An episode of fetal hypoxia, even early on in pregnancy, can produce severe neurologic and behavioral deficits in postnatal life and may be involved in the etiology of conditions such as cerebral palsy. These deficits may result from alterations in the amount or function of neurotropic factor(s) in developing brain. L-glutamate (Glu), an excitatory amino acid, plays a key role in brain development. Some evidence suggests that alterations in the amount of Glu can produce aberrant growth promotion and possibly neuronal death. While in vitro studies support this proposal, until recently it has not been possible to determine if hypoxia alters Glu release in the intact fetal brain. To that end, we developed the novel technique of in utero fetal microdialysis, in which microdialysis probes are implanted into the fetal sheep cerebral cortex. Using the surgically-recovered instrumented pregnant sheep, the release of Glu can be measured under basal and pathologic conditions in the absence of anesthetic agents. A further clinical concern is that pharmacologic treatments employed in high-risk pregnancy may affect fetal well-being during pathophysiologic insult. One such drug is magnesium sulfate (MgSO4), which is commonly used in premature and preeclamptic parturients. Such patients often have an ongoing increased risk of experiencing an episode of fetal hypoxia. Previous experimental studies have suggested that MgSO4 may impact negatively on the fetus during fetal/maternal stress. However, magnesium ion can interact at Glu receptors and may actually protect the fetal brain from a hypoxia-induced increase in Glu release. The overall aim of this proposal is to investigate the actions of MgSO4 on the preterm fetus during an episode of acute hypoxia, using in utero microdialysis. We will test two hypotheses: 1) MgSO4 worsens survival of the preterm fetus following acute hypoxia; and 2) MgSO4 changes cerebral cortical Glu release in preterm fetus following acute hypoxia. With qualitative histologic studies, we will also attempt to determine if magnesium sulfate alters the pattern of fetal hypoxic neurologic injury. MgSO4 is commonly used in high-risk pregnancies even though its action in the fetus during stress have not been well characterized. The present study is designed to mimic the clinical obstetrical use of MgSO4: e.g. a preterm parturient receiving MgSO4 who experiences sudden fetal compromise secondary to umbilical cord occlusion. Completion of this study will yield important new information about the effects of hypoxia and MgSO4 on the preterm fetus. These results will be useful in assessing if MgSO4 has potential as a pharmacologic intervention during fetal hypoxia, or, conversely, whether the use of MgSO4 in parturients at risk for an episode of fetal hypoxia should be re-evaluated.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Small Research Grants (R03)
Project #
5R03HD035236-02
Application #
2674089
Study Section
Pediatrics Subcommittee (CHHD)
Project Start
1997-09-24
Project End
2000-08-31
Budget Start
1998-09-01
Budget End
2000-08-31
Support Year
2
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Duke University
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
071723621
City
Durham
State
NC
Country
United States
Zip Code
27705
Reynolds, James D; Booth, John V; de la Fuente, Sebastian et al. (2003) A review of laparoscopy for non-obstetric-related surgery during pregnancy. Curr Surg 60:164-73
Reynolds, James D; Amory, David W; Grocott, Hilary P et al. (2002) Change in plasma glutamate concentration during cardiac surgery is a poor predictor of cognitive outcome. J Cardiothorac Vasc Anesth 16:431-6
Brewer, R P; Parra, A; Borel, C O et al. (2001) Intravenous magnesium sulfate does not increase ventricular CSF ionized magnesium concentration of patients with intracranial hypertension. Clin Neuropharmacol 24:341-5
Reynolds, J D; Grubbs, E G; Dexter, F et al. (2000) Acute cord occlusion increases blood ionized magnesium concentration in preterm fetal sheep during maternal magnesium sulfate exposure. Can J Physiol Pharmacol 78:301-6