Search

Background: Preterm birth is associated with impaired brain functions, but it is unknown whether fetal growth restriction (GR) makes these deficits worse. Using piglets as a model for preterm infants, we hypothesized that moderate GR reduces growth rate, physical activity, and spatial memory in the first weeks after preterm birth. Methods: Preterm pigs were delivered by caesarean section and fed until 19 days (n = 830 from 55 pregnant sows) and received intensive clinical care. GR pigs were classified as animals with the lowest 5–20% percentile birth weight within each litter and were compared with litter-mate controls (21–100% percentile birth weight). Basic motor skill development, physical activity, and morbidities (e.g., necrotizing enterocolitis) were recorded within the first week. Weight of internal organs and data from a T-maze spatial memory test were noted until 19 days. Results: Moderate GR and control preterm pigs (birth weights 728 ± 140 and 1,019 ± 204 g, respectively) showed similar relative weights of internal organs (relative to body), except higher adrenal gland weights in GR pigs (+20–50%, p < 0.05). This was associated with a tendency to higher plasma cortisol (p < 0.05 on day 11). GR preterm pigs showed delayed ability to stand and walk (days 2–5, p < 0.01), but physical activity and proportion of correct choices in a T-maze test (70.3 vs. 71.6%) were similar. Conclusion: Moderate GR has limited effect on motor function and spatial memory in the early postnatal period of preterm pigs, despite some initial delays in basic motor skills. In the postnatal period, moderately growth-restricted preterm infants may adapt well with regards to organ growth and neurodevelopment.

Necrotizing enterocolitis (NEC) increases the risk of brain injury and impaired neurodevelopment. Rapid brain maturation prior to birth may explain why preterm brains are particularly vulnerable to serious infections. Using pigs as models, we hypothesized that preterm birth was associated with altered blood-cerebrospinal fluid (CSF) barrier (BCSFB) function and cerebral structural deficits, and that NEC was associated with systemic inflammation, BCSFB disruption, and neuroinflammation. First, cesarean-delivered preterm and term pigs (n = 43–44) were euthanized at birth to investigate BCSFB function and markers of brain structural maturation, or on day 5 to measure markers of blood-brain barrier maturation in the hippocampus and striatum (experiment 1). Next, preterm pigs (n = 162) were fed increasing volumes of infant formula to assess NEC lesions, systemic inflammation, BCSFB permeability, cerebral histopathology, hippocampal micro­glial density, and cytokine levels on day 5 (experiments 2 and 3). In experiment 1, preterm newborns had increased CSF-plasma ratios of albumin and raffinose, reduced CSF glucose levels, as well as increased cerebral hydration and reduced white matter myelination compared with term animals. We observed lower hippocampal (but not striatal) perivascular astrocyte coverage for the first 5 days after preterm birth, accompanied by altered cell junction protein levels. In experiments 2 and– 3, piglets with severe NEC lesions showed reduced blood thrombocytes and increased plasma C-reactive protein and interleukin-6 levels. NEC was associated with increased CSF-plasma albumin and raffinose ratios, reduced CSF leukocyte numbers, and increased cerebral hydration. In the hippocampus, NEC was associated with pyramidal neuron loss and increased interleukin-6 levels. In the short term, NEC did not affect cerebral myelination or microglia density. In conclusion, altered BCSFB properties and brain structural deficits were observed in pigs after preterm birth. Acute gastrointestinal NEC lesions were associated with systemic inflammation, increased BCSFB permeability and region-specific neuronal damage. The results demonstrate the importance of early interventions against NEC to prevent brain injury in preterm infants.