Hypoxemia Near Mid-Gestation Has Long-term Effects on Fetal Brain Development

Abstract

We tested the hypotheses that an episode of hypoxemia near mid-gestation in fetal sheep has long-term effects on brain development and that the extent and type of damage is related to the stage of development within a particular brain structure at the time of the hypoxemia. Fetal sheep (n = 8) were made hypoxemic at 90 +/- 2 days (term approximately 147 days) by restricting the maternal blood supply to the placenta for 12 hours (h) using a vascular clamp so as to reduce fetal arterial O2 saturation by 50%-60%. Fetuses were killed 35 days later and the brains analysed histologically and immunohistochemically. Age-matched fetuses (n = 8) were used as controls. Gross brain damage was observed in only 1 fetus, the most acidemic during the period of hypoxemia. There was a reduction of 12% (p < 0.05) in the cross-sectional area of the cerebral cortex in hypoxemic fetuses compared with controls. In lobule 6 of the cerebella of hypoxemic fetuses, significant reductions were seen in (a) the volume density of Purkinje cells (33%), (b) the width of the molecular layer (13%), (c) the area of the inner granule cell layer (13%), (d) the area of the white matter (18%), and (e) the total cross-sectional area (15%). There were also significant reductions in the area of arborization of Purkinje cell dendritic trees (50%), in the branching density (25%), and in the number of dendritic spines (31%). In the ventral hippocampi of hypoxemic fetuses, there was a 36% reduction (p < 0.05) in the volume density of CA1 pyramidal cells and a 50% increase (p < 0.05%) in the number of astrocytes. We conclude that an episode of hypoxemia near mid-gestation reduces neuronal numbers in the hippocampus and cerebellum and probably also in the cerebral cortex. The growth of neural processes in a particular region will be significantly retarded if the hypoxemia occurs at an early stage of the growth of neural processes (e.g. cerebellum) but not if development is well advanced at the time of the insult (e.g. hippocampus). Damage is sustained in the white matter of the cerebral hemispheres if the insult is particularly severe. Together, these deficits could affect neural connectivity and impair postnatal brain function.

The Instrumented Fetal Sheep as a Model of Cerebral White Matter Injury in the Premature Infant

“…Preterm ovine white matter lesions were also detected after repeated systemic fetal endotoxin exposure that triggered both transient hypoxemia and hypotension [92,93]. The importance of cerebral ischemia is supported by studies where WMI was detected only infrequently in models of hypoxemia in which a restriction in uteroplacental blood flow resulted in decreased oxygen delivery and mild acidemia to the fetus without systemic hypotension or cerebral hypoperfusion [67,94,95]. A model of fetal metabolic acidemia induced by maternal hypoxemia similarly produced mild-to-moderate injury in mid-gestation and nearterm sheep [96].…”

“…Chronic instrumentation also allows a wide range of practical and clinically pertinent cerebral insults to be administered. These include global cephalic ischemia [65], systemic hypotension or hypoxemia [66][67][68], single or repeated cord occlusion [69][70][71], increased intracranial pressure [72], and administration of infectious agents or exogenous inflammatory mediators [73][74][75]. These insults can be graded in intensity and duration to mimic the human situation.…”

“…With models of maternal hypoxemia (e.g., high altitude or a low inspired oxygen fraction), fetal oxygenation falls while BP rises transiently, but then returns to normal, and then falls below normal [67,68,96,[103][104][105][106]. Perinatal hypoxic-ischemic encepatholpathy models that involve the entire body frequently use umbilical cord occlusion and are accompanied by reduced systemic fetal arterial oxygen tension and content [70,107,108].…”

Spatial Heterogeneity in Oligodendrocyte Lineage Maturation and Not Cerebral Blood Flow Predicts Fetal Ovine Periventricular White Matter Injury

“…PVWM lesions were infrequently detected in midgestation models of hypoxemia, where a restriction in uteroplacental blood flow resulted in decreased oxygen delivery and mild acidemia to the fetus without systemic hypotension or cerebral hypoperfusion (Rees et al, 1997(Rees et al, , 1999Mallard et al, 1998). Systemic fetal endotoxin exposure that triggered transient hypoxemia and hypotension generated superficial and PVWM lesions (Duncan et al, 2002;Dalitz et al, 2003).…”

Programming the brain: Common outcomes and gaps in knowledge from animal studies of IUGR

“…There is also considerable variability in the length, degree and timing of nutritional restriction 151 between studies [79][80][81][82][83][84][85][86][87][88], with some studies restricting throughout gestation or the entire length of 152 pregnancy studied [79,82,86,89], whilst others may only restrict during part of gestation [80,83,153 84, 88], or extend maternal nutrient restriction into lactation [85,87]. The patterns of restriction in 154 these models also differ from that in human IUGR due to placental insufficiency, which 155 progressively worsens during pregnancy [ Figure 2,14].…”