Iron and Retinopathy of Prematurity (ROP) (Fer-ROP)

Iron, Transferrin and Retinopathy of Prematurity (ROP): Towards New Pathophysiological Mechanisms.

The purpose of this study is to determine whether increased transferrin saturation in plasma (that reflects iron overload and/or low transferrin) is an independent risk factor for ROP development and severity.

Preterm infants born at <31 week's post-menstrual age (PMA) or ≤1250g of birth weight will be included. Iron parameters in plasma will be measured during the first month of life. Retinopathy of prematurity (ROP) will be screened as currently recommended. The relationship between plasma iron parameters and ROP development and/or severity will be established.

Study Overview

• Status: Recruiting
• Conditions: Retinopathy of Prematurity
• Intervention / Treatment: Biological: Plasma determination of iron, transferrin and ferritin; Other: Fundus Examination by wide field digital imaging camera (PanocamTM camera)

Detailed Description

The incidence of ROP, the main cause of vision impairment in children, is increasing parallel to the recent changes in practices targeting higher oxygen saturation in preterm babies in many countries following the publication of five trials that showed higher rates of death with lower oxygen saturations. The main risk factor for ROP development is oxygen excess. Oxygen contributes to the formation of reactive oxygen species and to lipid peroxidation which leads to vasoconstriction, vascular cytotoxicity, and arrest of vascular development causing ischemia of retinal neurons, thereby promoting the development of ROP.

90% of extremely low birth weight infants need red blood cell transfusions (RBCT) due to their immature erythropoiesis, frequent blood sampling and small circulating blood volume. RBCT are a major source of iron overload and ferritin plasma levels may remain elevated for several weeks after transfusions. It has been shown that blood transfusion is a risk factor of ROP in preterm infants. However, whether this relationship is mediated by an increased iron load remains controversial.

Only two studies, conducted before the 2000s, identified plasma iron overload as a risk factor for ROP. These studies with a limited number of patients, showed contradictory results, failing to draw a conclusion.

Excess iron worsens oxidative stress. Iron catalyzes the Fenton reaction which leads to the formation of reactive oxygen species. In addition a transferrin deficiency (the main iron chelator) has been suggested in premature infants. The oxidative stress observed in ROP could therefore be the consequence not only of oxygen therapy but also of iron overload.

The main objective of this study is to determine whether increased transferrin saturation in plasma (that reflects iron overload and/or low transferrin) is an independent risk factor for ROP development and severity.

The secondary aims/objectives are :

• Determine whether low transferrin level in plasma is an independent risk factor for ROP development and severity.
• Determine whether iron parameters imbalance in plasma are a risk factor for other comorbidities in Preterm infants i.e.:
• 1) sepsis
• 2) severe bronchopulmonary dysplasia
• 3) necrotizing enterocolitis (stage 2 or 3)
• 4) cystic periventricular leukomalacia
• 5) grade III or IV intraventricular haemorrhage

Study duration will be 29 months, with an inclusion period of 24 months and a last visit for ROP evaluation at 45 week's post-menstrual age (PMA).

A total of 175 patients should be included: 35 with ROP and 140 without ROP.

• Study Type: Observational
• Enrollment (Estimated): 175

Contacts and Locations

• Study Contact: Name: Alejandra DARUICH, MD, PhD; Phone Number: +33-(0)1-44-38-19-69; Email: alejandra.daruich-matet@aphp.fr
• Study Contact Backup: Name: Prissile BAKOUBOULA, PhD; Phone Number: +33-(0)1-71-19-64-94; Email: prissile.bakouboula@aphp.fr

Study Locations

• France
  • Paris, France, 75014
    • Recruiting
    • Pediatrics and neonatal intensive care department - Cochin hospital - Port Royal Maternity
    • Contact: Héloise TORCHIN, MD, PhD; Phone Number: +33 (0)1-58-41-36-07; Email: heloise.torchin@aphp.fr
    • Principal Investigator: Héloise TORCHIN, MD, PhD
  • Paris, France, 75015
    • Active, not recruiting
    • Ophtalmology department _ Necker Enfants Malades Hospital
  • Paris, France, 75015
    • Recruiting
    • Pediatrics and noenatal intensive care department - Necker-Enfants Malades Hospital
    • Contact: Elsa KERMOVANT, MD, PhD; Phone Number: 33-(0)1-71-69-65-43; Email: elsa.kermovant@aphp.fr
    • Principal Investigator: Elsa KERMOVANT, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 5 months to 7 months (Child)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Preterm infants born at <31 weeks' PMA or ≤1250 g of birth weight

Description

Inclusion Criteria:

• All infants born at <31 week's post-menstrual age (PMA) or ≤1250g of birthweight
• Admitted at two neonatology departments (level III) from birth
• With non-opposition consent of two parents

Exclusion Criteria:

• Congenital malformation
• Life-threatening condition (not expected to survive more than a few days)
• Absence of health care protection.

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Preterm infants; infants born at <31 week's post-menstrual age (PMA) or ≤1250g of birth weight	Biological: Plasma determination of iron, transferrin and ferritin; Iron, transferrin and ferritin levels in plasma; Other: Fundus Examination by wide field digital imaging camera (PanocamTM camera); ROP screening using wide field digital retinal imaging according to current recommendations.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
ROP screening	Presence of ROP development (any stage / any zone in at least one eye) during follow-up.	From 31 to 45 weeks' post menstrual age (PMA) [= (term + 4 weeks of life)].
Levels of transferrin saturation in plasma at 1 week of life	Blood dosage	at 1 week of life

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Levels of iron	Blood dosage, in µmol/l	at birth, 2, 3, and 4 weeks of life
Levels of transferrin	Blood dosage, in g/l	at birth, 2, 3, and 4 weeks of life
Levels of ferritin	Blood dosage, in µg/l	at birth, 2, 3, and 4 weeks of life
ROP's highest stage	according to International Classification of Retinopathy of Prematury (ICROP3 classification)	during follow-up about 5 months, up to 45 weeks' PMA
Need of treatment for ROP	Laser, anti-VEGF injections, surgery	during follow-up about 5 months, up to 45 weeks' PMA
Number of each intervention	Number of each intervention if a treatment was needed	during follow-up about 5 months, up to 45 weeks' PMA
Death or presence of severe co-morbidities in preterm infant	death or presence of monitoring : 1) severe bronchopulmonary dysplasia or 2) necrotizing enterocolitis (stage 2 or 3), or 3) cavitary periventricular leucomalacia or 4) intraventricular haemorrhage (grade III or IV).	At 36 weeks' PMA

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Collaborators: Fondation Université de Paris; Fondation VISIO
• Investigators: Principal Investigator: Alejandra DARUICH, MD, PhD, Assistance Publique - Hôpitaux de Paris; Study Chair: Elsa KERMOVANT, MD, PhD, Assistance Publique - Hôpitaux de Paris

Publications and helpful links

General Publications

• de Verdier K, Ulla E, Lofgren S, Fernell E. Children with blindness - major causes, developmental outcomes and implications for habilitation and educational support: a two-decade, Swedish population-based study. Acta Ophthalmol. 2018 May;96(3):295-300. doi: 10.1111/aos.13631. Epub 2017 Nov 23.
• Manley BJ, Kuschel CA, Elder JE, Doyle LW, Davis PG. Higher Rates of Retinopathy of Prematurity after Increasing Oxygen Saturation Targets for Very Preterm Infants: Experience in a Single Center. J Pediatr. 2016 Jan;168:242-244. doi: 10.1016/j.jpeds.2015.10.005. Epub 2015 Nov 6.
• BOOST II United Kingdom Collaborative Group; BOOST II Australia Collaborative Group; BOOST II New Zealand Collaborative Group; Stenson BJ, Tarnow-Mordi WO, Darlow BA, Simes J, Juszczak E, Askie L, Battin M, Bowler U, Broadbent R, Cairns P, Davis PG, Deshpande S, Donoghoe M, Doyle L, Fleck BW, Ghadge A, Hague W, Halliday HL, Hewson M, King A, Kirby A, Marlow N, Meyer M, Morley C, Simmer K, Tin W, Wardle SP, Brocklehurst P. Oxygen saturation and outcomes in preterm infants. N Engl J Med. 2013 May 30;368(22):2094-104. doi: 10.1056/NEJMoa1302298. Epub 2013 May 5.
• Sapieha P, Joyal JS, Rivera JC, Kermorvant-Duchemin E, Sennlaub F, Hardy P, Lachapelle P, Chemtob S. Retinopathy of prematurity: understanding ischemic retinal vasculopathies at an extreme of life. J Clin Invest. 2010 Sep;120(9):3022-32. doi: 10.1172/JCI42142. Epub 2010 Sep 1.
• Howarth C, Banerjee J, Aladangady N. Red Blood Cell Transfusion in Preterm Infants: Current Evidence and Controversies. Neonatology. 2018;114(1):7-16. doi: 10.1159/000486584. Epub 2018 Mar 16.
• Hesse L, Eberl W, Schlaud M, Poets CF. Blood transfusion. Iron load and retinopathy of prematurity. Eur J Pediatr. 1997 Jun;156(6):465-70. doi: 10.1007/s004310050641.
• Dani C, Reali MF, Bertini G, Martelli E, Pezzati M, Rubaltelli FF. The role of blood transfusions and iron intake on retinopathy of prematurity. Early Hum Dev. 2001 Apr;62(1):57-63. doi: 10.1016/s0378-3782(01)00115-3.
• Inder TE, Clemett RS, Austin NC, Graham P, Darlow BA. High iron status in very low birth weight infants is associated with an increased risk of retinopathy of prematurity. J Pediatr. 1997 Oct;131(4):541-4. doi: 10.1016/s0022-3476(97)70058-1.
• Hirano K, Morinobu T, Kim H, Hiroi M, Ban R, Ogawa S, Ogihara H, Tamai H, Ogihara T. Blood transfusion increases radical promoting non-transferrin bound iron in preterm infants. Arch Dis Child Fetal Neonatal Ed. 2001 May;84(3):F188-93. doi: 10.1136/fn.84.3.f188.
• Daruich A, Le Rouzic Q, Jonet L, Naud MC, Kowalczuk L, Pournaras JA, Boatright JH, Thomas A, Turck N, Moulin A, Behar-Cohen F, Picard E. Iron is neurotoxic in retinal detachment and transferrin confers neuroprotection. Sci Adv. 2019 Jan 9;5(1):eaau9940. doi: 10.1126/sciadv.aau9940. eCollection 2019 Jan.
• Hellstrom A, Engstrom E, Hard AL, Albertsson-Wikland K, Carlsson B, Niklasson A, Lofqvist C, Svensson E, Holm S, Ewald U, Holmstrom G, Smith LE. Postnatal serum insulin-like growth factor I deficiency is associated with retinopathy of prematurity and other complications of premature birth. Pediatrics. 2003 Nov;112(5):1016-20. doi: 10.1542/peds.112.5.1016.
• Luo XQ, Zhang CY, Zhang JW, Jiang JB, Yin AH, Guo L, Nie C, Lu XZ, Deng H, Zhang L. Identification of Iron Homeostasis Genes Dysregulation Potentially Involved in Retinopathy of Prematurity Pathogenicity by Microarray Analysis. J Ophthalmol. 2015;2015:584854. doi: 10.1155/2015/584854. Epub 2015 Oct 18.

Study record dates

Study Major Dates

• Study Start (Actual): April 28, 2022
• Primary Completion (Estimated): September 1, 2025
• Study Completion (Estimated): September 1, 2025

Study Registration Dates

• First Submitted: November 2, 2021
• First Submitted That Met QC Criteria: November 16, 2021
• First Posted (Actual): November 24, 2021

Study Record Updates

• Last Update Posted (Estimated): April 15, 2024
• Last Update Submitted That Met QC Criteria: April 12, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: ROP; prematurity; retinopathy; Preterm infants; Iron and transferrin
• Additional Relevant MeSH Terms: Eye Diseases; Infant, Newborn, Diseases; Pregnancy Complications; Obstetric Labor Complications; Obstetric Labor, Premature; Infant, Premature, Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Retinal Diseases; Premature Birth; Retinopathy of Prematurity
• Other Study ID Numbers: APHP211233; 2021-A02182 (Other Identifier: ID-RCB)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No