174 Chapter 8 Pasteurizationmayplaya role in theeffect of donor humanmilkonhealthoutcomes. Essential factors such as IGF-I and micronutrients are significantly reduced during pasteurization. (18) In a meta-analysis Villamore et al. found that pasteurization increased the risk of bronchopulmonary dysplasia. This would be in line with the negative association between donor human milk use and the occurrence of bronchopulmonary dysplasia we described in our study population in chapter 3. However, in our study population the proportion of donor human milk used was relatively small and infants were fed own mother’s milk for the majority. Therefore we cannot draw definitive conclusions from our findings. In fact, in another metaanalysis by Miller and colleagues the use of unpasteurised human milk was not found to reduce morbidity when compared to pasteurised human milk. (19) Based on these inconclusive results further investigation of the pasteurization process of donor human milk may be warranted, as optimizing of this process may increase the beneficial effect of donor human milk. The developing endocrine axis in relation to comorbidities in preterm infants Major comorbidities in preterm infants, such as sepsis, necrotizing enterocolitis, retinopathy of prematurity and bronchopulmonary dysplasia, are associated with low IGF-I levels.(20) Though causality could not be confirmed due to the observational design of our study, indeed in our study population the odds of BPD decreased with higher IGF-I levels. (Chapter 3) Moreover, thesemajor comorbidities are associated with a pro-inflammatory state. Indeed, higher levels of proinflammatory proteins such as IL-6 and CRP, have been associated with lower IGF-I levels in preterm infants. (21, 22) Speculating, this suggests that either low IGF-I elicits a pro-inflammatory state or a pro-inflammatory state suppresses IGF-I. In vitro studies showed that IGF-I can prevent apoptosis induced by TNF-alpha by triggering the signalling pathway that activates the XIAP protein which inhibits apoptosis. (23) Moreover, in mice, the administration of IGF-I before the inoculation with Pseudomonas aeruginosa, improved bacterial clearance and reduced death from severe sepsis. (23) These findings suggest that a lack of IGF-I results in less inhibition of inflammation and thus elicits a pro-inflammatory state. On the other hand, it could very well be that a pro-inflammatory state suppresses IGF-I. In the case of inflammation energy stores may be redirected to ward off pathogens while anabolic processes involving IGF-I, are suppressed. In line with that it has been hypothesized in previous studies that parenteral nutrition leads to lower IGF-I levels through the enhancement of an inflammatory state. (24) Nevertheless, certain microRNA’s, small non-coding RNA’s which regulate gene expression, have been found to be associated with the occurrence of inflammatory conditions in children and the down-regulation of the IGF-I receptor. (25) Hypothesizing this could imply that there is a common factor causing both inflammation and low IGF-I levels and subsequent impaired growth.
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