Iron and Retinopathy of Prematurity (ROP)

Overview

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.

Full Title of Study: “Iron, Transferrin and Retinopathy of Prematurity (ROP): Towards New Pathophysiological Mechanisms.”

Study Type

  • Study Type: Observational
  • Study Design
    • Time Perspective: Prospective
  • Study Primary Completion Date: May 2024

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.

Interventions

  • 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.

Arms, Groups and Cohorts

  • Preterm infants
    • infants born at <31 week’s post-menstrual age (PMA) or ≤1250g of birth weight

Clinical Trial Outcome Measures

Primary Measures

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

Secondary Measures

  • Levels of iron
    • Time Frame: at birth, 2, 3, and 4 weeks of life
    • Blood dosage, in µmol/l
  • Levels of transferrin
    • Time Frame: at birth, 2, 3, and 4 weeks of life
    • Blood dosage, in g/l
  • Levels of ferritin
    • Time Frame: at birth, 2, 3, and 4 weeks of life
    • Blood dosage, in µg/l
  • ROP’s highest stage
    • Time Frame: during follow-up about 5 months, up to 45 weeks’ PMA
    • according to International Classification of Retinopathy of Prematury (ICROP3 classification)
  • Need of treatment for ROP
    • Time Frame: during follow-up about 5 months, up to 45 weeks’ PMA
    • Laser, anti-VEGF injections, surgery
  • Number of each intervention
    • Time Frame: during follow-up about 5 months, up to 45 weeks’ PMA
    • Number of each intervention if a treatment was needed
  • Death or presence of severe co-morbidities in preterm infant
    • Time Frame: At 36 weeks’ PMA
    • 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).

Participating in This Clinical Trial

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.

Gender Eligibility: All

Minimum Age: 24 Weeks

Maximum Age: 31 Weeks

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Assistance Publique – Hôpitaux de Paris
  • Collaborator
    • Fondation VISIO
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Alejandra DARUICH, MD, PhD, Principal Investigator, Assistance Publique – Hôpitaux de Paris
    • Elsa KERMOVANT, MD, PhD, Study Chair, Assistance Publique – Hôpitaux de Paris
  • Overall Contact(s)
    • Alejandra DARUICH, MD, PhD, +33-(0)1-44-38-19-69, alejandra.daruich-matet@aphp.fr

References

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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.

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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.

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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.

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.

Hellström A, Engström E, Hård AL, Albertsson-Wikland K, Carlsson B, Niklasson A, Löfqvist C, Svensson E, Holm S, Ewald U, Holmström 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.

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.

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