The effects of chronic inflammation on circadian rhythms in the preterm fetus

Abstract

Circadian rhythms are important regulators of physiological activity, but little is known about fetal patterns, particularly during preterm life, and whether they can be altered by adverse events such as exposure to infection/inflammation. Our objective was to determine the effect of inflammation induced by low-dose lipopolysaccharide (LPS) on circadian rhythms of preterm fetuses. Preterm fetal sheep (0.7 gestation) were given a saline (n=8) or low-dose LPS (n=7) infusion (dose doubled/day from 200ng) for five days, and then studied a further five days without infusion. Fetal heart rate (FHR), mean arterial blood pressure (MAP), nuchal electromyogram (EMG) and electroencephalographic activity (EEG) were continuously measured. Light period was between 06.00h-18.00h. In controlsMAP increased and FHR fell over the experiment (P<0.001). MAP increased during the day, plateaued around 18.00h-02.00h, and then dipped (0.2-0.8mmHg) until 06.00h. FHR increased from 12.00h until 19.00h, plateaued until 21.00h-22.00h and then fell until 06.00h, (peak/nadir difference ~28bpm) with mixed FHR 06.00h-12.00h. LPS infusion suppressed the MAP increase (P<0.05), and post-infusion MAP increased day and night. LPS did not affect FHR, other than a brief tachycardia at infusion onset. EEG activity increased over the experiment (P<0.05) and SEF increased until 108d, then plateaued and fell. EEG power increased over the day whereas SEF increased over the night. LPS suppressed EEG power vs. controls (P<0.05), but there was some catch-up over the day and night post-infusion. LPS suppressed SEF the first day of infusion (P<0.05) but did not affect circadian patterning therein. However, the global SEF trajectory did not transition at 108d, but increased above controls (P<0.001). MAP and EEG power are surrogate measures of growth, suggesting fetal growth occurs over the day, consistent with maternal nutrient intake. Greater glucose availability may support neural network development of long-distance connections. Increased SEF at night may indicate a switch in energy use to local neural network development. LPS affects body and brain growth, with some catch-up post-infusion. Long-distance connections may be affected, but local neural network development may continue. This is consistent with neural network development after chorioamnionitis. The failure to transition SEF trajectory at 108d may reflect delayed sleep-state maturation.