Iron and Retinopathy of Prematurity (ROP)

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Retinopathy of Prematurity

Intervention / Treatment
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* Biological: Plasma determination of iron, transferrin and ferritin
* Other: Fundus Examination by wide field digital imaging camera (PanocamTM camera)


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 24 Weeks
Maximum Age: 31 Weeks

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

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

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ROP, retinopathy, prematurity, Iron and transferrin, Preterm infants