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.     

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.     

Dehydration increases the renal response to atrial natriuretic peptide in fetal sheep.

OBJECTIVE: In sheep, maternal water deprivation results in urinary natriuresis in spite of suppression of plasma atrial natriuretic factor levels. Near-term fetal sheep also have a urinary natriuresis without change in plasma atrial natriuretic factor during maternal dehydration. This study was designed to explore the role of plasma atrial natriuretic factor levels in fetal dehydration-natriuresis. STUDY DESIGN: Eight chronically instrumented preterm (113 +/- 1 days) ovine fetuses received two atrial natriuretic factor infusions (3 and 15 ng/kg/min) in a euhydrated state and after 48 +/- 1 hours of maternal water deprivation. RESULTS: Dehydration significantly increased maternal plasma osmolality (302 +/- 2 to 313 +/- 2 mOsm/kg water), sodium (148.1 +/- 0.8 to 154.3 +/- 0.4 mEq/L), chloride (112.4 +/- 0.6 to 116.8 +/- 0.9 mEq/L), and arginine vasopressin (4.2 +/- 1.2 to 23.0 +/- 4.0 pg/ml) and significantly decreased plasma atrial natriuretic factor (36 +/- 6 to 19 +/- 4 pg/ml) concentrations. Fetal plasma osmolality (296 +/- 1 to 308 +/- 2 mOsm/kg), atrial natriuretic factor (128 +/- 16 to 241 +/- 36 pg/ml), and arginine vasopressin (3.5 +/- 0.8 to 12.3 +/- 4.8 pg/ml) concentrations and urine osmolality (170 +/- 10 to 253 +/- 10 mOsm/kg), osmolar clearance (0.80 +/- 0.02 to 0.14 +/- 0.02 ml/kg/min), and fractional sodium excretion (3.3% +/- 1.7% to 8.5% +/- 2.1%) increased significantly with dehydration, whereas the plasma atrial natriuretic factor clearance decreased from 127 +/- 27 to 63 +/- 10 ml/kg/min. Dehydration had no effect on fetal hematocrit, vascular pressures, glomerular filtration rate, urine flow, or free water clearance. In euhydrated fetuses plasma atrial natriuretic factor increased from 128 +/- 16 to 287 +/- 46 pg/ml with sequential atrial natriuretic factor infusion, and no significant increases were observed in urine flow, fractional sodium excretion, and glomerular filtration rate. In contrast, atrial natriuretic factor infusion to dehydrated fetuses significantly increased urine flow (0.17 +/- 0.03 to 0.32 +/- 0.07 ml/kg/min), osmolar clearance (0.14 +/- 0.02 to 0.28 +/- 0.06 ml/kg/min), and fractional sodium excretion (8.5% +/- 2.1% to 14.8% +/- 4.0%). CONCLUSION: These results demonstrate that in the fetus at 113 days' gestation plasma atrial natriuretic factor levels increase with dehydration, probably a result of decreased plasma atrial natriuretic factor clearance, and the fetal renal responsiveness to atrial natriuretic factor infusion increases during maternal dehydration.     

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 fetal breathing and swallowing activity in response to plasma glucose changes.

Fetal swallowing activity generally occurs simultaneously with fetal breathing movements (FBM) in sheep. The present study investigated the FBM and swallowing responses to altered fetal plasma glucose. Fetal lambs were chronically prepared with laryngeal, esophageal and diaphragm electromyogram (EMG) wires, an esophageal flow probe and vascular catheters. Beginning at 138 +/- 1 day, FBM and swallowing were monitored during control periods and in response to intravenous glucose infusions (14 mg/kg/min for 120 min) to fetuses of fed and fasted ewes. Glucose infusions to fetuses of fed ewes resulted in significant increases in fetal plasma glucose (21.2 +/- 0.7 to 40.5 +/- 1.9 mg/dl) and time breathing (46.2 +/- 6.3 to 60.0 +/- 9.5 min/2 h). In response to maternal fasting, fetal glucose levels (13.4 +/- 1.0 mg/dl) and time breathing (23.0 +/- 7.2 min/2 h) decreased significantly. Glucose infusion to fetuses of fasted ewes resulted in significant increases in time breathing (50.3 +/- 13.4 min/2 h) and diaphragmatic EMG activity (1,295 +/- 654 to 3,012 +/- 1,182 spikes/2 h). There was no change from basal levels of fetal EMG swallows (83.2 +/- 4.3 swallows/2 h) or esophageal flow (40.8 +/- 7.9 ml/2 h) in response to maternal fasting or fetal glucose infusions.     

Fetal hypoxia elevates plasma atrial natriuretic factor concentration

Acute hypoxia in the fetus is associated with a reduction in fetal blood volume. We hypothesized that atrial natriuretic factor in the fetal circulation may be one of the factors that mediate this blood volume decrease. Thus the present study was designed to determine the effects of hypoxia on circulating concentrations of atrial natriuretic factor in fetal sheep and correlate these changes with fetal blood volume. Hypoxia was induced in chronically catheterized sheep fetuses by infusing nitrogen containing CO2 into the trachea of the ewe for 30 minutes. Fetal arterial PO2 decreased by 10.2 +/- 1.3 (SE) mm Hg. Plasma atrial natriuretic factor concentration rose concurrently with the fall in PO2 such that atrial natriuretic factor increased to 565 +/- 196 pg/ml from a basal level of 127 +/- 13 pg/ml (p less than 0.001). Fetal blood volume was reduced by 7.2% +/- 2.1% and was significantly related to changes in atrial natriuretic factor levels (p less than 0.0001). At the termination of hypoxia, PO2 returned to normal levels before plasma concentrations of atrial natriuretic factor fell to baseline values. Therefore fetal hypoxia appears to be a potent stimulus for elevating plasma concentration of atrial natriuretic factor in the fetus, and this rise in atrial natriuretic factor in the circulation may be partially responsible for the reduction in fetal blood volume observed during hypoxia.     

Human amniotic fluid urogastrone (epidermal growth factor) and fetal lung phospholipids

Urogastrone was measured by radioimmunoassay in amniotic fluid obtained from 186 complicated pregnancies at 22 to 40 weeks gestation. Amniocentesis was performed for a variety of indications to obtain information about fetal lung maturity or bilirubin levels before induction of labour or caesarean section in various obstetric conditions. In 114 specimens lung phospholipids extracted from amniotic fluid were also assayed using two-dimensional thin layer chromatography. Urogastrone concentrations became measurable at approximately 30 weeks gestation and thereafter there was a 10-fold rise in concentrations between 30 and 40 weeks gestation. This increase in urogastrone concentration was positively correlated with a rise in phosphatidylcholine and phosphatidylglycerol concentrations and the phosphatidylcholine (lecithin)/sphingomyelin ratio (L/S). These results are compatible with a role for urogastrone in human fetal lung maturation.     

Human amniotic fluid urogastrone (epidermal growth factor) and fetal lung phospholipids

Summary. Urogastrone was measured by radioimmunoassay in amniotic fluid obtained from 186 complicated pregnancies at 22 to 40 weeks gestation. Amniocentesis was performed for a variety of indications to obtain information about fetal lung maturity or bilirubin levels before induction of labour or caesarean section in various obstetric conditions. In 114 specimens lung phospholipids extracted from amniotic fluid were also assayed using two-dimensional thin layer chromatography. Urogastrone concentrations became measurable at approximately 30 weeks gestation and thereafter there was a 10-fold rise in concentrations between 30 and 40 weeks gestation. This increase in urogastrone concentration was positively correlated with a rise in phosphatidylcholine and phosphatidylglycerol concentrations and the phosphatidylcholine (lecithin)/sphingomyelin ratio (L/S). These results are compatible with a role for urogastrone in human fetal lung maturation.     

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.     

Amniotic fluid prolactin and fetal lung maturation

Concentrations of prolactin in amniotic fluid, fetal plasma, and maternal plasma were determined in 34 rhesus monkeys delivered by hysterotomy under general anesthesia at gestational ages of 110 to 160 days (term, 165 days). Included were 15 cases (gestational ages 110 to 143 days) in which the mothers received 2 mg of betamethasone intramuscularly daily for 3 days prior to delivery. Fetal lung maximum volumes were determined in addition to the following indices of fetal lung surfactant: lung alveolar stability, lung phosphatidylcholine concentrations, lung extract surface tensions, and amniotic fluid lecithin to sphingomyelin ratios. Amniotic fluid prolactin was found to correlate significantly with lung alveolar stability (r = 0.51; p less than 0.01), lung phosphatidylcholine (r = 0.51; p less than 0.01), lung extract surface tension (r = -0.39, p less than 0.05) and amniotic fluid lecithin/sphingomyelin ratio (r = 0.50; p less than 0.01). These correlations remained statistically significant even when the effects of gestational age were taken into account. These findings suggest that amniotic fluid may modulate fetal production of surfactant via its prolactin content.     

Atrial natriuretic factor maternal and fetal concentrations in severe preeclampsia

There is a reduction in intravascular volume in patients with preeclampsia. Since the secretion of atrial natriuretic factor by human atrial myocytes is stimulated by increased intraatrial pressure or atrial distention, we sought to determine whether circulating maternal plasma atrial natriuretic factor concentrations were lower in patients with preeclampsia compared to normal pregnant women. The level of alpha-human atrial natriuretic factor was measured by a specific radioimmunoassay. Maternal venous concentrations of a alpha-human atrial natriuretic factor were higher in patients with severe preeclampsia (116.12 +/- 13.37 pg/ml) than in normal pregnant women (80.30 +/- 4.02 pg/ml). Umbilical artery alpha-human atrial natriuretic factor concentrations were higher in fetuses born to patients with severe preeclampsia (197.68 +/- 29.10 pg/ml) than normal control subjects (118.00 +/- 12.52 pg/ml). Umbilical artery alpha-human atrial natriuretic factor concentrations were higher than umbilical or maternal venous concentrations. In cases of severe preeclampsia, despite the presumed volume changes, maternal atrial natriuretic factor concentrations are higher than in normal pregnant women. The fetus appears to produce its own atrial natriuretic factor. Umbilical artery atrial natriuretic factor concentrations in fetuses born to preeclamptic mothers are higher than those seen in normal control subjects.     

Ovine fetal cardiovascular responses to packed red blood cell transfusions

Fifteen transfusions were performed in normal or anemic chronically catheterized sheep fetuses ranging in weight from 0.73 to 3.62 kg and in age from 91 to 135 days' gestation (term = 147 days). During the transfusions, an average of 29.0 +/- 2.5 (SE) ml/kg of packed maternal red blood cells (hematocrit = 78%) were given intravenously over 30 minutes and fetal hematocrit increased from 28.5% +/- 1.2% to 43.8% +/- 1.6%. Circulating blood volume increased by 13.9 +/- 2.3 ml/kg at 1 hour after transfusion and remained at this level at 24 hours. An average of 15.1 +/- 2.4 ml/kg of plasma was lost from the circulation at 1 hour after the transfusion. Fetal vascular pressures increased significantly during the transfusions and the rise in arterial pressure was greater than that in venous pressure (p less than 10(-6]. Heart rate decreased by 23 beats/min at the end of the transfusion and remained 13 beats/min below control after 1 hour (p less than 10(-6]. From the measured blood volume changes, formulas were developed so that the fetal blood volume before the transfusion and the posttransfusion hematocrit could be accurately calculated (r greater than 0.90). Thus this study shows that packed cell transfusions increase fetal blood volume by only 50% of the transfused volume because of a loss of plasma from the circulation and that the pretransfusion blood volume and the posttransfusion hematocrit can be accurately calculated from readily measured variables.     

Determinants of fetal and maternal atrial natriuretic peptide concentrations at delivery in man

Matched maternal venous (MV), umbilical artery (UA) and umbilical vein (UV) concentrations of atrial natriuretic peptide [ANP] were measured in 36 normotensive women at term delivery (23 vaginal, 13 caesarean) and 17 non-pregnant women in the first half of the menstrual cycle. MV [ANP] at caesarean section was similar to that in non-pregnant women, but UA and UV [ANP] were higher (P less than 0.01 for both). UA, but not UV, [ANP] was markedly raised after vaginal delivery. Plasma concentrations of aldosterone [ALD] were measured in 16 of the matched sets of samples. No statistically significant association was found between [ANP] and [ALD] in either maternal or fetal samples. Neither maternal nor fetal [ANP] correlated with serum Na+ or osmolality, haematocrit, blood pressure or heart rate.     

Magnetic resonance spectroscopy to detect lecithin in amniotic fluid and fetal lung

BACKGROUND: Proton magnetic resonance spectroscopy is a noninvasive technique that detects molecules within a specified region in vivo. Lecithin, the major component of surfactant, has a characteristic magnetic resonance signal, but to our knowledge, it has never been reported in fetal lung or amniotic fluid (AF). The objective of this study was to characterize the lecithin signal in utero, which could lead to a noninvasive fetal lung maturity test. METHOD: Human fetal lung and AF pockets can be identified and studied with magnetic resonance spectroscopy with the use of a 1.5-tesla Vision whole-body magnetic resonance scanner (Siemens Medical Systems; Erlangen, Germany). Spectroscopy data are collected with a single-voxel-point-resolved spectroscopy sequence. After identification of fetal anatomy with the use of scout magnetic resonance images, magnetic resonance spectroscopy of human fetal lung and AF identifies a lecithin peak. EXPERIENCE: Three healthy gravidas near term were studied and lecithin peaks were identified in all. CONCLUSION: Lecithin can be identified in vivo with the use of volume-selected proton magnetic resonance spectroscopy. Patient comfort and extremely short scan times suggest that refined magnetic resonance spectroscopy might be a safe, quick, and comfortable test of fetal lung maturity.     

Determinants of fetal and maternal atrial natriuretic peptide concentrations at delivery in man

Summary. Matched maternal venous (MV), umbilical artery (UA) and umbilical vein (UV) concentrations of atrial natriuretic peptide [ANP] were measured in 36 normotensive women at term delivery (23 vaginal, 13 caesarean) and 17 non-pregnant women in the first half of the menstrual cycle. MV [ANP] at caesarean section was similar to that in nonpregnant women, but UA and UV [ANP] were higher ( P <0.01 for both). UA, but not UV, [ANP] was markedly raised after vaginal delivery. Plasma concentrations of aldosteronce[ALD] were measured in 16 of the matched sets of samples. No statistically significant association was found between [ANP] and [ALD] in either maternal or fetal samples. Neither maternal nor fetal [ANP] correlated with serum Na⁺ or osmolality, haematoerit, blood pressure or heart rate.     

Is human atrial natriuretic peptide in fetal blood useful as a parameter to detect the decompensate state of the fetal heart?

In nonimmunologic hydrops fetalis associated with heart anomaly, plasma human atrial natriuretic peptide (hANP) values in umbilical venous blood were significantly higher than those in normal infants. These findings indicate that significant release of hANP from atria is induced by the decompensatory state of the fetal heart.     

The use of amniotic fluid viscosity measurements to establish fetal lung maturity.

A Haake viscosimeter was used to determine the viscosity of amniotic fluid and this value correlated with fetal lung maturity. The results were evaluated along the weeks of pregnancy and compared to those obtained using Gluck's method (lecithin/sphingomyelin ratio (L/S). Using 91 separate amniotic fluid samples, free of meconium and blood contamination, we found that the new method was quick and easy to perform. Thirty-one neonates were delivered within 48 h of the amniotic fluid sampling and the percentage of correct prediction of respiratory distress syndrome (RDS) was 71% with a mature L/S ratio and 83% with viscosity less than 1.17 cP. In cases with an immature L/S ratio (value below 2) the correct prediction of RDS was 64%; with the fluorescence polarization (FP) technique it was 91%. We conclude that the amniotic fluid FP value is a reliable index of fetal lung maturity and risk for developing RDS and has also specific technical and diagnostic advantages over the L/S ratio.     

Hemorrhage-induced reductions in plasma atrial natriuretic factor in the ovine fetus.

To investigate the effects of blood volume reduction on fetal plasma atrial natriuretic factor concentrations, chronically catheterized ovine fetuses at 109 to 138 days' gestation were subjected either to withdrawal of two consecutive blood samples or to a moderate hemorrhage. In fetuses from which two blood samples of 3.5 ml each (approximately 1% of fetal blood volume) were withdrawn under basal conditions at 15- to 30-minute intervals, plasma atrial natriuretic factor concentrations in the second sample decreased by 17 +/- 7 pg/ml from 178 +/- 8 pg/ml in the first sample (p less than 0.02). If the fetal blood removed during the first sample was replaced with an equal volume of maternal blood, plasma atrial natriuretic factor concentrations did not change significantly. In these same samples, plasma arginine vasopressin and angiotensin II concentrations were unchanged between the two samples regardless of whether volume was replaced. In fetuses subjected to hemorrhages of 21% +/- 2% over 10 minutes without blood replacement, plasma atrial natriuretic factor concentration at 1.5 hours after hemorrhage was suppressed by 42 +/- 10 pg/ml from basal level of 139 +/- 9 pg/ml (p less than 0.05). Plasma atrial natriuretic factor returned to control levels by 5.5 hours after hemorrhage as blood volume returned to normal. Thus in the ovine fetus a reduction in blood volume results in a decrease in plasma atrial natriuretic factor concentrations. Also, atrial natriuretic factor appears to be more sensitive to changes in blood volume than other vasoactive hormones studied.