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In summary, fetal macrosomia occurs in almost one third of diabetic pregnancies regardless of class. Abnormal fetal fat stores lead to difficult labor, dystocia, and birth injury as well as postnatal metabolic transition. The abnormal body fat distribution at birth may destine some of these infants to lifelong obesity. Abnormal fetal growth in diabetic pregnancy appears to occur with any elevations in maternal glucose levels, however modest. Detection of macrosomia is therefore a major goal of diabetic pregnancy management.

Objective: We hypothesized that amnioinfusion with normal saline would increase fetal plasma sodium and chloride concentrations, resulting in a hyperchloremic acidosis, and that these alterations would not occur after amnioinfusion with lactated Ringer's solution., Methods: Chronically catheterized fetal sheep (137 +/- 1 days' gestation; mean +/- SE) were divided into three groups: control (n = 8), infused with normal saline (n = 10), and infused with lactated Ringer's solution (n = 10). The protocol consisted of a 30-minute pre-infusion period, a 1-hour amnioinfusion, and a 1-hour recovery period. During amnioinfusion, warmed solution was infused at a rate of 100 mL/minute for 1 hour. Fetal plasma and amniotic fluid electrolyte concentrations and osmolalities were measured every 20 minutes. Statistical analysis was by analysis of variance and linear regression., Results: Amniotic fluid electrolyte concentrations changed significantly (P < .001) in both amnioinfusion groups, resulting in amniotic fluid compositions that were essentially the same as the infused fluid 20 minutes after starting the amnioinfusion. Significant increases in fetal plasma Na+ and CI- concentrations (2-3 mEq/L) occurred in the normal-saline infusion group relative to both the control and lactated Ringer's groups (P < .001). The lactated Ringer's group demonstrated only a modest increase in plasma Na+ (P = .04) and no change in plasma Cl- concentration. Fetal arterial pH decreased (-0.015 U) in the normal-saline group, and the change in fetal pH was linearly related to the change in plasma Cl- concentration (r = -0.532, P = .004)., Conclusions: Normal-saline amnioinfusion can significantly alter fetal plasma electrolyte concentrations and blood pH, whereas amnioinfusion with lactated Ringer's solution results in minimal changes in fetal electrolytes and acid-base balance. The fetal plasma changes that occur during saline infusion are in the physiologic but not the pathologic range.

Objective: Our purpose was to define the accuracy of currently available methods of ultrasonographically estimating human fetal urinary flow rate in a controlled setting., Study Design: Eleven fetal cadavers were studied in a water bath. Saline solution was incrementally infused into the bladder to simulate a rate of 1 ml/min. Serial fetal bladder volumes were calculated from ultrasonographic measurements by means of the ovoid volume formula (ovoid volume = 4/3.pi.(D1.D2.D3)/8 and ellipse sagittal-area and coronal-area volume formulas that we previously reported (Sagittal-area volume = 0.46323 + 1.39394. Sagittal area and Coronal-area volume = 1.20640 + 1.07603. Coronal area). Fetal urinary flow rate was determined by (1) subtracting the mean of two fetal bladder volumes at the start and end of a simulated 30-minute bladder filling or (2) linear regression of three, four, five, and six fetal bladder volume observations against time. The means of fetal urinary flow rate estimates and errors derived with each method were compared to the actual rate of 1 ml/min by means of the Student t test., Results: The volume subtraction technique with ovoid volume yielded a fetal urinary flow rate of 1.68 ml/min (95% confidence interval 0.86 to 2.50 ml/min). Similar overprediction of fetal urinary flow rate occurred with regression with ovoid volume (1.45 ml/min, 95% confidence interval 0.61 to 2.29 ml/min). Estimated fetal urinary flow rates (from sagital-area volume and coronal-area volume (0.99 ml/min, 95% confidence interval 0.64 to 1.34 ml/min) were significantly more accurate than those from ovoid volume (p < 0.0001). Regression with 3 (95% confidence interval +/- 40%) or 4 points (95% confidence interval +/- 37%) was marginally less accurate than with 5 (95% confidence interval +/- 36%) or 6 points (95% confidence interval +/- 35%, p = 0.02)., Conclusions: Ultrasonographic estimates of fetal urinary flow rate based on the ovoid volume formula overestimate the true rate by 40% to 70%. Fetal urinary flow rate calculated by regression of three to six sagittal or coronal bladder area measurements is a better estimate of true rate with a satisfactory margin of uncertainty. This technique can be used to predict human fetal urinary flow rate with an expected accuracy of +/- 35%.

Objectives: This study was conducted to examine the reliability of fetal bladder volume predictions on the commonly used ovoid volume formula and to develop a simpler but equally accurate method requiring fewer measurements., Study Design: Nine hundred twenty seven measurements were obtained from 11 dead fetuses in a water bath. Known incremental volumes of saline solution were infused and the largest linear bladder dimensions length, depth, and width, were measured ultrasonographically. Bladder volumes were calculated with the ovoid volume formula, 4/3.pi.(Length.Depth.Width)/8, and compared with true volumes. The areas of the ultrasonographic planes observed during the measurement process were calculated and plotted against the true volume for regression analysis. The sagittal and coronal areas were converted into volumes with the regression equations 0.46323 + 1.39394. Sagittal area and 1.20640 + 1.07603. Coronal area, respectively., Results: The fetal bladder volumes from the ovoid formula had an average error of 6.4 ml, with a 95% confidence interval of +/- 14.1 ml. The fetal bladder volumes derived from sagittal and coronal area formulas had mean absolute errors of approximately 0 ml, with 95% confidence intervals of +/- 4.0 ml and +/- 4.4 ml, respectively. The best predictions were obtained with the sagittal area measurements., Conclusions: The ovoid volume formula overpredicts fetal bladder volume and has a wide 95% confidence interval. This inaccuracy probably affects measurements of fetal urinary flow rates. Use of the sagittal or coronal area affords improved accuracy and is easier and more convenient.

Objectives: The direct effects of furosemide infusion have not been systematically examined in the fetus. Our objective was to explore the hemodynamic and urinary responses to a 4-hour infusion of furosemide into fetal sheep., Study Design: Furosemide (0, 1, 5, or 10 mg/hr) was infused into the fetal inferior vena cava for 4 hours in 15 chronically catheterized near-term sheep., Results: Relative to vehicle infusion, furosemide produced dose-dependent increases in fetal arterial pressure (analysis of variance, p < 0.05 when comparing groups), fetal heart rate (p < 0.0001), urine flow (p < 0.0001), and urine osmolality, sodium, and chloride, concentrations (p < 0.0001). Concomitantly, there were dose-dependent decreases in fetoplacental blood volume, fetal plasma chloride (p < 0.0001) and fetal venous pressure (p < 0.05). The changes in urine flow rate and fetal arterial pressure were positively correlated (r = 0.46, p < 0.01), suggesting that the diuresis was mediated in part by fetal arterial pressure. The four-quadrant amniotic fluid index increased during the furosemide infusions but not during vehicle infusions (p = 0.022)., Conclusions: Furosemide infusion caused a marked dose-dependent diuresis in the ovine fetus that appears to be partly mediated by increases in vascular pressure. Although amniotic fluid volume increases and fetal blood volume decreases, the reduction in blood volume was small compared with the urine volume excreted.

Objective: The purpose of our study was to explore the urinary responses of the ovine fetus to indomethacin levels comparable with those used therapeutically in the human fetus., Study Design: After a 1-hour control period, chronically catheterized ovine fetuses between 125 and 139 days of gestation were given an intravenous bolus of indomethacin (0.05 mg/kg estimated fetal weight) followed by a 0.0025 mg/kg/min continuous infusion for 5 hours. The experimental group (n = 9) was compared with a vehicle-only infusion group (n = 10)., Results: There was a sustained 55.7% +/- 9.5% (mean +/- SEM) decrease in urinary output by 2 hours of indomethacin infusion (p < 0.00001, analysis of variance). Urinary osmolality, potassium, and chloride concentrations underwent sustained increases during the infusion period (p < 0.005). Free water clearance decreased by 67.5% +/- 12.0% (p < 0.001). Fetal arterial pressure increased only transiently (p < 0.05), and increases in venous pressure (p = 0.013) and heart rate (p < 0.0001) were sustained. Fetal plasma arginine vasopressin concentration increased during indomethacin infusion (p < 0.05) and was correlated with the fall in urinary flow rate and free water clearance (p = 0.002). During vehicle infusion no significant changes were observed in any of the variables., Conclusions: Our data indicate that the fetus undergoes antidiuresis when exposed to low levels of indomethacin and that the observed antidiuresis is mediated by a decrease in free water clearance. The reduction in free water clearance may be mediated by increases in plasma arginine vasopressin concentrations.

Objective: Our objective was to explore the urinary and cardiovascular responses of the near-term ovine fetus to plasma indomethacin levels similar to those in the human neonate undergoing indomethacin therapy., Study Design: Chronically catheterized ovine fetuses between 125 and 139 days of gestation were studied. After a 1-hour control period we gave a bolus of 0.35 mg/kg estimated fetal weight of indomethacin into a fetal vein, followed by a 0.017 mg/kg/min continuous infusion for 5 hours (n = 9). Results were compared with a vehicle-infusion-only group (n = 10)., Results: During the first 3 hours of indomethacin infusion, fetal urinary output was increased by an average of 84.9% +/- 55.6% (analysis of variance, p less than 0.01). Urinary osmolality and sodium and chloride concentrations underwent sustained increases throughout the infusion period (p less than 0.001). Sodium excretion increased by 212% +/- 111% (p less than 0.05). Fetal arterial and venous pressures increased (p less than 0.001), and the change in urinary flow correlated positively with the change in arterial pressure (R = 0.55, p = 0.014). Fetal heart rate increased by 10% +/- 4% 1 hour after the bolus and remained elevated throughout the remainder of the infusion relative to vehicle-infused animals (p less than 0.001). Vehicle infusion had no effect on any fetal variable., Conclusions: This study does not support the hypothesis that indomethacin acutely reduces urinary flow rate in the late-gestation ovine fetus. Further, the observed urinary flow increases may be mediated in part by a pressure diuresis.

Conflicting indirect data exist as to whether diurnal variations occur in fetal urine flow rate. In addition, the extent of diurnal rhythms in fetal venous pressure or arterial pressure is unknown, although 24-h rhythms do exist in fetal heart rate. In the present study, we used on-line computer techniques to continuously monitor these variables in chronically catheterized ovine fetuses. Fetal urine flow rate and vascular pressures were successfully recorded in 6 of 11 animals over a 24-h period on 21 days out of a total of 45 days of monitoring. We found highly significant diurnal variations in fetal urine flow rate (P less than 10(-6). Hourly means displayed a maximum at 2130 h and a minimum at 1330 h with a maximum amplitude of 28 +/- 5% of the 24-h mean. A secondary maximum (at 0630 h) and minimum (at 0330 h) of smaller amplitude also occurred. There were simultaneous and highly significant (P less than 0.0001) diurnal rhythms in fetal arterial pressure (+/- 2%), venous pressure (+/- 7%), and heart rate (+/- 5%). The maxima in arterial pressure and heart rate occurred within 1 h of the maximum in urine flow, while venous pressure changes were opposite those in arterial pressure. Hourly mean urine flow correlated significantly with arterial pressure but not venous pressure or heart rate, suggesting that the observed 24-h variations in fetal urine flow rate may be partially mediated by a pressure diuresis.(ABSTRACT TRUNCATED AT 250 WORDS)

With rapid intravenous infusion of very large volumes of isotonic saline solutions into the fetus, the fluid could stay within the fetal body, thereby creating hydrops fetalis, be transferred into the amniotic fluid through the fetal kidneys, thereby creating polyhydramnios, or be transferred across the placenta into the maternal circulation. This study was designed to explore these possibilities. After a 1-hour control period, 10 near-term chronically catheterized ovine fetuses were infused intravenously with 4 L (greater than 100% of fetal weight) of either isotonic saline solution or lactated Ringer's solution over 4 hours. Fetal arterial pressure was significantly elevated by 7 mm Hg throughout the infusion (p less than 0.00001). Venous pressure underwent a transient rise (4.8 mm Hg) at 20 minutes of infusion and remained elevated (2.7 mm Hg) during the rest of the infusion (p less than 0.00001). Fetal urine flow increased by an average of 5.7 +/- 0.4 ml/min throughout the infusion (p less than 0.00001) and accounted for 34.1% +/- 2.6% of the infused volume. Estimated fetal extracellular fluid volume increased by 17.7% +/- 1.8% of the infused volume. Because fetal fluid retention, urine flow, and amniotic fluid volume changes accounted for only half of the infused fluid, the remainder of the infused volume must have crossed the placenta and entered the maternal circulation. Given the above changes in vascular pressures, this requires a filtration coefficient of the placenta 50 to 100 times the previously reported values. Thus we conclude that relatively small changes in fetal vascular pressures dramatically alter the filtration capacity of the ovine placenta and transplacental volume flow.

Cocaine is a potent vasoconstrictive agent that is currently the subject of widespread drug abuse. Because little is known of the physiologic responses to cocaine in pregnancy, the effects of intravenous cocaine on uterine blood flow and other maternal and fetal cardiovascular parameters were studied. Eight ewes in late pregnancy were equipped with electromagnetic flow probes around both uterine arteries and catheters were placed in the maternal and fetal inferior vena cavae and aortas. Bolus intravenous infusion of 0.5 and 1.0 mg/kg of maternal body weight achieved peak plasma cocaine levels similar to those observed in human subjects after abuse of the drug (mean level = 229 to 400 ng/ml, n = 8). After bolus infusion of 0.5 or 1.0 mg/kg of cocaine, mean maternal arterial pressure increased 32% and 37%, respectively (p less than 0.005). Fetal blood pressure rose 12.6% after a dosage of 0.5 mg/kg of cocaine. These cocaine infusions significantly decreased uterine blood flow by 36% and 42% for a duration of 15 minutes (p less than 0.005). Analysis of maternal catecholamine responses demonstrated a significant (210%) rise in plasma norepinephrine levels after cocaine infusion. These studies demonstrate that cocaine, when administered in doses that produce plasma levels observed in humans, significantly decreases uterine blood flow for a duration of greater than or equal to 15 minutes while inducing a hypertensive response in the pregnant ewe and fetus.