Date of Award


Degree Type


Degree Name

Master of Science


Physiology and Pharmacology


Dr. Robert Gagnon

Second Advisor

Dr. Bryan Richardson

Third Advisor

Dr. Victor Han


Variable-type fetal heart rate (FHR) decelerations due to umbilical cord compression are seen in 5-10% of antepartum FHR tracings and placental insufficiency complicates 4% of all pregnancies. It has been previously reported that fetal sheep cerebral oxygen delivery is markedly reduced during intermittent severe cord occlusion (UCO) and during prolonged placental insufficiency induced by placental embolization (EMB). Although apoptosis or programmed cell death plays a crucial role in normal fetal development, it may also be activated by hypoxic insult. The purpose of the study was to compare the degree of apoptosis caused by prolonged hypoxia induced by EMB and intermittent hypoxia induced by UCO in the near term ovine fetus. We hypothesize that acute intermittent or prolonged hypoxia would cause a significant increase in placental and fetal brain apoptosis. Twenty one near term (125-127d) sheep were studied over a two day period and divided into three groups; control (CON), EMB, and UCO. The UCO had complete cord occlusion for two minutes every hour, six times a day for two days. The EMB group had microsphere injections into the umbilical arterial circulation until fetal arterial O2 content (CaO2) was maintained at 50% of baseline value for 24 h. Paraffin sections of the placenta and fetal brain were stained using the TUNEL assay method. Twelve non-overlapping high powered fields at 40x magnification were analyzed by an observer blinded to the different treatments. The apoptotic indices are presented as the number of TUNEL positive cells/1000 cells ±S.E.M. UCO caused brief severe 80-90% reduction in CaO2 (ANOVA P<0.001) with return to pre-UCO level by 5 min post-UCO. In contrast, EMB caused fetal hypoxemia with a sustained 50% decrease in Caθ2 (ANOVA P<0.001) for 24 h post-EMB. In the cerebellar white matter, there was a 3 fold increase in the number of TUNEL positive cells/1000 between CON and either UCO or EMB animals (ANOVA p=0.017). There was also a significant increase in the number of TUNEL positive cells/1000 cells in the superficial layers of the frontal cortical grey matter (ANOVA p=0.014). An increasing trend was observed in all other brain regions including the hippocampus, thalamus, caudate nucleus, cerebral white matter and grey matter (4-6) but these were not significant. There was no significant difference in the number of TUNEL positive cells/1000 cells within the placenta. Fetal sheep cerebellar white matter appears to be susceptible to both acute intermittent severe hypoxia and prolonged moderate hypoxia while layers 1-3 of the frontal cortical grey matter are susceptible only to prolonged hypoxia. This susceptibility to hypoxia is associated with an increase in TUNEL positive cells which may represent alteration in fetal neurodevelopment in FGR fetuses.



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