamor-Martinez E, Cavallaro G, Raffaeli G, Mohammed Rahim OMM, Gulden S, Ghazi AMT, et al. Chorioamnionitis as a risk factor for retinopathy of prematurity: An updated systematic review and meta-analysis. PLoS One. 2018;13:e0205838.

    PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  55. Romero R, Dey S, Fisher S. Preterm labor: one syndrome, many causes. Science 2014;345:760ā€“5.

    CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  56. Sproston NR, Ashworth JJ. Role of C-reactive protein at sites of inflammation and infection. Front Immunol. 2018;9:754.

    PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  57. Berczi I. Neurohormonal host defense in endotoxin shock. Ann N Y Acad Sci. 1998;840:787ā€“802.

    CASĀ  PubMedĀ  Google ScholarĀ 

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Funding

This research was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (No. 2020R1F1A1048362). The funders had no role in the design of this study, data collection, data analyses, data interpretation, or in the writing of this manuscript.

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JSS: protocol/project development, data analysis, manuscript writing/editing. SJW: protocol/project development, data analysis, manuscript writing/editing. KHP: conceptualization, protocol/project development, supervision, funding acquisition, data analysis, manuscript writing/editing. HK: data collection or management, data analysis, manuscript editing. KNL: data collection or management, data analysis. YMK: data collection or management, data analysis, ELISA assay.

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Correspondence to Kyo Hoon Park.

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Song, J.S., Woo, S.J., Park, K.H. et al. Association of inflammatory and angiogenic biomarkers in maternal plasma with retinopathy of prematurity in preterm infants. Eye 37, 1802ā€“1809 (2023). https://doi.org/10.1038/s41433-022-02234-9

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