The long term consequences of preterm birth in guinea pigs

Abstract

Background: Preterm birth has long been associated with impaired long term neurodevelopmental and health outcomes in ex-preterm adults and children. However, the precise mechanism linking preterm birth and impaired outcomes has not been elucidated. One possible mechanism reflects the altered neurohormonal environment in the newborn preterm infant. Following preterm birth, there is a pronounced drop in circulating IGF-I levels. IGF-I-mediated actions in the immature brain are therefore significantly reduced compared to a fetus of equivalent gestational age. As IGF-I has important effects on neural development, we hypothesise that this drop in IGF-I levels may at least partially explain preterm-associated brain injury. Using our novel preterm guinea pig paradigm we have tested the effect of neonatal treatment with long acting PEGylated IGF-I on growth, metabolic, and neurodevelopmental outcomes. Methods: Healthy sows were randomised to induced preterm delivery at day 62 of a 69 day pregnancy or allowed to continue to term. Preterm guinea pig pups were randomly assigned to either the control arm, or to receive PEG-IGF-I therapy. Term-born animals received no postnatal intervention. Fasting blood glucose measurements were made weekly on all animals and growth monitored. At Day 25 corrected postnatal age, term, preterm, and IGF-I treated animals underwent behavioural testing. At Day 28 corrected age animals underwent glucose tolerance tests, and were then euthanized and brain tissue was collected. Results: Preterm male guinea pigs gained weight, but not length faster than their term born counterparts, and had a greater ponderal index at Day 28. Preterm males displayed more hyperactive behaviour in Open Field testing, and had a smaller brain for their body weight at post-mortem. Preterm females spent less time in corners during behavioural testing, and had lower brain weight. Preterm females also had impaired glucose tolerance. PEG-IGF-I treated males had a growth trajectory that was more similar to term-born than preterm animals. They also appeared to have more ‘term-like’ behaviour than untreated preterm animals. Conclusion: Our guinea pig paradigm uses a standard laboratory species to effectively ‘model’ the sequelae of preterm birth. We have demonstrated persistent changes in growth, body composition and behaviour consequent on preterm birth. Our study numbers for investigating the therapeutic potential of PEG-IGF-I are still too small to determine whether or not this may be a clinically useful therapeutic option, but early results are promising.