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Hyperbilirubinemia and retinopathy of prematurity: a retrospective cohort study

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Abstract

Retinopathy of prematurity (ROP) is a vasoproliferative retinal disease in preterm infants. Oxidative stress plays a key role in the pathogenesis of ROP. Due to its antioxidant effects, bilirubin has been proposed to be protective against ROP. This study explored the association between hyperbilirubinemia and ROP. We analyzed a 10-year cohort from a neonatal intensive care unit in Milan, Italy, including 1606 infants born under 32 weeks and/or < 1500 g. Data from 1606 infants meeting specific inclusion criteria were reviewed. Eighty infants were excluded due to lack of data, 1526 were deemed eligible for analysis, and 1269 had hyperbilirubinemia requiring phototherapy. There was a higher incidence of ROP among infants with hyperbilirubinemia (13.8%) versus those without (7.8%, p<0.01). Infants with any ROP, non-severe or severe ROP, were exposed to hyperbilirubinemia for a significantly higher number of days compared with those without ROP. Each additional day of exposure increases the risk of develo** any ROP by 5%, non-severe ROP by 4%, and severe ROP by 6%. However, this correlation was not observed in infants with gestational age less than 27 weeks and/or body weight less than 1000 g.

    Conclusion: Our data show that hyperbilirubinemia requiring phototherapy is associated with an increased risk of develo** ROP. However, severe hyperbilirubinemia and ROP share many of their risk factors. Therefore, rather than being a risk factor itself, hyperbilirubinemia may be a surrogate for other risk factors for ROP.

    Clinical Trial Registration: NCT05806684.

What is Known:

• The development of retinopathy of prematurity (ROP) is influenced by several critical risk factors, including low gestational age, low birth weight, supplemental oxygen use, and increased oxidative stress.

• In vitro, unconjugated bilirubin is an effective scavenger of harmful oxygen species and a reducing agent, highlighting its potential protective role against oxidative stress.

What is New:

• Hyperbilirubinemia requiring phototherapy was associated with an increased risk of develo** ROP, but this association was not observed in the most vulnerable population of extremely preterm infants.

• Every additional day of phototherapy for hyperbilirubinemia increases the risk of ROP by 5% for any ROP, 4% for non-severe ROP, and 6% for severe ROP.

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Data availability

https://classic.clinicaltrials.gov/ct2/show/NCT05806684.

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Funding

This study was (partially) funded by the Italian Ministry of Health—Current Research IRCCS.

Author information

Author notes

  1. Silvia Gulden and Gaia Cervellini contributed equally to this work.

  2. Eduardo Villamor and Giacomo Cavallaro contributed equally to this work.

Authors and Affiliations

  1. Neonatal Intensive Care Unit, Sant’Anna Hospital, 22042, Como, Italy

    Silvia Gulden & Marta Colombo

  2. Neonatal Intensive Care Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122, Milan, Italy

    Gaia Cervellini, Maria Beatrice Marangoni, Vittoria Taccani, Nicola Pesenti, Genny Raffaeli, Gabriella Araimo, Monica Fumagalli & Giacomo Cavallaro

  3. Department of Clinical Sciences and Community Health, Università degli Studi di Milano, 20122, Milan, Italy

    Gaia Cervellini, Maria Beatrice Marangoni, Vittoria Taccani, Genny Raffaeli & Monica Fumagalli

  4. Revelo Datalabs S.R.L, 20142, Milan, Italy

    Nicola Pesenti

  5. Neonatal Intensive Care Unit, Clínica Universidad de Navarra, 28027, Madrid, Spain

    Felipe Garrido

  6. Department of Ophthalmology, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, 20122, Milan, Italy

    Silvia Osnaghi

  7. Division of Neonatology, MosaKids Children’s Hospital, Maastricht University Medical Center (MUMC+), Research Institute for Oncology and Reproduction (GROW), Maastricht University, 6202AZ, Maastricht, The Netherlands

    Eduardo Villamor

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Contributions

S.G., G.R., M.B.M., G.A., M.F., F.G., S.O., E.V., and G.C. (Giacomo Cavallaro) contributed to the study’s conception and design; S.G., G.R., G.C. (Gaia Cervellini), M.C., V.T., F.G., E.V., and G.C. (Giacomo Cavallaro) contributed to the study’s methodology, investigation, and data curation; S.G., G.C. (Gaia Cervellini), M.C., V.T., M.B.M., and S.O. contributed to data collection; N.P. performed the statistical analysis; S.G., G.C. (Gaia Cervellini), G.R., M.B.M., and G.C. (Giacomo Cavallaro) wrote the initial draft preparation of the manuscript; S.G., G.R., G.C. (Gaia Cervellini), M.B.M., G.A., F.G., E.V., and G.C. (Giacomo Cavallaro) wrote, reviewed, and edited the manuscript; The co-first S.G. and G.C. (Gaia Cervellini), and co-last E.V. and G.C. (Giacomo Cavallaro) authorship contributed equally and have the right to list their name as first or last in their Curriculum Vitae. E.V. and G.C. (Giacomo Cavallaro) contributed equally to the visualization of the manuscript; G.C. (Giacomo Cavallaro) contributed to the supervision and project administration of the study. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Genny Raffaeli.

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Communicated by Daniele De Luca

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Gulden, S., Cervellini, G., Colombo, M. et al. Hyperbilirubinemia and retinopathy of prematurity: a retrospective cohort study. Eur J Pediatr (2024). https://doi.org/10.1007/s00431-024-05630-3

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