Abstract
Perinatal infection/inflammation can trigger preterm birth and contribute to neurodevelopmental disability. There are currently no sensitive, specific methods to identify perinatal infection. We investigated the utility of time, frequency and non-linear measures of fetal heart rate (FHR) variability (FHRV) to identify either progressive or more rapid inflammation. Chronically instrumented preterm fetal sheep were randomly assigned to one of three different 5d continuous i.v. infusions: 1) control (saline infusions; n = 10), 2) progressive lipopolysaccharide (LPS; 200 ng/kg over 24 h, doubled every 24 h for 5d, n = 8), or 3) acute-on-chronic LPS (100 ng/kg over 24 h then 250 ng/kg/24 h for 4d plus 1 μg boluses at 48, 72, and 96 h, n = 9). Both LPS protocols triggered transient increases in multiple measures of FHRV at the onset of infusions. No FHRV or physiological changes occurred from 12 h after starting progressive LPS infusions. LPS boluses during the acute-on-chronic protocol triggered transient hypotension, tachycardia and an initial increase in multiple time and frequency domain measures of FHRV, with an asymmetric FHR pattern of predominant decelerations. Following resolution of hypotension after the second and third LPS boluses, all frequencies of FHRV became suppressed. These data suggest that FHRV may be a useful biomarker of rapid but not progressive preterm infection/inflammation.
Highlights
Materials and methodsThe preterm fetal sheep at 0.7 gestation is neurologically comparable to the human brain at 28–32 weeks of g estation[26], before the onset of cortical m yelination[27]
Perinatal infection/inflammation can trigger preterm birth and contribute to neurodevelopmental disability
Fetal sheep exposed to acute severe inflammation induced by high-dose lipopolysaccharide (LPS), a component of the cell wall of gram-negative bacteria, develop transient hypotension with biphasic changes in time domain measures of fetal heart rate variability (FHRV) characterized by an initial increase followed by suppression of FHRV21,22
Summary
The preterm fetal sheep at 0.7 gestation is neurologically comparable to the human brain at 28–32 weeks of g estation[26], before the onset of cortical m yelination[27] These studies used LPS derived from Escherichia coli, serotype 055:B5 (Sigma Aldrich, St. Louis, MO, USA). LPS was dissolved in saline at a concentration of 50 ng/mL, and initially infused at a rate of 0.1 μg/kg/24 h (83.3 μL/h) from 0–24 h of the experiment. Baseline samples were taken 30 min before the rate of infusion of LPS was increased or a bolus was given. On the days of LPS infusions (day 0–4), additional samples were taken at 2 and 6 h after infusion rates were increased or boluses were administered. Sample Asymmetry was calculated from epochs consisting of 4096 consecutive RR intervals (approximately 20 min of data)[44].
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