Antenatal Dexamethasone after Asphyxia Increases Neural Injury in Preterm Fetal Sheep

Abstract

Background and PurposeMaternal glucocorticoid treatment for threatened premature delivery dramatically improves neonatal survival and short-term morbidity; however, its effects on neurodevelopmental outcome are variable. We investigated the effect of maternal glucocorticoid exposure after acute asphyxia on injury in the preterm brain.MethodsChronically instrumented singleton fetal sheep at 0.7 of gestation received asphyxia induced by complete umbilical cord occlusion for 25 minutes. 15 minutes after release of occlusion, ewes received a 3 ml i.m. injection of either dexamethasone (12 mg, n = 10) or saline (n = 10). Sheep were killed after 7 days recovery; survival of neurons in the hippocampus and basal ganglia, and oligodendrocytes in periventricular white matter were assessed using an unbiased stereological approach.ResultsMaternal dexamethasone after asphyxia was associated with more severe loss of neurons in the hippocampus (CA3 regions, 290±76 vs 484±98 neurons/mm2, mean±SEM, P<0.05) and basal ganglia (putamen, 538±112 vs 814±34 neurons/mm2, P<0.05) compared to asphyxia-saline, and with greater loss of both total (913±77 vs 1201±75/mm2, P<0.05) and immature/mature myelinating oligodendrocytes in periventricular white matter (66±8 vs 114±12/mm2, P<0.05, vs sham controls 165±10/mm2, P<0.001). This was associated with transient hyperglycemia (peak 3.5±0.2 vs. 1.4±0.2 mmol/L at 6 h, P<0.05) and reduced suppression of EEG power in the first 24 h after occlusion (maximum −1.5±1.2 dB vs. −5.0±1.4 dB in saline controls, P<0.01), but later onset and fewer overt seizures.ConclusionsIn preterm fetal sheep, exposure to maternal dexamethasone during recovery from asphyxia exacerbated brain damage.

Effect of Betamethasone on Fetal Pulmonary and Umbilical Artery Doppler Velocimetry and Relationship With Respiratory Distress Syndrome Development

“…Such a treatment might increase unwanted side effects on the development of different organ systems: eg, neurodevelopmental effects of maternal glucocorticoid treatment are variable. 20,21 Different from some other recent reports, we did not find any PA Doppler differences in fetuses with and without RDS. Also, there were no differences in PA Doppler results before and after steroid administration, but we observed a decreased UA PI in fetuses who developed RDS after steroid administration.…”

“…Here, this question may be asked: Is steroid treatment performed unnecessarily in some patients who in fact actually will not really have premature birth? Such a treatment might increase unwanted side effects on the development of different organ systems: eg, neurodevelopmental effects of maternal glucocorticoid treatment are variable …”

Maternal treatment with glucocorticoids modulates gap junction protein expression in the ovine fetal brain

“…Full term gestation is in sheep is 145–147 days. Therefore, the neurodevelopment of the sheep fetus in the current study at 107 days of gestation, is approximately similar to that of preterm human infants between 28 to 32 weeks of gestation (McIntosh et al, 1979, Back et al, 2006, Koome et al, 2013). …”

“…Although theoretically the increased connexin expression could have contributed to increases in apoptosis reported after dexamethasone (Zuloaga et al, 2011, Bhatt et al, 2013), our previous findings reveal that apoptosis did not increase after our dexamethasone regimen in the fetal sheep brain (Malaeb et al, 2009). On the other hand, the glucocorticoid related enhanced connexin expression that we observed could potentially accentuate injury under adverse fetal conditions such as asphyxia (Koome et al, 2013). …”

Hypoglycaemia and hyperglycaemia are associated with unfavourable outcome in infants with hypoxic ischaemic encephalopathy: a post hoc analysis of the CoolCap Study

“…In contrast, in newborn piglets, hyperglycaemia impaired recovery of brain cell membrane function and energy metabolism 35. Further, hyperglycaemia following maternal dexamethasone treatment after asphyxia in fetal sheep was associated with increased brain injury 36. It may be that these contrasting results reflect more adverse effects of greater durations of hyperglycaemia or a deleterious effect of the combination of high levels of glucocorticoids with hyperglycaemia.…”