Glucose-regulatory hormones and growth in very preterm infants fed fortified human milk.

BACKGROUND: Bovine colostrum (BC) contains a range of milk bioactive components, and it is unknown how human milk fortification with BC affects glucose-regulatory hormones in very preterm infants (VPIs). This study aimed to investigate the associations between hormone concentrations and fortification type, birth weight (appropriate/small for gestational age, AGA/SGA), milk intake, postnatal age, and body growth. METHODS: 225 VPIs were randomized to fortification with BC or conventional fortifier (CF). Plasma hormones were measured before, one and two weeks after start of fortification. ΔZ-scores from birth to 35 weeks postmenstrual age were calculated. RESULTS: Compared with CF, infants fortified with BC had higher plasma GLP-1, GIP, glucagon, and leptin concentrations after start of fortification. Prior to fortification, leptin concentrations were negatively associated with growth, while IGF-1 concentrations associated positively with growth during fortification. In AGA infants, hormone concentrations generally increased after one week of fortification. Relative to AGA infants, SGA infants showed reduced IGF-1 and leptin concentrations. CONCLUSION: Fortification with BC increased the plasma concentrations of several glucose-regulatory hormones. Concentrations of IGF-1 were positively, and leptin negatively, associated with growth. Glucose-regulatory hormone levels were affected by birth weight, milk intake and postnatal age, but not closely associated with growth in VPIs. IMPACT: Little is known about the variation in glucose-regulatory hormones in the early life of very preterm infants (VPIs). This study shows that the levels of glucose-regulatory hormones in plasma of VPIs are highly variable and modified by birth weight (appropriate or small for gestational age, AGA or SGA), the type of fortifier, enteral nutritional intake, and advancing postnatal age. The results confirm that IGF-1 levels are positively associated with early postnatal growth in VPIs, yet the levels of both IGF-1 and other glucose-regulatory hormones appeared to explain only a small part of the overall variation in growth rates.

Insulin-like growth factor 1 associated with altered immune responses in preterm infants and pigs.

BACKGROUND: Preterm infants show low blood levels of insulin-like growth factor 1 (IGF-1), known to be negatively correlated with Interleukin-6 (IL-6). We hypothesized that circulating IGF-1 is associated with systemic immune-markers following preterm birth and that exogenous IGF-1 supplementation modulates immune development in preterm pigs, used as model for preterm infants. METHODS: Plasma levels of IGF-1 and 29 inflammatory markers were measured in very preterm infants (n = 221). In preterm pigs, systemic immune development, assessed by in vitro challenge, was compared between IGF-1 treated (2.25 mg/kg/day) and control animals. RESULTS: Preterm infants with lowest gestational age and birth weight showed the lowest IGF-1 levels, which were correlated not only with IL-6, but a range of immune-markers. IGF-1 supplementation to preterm pigs reduced plasma IL-10 and Interferon-γ (IFN-γ), IL-2 responses to challenge and reduced expression of genes related to Th1 polarization. In vitro addition of IGF-1 (100 ng/mL) further reduced the IL-2 and IFN-γ responses but increased IL-10 response. CONCLUSIONS: In preterm infants, plasma IGF-1 correlated with several immune markers, while supplementing IGF-1 to preterm pigs tended to reduce Th1 immune responses. Future studies should document whether IGF-1 supplementation to preterm infants affects immune development and sensitivity to infection. IMPACT: Supplementation of insulin-like growth factor 1 (IGF-1) to preterm infants has been proposed to promote postnatal growth, but its impact on the developing immune system is largely unknown. In a cohort of very preterm infants, low gestational age and birth weight were the primary predictors of low plasma levels of IGF-1, which in turn were associated with plasma immune markers. Meanwhile, in immature preterm pigs, experimental supplementation of IGF-1 reduced Th1-related immune responses in early life. Supplementation of IGF-1 to preterm infants may affect the developing immune system, which needs consideration when evaluating overall impact on neonatal health.

Gut development following insulin-like growth factor-1 supplementation to preterm pigs.

BACKGROUND: Reduced insulin-like growth factor-1 (IGF-1) levels may contribute to impaired organ development in preterm infants. Using preterm pigs as a model, we hypothesized that IGF-1 supplementation improves health and gut development during the first three weeks of life. METHODS: First, clinical and organ endpoints were compared between artificially-reared, cesarean-delivered preterm pigs and vaginally-delivered, sow-reared term pigs at 5, 9 and 19 days. Next, preterm pigs were treated with recombinant human IGF-1 for 19 days (2.25 mg/kg/day, systemically). RESULTS: Relative to term pigs, preterm pigs had lower body weight, fat, bone contents, relative weights of liver and spleen and a longer and thinner intestine at 19 days. Preterm birth reduced intestinal villi heights and peptidase activities, but only at 5 and 9 days. In preterm pigs, IGF-1 reduced mortality primarily occurring from gastrointestinal complications and with a tendency towards salvaging smaller pigs. IGF-1 supplementation also increased spleen and kidney weights, small intestine length and maltase to lactase activity, reflecting gut maturation. CONCLUSION: Preterm birth affects body composition and gut maturation in the first 1-2 weeks, but differences are marginal thereafter. Supplemental IGF-1 may improve gut health in pigs and infants in the first few weeks after preterm birth. IMPACT: Insulin-like growth factor 1 (IGF-1) supplementation may improve gut health and development in prematurity, but whether the effects are sustained beyond the immediate postnatal period is unclear. In preterm pigs, the prematurity effects on IGF-1 and gut health deficiencies are most pronounced during the first week of life and diminishes thereafter. In preterm pigs, IGF-1 supplementation beyond the first week of life reduced mortality. The present study provides evidence of a sustained effect of IGF-1 supplementation on the gastrointestinal tract after the immediate postnatal period.

Clinical outcome and gut development after insulin-like growth factor-1 supplementation to preterm pigs.

Background: Elevation of circulating insulin-like growth factor-1 (IGF-1) within normal physiological levels may alleviate several morbidities in preterm infants but safety and efficacy remain unclear. We hypothesized that IGF-1 supplementation during the first 1-2 weeks after preterm birth improves clinical outcomes and gut development, using preterm pigs as a model for infants. Methods: Preterm pigs were given vehicle or recombinant human IGF-1/binding protein-3 (rhIGF-1, 2.25 mg/kg/d) by subcutaneous injections for 8 days (Experiment 1, n = 34), or by systemic infusion for 4 days (Experiment 2, n = 19), before collection of blood and organs for analyses. Results: In both experiments, rhIGF-1 treatment increased plasma IGF-1 levels 3-4 fold, reaching the values reported for term suckling piglets. In Experiment 1, rhIGF-1 treatment increased spleen and intestinal weights without affecting clinical outcomes like growth, blood biochemistry (except increased sodium and gamma-glutamyltransferase levels), hematology (e.g., red and white blood cell populations), glucose homeostasis (e.g., basal and glucose-stimulated insulin and glucose levels) or systemic immunity variables (e.g., T cell subsets, neutrophil phagocytosis, LPS stimulation, bacterial translocation to bone marrow). The rhIGF-1 treatment increased gut protein synthesis (+11%, p < 0.05) and reduced the combined incidence of all-cause mortality and severe necrotizing enterocolitis (NEC, p < 0.05), but had limited effects on intestinal morphology, cell proliferation, cell apoptosis, brush-border enzyme activities, permeability and levels of cytokines (IL-1ß, IL-6, IL-8). In Experiment 2, rhIGF-1 treated pigs had reduced blood creatine kinase, creatinine, potassium and aspartate aminotransferase levels, with no effects on organ weights (except increased spleen weight), blood chemistry values, clinical variables or NEC. Conclusion: Physiological elevation of systemic IGF-1 levels for 8 days after preterm birth increased intestinal weight and protein synthesis, spleen weight and potential overall viability of pigs, without any apparent negative effects on recorded clinical parameters. The results add further preclinical support for safety and efficacy of supplemental IGF-1 to hospitalized very preterm infants.

Dopamine therapy does not affect cerebral autoregulation during hypotension in newborn piglets.

BACKGROUND: Hypotensive neonates who have been treated with dopamine have poorer neurodevelopmental outcome than those who have not been treated with dopamine. We speculate that dopamine stimulates adrenoceptors on cerebral arteries causing cerebral vasoconstriction. This vasoconstriction might lead to a rightward shift of the cerebral autoregulatory curve; consequently, infants treated with dopamine would have a higher risk of low cerebral blood flow at a blood pressure that is otherwise considered "safe". METHODS: In anaesthetized piglets, perfusion of the brain, monitored with laser-doppler flowmetry, and cerebral venous saturation was measured at different levels of hypotension. Each piglet was studied in two phases: a phase with stepwise decreases in MAP and a phase with stepwise increases in MAP. We randomized the order of the two phases, whether dopamine was given in the first or second phase, and the infusion rate of dopamine (10, 25, or 40 µg/kg/min). In/deflation of a balloon catheter, placed in vena cava, induced different levels of hypotension. At each level of hypotension, fluctuations in MAP were induced by in/deflations of a balloon catheter in descending aorta. RESULTS: During measurements, PaCO2 and arterial saturation were stable. MAP levels ranged between 14 and 82 mmHg. Cerebral autoregulation (CA) capacity was calculated as the ratio between %-change in cerebrovascular resistance and %-change in MAP induced by the in/deflation of the arterial balloon. A breakpoint in CA capacity was identified at a MAP of 38±18 mmHg without dopamine and at 44±18, 31±14, and 24±14 mmHg with dopamine infusion rates of 10, 25, and 40 µg/kg/min (p = 0.057). Neither the index of steady-state cerebral perfusion nor cerebral venous saturation were affected by dopamine infusion. CONCLUSION: Dopamine infusion tended to improve CA capacity at low blood pressures while an index of steady-state cerebral blood flow and cerebral venous saturation were unaffected by dopamine infusion. Thus, dopamine does not appear to impair CA in newborn piglets.