Iron and Retinopathy of Prematurity (ROP)

Retinopathy of Prematurity Clinical Trial

— Fer-ROP  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05133999
• Other study ID #: APHP211233
• Secondary ID: 2021-A02182
• Status: Recruiting
• Start date: April 28, 2022
• Est. completion date: September 2025

Study information

• Verified date: April 2024
• Source: Assistance Publique - Hôpitaux de Paris
• Contact: Alejandra DARUICH, MD, PhD
• Phone: +33-(0)1-44-38-19-69
• Email: alejandra.daruich-matet[@]aphp.fr
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 175
• Est. completion date: September 2025
• Est. primary completion date: September 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 24 Weeks to 31 Weeks

Eligibility

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.

Related Conditions & MeSH terms

• Premature Birth
• Retinal Diseases
• Retinopathy of Prematurity

Intervention

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.

Locations

Country	Name	City	State
France	Ophtalmology department _ Necker Enfants Malades Hospital	Paris
France	Pediatrics and neonatal intensive care department - Cochin hospital - Port Royal Maternity	Paris
France	Pediatrics and noenatal intensive care department - Necker-Enfants Malades Hospital	Paris

Sponsors (3)

Lead Sponsor	Collaborator
Assistance Publique - Hôpitaux de Paris	Fondation Université de Paris, Fondation VISIO

Country where clinical trial is conducted

France, 

References & Publications (12)

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

* Note: There are 12 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)].
Primary	Levels of transferrin saturation in plasma at 1 week of life	Blood dosage	at 1 week of life
Secondary	Levels of iron	Blood dosage, in µmol/l	at birth, 2, 3, and 4 weeks of life
Secondary	Levels of transferrin	Blood dosage, in g/l	at birth, 2, 3, and 4 weeks of life
Secondary	Levels of ferritin	Blood dosage, in µg/l	at birth, 2, 3, and 4 weeks of life
Secondary	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
Secondary	Need of treatment for ROP	Laser, anti-VEGF injections, surgery	during follow-up about 5 months, up to 45 weeks' PMA
Secondary	Number of each intervention	Number of each intervention if a treatment was needed	during follow-up about 5 months, up to 45 weeks' PMA
Secondary	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