Physiologic variability and fetal electrocortical activity

The relationship between fetal electrocortical activity and multiple fetal parameters was examined in chronically instrumented fetal lambs. Consistent small but significant changes in fetal heart rate, mean arterial pressure, umbilical blood flow, and the cerebral uptake of glucose relative to oxygen were observed as fetal electrocortical activity cyclically shifted between high-voltage slow activity and low-voltage fast activity. Cardiovascular parameters were higher and the cerebral uptake of glucose relative to oxygen was lower during high-voltage slow activity than during low-voltage fast activity. The implication of these observations is discussed.     

Effects of clonidine on breathing movements and electrocortical activity in the fetal lamb

Clonidine is a recommended antihypertensive for use during pregnancy, although little is known of its fetal effects. This study examines the effects of clonidine on breathing and sleep-state cycling in fetal lambs. Clonidine was infused into a fetal lateral ventricle for up to 24 hours at 128 to 135 days' gestation. Control infusions of artificial cerebrospinal fluid had no effect. Clonidine infusion significantly reduced the incidence and episode duration of fetal breathing for the duration of the infusion period. Cycling of electrocortical activity became irregular and rapid, and the incidence of high-voltage electrocortical activity (equivalent to quiet sleep) was reduced. Fetal heart rate decreased but arterial pressure was unaffected. After infusion the breathing incidence and episode duration both increased significantly compared with control, with continuous high-amplitude breathing for several hours, whereas the incidence of high-voltage electrocortical activity remained low. Because lung development is promoted by fetal breathing, long-term use of clonidine during pregnancy could slow lung development by reducing fetal breathing activity.     

Pre-ejection period of cardiac cycles in fetal lamb.

The pre-ejection period (PEP) of the fetal cardiac cycle was studied on 22 chronically instrumented pregnant ewes. The PEP was measured from the onset of the Q wave on fetal electrocardiogram to the onset of the upstroke on the fetal arterial blood pressure curve. Lengthening of the PEP was observed in association with an increase in gestational age, fetal body weight, fetal brow-rump length, and fetal heart weight. Consequently, the PEP values were calculated to those at fetal heart weight of 10 grams. The PEPc (calculated) was prolonged by acidosis but no significant relationship was found between the PEPc and arterial blood pO2. An increase in coronary blood flow was associated with a shortening of the PEPc in the fetuses under normal physiologic conditions. Fetal hypoxemia and respiratory acidosis created by administration of 10 per cent O2 and 20 per cent CO2 with 20 per cent O2 to the mother increased fetal coronary flow and was in general associated with a prolonged pre-ejection period.     

Cardiovascular effects of fever in the ewe and fetal lamb.

Ewes carrying fetuses with permanently implanted cannulas developed fevers following intravenous injections of bacterial pyrogen (1 microng). During the rising phase of the fever, maternal heart rate increased, but no consistent changes in mean arterial blood pressure (MABP), arterial pH, PO2, or PCO2 were observed during the course of the fever. Fetal temperature, which was initially 0.3 to 0.8 degrees C. higher than maternal temperature rose in parallel with the ewe's temperature. During the maternal fever, fetal MABP, pH, PO2, and PCO2 remained unchanged, but on several occasions the fetal heart rate developed irregularities that persisted after the fever had subsided. These observations suggest that maternal fever does not appear to have adverse effects on fetal oxygenation but has a variable effect on cardiovascular function.     

Effects of acute hypoxemia on fetal movement in the fetal lamb

Chronically instrumented pregnant models were established using 5 Dorset-Rambouillet pregnant ewes with gestational age between 120 and 138 days. Observation of fetal movements were started on the 3rd postoperative day or later when recovery from the surgery to the physiological condition was confirmed by maternal and fetal biophysical parameters. Fetal movements were observed using real-time ultrasound equipment with linear-array transducer placed on the maternal abdomen. Observation encompassed the control period which lasted one hour followed by an experimental period of fetal hypoxemia created by decreasing maternal FIO2. Observation was also continued during the recovery period when the mother was re-exposed to room air. Maternal and fetal samples were periodically obtained during these periods. Frequency of fetal movements was studied in 10 minute periods under the control and hypoxemic conditions. All fetuses exhibited movements during the control period, ranging 1-42 movements/10 minutes, the mean incidence being 16.9 movements/10 minutes. During fetal hypoxemia (average PaO2 decrease: 8.6 mmHg), fetal movements were significantly reduced to 5.5 movements/10 minutes with complete cessation in some cases. In 4 animals which exhibited complete cessation of both fetal movement (FM) and fetal breathing movement (FBM), FBM disappeared before FM, and reappearance of FM was following by FBM during recovery from hypoxemia.     

Accuracy of echocardiography measurements in the fetal lamb

Echocardiography is becoming an important noninvasive method to evaluate the heart of the human fetus. Validation of this technique, however, is lacking. To establish the correlation of M-mode and two-dimensional echocardiography with direct invasive methods, the size and volume of the heart of 10 fetal lambs were determined. Both M-mode echocardiography as well as the two-dimensional method were found to correlate well with direct measurements. As determined by all three modalities, the right ventricular cavity was found to be larger than the left ventricular cavity. Intraventricular septum thickness was best measured by the two-dimensional technique, whereas posterior wall dimensions were difficult to assess by this technique. This is the first study that attempts to validate echocardiography as it pertains to the fetus. It shows that a good correlation between invasive and noninvasive methodology can be obtained. Encouraging findings may lead other investigators to use such techniques in the human fetus to quantify ventricular size and output under normal and abnormal conditions.     

Effects of thyrotropin-releasing hormone in the fetal lamb

Thyrotropin-releasing hormone causes neurobehavioral arousal and stimulates breathing in adult, newborn, and preterm experimental animals. Its effects on behavioral state, breathing, blood pressure, and heart rate were studied in the chronically instrumented late term fetal lamb. Fetal intravenous administration of thyrotropin-releasing hormone resulted in behavioral arousal with electrocortical desynchronization, increased body and eye movements, rapid and deep breathing movements, and a transient bradycardia followed by prolonged tachycardia, associated with an increase in both systolic and diastolic blood pressure. The effects were similar following intracisternal administration of thyrotropin-releasing hormone. The effects of thyrotropin-releasing hormone on behavior, but not breathing, was abolished in the presence of muscarinic blockade. Thyrotropin-releasing hormone may play a role in the modulation of central regulation of cardiovascular, respiratory, and behavioral activity in the fetus.     

Sources and disposition of fetal glucose: studies in the fetal lamb

Three aspects of fetal glucose metabolism are studied in the pregnant sheep: source of fetal glucose, rates and routes of fetal glucose disposal, and how these processes are regulated in the fetus. However, extrapolation of findings in the fetal sheep to the condition existing in the human must be made with great caution. This is mainly due to the fact that sheep are ruminants that obtain much of their energy from volatile fatty acids and fetal sheep have low glucose and high fructose concentrations.     

The increase in fetal hemoglobin synthesis in the fetal lamb during hyperglycemic hypoxemia

To determine whether fetal hypoxemia induced by hyperglycemia has any effect on the proportions of fetal and adult hemoglobin synthesized during fetal development, hemoglobin synthesis was determined after a period of hyperglycemic hypoxemia in the fetal lamb. These experiments were carried out at a time in gestation during the switch from fetal to adult hemoglobin. Twelve catheterized fetal sheep were included in this study. Seven were made hyperglycemic by glucose infusions during 5 days (group I) and five were control animals (group II) that received saline solution infusions (0.45 gm/dl). In group I, glycemia increased from 14.7 +/- 5.0 to 54.6 +/- 16.4 mg/dl (p less than 0.001), whereas oxygen content decreased from 8.5 +/- 1.7 to 6.4 +/- 2.2 ml/dl (p less than 0.01). Red blood cells obtained before and after 5 days of glucose or saline solution infusions were incubated in an amino acid mixture containing 14C-leucine. The hemoglobins were then subjected to polypeptide chain elution with carboxymethyl cellulose chromatography. The amount of fetal hemoglobin synthesized was determined by the ratio of radioactive gamma-chain to total of radioactive non-alpha-chains. The data demonstrated that the hyperglycemic fetus synthesizes more fetal hemoglobin than expected for the period of fetal development (78.0% +/- 10.9% versus 59.8% +/- 11.3%, p less than 0.02).     

Ultrasound evaluation of tachycardia-induced hydrops in the fetal lamb

Nonimmune hydrops was induced in six fetal lambs at 120 days' gestation by right atrial pacing at 300 beats/min. Biochemical, hemodynamic, and Doppler parameters were observed and monitored by real-time ultrasound during the creation (18 to 42 hours) and resolution of hydrops. The significant changes seen were hypoproteinemia (34.3 to 29.0 mg/100 ml), venous hypertension (24.6 to 31.3 mm Hg), decreases in thoracic aorta flow, and decreases in systolic/diastolic ratios in the aorta and umbilical artery. These changes were reversed with the discontinuation of pacing and the resolution of fetal hydrops.     

Natural protective mechanisms against endoscopic white-light injury in the fetal lamb eye.

OBJECTIVE: To evaluate light transmission, possible light trauma, and techniques for protection of the fetal eyes during intrauterine videoendoscopic surgery in a sheep model. METHODS: In vitro studies were done at various gestational ages, including spectrometry of light output by a halogen light source and telescope and light transmission by spectrophotometry in the range of 180-3000 nm through amniotic fluid (AF) and fetal eyelids. In vivo electron-microscopic, morphologic analysis of the retinas of 65-, 95-, 108-, and 112-day-old fetal lambs with (n = 8) and without (n = 8) 30 minutes' light exposure to the open eye was also done. RESULTS: The light spectrum at the tip of the telescope was 400-750 nm, with a maximum irradiance of 3x10(-3) W/cm2 at 580 nm. In the ultraviolet spectrum (less than 300 nm), irradiance was less than 0.5x10(-3) W/cm2. Light transmission through ovine AF ranged from 30% at 300 nm to 89% at 700 nm at 84 days' gestation, decreasing to less than 0.01% (300 nm) and 70% (700 nm) at 112 days. Fetal eyelids did not transmit more than 1% of light (any wavelength). After direct in vivo light exposure, no retinal damage was found. Photoreceptors were present from 108 days onward, but chromophores were scant or absent at all ages studied. CONCLUSION: The light spectrum of a standard endoscope is limited to 400-750 nm; ultraviolet light is filtered out. The AF transmits harmful blue light poorly. Fetal eyelids seem to protect the eye by extremely low transmission and light dispersion. Even with the eye open, no morphologic retinal damage was found. The strong light sources used with fetal endoscopy did not appear to pose a threat to the fetal retina.     

Autonomic nervous system regulation of baseline heart rate in the fetal lamb.

OBJECTIVE: We examined 29 chronically instrumented fetal lambs from 125 to 143 days' gestation to investigate the effects of fetal behavioral states and autonomic nervous system maturation on baseline fetal heart rate. STUDY DESIGN: Behavioral states were defined from electrocorticographic analysis as low-voltage fast activity or high-voltage slow activity. Decrease and increase in baseline fetal heart rate subsequent to administration of propranolol and methylatropine represented beta-sympathetic and parasympathetic activity. RESULTS: Baseline fetal heart rate decreased with gestation in both states, with steeper regression in low-voltage fast activity (p less than 0.001). Positive correlation was noted between gestational age and percent decrease baseline fetal heart rate in both states with steeper regression in high-voltage slow activity (p less than 0.001), and between gestational age and percent increase baseline fetal heart rate with steeper regression in low-voltage fast activity (p less than 0.001). Fetal heart rate beta-sympathetic and parasympathetic tones increased with age in both states, with elevation of beta-sympathetic tone in high-voltage slow activity and parasympathetic tone in low-voltage fast activity. CONCLUSION: Sympathetic and parasympathetic systems influence baseline fetal heart rate in these behavioral states and with age.     

Experimentally produced sinusoidal fetal heart rate pattern in the chronically instrumented fetal lamb

A sinusoidal fetal heart rate and elevated fetal arginine vasopressin levels were found in two bled fetal lambs. Arginine vasopressin was continuously infused intravenously in chronically instrumented fetal lambs at rates ranging between 1.0 and 90 mlU/kg/min. No sinusoidal heart rate occurred in 21 experiments on six control animals with intact vagal nerves. Atropine at doses less than 0.4 mg had no effect (six experiments on three animals). Higher doses of atropine (greater than 1.2 mg) resulted in sinusoidal heart rate (24 experiments on six animals). Twenty-three infusions were performed in five bilaterally vagotomized fetuses, and the sinusoidal heart rate was successfully induced in 17 experiments. The arginine vasopressin infusion rate was less than 1.5 mlU/kg/min on the six occasions in which the sinusoidal heart rate did not appear. All sinusoidal heart rate patterns were associated with fluctuation of fetal arterial pressure at the same frequency. There was a linear correlation between the amplitude of sinusoidal heart rate and magnitude of arterial blood pressure fluctuation. The amplitude of sinusoidal heart rate increased with the concentration of arginine vasopressin infused. Modification of sinusoidal heart rate pattern was attempted with use of sympathetic agonists and antagonists. The possible etiology and mechanisms of sinusoidal heart rate pattern are discussed.     

Drug accumulation in lung fluid of the fetal lamb after maternal or fetal administration

The pharmacokinetic characteristics of the antiemetic drug metoclopramide and the antihistamine diphenhydramine have been determined in a chronically catheterized pregnant sheep preparation. Metoclopramide and diphenhydramine were administered by separate maternal and fetal intravenous infusions to a steady state as well as by maternal intravenous bolus dosing. Drug concentrations in the maternal and fetal plasma and the amniotic and tracheal fluids were measured by means of capillary gas-liquid chromatographic assay techniques. Both metoclopramide and diphenhydramine were excreted into tracheal fluid in substantial quantities. Tracheal metoclopramide concentrations were found to exceed fetal plasma levels by about fifteen-fold while diphenhydramine attained maximal excretion in tracheal fluid of about five times that seen in fetal plasma. Drug levels were observed to accumulate slowly in amniotic fluid and eventually to exceed tracheal concentrations. The markedly elevated concentrations of these drugs in fetal lung fluid suggests that the fetal lung may be an important route of drug distribution, elimination, and excretion.     

Tissue heating effect of pulsed Doppler ultrasound in the live fetal lamb brain.

A series of experiments in fetal lambs investigated the heating effects of pulsed Doppler ultrasound on fetal brain tissue. In dead lamb brain, tissue heating was observed at the skull bone-to-brain interface. Minimal or no temperature rise was found in the live lamb, suggesting that the intact circulation conducts away any potential heating. The choice of animal model and the state of the circulation influence the results obtained. This will of course have implications for clinical practice.     

Contribution of the fetal baroreceptor reflex to the low frequency component of fetal heart rate fluctuations

OBJECTIVE: The objective of this study was to examine whether the fetal baroreceptor reflex contributed to the low frequency component (LF: 0.025-0.125 cycles/beat) of fetal heart rate fluctuations. METHODS: Sheep fetuses in late gestation with normoxemia were used. The baroreceptor function was expressed as the baroreceptor reflex sensitivity (BRS) based on the change of the R-R interval in response to the elevation of blood pressure by noradrenaline (Nor-Ad). A frequency analysis was conducted by the autoregression method on heart rate fluctuations and blood pressure fluctuations in 300 stable heart beats immediately before the Nor-Ad test. The gain and the coherence from blood pressure LF to heart rate LF were calculated. The correlations between the BRS and the power values of heart rate LF, blood pressure LF, and the gain or the coherence were examined. RESULTS: The BRS and the gain showed a positive correlation (p < 0.01). There was a negative correlation between the heart rate LF and the BRS, and between the blood pressure LF and the BRS (p < 0.01, p < 0.005). CONCLUSIONS: This study showed that fetal BRS was involved in the change of LF in fetal heart rate fluctuation. Baroreceptor function should be considered when examining the change of LF domain in fetal heart beat fluctuation.