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ABSTRACT: The purpose of this study was (1) to determine the ability of the ovine fetus to recover from a self-limiting asphyxial insult and (2) to monitor cardiovascular and biophysical activity as potential markers of such an insult or underlying neurologic impairment.
Nineteen fetal sheep were studied (12 hypoxia and 7 control) at 0.9 of gestation during a 24-hour control period, up to 8 hours of either sustained hypoxemia or room air, and for a 40-hour recovery period. Fetal heart rate, blood pressure, electrocortical activity, electroocular activity, and breathing movements were monitored continuously. Fetal arterial blood was sampled at set times for blood gases, pH, lactate, and catecholamine levels.
Induced fetal hypoxemia resulted in a lactic metabolic acidosis that progressively worsened, with death occurring in three of the animals during the early recovery period. The remaining animals showed a rapid metabolic and endocrine normalization of values by 24 hours. Fetal cardiovascular and biophysical measurements likewise returned to control values during the early recovery period, although three animals had seizure-like activity.
The near-term ovine fetus surviving a sustained asphyxial insult sufficient to induce neuropathologic change within the brain demonstrates a normalization of biophysical activity during the early period of recovery, although seizure-like activity may subsequently be evident.
American Journal of Obstetrics and Gynecology 06/1994; 170(5 Pt 1):1433-41. · 3.47 Impact Factor
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ABSTRACT: The purpose of our study was to examine the effects of induced hypoxia on endocrine, cardiovascular, and biophysical measurements of the ovine fetus at 0.6 (83 to 93 days) of gestation and to compare the fetal responses at this earlier gestation with those reported near term.
Fourteen fetal sheep were studied (9 in the hypoxia group and 5 in the control group) at 0.6 of gestation during a 24-hour control period, 8 hours of either sustained hypoxemia or room air, and a 40-hour recovery period.
Induced fetal hypoxemia resulted in a progressive lactic metabolic acidosis; however, all fetuses had recovered within 24 hours. The fetal endocrine response was variable with norepinephrine, the only measured hormone showing a significant hypoxia-related increase (p less than 0.05). Fetal heart rate and mean arterial blood pressure showed little hypoxia-induced change, although fetal heart rate was significantly increased over the first 2 hours (p less than 0.05). The percent time fetal breathing movements, electroocular activity, and nuchal muscle activity likewise showed little hypoxia-induced change.
The cardiovascular and biophysical response of the preterm fetus to induced hypoxemia is thus much less pronounced than that of the older gestational-aged fetus; this difference may impact on survival and the success of antenatal assessment protocols.
American Journal of Obstetrics and Gynecology 09/1992; 167(2):531-40. · 3.47 Impact Factor
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ABSTRACT: Prostaglandins (PGs) have been implicated as mediators of the ethanol-induced suppression of ovine fetal breathing movements (FBM). The objectives of the present study were to determine the ontogeny of the in vitro efflux of PGE2 and 6-keto PGF1 alpha in ovine fetal brain stem during the second half of gestation and to determine the effect of in vitro ethanol exposure on the efflux of these PGs. Ovine fetal brain stem tissue was obtained at mean gestational ages of 80 days (n = 6), 105 days (n = 10), and 135 days (n = 16) by rapid excision following maternal euthanization. Tissue slices (400 microM thickness) were prepared from the lower pons-medulla region of the brain stem. After a 1-hr equilibration period in artificial cerebrospinal fluid, efflux of PGE2 and 6-keto PGF1 alpha in the brain stem was determined using the brain slice-superfusion method, and the PGE2 and 6-keto PGF1 alpha concentrations in the superfusate were determined by specific radioimmunoassay. The mean spontaneous efflux of PGE2 and 6-keto PGF1 alpha expressed as pmol PG/gram wet weight of tissue/5-min collection period was, respectively, 31.9 +/- 4.2 and 26.6 +/- 2.4 at 80 days, 38.3 +/- 5.2 and 29.6 +/- 2.2 at 105 days, and 57.4 +/- 3.1 and 27.1 +/- 1.1 at 135 days of gestation. In vitro exposure to 20, 40, and 80 mM ethanol did not affect PG efflux in the brain stem at 80 and 105 days of gestation. In vitro ethanol exposure decreased PGE2 and 6-keto PGF1 alpha efflux at 135 days of gestation to 36.8 +/- 5.3% and 41.6 +/- 4.3% of spontaneous efflux within 15 min, respectively; this effect of ethanol was not dose-dependent. The data do not support the hypothesis that ethanol increases PG efflux in the ovine fetal brain stem. In view of these findings and the data implicating PGs in the mechanism of ethanol-induced suppression of FBM, it is possible that ethanol acts at either central sites rostral to the brain stem (i.e., upstream CSF) or peripheral sites to increase the synthesis of PGs and their efflux into the systemic circulation, with subsequent transfer to the respiratory control region(s) of the brain stem.
Alcoholism Clinical and Experimental Research 07/1992; 16(3):443-8. · 3.34 Impact Factor
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ABSTRACT: A study was performed to examine the role of prostaglandins (PGs) in the mechanism of the ethanol-induced suppression of FBM, in which the objective was to test the hypothesis that fetal administration of PGE2 can suppress the incidence of FBM following reversal of ethanol-induced suppression of FBM by indomethacin, a fatty acid cyclooxygenase inhibitor. Instrumented near-term pregnant ewes received 1-h maternal infusion of ethanol (1 g/kg maternal body weight) followed 0.5 h later by a 3-h fetal infusion of indomethacin (1 mg/kg fetal body weight/h), and then a 2-h fetal infusion of PGE2 (400 ng/kg fetal body weight/min). Prior to drug administration, FBM occurred approximately 36.1 +/- 2.6% of the time. FBM were suppressed during the period of ethanol infusion (9.6 +/- 1.7%); the ethanol-induced suppression of FBM was reversed by fetal indomethacin treatment (77.5 +/- 14.1%); shortly after the onset of fetal PGE2 infusion, the incidence of FBM decreased to a 2-h mean incidence of 14.1 +/- 4.2%, which was similar in magnitude to that observed after maternal ethanol infusion. After the completion of PGE2 infusion, the incidence of FBM rapidly increased to a peak incidence of 83.4 +/- 19.2%, which was indicative of a prolonged effect of indomethacin on FBM. The data indicate that PGs mediate the ethanol-induced suppression of ovine FBM and that the action of indomethacin to antagonize ethanol-induced suppression of FBM is primarily due to its inhibition of PG synthesis.
Journal of developmental physiology 11/1991; 16(4):239-42.
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ABSTRACT: The purpose of this review is to critically examine the effects of ethanol on the embryo-fetus. There has been a tremendous amount of human epidemiological and experimental animal research on the characterization of the anomalies produced by chronic prenatal ethanol exposure and the identification of critical periods of vulnerability and critical amounts of ethanol necessary to produce fetal effects and (or) abnormal development. Few studies have examined the underlying mechanism(s) of the action of ethanol, and even fewer studies have examined the effects of single-dose ethanol exposure on the embryo-fetus. In this review, the current state of knowledge of the effects of chronic use of ethanol on the embryo-fetus is summarized. The primary focus of the review is on the embryonic-fetal effects of acute ethanol exposure, with particular emphasis on the ethanol-induced suppression of fetal breathing movements, as this effect appears to be a very sensitive index of acute exposure of the near-term fetus to ethanol. Factors to be considered in the selection of experimental animals to investigate the mechanism of action of ethanol and to study the acute effects of ethanol are discussed. Postulated mechanisms of action of ethanol on the embryo-fetus are evaluated with a focus on the role of prostaglandins. Finally, future directions in this field of research are proposed.
Canadian Journal of Physiology and Pharmacology 06/1991; 69(5):550-69. · 1.95 Impact Factor
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ABSTRACT: The effect of in vitro incubation with ethanol (10-80 mM) on 15-hydroxyprostaglandin dehydrogenase (15-OH-PGDH) activity was determined in the brain stem (pons and medulla) of the fetal sheep at a mean gestational age of 126 days (term: about 147 days). Enzyme activity was determined by measuring the rate of oxidation of PGE2 to 15-keto-PGE2 using a radiometric assay. There was no statistically significant ethanol-induced inhibition of 15-OH-PGDH activity. The data apparently do not support the hypothesis that acute in vitro exposure to ethanol directly inhibits 15-OH-PGDH activity in the near-term fetal brain stem.
Developmental pharmacology and therapeutics 02/1991; 16(1):48-52.
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ABSTRACT: The effects of indomethacin on the ethanol-induced suppression of fetal breathing movements and fetal arterial plasma and cerebrospinal fluid (CSF) PGE2 concentrations and maternal arterial plasma PGE2 concentration were determined in the near-term fetal lamb. Eight conscious instrumented pregnant ewes (between 130 and 133 days of gestation; term, 147 days) received 1-h maternal intravenous infusion of 1 g ethanol/kg total body weight, and the fetus received 6-h intravenous infusion of indomethacin (1 mg/h per kg fetal body weight) commencing 30 min later. Serial fetal and maternal arterial blood samples (n = 8) and fetal CSF samples (n = 5) were collected at selected times throughout the 12-h study for the determination of PGE2 concentration. Fetal breathing movements were monitored continuously throughout the experimental period. Maternal ethanol infusion resulted in initial suppression (P less than 0.05) of fetal breathing movements for 2 h below pretreatment value, followed by a rapid increase in the incidence of fetal breathing movements after the onset of fetal indomethacin treatment. Fetal and maternal plasma PGE2 concentrations and fetal CSF PGE2 concentration were increased (P less than 0.05) above the pre-infusion value during the administration of ethanol and 1 h thereafter. Fetal indomethacin treatment suppressed (P less than 0.05) to undetectable levels fetal plasma and CSF PGE2 concentrations, which then became similar (P greater than 0.05) to pretreatment by 12 h. There was a positive correlation between fetal plasma and CSF PGE2 concentrations. There was an inverse correlation between the incidence of fetal breathing movements and fetal CSF PGE2 concentration.(ABSTRACT TRUNCATED AT 250 WORDS)
Journal of developmental physiology 08/1990; 14(1):29-35.
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ABSTRACT: The effect of maternal administration of ethanol on fetal and maternal plasma prostaglandin E2 (PGE2) concentrations and fetal breathing movement was determined in the near-term pregnant ewe. Six conscious instrumented pregnant ewes (between 129 and 134 days of gestation; term, 147 days) were studied on two successive days (day 1 and day 2). On each of the two days of the experiment, there was a 1-h period of maternal infusion of ethanol (1 g ethanol/kg total body weight) or an equivalent volume of normal saline. Animals were assigned to two groups with one group (n = 3) receiving ethanol on day 1 and saline on day 2, and the other group (n = 3) receiving saline on day 1 and ethanol on day 2. Fetal and maternal blood samples were collected at selected times for blood ethanol determination (n = 2), and plasma was obtained for the determination of PGE2 concentration (n = 6). Fetal breathing movements were monitored continuously during the experimental periods. Maternal saline infusion had no effect (P greater than 0.05) on fetal breathing movement and fetal and maternal plasma PGE2 concentrations (187 +/- 25 (SEM) pg/ml and 196 +/- 32 pg/ml, respectively). Maternal ethanol infusion suppressed (P less than 0.05) fetal breathing movement below preinfusion levels for 8 h and increased (P less than 0.05) both fetal and maternal plasma PGE2 concentrations to 314 +/- 55 pg/ml and 306 +/- 25 pg/ml, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
Journal of developmental physiology 08/1990; 14(1):23-8.
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Canadian Journal of Anaesthesia 06/1990; 37(4 Pt 2):S2. · 2.35 Impact Factor
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ABSTRACT: In order to determine the effects of fetal hypoxemia on renal blood flow, glomerular filtration rate (GFR) and urethral and urachal urine output, we examined the effects of 3 h maternally-induced (9% O2, 3% CO2, 88% N2) fetal hypoxaemia on 10 chronically-instrumented fetal sheep between 127-135 days of gestation. Fetal arterial pH fell significantly during the second and third hours of hypoxia and this coincided with a significant increase in fetal arterial blood pressure (P less than 0.05). During the second hour of hypoxia, with mild acidaemia, fetal GFR decreased significantly and then, during the third hour, fetal GFR, urethral and total urine output were significantly elevated. During the 2-h recovery period urachal and total, but not urethral urine output, were significantly elevated (P less than 0.05). The data suggested that the increase in GFR and urine output measured during the third hour of hypoxia and the recovery period may reflect a pressure diuresis.
Journal of developmental physiology 01/1990; 12(6):323-8.
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ABSTRACT: Thirteen healthy pregnant women between 37 and 41 weeks' gestational age were studied to examine effects of a 5-second external vibratory stimulus (100 Hz, square wave) on fetal heart rate, fetal breathing, and gross fetal body movement patterns. All fetuses were stimulated during an episode of low fetal heart rate variability (mean minute range less than or equal to 32 milliseconds for greater than or equal to 5 minutes) lasting at least 5 minutes. There was an immediate and sustained increase in long-term FHR variability, number of FHR accelerations, and gross fetal body movements after stimulation. Fetuses made breathing movements more irregularly after vibratory stimulus. We hypothesize that external low-frequency vibratory stimulus, applied during episodes of low fetal heart rate variability, causes a change from a state of quiet sleep to a state of rapid-eye-movement sleep in healthy term fetuses.
American Journal of Obstetrics and Gynecology 01/1990; 161(6 Pt 1):1479-85. · 3.47 Impact Factor
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ABSTRACT: The effect of indomethacin on the ethanol-induced suppression of fetal breathing movements, low-voltage electrocortical (ECoG) activity, and electro-ocular (EOG) activity was studied in the near-term fetal sheep. Ten conscious instrumented pregnant ewes (between 129 and 131 days of gestation; term, 147 days) received 1-h maternal intravenous infusion of 1 g ethanol/kg total body weight and simultaneous fetal treatment with either indomethacin (2 mg/kg fetal body weight/h) (n = 5) or an equivalent volume of phosphate buffer (n = 5) intravenously for 9 h. Fetal ECoG activity, EOG activity, and fetal breathing movements were monitored continuously over the experimental periods. In animals treated with ethanol and buffer (n = 5), fetal breathing movements were suppressed for 8 h and low-voltage ECoG and EOG activity was suppressed for 2 h below preinfusion levels. In animals treated with ethanol and indomethacin (n = 5), fetal breathing movements were elevated for 13 h but low-voltage ECoG and EOG activity remained suppressed for 3 h below preinfusion levels. The data suggests that indomethacin can antagonize the ethanol-induced suppression of fetal breathing movements, but does not alter the ethanol-induced suppression of ECoG or EOG activity.
Journal of developmental physiology 09/1989; 12(2):69-75.
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ABSTRACT: The effect of ethanol on maternal and fetal blood gases and acid-base balance was determined in six conscious instrumented near-term pregnant ewes for maternal intravenous infusion of 3 g ethanol/kg total body weight administered as six doses of 0.5 g ethanol/kg total body weight over 8 h. Maternal and fetal blood ethanol concentrations, determined in two animals, were maximal at 8 h (3.74 and 3.82 mg/mL, respectively) and were virtually identical during the 24-h study. Maternal and fetal blood gases and acid-base balance were not significantly altered during and after ethanol administration compared with preinfusion values. The data demonstrate that, during near-term ovine pregnancy, the equivalent of a binge-type drinking episode does not produce fetal hypoxia or acidosis. Furthermore, these data do not support the postulated involvement of ethanol-induced fetal hypoxia in the mechanism of ethanol teratogenesis.
Canadian Journal of Physiology and Pharmacology 07/1989; 67(6):686-8. · 1.95 Impact Factor
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ABSTRACT: The effect of short-term maternal ethanol administration on the ethanol-induced suppression of fetal breathing movements, electrocortical (ECoG) activity, and electroocular (EOG) activity was determined in the near-term fetal sheep. Twelve conscious instrumented pregnant ewes (between 125 and 139 days of gestation; term, 147 days) received 1-h intravenous infusion of 1 g ethanol/kg total body weight daily for six days (n = 6) or an equivalent volume of normal saline daily for six days (n = 6). On the seventh day, the ethanol- and saline-pretreated animals were administered 1 g ethanol/kg total body weight. A further six ewes received 1-h intravenous infusion of 1 g ethanol/kg total body weight (n = 3) or an equivalent volume of normal saline (n = 3) daily for thirteen days with both groups receiving 1 g ethanol/kg total body weight on day fourteen. Fetal ECoG and EOG activities, and fetal breathing movements were monitored continuously over the post- operative and experimental periods. Saline infusion had no significant effect on the parameters studied. Fetal breathing movements were suppressed for 8 h after the first ethanol dose, and were not significantly suppressed after fourteen days of once-daily, maternal ethanol administration. Low-voltage ECoG and EOG activities were suppressed for 3 h after the first ethanol dose, and were not significantly suppressed after seven days of repeated ethanol administration. Maternal and fetal blood gases and acid-base balance were not significantly affected by maternal ethanol administration. These data demonstrate that short-term maternal administration of ethanol results in the development of tolerance to ethanol in the mature fetus.
Journal of developmental physiology 04/1989; 11(3):189-97.
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ABSTRACT: The activity of alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) was determined in the near-term pregnant ewe. There was little ADH activity in fetal liver (4.4%) and placenta (0.2%) compared with maternal liver. Low KM (microM acetaldehyde) ALDH activity was similar in the three tissues. High KM (mM acetaldehyde) ALDH activity was less in fetal liver (57%) and placenta (16%) compared with maternal liver. These data and the pharmacokinetics of ethanol and its proximate metabolite, acetaldehyde, in the near-term pregnant ewe indicate that ethanol elimination from the maternal-fetal unit is regulated primarily by maternal hepatic ADH-catalyzed biotransformation of ethanol, and low KM ALDH activity in the fetal liver and placenta protects the fetus from exposure to ethanol-derived acetaldehyde, which is produced primarily in the maternal compartment.
Developmental pharmacology and therapeutics 02/1989; 12(1):35-41.
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ABSTRACT: Seven pregnant women with early-onset (less than 32 weeks' gestation) intrauterine growth retardation were studied to examine fetal heart rate and fetal activity patterns after vibratory acoustic stimulation. All studies were done between 26 and 32 weeks' gestation. All fetuses but one were not acidotic at birth. There was a reduced time during which accelerations (50% less), long-term fetal heart rate variability (25% less), and body movements (60% less) occurred in small-for-gestational-age fetuses compared with these times in age-matched normally grown fetuses. Fetal heart rate and fetal activity patterns were not significantly altered after stimulation with the electronic artificial larynx. We hypothesized that severe, early-onset (less than 32 weeks' gestation), chronic nutritional deprivation of human fetuses is associated with a delay in the functional maturation of fetal sensory receptors.
American Journal of Obstetrics and Gynecology 02/1989; 160(1):160-5. · 3.47 Impact Factor
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ABSTRACT: Ethanol (2 gm/kg of maternal body weight administered in four equal doses of 0.5 gm/kg over 5 hours) was infused intravenously into nine chronically prepared pregnant ewes between 124 and 137 days' gestation. The data demonstrated a dose-response relationship between fetal arterial ethanol concentrations and the incidence of fetal breathing movements. Suppression of normal fetal electrocortical activity occurred at a low ethanol concentration and returned to control values at a time of very high arterial ethanol concentrations. This experimental model of a binge drinking episode further supports the hypothesis that ethanol suppresses fetal breathing movements by a direct central mechanism rather than indirectly by alteration of electrocortical activity.
American Journal of Obstetrics and Gynecology 01/1989; 159(6):1424-9. · 3.47 Impact Factor
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ABSTRACT: Forty-three healthy pregnant women between 26 and 40 weeks' gestation were studied to determine the influence of prestimulation basal heart rate on the maximum amplitude of the first fetal heart rate acceleration after external vibratory acoustic stimulation. A significant negative correlation was found between the maximum amplitude of the first fetal heart rate acceleration and the prestimulation basal fetal heart rate from 30 weeks to term. In the presence of fetal tachycardia (basal fetal heart rate greater than 160 beats/min), more than 50% of fetal heart rate accelerations after stimulus were less than 15 beats/min amplitude. There was also a significant maturational process in the immediate fetal heart rate response to vibratory acoustic stimulation that occurred between 26 to 28 and 30 to 32 weeks characterized by a prolonged increase in basal fetal heart rate and an increase in the maximum amplitude of the first acceleration after stimulation.
American Journal of Obstetrics and Gynecology 11/1988; 159(4):835-9. · 3.47 Impact Factor
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ABSTRACT: Twelve healthy pregnant women between 37 and 41 weeks' gestational age were studied to determine the effects of external vibratory acoustic stimulation on the blood flow velocity waveform in the umbilical and uterine arteries. There was a significant decrease in umbilical peak-systolic/end-diastolic ratio during the first 5 minutes after stimulus after comparison with control ratios. Analysis of the frequency distribution of instantaneous fetal heart rate values during Doppler measurements suggested that the decrease in umbilical peak-systolic/end-diastolic ratio was due to fetal tachycardia rather than a change in the placental vascular resistance. The uterine artery peak-systolic/end-diastolic ratio was not altered after vibratory acoustic stimulation.
American Journal of Obstetrics and Gynecology 10/1988; 159(3):574-8. · 3.47 Impact Factor
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ABSTRACT: A chronic fetal sheep preparation was developed to measure, without interruption in utero, urethral and urachal urine output to the amniotic and allantoic sacs, respectively. Fetal urethral, urachal and total urine output was measured during a 5 day post-operative period, in late gestation. Total fetal urine output increased from day 1 to a volume of 1216 +/- 115 ml/day (SEM) on day 5 post-operative. Urachal urine output increased significantly from 12 ml/day on day 1 to 467 ml/day on day 5 (P less than 0.05). Fetal arterial blood gases, pH and immunoreactive ACTH, cortisol and immunoreactive arginine vasopressin concentrations were stable throughout the 5-day recovery period. Fetal urachal urine output to the allantoic cavity and total fetal urine output appears to require 4-5 days to stabilize post-operatively. Fetal urine is a major source of amniotic and allantoic fluid in late gestation and the volume of these sacs may be influenced, in part, by the distribution of urethral and urachal urine output.
Journal of developmental physiology 09/1988; 10(4):309-19.
