84 Chapter 4 to lower IGF-1 levels. Indeed, a pro-inflammatory state in preterm infants has been associated with decreased IGF-1 levels (24). It has also been demonstrated that colostrum and maternal milk contain high concentrations of anti-inflammatory cytokines (25). These anti-inflammatory cytokines could potentially lower the relatively pro-inflammatory state in the immature gut and consequentially increase IGF-1 levels. In one study, preterm infants who received own mother’s milk from birth were shown to have higher levels of IGF-1 at term equivalent age compared to those who were formula fed from birth (26). Moreover, animal studies found that in a state of inflammation or nutrient deprivation, parenteral feeding was associated with lower IGF-1 levels compared to enteral feeding. This appears to be due to a decrease in pro-inflammatory cytokines after enteral feeding (9, 10). This leads us to believe that the neutralizing effect of anti-inflammatory cytokines, which are particularly abundant in colostrum and breast milk, is diminished and results in lower IGF-1 levels when parenteral nutrition is increased. It could also be suggested that infants who received relatively higher proportions of parenteral nutrition were the more vulnerable, smaller, younger, and iller infants, and thus the association with lower IGF-1 levels. However, after correcting for gestational age, weight, and comorbidities, parenteral nutrition remained a significant predictor of IGF-1 levels. Window of Effect of Nutrient Intake on IGF-1 Levels In our population, the influence of nutrition on IGF-1 levels seemed to be most apparent between 30 and 33 weeks PMA. Hypothesizing, preterm infants may have to reach a certain level of maturity before an impact of nutrition on the IGF-1 axis can be noted. In support of this, Smith and colleagues found that the magnitude of the rise in IGF-1 levels per gram protein increased with increasing gestational and postnatal age. Hansen-Pupp and colleagues also found nutrient intake not to influence IGF-1 levels at lower postmenstrual ages, but only from 32 weeks PMA onwards. Speculatively, other factors than maturity could influence when IGF-1 levels start to respond to nutrient intake. Of note, in our study, in a set of infants who were ill, a positive association between total protein intake and IGF-1 levels was already found at 28 weeks PMA. This was in contrast to the other macronutrients and total energy intake, which only showed positive associations with IGF-1 levels from 30 weeks PMA onwards. Among the set of infants of whom blood was sampled at 28 weeks, all but one had a recent history of sepsis and anemia requiring erythrocyte transfusion. It could be speculated that the state of inflammation triggered a higher sensibility of the IGF-1 axis to protein uptake. Despite their IGF-1 levels still being low, 1 g of protein might have triggered more increase in IGF-1 compared to infants who were not ill. It is noteworthy that in our population, no associations between nutrient intake and IGF-1 levels were found at 34 and 35 weeks PMA, in contrast to other studies
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