Mild chronic hypoxia modifies the fetal sheep neural and cardiovascular responses to repeated umbilical cord occlusion

Abstract

We have shown that 5 days of mild hypoxia has significant effects on fetal ECoG activity, heart rate and blood pressure. We now studied if mild prolonged hypoxemia had an adverse effect on the fetal cardiovascular and neural responses to repeated cord occlusion and on the magnitude of neuronal damage. Fetal and maternal catheters were placed at 120 days' gestation and animals allocated at random to receive intratracheal maternal administration of nitrogen (n=8) or compressed air in controls (n=7). Five days after surgery, nitrogen infusion was adjusted to reduce fetal brachial artery pO(2) by 25%. After 5 days of chronic hypoxemia, the umbilical cord was completely occluded for 5 min every 30 min for a total of four occlusions. Data are presented as mean+/-SEM and were analyzed by two-way ANOVA or two-sample t-test. Nitrogen infusion decreased fetal pO(2) by 26% (20.5+/-1.7 vs. 14.3+/-0.8 mm Hg) without changing fetal pCO(2) or pH. Pre-existing hypoxia fetuses had a greater terminal fall in heart rate in occlusions II, III and IV, and also had a more severe terminal hypotension in the final occlusion. Pre-existing hypoxia was associated with a greater fall in spectral edge frequency during occlusions from 14.4+/-0.9 Hz to 6.9+/-0.4 Hz vs. 13.6+/-1.64 Hz to 10.6+/-0.77 Hz in controls, p<0.05. In addition, during the three-day post-occlusion period, the contribution of theta and alpha band frequencies to total ECoG activity was significantly lower in the pre-existing hypoxia fetuses (p<0.05). These effects were associated with increased neuronal loss in the striatum (p<0.05). In summary, the cardiovascular and neural response indicates a detrimental effect of pre-existing mild hypoxia on fetal outcome following repeated umbilical cord occlusions.

Figure 1

Effect of repeated total umbilical cord occlusions on fetal heart rate (FHR;●) and mean arterial blood pressure (MAP;○) in fetal sheep. Four five-min occlusions (I, II, III, IV) in control (A, n=7) and pre-existing hypoxia group (B, n=8). Shaded area represents the occlusion period, the periods where maxima and minima values were determined for MAP (open bars) and for FHR (solid bars) are also depicted.

Figure 2

Magnitude of the fetal heart rate changes during the first minute (A) and during the last minute (B) and magnitude of the arterial blood pressure changes during the hypertensive phase (C) and during the last minute (D) of umbilical cord occlusion. Control (□, n=7) and pre-existing hypoxia (■, n=8) group. Values are mean±SEM, * p<0.05.

Figure 3

Fetal responses during the first twelve hours after umbilical cord occlusions. Changes in fetal heart rate (FHR), arterial blood pressure (FABP), spectral edge frequency (SEF) and ECoG amplitude are shown. † p<0.05 vs Day -1; * p<0.05 vs control.

Figure 4

Effects of four 5-min umbilical cord occlusions on ECoG spectral frequencies. Changes in median frequency (A), spectral edge frequency (SEF, B) and frequency bands (Delta, C; Theta, D; Alpha, E and Beta₁, F)relative to pre-occlusion values (Day -1; dotted line) in control (□, n=5) and pre-hypoxic (■, n=6) fetuses. * p<0.05 vs Day -1; # p<0.05 vs control.

Figure 5

Power Spectrum Analysis of fetal ECoG in the days following the occlusion period. Relative spectral power of Theta (A) and Alpha (B) bands for total ECoG and in the low voltage state Theta (C) and Alpha (D). Control (□, n=5) and pre-existing hypoxia (■, n=6) group, *p<0.05 by ANOVA.

Figure 6

Representative microphotographs of DAPI (A, B) and Fluoro Jade-B (C, D) staining in basal ganglia sections of control (A, C) and pre-existing hypoxia (B, D) fetuses brain. Bar = 50 μm. Low resolution microphotograph showing the areas (boxes) used to measure cortical (1) and striatal (2) neuronal damage (E). Bar= 5 mm