Ovine fetal cardiorespiratory response to nicardipine

Nicardipine, a calcium antagonist associated with decreased uterine blood flow in near-term pregnant rabbits and fetal asphyxia after maternal administration in the rhesus monkey and sheep, was infused directly to the fetus in six chronically prepared pregnant ewes at 128 days' gestation. Changes in fetal mean arterial and diastolic blood pressure levels at 2 and 30 minutes after bolus injection of 50 micrograms were minimal; by 60 minutes these values had returned to preinfusion levels. No significant changes were observed after infusion of 100 micrograms of nicardipine. Fetal heart rate, fetal arterial blood gas values, and maternal cardiovascular variables did not change at either dose. Fetal plasma concentrations of nicardipine were 78 +/- 28 ng/ml and 114 +/- 48 ng/ml at 30 minutes after infusion of 50 micrograms and 100 micrograms, respectively, well within the range previously reported to be associated with fetal asphyxia. These data suggest that the previously reported fetal acidosis from maternal infusion of nicardipine may be primarily due to a decrease in maternal uterine blood flow rather than a direct fetal effect of the drug.     

Ovine fetal swallowing: expression of preterm neurobehavioral rhythms

OBJECTIVE: Fetal swallowing contributes importantly to amniotic fluid volume regulation and fetal gastrointestinal maturation. Near-term ovine fetal swallowing occurs in discrete bouts of activity (at approximately 30-min intervals) in association with fetal electrocortical voltage changes. Thus, swallowing rhythms have been hypothesized to be entrained to fetal neurobehavioral states. In the preterm ovine fetus, electrocortical activity does not demonstrate differentiation into high- and low-voltage periods until 120-130 days' gestation. We sought to quantify patterns of preterm (114 days, 0.75 gestation) ovine fetal swallowing activity and volume, and, in view of the lack of electrocortical pattern changes, to explore whether swallowing activity was regulated by an independent central pacemaker. METHODS: Six singleton ovine pregnancies were chronically prepared with fetal and maternal femoral artery and vein catheters. Biparietal electrocortical electrodes were placed on the fetal skull. Following a minimum 5-day recovery period, fetuses were studied at 114 +/- 1 days. Patterns of fetal swallowing behavior were quantified by computer analysis of laryngeal-esophageal electromyography (EMG) and thoracic esophageal fluid flow during a 12-h period. RESULTS: Esophageal fluid flow was bidirectional, although antegrade flow predominated, leading to an average fluid acquisition rate of 13 +/- 3 ml/h (7.3 +/- 1.8 ml/h per kg) during the 12-h study (302 +/- 87 ml/day). Propagated esophageal EMG activity, representing coordinated 'swallows', averaged 56 +/- 6 swallows/h and correlated well with net esophageal fluid flow. 'Bouts' of swallowing activity (> or = 3 swallows/min) averaged 9 +/- 1 swallows/bout, lasted 1.8 +/- 1.4 min and accounted for 31 +/- 4% of the swallowed volume. Despite the absence of fetal electrocortical high-voltage/low-voltage transitions, there was a 26.1 +/- 3.9-min interval between periods of swallowing bout activity. CONCLUSIONS: Preterm (0.75 gestation) ovine fetal volume swallowed (302 ml/day) and volume swallowed for body weight (175 ml/day per kg) was significantly less than that previously noted at 0.85 gestation (831 ml/day, 274 ml/day per kg, respectively; p < 0.05) although the rates of swallowing activity were similar. The presence of swallowing bout activity at periodic intervals, in the absence of electrocortical differentiation, suggests an intrinsic central pacemaker regulating preterm fetal neurobehavior.     

Human fetal breathing response to intravenous glucose is directly related to gestational age

This prospective longitudinal study examined human fetal breathing activity over the second half of pregnancy both in the fasting state and after intravenous glucose administration. There was a linear relationship between gestational age and percent time spent breathing after glucose between 19 and 38 weeks' gestation. However, no such correlation could be demonstrated between gestational age and fetal breathing activity in the fasting state.     

Gestational age alters fetal breathing response to intravenous insulin and intravenous glucose administration

An upward change in human maternal plasma glucose concentration is known to increase the percent of time spent in fetal breathing during the late third trimester of human pregnancy. We examined the fetal breathing effects of upward change in plasma glucose (after intravenous glucose administration) and downward change (after intravenous insulin administration) at two different times of day (8 AM and 4 PM) at both 24 and 36 weeks of gestation. No change in the percent of time spent in fetal breathing was seen after insulin infusion. Fetal breathing increased after glucose infusion at 36 weeks of gestation but not at 24 weeks. Responses did not differ between tests performed at 8 AM and 4 PM.     

Ovine maternal and fetal renal vasopressin receptor response to maternal dehydration.

OBJECTIVE: Arginine vasopressin secretion increases in response to increased plasma osmolality or hypovolemia. Dehydration-induced increases in plasma arginine vasopressin levels have been shown to down-regulate arginine vasopressin V2 receptors in adult rat kidneys. Our study determined ovine maternal and fetal renal arginine vasopressin receptor characteristics and receptor response to maternal dehydration. STUDY DESIGN: Eight pregnant ewes (113 +/- 1 days) were dehydrated for 72 hours; eight animals served as controls. Renal medullary tissue was isolated from maternal and fetal kidneys, and arginine vasopressin receptor characteristics determined with saturation and competition assays using tritiated arginine vasopressin, arginine vasopressin, and arginine vasopressin analogs. RESULTS: Euhydrated maternal and fetal renal medullary arginine vasopressin receptor dissociation constant (3.0 +/- 0.3 and 1.9 +/- 0.3 nmol/L) and maximal binding capacity (149 +/- 15 and 111 +/- 33 fmol/mg protein) values were similar. Pharmacologic profiles with selective agonists indicated a predominance of V2 receptors. Dehydration significantly increased maternal and fetal plasma osmolalities (304 +/- 2 to 320 +/- 2; 296 +/- 1 to 319 +/- 3 mOsm/kg water, respectively) and arginine vasopressin levels (3.8 +/- 1.4 to 29.3 +/- 4.6; 4.4 +/- 1.0 to 16.9 +/- 5.0 pg/ml, respectively) but had no effect on arginine vasopressin receptor binding. CONCLUSION: Specific, saturable, single-site tritiated arginine vasopressin binding is present in ovine maternal and fetal renal medullary membranes. Ovine maternal and fetal renal arginine vasopressin receptors do not down-regulate in response to dehydration-induced elevations in plasma arginine vasopressin levels.     

Ovine hourly fetal urine production: relation to fetal electrocortical activity

OBJECTIVE: Ultrasound studies of hourly urine production rate in human fetuses have suggested that a fall in urine production occurs in state 2F (fetal quiet sleep) secondary to a state-dependent decrease in renal blood flow. We sought to ascertain the relationship between fetal hourly urine production rate and behavioral state in the near-term ovine fetus, a model in which urine production and fetal brain activity can be directly measured. METHODS: Six ewes with singleton pregnancies were prepared with vascular and amniotic fluid catheters. Fetuses were prepared with hindlimb vascular catheters, a bladder catheter, and biparietal ECoG electrodes. After at least 5 days of recovery (ga 130 +/- 2 days; term = 145-150 days), each animal was monitored for a 6-h period. Urine production was measured by draining the bladder catheter through a drop counter and fetal ECoG was continuously recorded (sampling rate of 50 Hz). ECoG activity was analyzed using power spectral analysis and periods of active and quiet sleep identified using both signal amplitude and corresponding 85% spectral edge frequency. RESULTS: Basal fetal arterial pH (7.36 +/- 0.01), pO2 (22.0 +/- 1.2 mmHg) and pCO2 (47.0 +/- 1.6 mmHg) and plasma (295 +/- 2 mOsm/kg) and urine (179 +/- 3 mOsm/kg) osmolalities were within normal ranges. Active and quiet sleep comprised 50 +/- 2 and 43 +/- 1% time, respectively. There was no difference in hourly urine production rate in active sleep (21.4 +/- 9.7 ml/h) and quiet sleep (18.8 +/- 7.7 ml/h). CONCLUSIONS: 1) Hourly fetal urine production rate is independent of ECoG activity state in the near-term ovine fetus. 2) Assuming only minor species differences, ultrasound measurement of human fetal hourly urine production rate can be performed without concern for fetal neurobehavioral state changes.     

Cardiovascular changes associated with fetal breathing.

Studies were carried out on seven fetal lambs, 3 to 1 weeks prior to the expected date of delivery to determine if, during fetal breathing, cardiovascular events were similar to those described as occurring with respiration after birth. The following changes were observed; (1) a slight decrease in pressures with the initiation of the rapid inspiratory movements followed by: (2) a marked elevation of the systolic and diastolic pressures; (3) a cyclic variation characterized by a fall in arterial pressure with inspiration; (4) a variable acceleration of the heart rate; and finally, (5) a typical respiratory arrhythmia. These findings demonstrated that, during fetal respiratory movements, there are some cardiovascular changes which are specific to this period of life. There are other changes which are identical to what has been observed after birth. These latter cardiovascular changes imply that the endotracheal pressure variations are the reflection of authentic inspiratory movements under the influence of the central nervous system.     

Ovine fetal lung fluid response to atrial natriuretic factor

The fetal lung is an important site of fluid production and is postulated to serve a regulatory role in fetal fluid balance. To assess the role of atrial natriuretic factor on fetal lung liquid production, we studied the effect of intravenous atrial natriuretic factor infusion on tracheal fluid production in fetal sheep with chronic vascular and tracheal catheters. Ovine fetuses (mean gestation = 130 days +/- 1 day) received successive 40-minute intravenous infusions of increasing doses of synthetic fragment 1-28 atrial natriuretic factor (5, 25, and 100 ng/min.kg-1). In response to the 25 ng/min.kg-1 infusion, fetal tracheal fluid production decreased from 1.2 +/- 0.3 ml/10 min to 0.6 +/- 0.2 ml/10 min (p less than 0.05), and remained suppressed during the 100 ng/min.kg-1 infusion (0.5 +/- 0.2 ml/10 min). There was a significant inverse correlation between tracheal fluid production and fetal plasma atrial natriuretic factor levels (r = -0.61, p less than 0.001). Basal tracheal fluid sodium and potassium concentrations (147 +/- 1 mEq/L and 5 +/- 1 mEq/L) and osmolality (291 +/- 3 mOsm) did not change during the atrial natriuretic factor infusion periods. The observation that atrial natriuretic factor acts to decrease fetal lung fluid production suggests that atrial natriuretic factor may be important in the fetal adaptive response to extrauterine life.     

Maternal dietary substrates and human fetal biophysical activity. I. The effects of tryptophan and glucose on fetal breathing movements

To study the effects of L-tryptophan and glucose on fetal breathing activity, we examined 40 women with normal term pregnancies, randomly assigned to four equal groups who either continued fasting (group C), received 1 gm of oral tryptophan (group T), received 100 gm of oral glucose (group G), or received both substrates (group T + G). Studies lasted 210 minutes, during which fetal breathing movements were observed with real-time ultrasonography and entered and analyzed for incidence, rate, and variability on a microcomputer. Plasma glucose and tryptophan levels were determined every 30 minutes. The incidence of fetal breathing movements declined in group C and rose significantly in the other groups. Breathing rates were unchanged in groups C and T but rose significantly in groups G and T + G during peak breathing intervals. Breath interval variability did not change significantly in any study group. Maternal administration of tryptophan is associated with an alteration in fetal breathing activity but to a lesser degree than that observed after maternal glucose loading.     

Absence or impaired response of fetal breathing to intravenous glucose is associated with pulmonary hypoplasia in congenital myotonic dystrophy

Two fetuses of a patient affected with myotonic dystrophy were studied ultrasonically from 28 to 34 weeks' gestation. After a 1-hour observation period, an intravenous injection of 25 gm of 50% glucose solution was given to the mother. Fetal breathing movements were 0% during the control period and increased to only 10% at 90 minutes after the injection of glucose; the episode lasted approximately 30 minutes. The infants, who were delivered at 33 and 35 weeks, had generalized hypotonia, normal arterial cord blood gases, and died shortly after birth from pulmonary insufficiency, in spite of maximum ventilatory support. Postmortem pulmonary hypoplasia was confirmed by a lung weight/body weight ratio of less than 0.019. We postulate that fetal breathing activity and its response to the injection of glucose may be a potential clinical test by which normal fetuses can be differentiated from fetuses affected by neuromuscular disorders, including myotonic dystrophy.     

Ovine fetal lung fluid response to intravenous saline solution infusion: fetal atrial natriuretic factor effect

The fetal lung, a significant source of in utero fluid production, has been postulated to serve a regulatory role in maintenance of fetal body fluid homeostasis. Whereas the fetus responds to intravascular saline solution infusions with increased urine output, the fetal lung fluid response to this stimulus is unclear. Tracheal fluid output was measured in four chronically catheterized ovine fetuses (mean gestation, 129 +/- 1 days) subjected to successive 40-minute intravenous 0.9% saline solution infusions at rates of 0.5 and 1 ml/min/per kilogram of body weight. Tracheal fluid output decreased significantly (1.7 +/- 0.1 to 1.1 +/- 0.1 ml/10 min, p less than 0.01) during the infusion and returned to basal levels during the recovery period. Lung fluid osmolality and electrolyte concentration did not change. Fetal plasma atrial natriuretic factor increased significantly in response to the saline solution infusion (364 +/- 90 to 790 +/- 286 pg/ml, p less than 0.05) and returned to basal levels during the recovery period. There was a significant inverse correlation between plasma atrial natriuretic factor levels and tracheal fluid output. These results suggest that increased fetal plasma atrial natriuretic factor decreases lung fluid production. Lung fluid does not appear to compensate for fetal body water excess. Rather, lung fluid production appears to promote intrauterine pulmonary growth and to facilitate the transition to the extrauterine environment.     

Effect of maternal intravenous glucose administration on fetal heart rate patterns and fetal breathing

This study was undertaken to evaluate the effect of maternal intravenous (IV) administration of glucose on fetal breathing and its associated fetal heart patterns. Sixteen healthy women at term gestation participated in the study. The outcome of each of the pregnancies was normal. Fetal breathing and fetal electrocardiograms were simultaneously recorded by real time sonography and a fetal monitor respectively, and then digitized into a microcomputer. These women were studied for a 25-minute control period, given 50 gm of glucose IV and then, 20 minutes later, restudied for an additional 25-minute period. The results indicate that fetal breathing movements lasted for 24.8 +/- 6.2 percent of the time during the control period (mean +/- SEM) and were increased to 63.2 +/- 11.5 percent following the injection of glucose (P less than 0.01). Fetal heart rate decreased during fetal breathing by 2.3 and 2.1 beats per minute, before and after glucose administration, respectively (NS). Fetal breathing was associated with increased beat-to-beat variability by 1.32 +/- 0.5 and 1.27 +/- 0.3, before and after glucose administration, respectively (NS). This study confirms previous reports that the amount of time the fetus spends making breathing movements is significantly increased following maternal glucose administration, and demonstrates that the injection of glucose does not alter the modulation of fetal heart rate and beat-to-beat variability by fetal breathing.     

Patterns of human fetal breathing activity at 34 to 35 weeks' gestational age.

Continuous measurements of human fetal breathing movements at 34 to 35 weeks' gestational age were made with an ultrasonic real-time scanner for periods of 24 hours in 11 women. A significant increase occurred in fetal breathing activity during the second and third hour following meals and this pattern apparently followed an increase in maternal plasma glucose concentration. There was a prolonged significant increase in fetal breathing activity between 0100 and 0700 hours. Increases in human fetal breathing activity accompanied by increased gross fetal body movements occurred for periods of 20 to 60 minutes out of every 1.0 to 1.5 hours of observation time. It was concluded that the percentage of time spent breathing by normal fetuses was related to time of day and maternal meals. The alternating changes of fetal activity and inactivity observed may represent biologic changes of sleep state in the human fetus in utero at 34 to 35 weeks' gestational age. It will be important to account for these three patterns of fetal breathing activity in clinical studies which examine the usefulness of fetal breathing movements in assessing fetal health.     

Human fetal breathing activity during electively induced labor at term.

Human fetal breathing movements were measured during the first stage of electively induced labor in 20 healthy term pregnancies. Fetuses made breathing movements 25.6% of the time during a 1 hour control period and breathing decreased significantly to 8.3% during latent-phase labor and further decreased to 0.8% during active labor (P less than 0.001). Patterns of increased fetal breathing activity accompanied by increased gross fetal body movements and increased fetal heart rate variability for periods of 20 to 60 minutes out of every 1.0 to 1.5 hours were observed, and the intermittent patterns of increased body movement and heart rate variability continued throughout the first stage of labor despite the decrease in fetal breathing activity during latent- and active-phase labor. It will be important to account for rest activity patterns when interpreting variability of heart rate during labor. The absence of fetal breathing activity during electively induced labor at term is not a clinical indicator of fetal ill health.     

Effect of maternal glucose load on fetal activity.

The effect of a MGL upon fetal activity has been studied in 39 normal and 54 high-risk pregnant patients between 30 and 42 weeks' gestation. The perinatal morbidity and mortality rates were significantly lower in the group showing an increase in fetal activity following a MGL. It is suggested that this may be useful for identifying the fetus at risk.     

Maternal hypoxemia and fetal breathing movements.

Fetal breathing movements (FBM) were observed daily using a real-time B-mode ultrasound method in a patient with sickle cell anemia in crisis. Observations were made on 2 occasions in the presence of maternal hypoxemia (PO2 less than or equal to 40 mmHg), and FBM were noted to be absent. Conversely, when maternal PO2 was 60 mmHg or greater, FBM were present 23--80% of the time. The FBM were reduced or absent within 90 minutes of maternal Demerol injection. These observations suggest that the human fetal response to hypoxemia may be similar to that observed under expermental conditions in the animal fetus.     

Electrocortical activity, electroocular activity, and breathing movements in fetal sheep with prolonged and graded hypoxemia.

OBJECTIVE: Our objective was to determine the effect of a prolonged and graded reduction in fetal arterial oxygen saturation on electrocortical activity and associated biophysical variables. STUDY DESIGN: Fourteen unanesthetized fetal sheep were studied between 126 and 135 days' gestation with continuous monitoring of electrocortical and electroocular activity and breathing movements, during a 24-hour control period, and subsequently during 4 days of prolonged and graded hypoxemia induced by progressively lowering the maternal inspired oxygen concentration. RESULTS: Graded reduction in fetal arterial oxygen saturation resulted in little change in arterial pH until close to 30% when metabolic acidemia was apparent. The incidence of low-voltage electrocortical activity, electroocular activity, and breathing movements were marginally decreased with hypoxemia alone; however, a significant decrease was not apparent until associated with the onset of fetal acidemia. CONCLUSION: Hypoxemia of a chronic nature must approach the level at which acidemia becomes apparent before a marked change in fetal behavioral activity is noted.     

Cigarette smoking and fetal breathing movements.

Cigarette smoking caused a reduction in the incidence of fetal breathing movements in normal and abnormal pregnancies. The size of the reduction varied, being greatest in small-for-dates pregnancies and pregnancies complicated by fetal distress in labour and least in pre-eclamptic pregnancies. The fall in the amount of fetal breathing movements was significantly related to the rise in maternal plasma nicotine after smoking but was unrelated to the rise in barboxyhaemoglobin. Smoking non-nicotine (herbal) cigarettes produced increases in carboxyhaemoglobin concentrations similar to those observed after smoking tobacco cigarettes, and was not associated with a fall in the incidence of fetal breathing movements. Chewing gum containing nicotine produced rises in plasma nicotine concentration similar to those observed after smoking tobacco cigarettes and was associated with a significant reduction in the incidence of fetal breathing movements. Hence nicotine appeared to be the factor in cigarette smoke responsible for the reduction in the incidence of fetal breathing movements. Nicotine was present in the cord blood of infants whose mothers smoked. The possible mechanism by which nicotine caused a reduction in the incidence of fetal breathing movements and its possible relevance to the detrimental effects of smoking on the fetus are considered.     

Fetal breathing movements and fetal distress.

Twenty-seven pregnancies were monitored by antenatal cardiotocographs, daily fetal movement counts and an assessment of fetal breathing activity by real time scanning, and the results of these tests were related to the development of fetal distress during the first stage of labour. The proportion of time during which fetal breathing movements were present, determined over only a short period of time, was found to be a useful predictor of fetal behaviour during a labour.