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Prenatal and postnatal inflammation-related risk factors for retinopathy of prematurity

Journal of Perinatology volume 39, pages 964–973 (2019)Cite this article

Subjects

Abstract

Objective

To evaluate the relationship between prenatal and postnatal inflammation-related risk factors and severe retinopathy of prematurity (ROP).

Study design

The study included infants born <30 weeks in California from 2007 to 2011. Multivariable log-binomial regression was used to assess the association between prenatal and postnatal inflammation-related exposures and severe ROP, defined as stage 3–5 or surgery for ROP.

Results

Of 14,816 infants, 10.8% developed severe ROP. Though prenatal inflammation-related risk factors were initially associated with severe ROP, after accounting for the effect of these risk factors on gestational age at birth through mediation analysis, the association was non-significant (P = 0.6). Postnatal factors associated with severe ROP included prolonged oxygen exposure, sepsis, intraventricular hemorrhage, and necrotizing enterocolitis.

Conclusion

Postnatal inflammation-related factors were associated with severe ROP more strongly than prenatal factors. The association between prenatal inflammation-related factors and ROP was explained by earlier gestational age in infants exposed to prenatal inflammation.

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References

  1. Horbar JD, Edwards EM, Greenberg LT, Morrow KA, Soll RF, Buus-Frank ME, et al. Variation in performance of neonatal Intensive care units in the United States. JAMA Pediatr. 2017;171:e164396.

    Article  Google Scholar 

  2. Early Treatment for Retinopathy of Prematurity Cooperative Group, 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;128:663–71.

    Article  Google Scholar 

  3. Chen J, Smith LEH. Retinopathy of prematurity. Angiogenesis. 2007;10:133–40.

    Article  Google Scholar 

  4. Lee J, Dammann O. Perinatal infection, inflammation, and retinopathy of prematurity. Semin Fetal Neonatal Med. 2012;17:26–9.

    Article  Google Scholar 

  5. Hartnett ME, Penn JS. Mechanisms and management of retinopathy of prematurity. N Engl J Med. 2012;367:2515–26.

    Article  CAS  Google Scholar 

  6. 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 Neuroinflamm. 2017;14:165.

    Article  Google Scholar 

  7. 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;1989:e12986.

    Article  Google Scholar 

  8. Beaudry-Richard A, Nadeau-Vallée M, Prairie É, Maurice N, Heckel É, Nezhady M, et al. Antenatal IL-1-dependent inflammation persists postnatally and causes retinal and sub-retinal vasculopathy in progeny. Sci Rep. 2018;8:11875.

    Article  Google Scholar 

  9. Szade A, Grochot-Przeczek A, Florczyk U, Jozkowicz A, Dulak J. Cellular and molecular mechanisms of inflammation-induced angiogenesis. IUBMB Life. 2015;67:145–59.

    Article  CAS  Google Scholar 

  10. Yu H, Yuan L, Zou Y, Peng L, Wang Y, Li T, et al. Serum concentrations of cytokines in infants with retinopathy of prematurity. APMIS Acta Pathol Microbiol Immunol Scand. 2014;122:818–23.

    Article  CAS  Google Scholar 

  11. Gardiner TA, Gibson DS, de Gooyer TE, de la Cruz VF, McDonald DM, Stitt AW. Inhibition of tumor necrosis factor-alpha improves physiological angiogenesis and reduces pathological neovascularization in ischemic retinopathy. Am J Pathol. 2005;166:637–44.

    Article  CAS  Google Scholar 

  12. Hong HK, Lee HJ, Ko JH, Park JH, Park JY, Choi CW, et al. Neonatal systemic inflammation in rats alters retinal vessel development and simulates pathologic features of retinopathy of prematurity. J Neuroinflamm. 2014;11:87.

    Article  Google Scholar 

  13. Tremblay S, Miloudi K, Chaychi S, Favret S, Binet F, Polosa A, et al. Systemic inflammation perturbs developmental retinal angiogenesis and neuroretinal function. Invest Ophthalmol Vis Sci. 2013;54:8125–39.

    Article  CAS  Google Scholar 

  14. Thomas W, Speer CP. Chorioamnionitis: important risk factor or innocent bystander for neonatal outcome? Neonatology. 2011;99:177–87.

    Article  Google Scholar 

  15. Combs CA, Gravett M, Garite TJ, Hickok DE, Lapidus J, Porreco R, et al. Amniotic fluid infection, inflammation, and colonization in preterm labor with intact membranes. Am J Obstet Gynecol. 2014;210:125.e1–15.

    Article  Google Scholar 

  16. Yoon BH, Romero R, Park JS, Kim CJ, Kim SH, Choi JH, et al. Fetal exposure to an intra-amniotic inflammation and the development of cerebral palsy at the age of three years. Am J Obstet Gynecol. 2000;182:675–81.

    Article  CAS  Google Scholar 

  17. Nelson KB, Dambrosia JM, Grether JK, Phillips TM. Neonatal cytokines and coagulation factors in children with cerebral palsy. Ann Neurol. 1998;44:665–75.

    Article  CAS  Google Scholar 

  18. Fortes Filho JB, Costa MC, Eckert GU, Santos PGB, Silveira RC, Procianoy RS. Maternal preeclampsia protects preterm infants against severe retinopathy of prematurity. J Pediatr. 2011;158:372–6.

    Article  Google Scholar 

  19. Hendson L, Russell L, Robertson CMT, Liang Y, Chen Y, Abdalla A, et al. Neonatal and neurodevelopmental outcomes of very low birth weight infants with histologic chorioamnionitis. J Pediatr. 2011;158:397–402.

    Article  Google Scholar 

  20. 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;105:189–99.

    Article  Google Scholar 

  21. Kim SJ, Port AD, Swan R, Campbell JP, Chan RVP, Chiang MF. Retinopathy of prematurity: a review of risk factors and their clinical significance. Surv Ophthalmol. 2018;63:618–37.

    Article  Google Scholar 

  22. Slidsborg C, Jensen A, Forman JL, Rasmussen S, Bangsgaard R, Fledelius HC, et al. Neonatal risk factors for treatment-Demandingretinopathy of prematurity: a Danish National Study. Ophthalmology. 2016;123:796–803.

    Article  Google Scholar 

  23. 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;123:804–16.

    Article  Google Scholar 

  24. California Perinatal Quality Care Collaborative |. Available at: https://www.cpqcc.org/.

  25. Vermont Oxford Network – Improving care for infants and their families. Available at: https://public.vtoxford.org/.

  26. Fierson WM, American Academy of Pediatric Section on Ophthalmology, American Academy of Ophthalmology, American Association for Pediatric Ophthalmology and Strabismus, American Association of Certified Orthoptists. Screening Examination of Premature Infants for Retinopathy of Prematurity. Pediatrics. 2013; 131:189–95.

  27. Segovia SA, Vickers MH, Reynolds CM. The impact of maternal obesity on inflammatory processes and consequences for later offspring health outcomes. J Dev Orig Health Dis. 2017;8:529–40.

    Article  CAS  Google Scholar 

  28. Kim SM, Romero R, Park JW, Oh KJ, Jun JK, Yoon BH. The relationship between the intensity of intra-amniotic inflammation and the presence and severity of acute histologic chorioamnionitis in preterm gestation. J Matern Fetal Neonatal Med. 2015;28:1500–9.

    Article  Google Scholar 

  29. Boisen AB, Knorr S, Hansen TK, Vlachova Z, Bytoft B, Damm P, et al. Signs of low-grade systemic inflammation in female offspring of women with type 1 diabetes: the EPICOM study. Diabetes Metab. 2016;42:462–5.

    Article  CAS  Google Scholar 

  30. Sharma K, Singh R, Kumar M, Gupta U, Rohil V, Bhattacharjee J. First-trimester inflammatory markers for risk evaluation of pregnancy hypertension. J Obstet Gynaecol India. 2018;68:27–32.

    Article  CAS  Google Scholar 

  31. Kalagiri RR, Carder T, Choudhury S, Vora N, Ballard AR, Govande V, et al. Inflammation in complicated pregnancy and its outcome. Am J Perinatol. 2016;33:1337–56.

    Article  Google Scholar 

  32. Musilova I, Andrys C, Drahosova M, Soucek O, Stepan M, Bestvina T, et al. Intraamniotic inflammation and umbilical cord blood interleukin-6 concentrations in pregnancies complicated by preterm prelabor rupture of membranes. J Matern Fetal Neonatal Med. 2017;30:900–10.

    Article  CAS  Google Scholar 

  33. Cardenas I, Means RE, Aldo P, Koga K, Lang SM, Booth CJ, et al. Viral infection of the placenta leads to fetal inflammation and sensitization to bacterial products predisposing to preterm labor. J Immunol. 2010;185:1248–57.

    Article  CAS  Google Scholar 

  34. WHO:: Global Database on Body Mass Index. Available at: http://apps.who.int/bmi/index.jsp?introPage=intro_3.html.

  35. Kennedy KA, Wrage LA, Higgins RD, Finer NN, Carlo WA, Walsh MC, et al. Evaluating retinopathy of prematurity screening guidelines for 24- to 27-week gestational age infants. J Perinatol. 2014;34:311–8.

    Article  CAS  Google Scholar 

  36. Al-Abdi SY, Al-Aamri MA. A systematic review and meta-analysis of the timing of early intraventricular hemorrhage in preterm neonates: clinical and research implications. J Clin Neonatol. 2014;3:76–88.

    Article  Google Scholar 

  37. Yee WH, Soraisham AS, Shah VS, Aziz K, Yoon W, Lee SK, et al. Incidence and timing of presentation of necrotizing enterocolitis in preterm infants. Pediatrics. 2012;129:e298–304.

    Article  Google Scholar 

  38. Lange T, Vansteelandt S, Bekaert M. A simple unified approach for estimating natural direct and indirect effects. Am J Epidemiol. 2012;176:190–5.

    Article  Google Scholar 

  39. Vanderweele TJ. Explanation in causal inference: methods for mediation and interaction. New York, NY, US: Oxford University Press; 2015.

    Google Scholar 

  40. R: The R Project for Statistical Computing. Available at: https://www.r-project.org/.

  41. 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.

    Article  Google Scholar 

  42. Wilcox AJ, Weinberg CR, Basso O. On the pitfalls of adjusting for gestational age at birth. Am J Epidemiol. 2011;174:1062–8.

    Article  Google Scholar 

  43. York JR, Landers S, Kirby RS, Arbogast PG, Penn JS. Arterial oxygen fluctuation and retinopathy of prematurity in very-low-birth-weight infants. J Perinatol. 2004;24:82–7.

    Article  Google Scholar 

  44. Wu C, Löfqvist C, Smith LEH, VanderVeen DK, Hellström A.WINROP Consortium Importance of early postnatal weight gain for normal retinal angiogenesis in very preterm infants: a multicenter study analyzing weight velocity deviations for the prediction of retinopathy of prematurity. Arch Ophthalmol. 2012;130:992–9.

    Article  Google Scholar 

Download references

Acknowledgements

G.P.G. is supported in part by the Stanford Maternal & Child Health Research Institute. S.A.L. is supported in part by postdoctoral fellowship F32HD091945 from the Eunice Kennedy Shriver National Institute of Child Health and Development and a postdoctoral fellowship from the Stanford Maternal & Child Health Research Institute.

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Authors and Affiliations

  1. Division of Neonatal and Developmental Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA

    Gregory P. Goldstein, Stephanie A. Leonard, Peiyi Kan, Henry C. Lee & Suzan L. Carmichael

  2. Center for Population Health Sciences, Stanford University School of Medicine, Stanford, CA, USA

    Stephanie A. Leonard & Suzan L. Carmichael

  3. Division of Pediatric Ophthalmology, Department of Ophthalmology, Stanford University School of Medicine, Stanford, CA, USA

    Euna B. Koo

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  1. Gregory P. Goldstein
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All authors contributed substantially to the study and approved the final version.

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Correspondence to Gregory P. Goldstein.

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Goldstein, G.P., Leonard, S.A., Kan, P. et al. Prenatal and postnatal inflammation-related risk factors for retinopathy of prematurity. J Perinatol 39, 964–973 (2019). https://doi.org/10.1038/s41372-019-0357-2

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