Is there a causal relationship between the receipt of blood transfusions and the development of chronic lung disease of prematurity?

The number and total volume of blood transfusions received by premature babies is, after gestational age and birth weight a good predictor of the likelihood of developing chronic lung disease of prematurity (CLD) and retinopathy of prematurity (ROP). Oxidative damage, inflammation and pulmonary infections are also strongly associated with the development of CLD. It is currently not clear whether there is a causal relationship between the receipt of blood transfusions and oxidative damage, infection, inflammation and CLD in these babies. Strong arguments may be made both for and against a causal relationship. The babies who receive blood transfusions are usually smaller than those who do not, and are ventilated, often with high oxygen levels, for a longer period of time. The longer the baby is on a ventilator the more likely it is to develop pulmonary infection and inflammation. All these factors will promote free radical production and oxidative damage irrespective of the receipt of blood transfusion. This would argue against a causal relationship. On the other hand, an argument may be presented which is based on iron promoted free radical generation, infection and fibrosis consequent to the breakdown of haeme released from transfused erythrocytes. Haeme is broken down by haeme oxygenase (HO) to iron, CO and bilirubin. Under normal circumstances the products of HO activity are beneficial to the organism, but when HO activity is excessive, the products are potentially damaging. Free iron, (in the Fe2+ form) if not sequestered with protein or urate, will generate highly toxic free radicals via the Fenton and Heber-Wiess reactions, predispose the tissue to infection and promote fibrosis. The iron chelating ability of the premature baby appears to be limited so that it would be difficult to deal with any increase in free iron production. Free iron will in turn induce HO activity leading to a potentially serious positive feedback process. The lung is particularly sensitive to iron induced HO activity. In addition, HO activity may be enhanced by other events occurring in the premature lung such as the production of proinflammatory cytokines and the reduced level of glutathione. Thus, the possibility of a causal relationship clearly exists and needs to be examined. This can be attempted by measuring the products of HO activity in relation to the receipt of blood transfusions.