Fetal Arterial Oxygen Content Research Articles

Anemic hypoxemia reduces myoblast proliferation and muscle growth in late-gestation fetal sheep.

Fetal skeletal muscle growth requires myoblast proliferation, differentiation, and fusion into myofibers in addition to protein accretion for fiber hypertrophy. Oxygen is an important regulator of this process. Therefore, we hypothesized that fetal anemic hypoxemia would inhibit skeletal muscle growth. Studies were performed in late-gestation fetal sheep that were bled to anemic and therefore hypoxemic conditions beginning at ∼125 days of gestation (term = 148 days) for 9 ± 0 days (n = 19) and compared with control fetuses (n = 16). A metabolic study was performed on gestational day ∼134 to measure fetal protein kinetic rates. Myoblast proliferation and myofiber area were determined in biceps femoris (BF), tibialis anterior (TA), and flexor digitorum superficialis (FDS) muscles. mRNA expression of muscle regulatory factors was determined in BF. Fetal arterial hematocrit and oxygen content were 28% and 52% lower, respectively, in anemic fetuses. Fetal weight and whole body protein synthesis, breakdown, and accretion rates were not different between groups. Hindlimb length, however, was 7% shorter in anemic fetuses. TA and FDS muscles weighed less, and FDS myofiber area was smaller in anemic fetuses compared with controls. The percentage of Pax7+ myoblasts that expressed Ki67 was lower in BF and tended to be lower in FDS from anemic fetuses indicating reduced myoblast proliferation. There was less MYOD and MYF6 mRNA expression in anemic versus control BF consistent with reduced myoblast differentiation. These results indicate that fetal anemic hypoxemia reduced muscle growth. We speculate that fetal muscle growth may be improved by strategies that increase oxygen availability.

Chronic anemic hypoxemia increases plasma glucagon and hepatic PCK1 mRNA in late-gestation fetal sheep.

Hepatic glucose production (HGP) normally begins just prior to birth. Prolonged fetal hypoglycemia, intrauterine growth restriction, and acute hypoxemia produce an early activation of fetal HGP. To test the hypothesis that prolonged hypoxemia increases factors which regulate HGP, studies were performed in fetuses that were bled to anemic conditions (anemic: n = 11) for 8.9 ± 0.4 days and compared with control fetuses (n = 7). Fetal arterial hematocrit and oxygen content were 32% and 50% lower, respectively, in anemic vs. controls (P < 0.005). Arterial plasma glucose was 15% higher in the anemic group (P < 0.05). Hepatic mRNA expression of phosphonenolpyruvate carboxykinase (PCK1) was twofold higher in the anemic group (P < 0.05). Arterial plasma glucagon concentrations were 70% higher in anemic fetuses compared with controls (P < 0.05), and they were positively associated with hepatic PCK1 mRNA expression (P < 0.05). Arterial plasma cortisol concentrations increased 90% in the anemic fetuses (P < 0.05), but fetal cortisol concentrations were not correlated with hepatic PCK1 mRNA expression. Hepatic glycogen content was 30% lower in anemic vs. control fetuses (P < 0.05) and was inversely correlated with fetal arterial plasma glucagon concentrations. In isolated primary fetal sheep hepatocytes, incubation in low oxygen (3%) increased PCK1 mRNA threefold compared with incubation in normal oxygen (21%). Together, these results demonstrate that glucagon and PCK1 may potentiate fetal HGP during chronic fetal anemic hypoxemia.

Persistent changes in arterial blood gases in fetal sheep

Two anaesthetic protocols were compared using pregnant sheep. In both groups of animals, anaesthesia was induced using an intravenous (i.v.) injection of diazepam and ketamine. The ewes were then intubated for positive pressure ventilation using 0.8 L/min of nitrous oxide and 2 L/min oxygen with 1.1-1.8% halothane. If the ewe showed any signs of awakening, one of two protocols was followed. First, the halothane concentration was increased to 2-3% until the ewe was completely anaesthetized. Second, the halothane concentration was not altered, but the ewe was given doses of i.v. diazepam (0.1 mg/kg) and ketamine (1 mg/kg) until again completely anaesthetized. At the completion of surgery, maternal recovery was rapid and similar between the two groups. However, five days after surgery, the fetal arterial Po(2) and oxygen content of the fetuses receiving additional halothane (1.9 +/- 0.2 kPa and 4.4 +/- 1.0 mL/100 mL) were statistically significantly depressed when compared with the fetuses receiving additional diazepam and ketamine (2.9 +/- 0.1 kPa and 7.0 +/- 0.5 mL/100 mL). These results led us to conclude that certain anaesthetic protocols, in spite of good maternal recovery, can lead to deleterious effects upon the fetus that persist for at least five days after surgery.

Myocardial vascular and metabolic adaptations in chronically anemic fetal sheep

Little is known about the vascular and metabolic adaptations that take place in the fetal heart to maintain cardiac function in response to increased load. Chronic fetal anemia has previously been shown to result in increased ventricular mass, increased myocardial vascularization, and increased myocardial expression of hypoxia-inducible factor-1 (HIF-1) and vascular endothelial growth factor (VEGF). We therefore sought to determine whether chronic fetal anemia induces expression of HIF-1-regulated angiogenic factors and glycolytic enzymes in the fetal myocardium. Anemia was produced in chronically instrumented fetal sheep by daily isovolemic hemorrhage (80-100 ml) for either 3 (n = 4) or 7 days (n = 11) beginning at 134 days of gestation (term 145 days). Catheterized, nonbled twins served as controls. Isovolemic hemorrhage over 7 days resulted in decreased fetal hematocrit (37 +/- 1 to 20 +/- 1%) and arterial oxygen content (6.5 +/- 0.4 to 2.8 +/- 0.2 ml O2/dl). Myocardial blood flow and vascularization were significantly increased after 7 days of anemia. Myocardial HIF-1 protein expression and VEGF (left ventricular), VEGF receptor-1 (right ventricular), and VEGF receptor-2 (right ventricular, left ventricular) mRNA levels were elevated (P < 0.05) in 7-day anemic compared with control animals. Myocardial expressions of the glycolytic enzymes aldolase, lactate dehydrogenase A, phosphofructokinase (liver), and phosphoglycerol kinase were also significantly elevated after 7 days of anemia. Despite the absence of a significant increase in myocardial HIF-1alpha protein in 3-day anemic fetuses, expressions of VEGF, VEGF receptor-1, and the glycolytic enzymes were greater in 3-day compared with 7-day anemic animals. These data suggest that HIF-1 likely participates in the fetal myocardial response to anemia by coordinating an increase in gene expressions that promote capillary growth and anaerobic metabolism. However, factors other than HIF-1 also appear important in the regulation of these genes. We speculate that the return of mRNA levels of angiogenic and glycolytic enzymes toward control levels in the 7-day anemic fetus is explained by a significantly increased resting myocardial blood flow, resulting from coronary vascular growth and increased coronary conductance, and a return to a state of adequate oxygen and nutrient delivery, obviating the need for enhanced transcription of genes encoding angiogenic and glycolytic enzymes.

Adrenomedullin expression during hypoxia in fetal sheep

We asked how adrenomedullin (AM), a vasodilator peptide, was distributed in fetal sheep organs and whether expression of AM would be upregulated in response to moderate acute fetal hypoxia in vivo. In four sheep at day 126-130 of gestation, nitrogen was added to the inspired air by tracheal infusion to reduce fetal arterial oxygen content for a period of 4 h. Control fetuses were from four ewes given a tracheal infusion of room air. Fetal and maternal blood samples were taken prior to and during hypoxia/sham hypoxia. Fetal tissue samples were frozen for RNA analysis and fixed for immunohistochemistry. In hypoxic fetuses, arterial oxygen content was significantly reduced to 50% compared with sham fetuses with no change in arterial pH in either group. Plasma ACTH levels rose significantly at 2 and 4 h in hypoxic fetuses only. Initial plasma concentrations of AM in control and hypoxic fetuses were 457 +/- 20 and 430 +/- 35 pg mL(-1) and did not change during the experiment. The relative abundance of AM mRNA was placental cotyledons >> lung > cerebral cortex approximately equal to renal cortex > left ventricle approximately equal to right ventricle > adrenal gland > renal medulla > aorta approximately equal to liver. Immunohistochemical staining for AM confirmed distinct labelling in organs with significant expression. AM mRNA level increased significantly in cerebral cortex of hypoxic fetuses. Our results show expression of AM in placenta and in several fetal organs in late gestation sheep. AM may participate in the cerebral vasodilatation that is an integral part of the fetal response to hypoxia.

Amniotic fluid and fetal urinary responses to severe placental insufficiency in sheep

Objective: Our purpose was to test the hypothesis that severe placental insufficiency leads to reductions in fetal urine production and amniotic fluid volume in late-gestation fetal sheep. Study Design: At 0.85 of gestation, chronically catheterized fetal sheep with ligated urachus were either embolized for 5 days by repeated injection of boluses of 15-μm microspheres into the common fetal umbilical artery until fetal arterial oxygen content was reduced by 50% (n = 6) or were infused with saline solution (n = 6). Amniotic fluid volume was measured daily before embolization by means of an indicator dilution technique and by drainage at autopsy. Fetal urine production, heart rate, and mean arterial blood pressure were measured continuously for 1 hour before embolization and 1 hour after embolization each day. Fetal arterial blood gases, oxygen content, electrolytes, and osmolality were also monitored. Results: Five days of placental insufficiency, which reduced fetal arterial oxygen content by 50% and arrested fetal growth, resulted in a reduced amniotic fluid volume without a reduction in fetal urine production. Compared with that of controls, amniotic fluid volume was reduced over the 5-day period by 547 ± 144 mL (−62%, P <.01). Amniotic fluid composition was also altered, with a significant increase in lactate and sodium concentrations and osmolality on days 4 to 5. On days 2 to 5, there was a progressive increase in amniotic fluid osmolality above that of controls, which paralleled the changes in amniotic fluid sodium concentration (P <.05). Fetuses became hypertensive on days 2 to 4 of embolization, although this response was attenuated by day 5. Conclusions: Chronic severe placental insufficiency caused a reduction in amniotic fluid volume not attributable to reduced fetal urine production. Changes in amniotic fluid composition induced by placental insufficiency suggest an excess intramembranous absorption of amniotic fluid water, in relation to solutes, into the fetal and maternal compartments, which may lead to the development of oligohydramnios. (Am J Obstet Gynecol 2002;186:1076-84)

Fetal Oxygen Content is Restored After Maternal Hemorrhage and Fluid Replacement with Polymerized Bovine Hemoglobin, but Not with Hetastarch, in Pregnant Sheep

We investigated the ability of hemoglobin-based oxygen carrying solutions (HBOCs) to alleviate fetal hypoxemia from maternal hemorrhage. Fifteen pregnant ewes (132-day gestational age) were hemorrhaged 20 mL/kg over 1 h; they were randomized to receive 20 mL/kg IV of HBOC, hetastarch (HTS), or autologous blood (BLD) (n = 5 each) over 30 min and were monitored for 2 h. Hemorrhage significantly (P < or = 0.05) decreased maternal mean blood pressure (from 98 to 48 mm Hg, median), arterial oxygen content (from 12.2 to 11.1 mL/dL), and fetal arterial oxygen content (from 8.1 to 3.9 mL/dL). Fluid replacement restored maternal blood pressure in all groups, although maternal oxygen content immediately returned to baseline only after BLD or HBOC. Maternal oxygen saturation decreased after HBOC (from 98% to 88%). Fetal oxygen content rapidly returned to baseline with either BLD (7.1 mL/dL) or HBOC (8.0 mL/dL) but was never restored with HTS (4.7 mL/dL), and, 60 min after fluid replacement, it was higher with HBOC (8.3 mL/dL) than with HTS (4.7 mL/dL). Fetal plasma-free hemoglobin did not change after HBOC. In conclusion, maternal fluid replacement with HBOC or BLD effectively restored fetal oxygenation, primarily by restoring maternal oxygen content, whereas HTS did not. Hemoglobin solutions eliminate many limitations of blood transfusions. Our results show that fluid replacement with either blood or a hemoglobin solution, compared with hetastarch, restored fetal oxygenation in pregnant ewes after hemorrhage. If applicable to women, these results suggest a potential for the use of hemoglobin solutions in obstetrics.

Changes in surfactant-associated protein mRNA profile in growth-restricted fetal sheep.

To test the hypothesis that chronic placental insufficiency resulting in fetal growth restriction causes an increase in fetal lung surfactant-associated protein (SP) gene expression, we embolized chronically catheterized fetal sheep (n = 6) daily using nonradioactive microspheres in the abdominal aorta for 21 days (between 0.74 and 0.88 of gestation) until fetal arterial oxygen content was reduced by approximately 40-50%. Control animals (n = 7) received saline only. Basal fetal plasma cortisol concentration was monitored. At the end of the experiment, fetal lung tissues were collected, and ratios of tissue levels of SP-A, SP-B, and SP-C mRNA to 18S rRNA were determined by standard Northern blot analysis. Total DNA content of fetal lungs was reduced by 30% in the embolized group compared with control group (P = 0.01). There was a 2.7-fold increase in fetal lung SP-A mRNA (P < 0.05) and a 3.2-fold increase in SP-B mRNA (P < 0.01) in the chronically embolized group compared with those in the control group. SP-A and SP-B mRNA tissue levels were highly correlated with the mean fetal plasma cortisol levels on days 20-21 (r = 0.90, P < 0.01 for SP-A mRNA and r = 0.94, P < 0.01 for SP-B mRNA). SP-C mRNA tissue levels were not significantly affected by placental insufficiency. We conclude that fetal growth restriction due to placental insufficiency is associated with alterations in fetal lung SP, suggesting enhanced lung maturation that was highly dependent on the degree of increase in fetal plasma cortisol levels.

Hepatic Metabolism During Acute Hypoxia in Fetal Lambs † 273

The fetal liver is a principal organ for the metabolic response to acute hypoxia in-utero. To better understand its biochemical role, we simultaneously studied fetal and hepatic changes in blood flow, oxygen consumption, and lactate and pyruvate metabolism during normal and hypoxic conditions.Methods: In 7 pregnant ewes, sampling catheters were placed across the umbilical and fetal left hepatic circulations. After recovery, indocyanine green (ICG) and tritiated water were infused at a constant rate into the fetus for measurement of left hepatic blood flow and umbilical blood flow, respectively. Each study day, blood samples were taken for ICG, tritiated water, oxygen, lactate, and pyruvate concentrations under normal conditions and hypoxia induced by occlusion of the maternal common internal iliac artery for 30 minutes. Using the Fick principle, substrate uptake for both control and hypoxia was calculated using the concentration difference across the left hepatic and umbilical circulations. Animals were recovered for at least 24 hours prior to the next study day, and each animal was studied no more than 3 times. At autopsy, catheter placement was verified and the fetal liver transected into left and right hepatic lobes and weighed. Paired samples were analyzed by paired 2-tailed t-test. Results: 17 paired control/hypoxia studies were obtained in 7 animals. Values are mean(±SD) control versus hypoxia. Fetal arterial oxygen content was 2.60(0.50) and decreased to 1.21(0.26) mM (p<0.001) with occlusion. Umbilical blood flow increased from 223.11(27.16) to 294.60(52.09) ml/min/kg(p<0.001). Left hepatic blood flow was 371.10(127.88) and 405.85(199.68) ml/min/gm (NS). Fetal oxygen uptake decreased, 0.33(0.03) to 0.24(0.04) uM/min/gm (p<0.001). Left hepatic oxygen uptake did not change, 1.61(0.32) versus 1.63(0.28) uM/min/gm (NS). Fetal lactate uptake 0.021(0.008) went to production (-)0.022(0.033) uM/min/gm (p<0.001). Left hepatic lactate uptake increased, 0.515(0.116) to 0.827(0.331) uM/min/gm (p<0.001). Fetal pyruvate production increased, (-)0.001(0.001) to (-)0.003(0.002) uM/min/gm, as did left hepatic pyruvate production, (-)0.057(0.024) to (-)0.156(0.043) uM/min/gm(p<0.001). Conclusions: The fetus maintained a constant left hepatic oxygen consumption and blood flow in the presence of acute hypoxia and decreased fetal oxygen uptake. In addition, during fetal lactate production, the fetal liver increased lactate consumption while increasing pyruvate production. We speculate a biochemical exchange of lactate for pyruvate occurs as the liver works to restore metabolic homeostasis.

Chronic hypoxemia causes extracellular glutamate concentration to increase in the cerebral cortex of the near-term fetal sheep

Fetal hypoxia is an important cause of neurologic morbidity and mortality. Hypoxia-induced increase in extracellular glutamate concentration can lead to excitotoxic neuronal death in adults. The objective of this study was to test whether chronic fetal hypoxemia increases extracellular glutamate concentration in the unanesthetized intact cerebral cortex of the near-term fetal sheep. Microdialysis probes were implanted into the parasagittal parietal cortex and periventricular white matter of near-term fetal sheep. At 124±1 days of gestation, extracellular glutamate concentration was determined before and during 24 h of fetal hypoxemia. Chronic hypoxemia was produced by tightening a vascular occluder placed around the maternal common iliac artery. Larger decreases in fetal arterial oxygen content were associated with larger increases in extracellular glutamate concentration in the parietal cortex (Kendall's τ=0.81, N=7, p=0.005). No such relationship was detected in the periventricular white matter. Chronic hypoxemia increases extracellular glutamate concentration in the intact cerebral cortex of the unanesthetized near-term fetal sheep.

Fetal heart rate patterns in growth-restricted fetal sheep induced by chronic fetal placental embolization

OBJECTIVE: Our purpose was to test the hypothesis that chronic placental insufficiency and intrauterine growth restriction in fetal sheep causes a decrease in the number of fetal heart rate accelerations and fetal heart rate variability. STUDY DESIGN: Chronically catheterized fetal sheep were embolized ( n = 6) daily with 15 to 50 μm latex microspheres for 21 days between 0.74 and 0.88 of gestation into the abdominal aorta, until fetal arterial oxygen content was decreased by 40% to 50% of the preembolization value. Control animals ( n = 6) received saline solution only. Signals from chest electrodes were analyzed on-line with the Sonicaid System 8000 in 2-hour epochs every 6 hours starting at 8 am over the first 48 hours of hypoxemia and for 2 hours between 8 and 10 am every other day from day 3 to day 21 of hypoxemia. Umbilical artery Doppler-derived resistance index and fetal plasma catecholamine concentrations were also measured. RESULTS: Embolized fetuses had asymmetric intrauterine growth restriction and became chronically hypoxemic ( p < 0.001) with a progressive increase in the umbilical artery resistance index ( p < 0.001). During the first 48 hours of hypoxemia the number of accelerations and decelerations and both short- and long-term fetal heart rate variability increased initially, followed by a return to control levels by 20 hours after the onset of embolization. After 21 days of hypoxemia the number of accelerations was significantly reduced by 30% compared with controls ( p < 0.05). Both short- and long-term fetal heart rate variability in control fetuses gradually increased with advancing gestational age ( p < 0.001 and p < 0.01, respectively), whereas in embolized fetuses the fetal heart rate variability remained unchanged and was 20% lower than that of controls on day 21 (both p < 0.01). CONCLUSION: Intrauterine growth restriction and long-term hypoxemia in fetal sheep are associated with a decrease in short- and long-term fetal heart rate variability, possibly because of a delay in the normal maturational changes of the autonomic control of fetal heart rate. (Am J Obstet Gynecol 1997;176:282-90.)

Effects of long-term hypoxemia on pituitary-adrenal function in fetal sheep.

To test the hypothesis that long-term hypoxemia causes premature activation of the fetal pituitary-adrenal function, we embolized the fetal side of the placenta in pregnant sheep and examined the changes in concentrations of immunoreactive adrenocorticotropic hormone (irACTH), cortisol, and prostaglandin E2 (PGE2) in fetal plasma, and levels and localization of proopiomelanocortin (POMC) mRNA in the pars distalis and the pars intermedia of the fetal pituitary. Twelve fetal sheep were studied (6 embolized and 6 control) for 21 days between 0.74 and 0.88 of gestation. Daily injections of nonradiolabeled microspheres were given into the fetal abdominal aorta to decrease fetal arterial oxygen content by 40-50% of the preembolization values. In the embolized group, concentrations of irACTH, PGE2, and cortisol in fetal plasma increased gradually and were significantly (P < 0.05) elevated above those of controls after day 10, day 16, and day 20, respectively. POMC mRNA levels in the pars distalis of the fetal pituitary were not different from those of controls but were significantly reduced in the pars intermedia (P < 0.05). We conclude that levels of POMC mRNA in the pars distalis are unchanged during long-term hypoxemia possibly because of negative feedback effects of elevated cortisol on the pituitary gland. During long-term fetal hypoxemia, there is a differential regulation of POMC mRNA expression in the pars distalis and pars intermedia.

Fetal placental embolization in the late-gestation ovine fetus: Alterations in umbilical blood flow and fetal heart rate patterns

OBJECTIVE: Our goal was to determine the effect of chronic and acute umbilical-placental embolization on placental hemodynamic and fetal heart rate patterns in relation to fetal oxygenation in the near-term ovine fetus. STUDY DESIGN: Daily fetal placental embolization was performed during 10 days in 9 sheep fetuses until fetal arterial oxygen content decreased by ~30%. Nine control fetuses received saline solution. Mean and pulsatile umbilical blood flow, perfusion pressure, placental vascular resistance, fundamental impedance, pressure pulsatility index, and umbilical artery resistance index corrected to a fetal heart rate of 160 beats/min were measured. On day 10 both groups were acutely embolized until fetal arterial pH decreased to ~7.00. Fetal heart rate was measured with the Sonicaid System 8000 (Oxford Sonicaid, Oxford, United Kingdom). RESULTS: Chronic fetal placental embolization was associated with a progressive reduction in umbilical blood flow ( p < 0.00001) and fetal arterial oxygen content ( p < 0.001) whereas fetal heart rate patterns remained unaltered. A chronic increase in umbilical artery resistance index corrected to a fetal heart rate of 160 beats/min could be entirely explained only if the changes in umbilical artery pressure pulsatility index and the fundamental impedance were taken into account, in addition to the changes observed in placental vascular resistance. During acute embolization leading to a 50% reduction in umbilical blood flow ( p < 0.0002) and a three times increase in placental vascular resistance ( p < 0.0001), the most consistent change in fetal heart rate patterns related to progressive metabolic acidosis was an 84% decrease in absolute acceleration frequency ( p < 0.0001) whereas short-term fetal heart rate variability remained unaltered. CONCLUSION: Changes in umbilical artery resistance index induced by chronic umbilical-placental embolization resulting in fetal hypoxemia occurred before any changes in fetal heart rate patterns were detectable. A decrease in the absolute acceleration frequency was the only component of fetal heart rate patterns related to progressive metabolic acidosis in the near-term ovine fetus. (A M J O BSTET G YNECOL 1996;175:63-72.)

Effect of prolonged uterine blood flow reduction on fetal growth in sheep.

The purpose of the present investigation was to study the effect of 7 days of uterine blood flow reduction on fetal growth. Reduction in uterine blood flow was accomplished by external occlusion of the terminal aorta in 20 pregnant sheep. Linear growth was monitored daily by means of a crown-rump length measuring device. The deliveries of oxygen, glucose, and lactate to the fetus, as well as their uptakes by the fetus, were determined before and after 7 days of uterine blood flow reduction and correlated with rates of fetal growth. Identical studies were conducted in nine control animals. Uterine blood flow reduction resulted in a significant decrease in fetal oxygen delivery and fetal arterial oxygen content. Linear growth rate decreased by 38% in the occluded animals during hypoxemia. In addition, there was a 20% reduction in daily weight gain in occluded animals compared with controls. There were no differences in the uptakes of oxygen, glucose, and lactate by the fetus. Positive correlations were found between linear growth rate and fetal arterial oxygen content (r2 = 0.25, P = 0.0001) and between linear growth rate and fetal oxygen delivery (r2 = 0.21, P = 0.0006). The correlations between linear growth rate and fetal oxygenation provide strong evidence of the central role of oxygen in the regulation of fetal growth.

Increased fetal plasma prostaglandin E 2 concentrations during fetal placental embolization in pregnant sheep

OBJECTIVE: The purpose of this study was to examine the effect of chronic fetal placental embolization on fetal plasma prostaglandin E 2 concentrations. STUDY DESIGN: Fourteen pregnant sheep were studied (seven embolized and seven controls) for 10 days between 0.84 and 0.91 of gestation. Daily injections of nonradioactive microspheres were made to decrease fetal arterial oxygen content by 30% to 35% of preembolization values. RESULTS: In response to repeated embolization, fetal plasma prostaglandin E 2 concentrations increased significantly on day 1, declined to near control levels on days 2 to 6, but were significantly elevated again after day 7. Maternal prostaglandin E 2 levels remained unchanged throughout the study. Fetal plasma prostaglandin E 2 levels increased significantly with decreasing fetal oxygenation when fetal arterial oxygen content was <2.0 mmol/L. CONCLUSION: We conclude that there is increased production of prostaglandin E 2 by the placenta during progressive fetal hypoxemia induced by fetal placental embolization. We speculate that the progressive increase in prostaglandin E 2 may be an important hormonal adaptive mechanism to maintain fetal homeostasis during the development of placental insufficiency.

Alterations in fetal and placental deoxyribonucleic acid synthesis rates after chronic fetal placental embolization

OBJECTIVE: Fetal growth and development are closely related to normal placental growth and function. We performed a study to determine the effect of a 10-day period of fetal hypoxemia induced by umbilical-placental hypoperfusion on tissue deoxyribonucleic acid synthesis rates in the 0.84 to 0.91 of gestation ovine fetus and placenta. STUDY DESIGN: Daily fetal placental embolization was performed in four chronically catheterized sheep fetuses until fetal arterial oxygen content decreased by ∼30% compared with preembolization values. Five control fetuses received vehicle only. On experimental day 10, the deoxyribonucleic acid synthesis rate was determined by injecting tritiated thymidine (1 mCi/kg) intravenously approximately 8 hours before the end of the study. RESULTS: Fetal arterial oxygen decreased from 3.2 ± 0.1 (SEM) mmol/L preembolization to 2.2 ± 0.2 mmol/L on day 10 ( p < 0.001) and remained unchanged in controls. On day 10 deoxyribonucleic acid synthesis rates were significantly reduced in embolized fetuses compared with controls, by 38% in cotyledons (83.0 ± 15.1 vs 133.7 ± 9.9 disintegrations/min/μg deoxyribonucleic acid, ( p < 0.05), 28% in the left ventricular wall (36.8 ± 3.7 vs 51.0 ± 4.7 disintegration/min/μg deoxyribonucleic acid, p < 0.05), and 45% in the quadrieps muscle (15.4 ± 4.0 vs 28.1 ± 3.0 disintegration/min/μg deoxyribonucleic acid, p < 0.05). Tritiated thymidine autoradiography demonstrated that cotyledonary deoxyribonucleic acid synthesis occurred exclusively in the fetal trophoblasts cells. CONCLUSION: We concluded that a reduction in cotyledonary, quadriceps muscle, and left ventricular myocardium deoxyribonucleic acid synthesis rates are the earliest adaptive mechanisms of fetal growth associated with development of umbilical-placental insufficiency. We speculate that alteration in the myocardial deoxyribonucleic acid synthesis rate could be a major contributing factor in the deterioration of fetal myocardial function associated with increased placental vascular resistance.

Haemodynamic responses to an angiotensin II receptor antagonist (GR 117289) in maternal and fetal sheep.

An AT1-specific angiotensin II receptor antagonist (GR117289; 1 mg/kg I.V. bolus) was administered daily to ten chronically catheterized, normotensive ewes during late pregnancy (from 126 +/- 1 days) until parturition (139 +/- 1 days); five control animals received an equivalent volume of vehicle solution. Following drug administration, mean maternal blood pressure decreased from 87 +/- 1 mmHg to a minimum of 79 +/- 1 mmHg at 0.5 h (P < 0.05; n = 10) and remained low for 4-6 h without any concomitant change in fetal blood pressure or maternal and fetal heart rates. In animals fitted with flow probes, uterine blood flow decreased from 443 +/- 21 to 363 +/- 27 ml/min at 0.5 h post-drug (P < 0.05; n = 6); this change was positively correlated with the reduction in maternal blood pressure. The mean decrements in uterine and umbilical blood flows measured by steady-state infusion of tritiated water were -611 +/- 171 ml/min at 4-6 h (P < 0.05; n = 5) and -71 +/- 19 ml/min at 0.5-1 h (P < 0.05; n = 5), respectively. Significant reductions (P < 0.05; n = 10) in fetal arterial oxygen tension (-1.6 +/- 0.4 mmHg), saturation (-6.6 +/- 1.6%) and content (-0.3 +/- 0.1 mumol/ml) were evident at 0.5 h post-drug and were maintained for 6-12 h. Umbilical oxygen delivery decreased at 0.5-1 h following drug administration (P < 0.01; n = 5), but was unaccompanied by any significant change in fetal oxygen consumption. Chronic decreases in daily fetal pH and blood oxygen content occurred in GR117289-treated ewes. There were no significant differences in gestational length or neonatal outcome between vehicle- and GR117289-treated groups of ewes with single fetuses.

Cerebral metabolism and electrocortical activity in the chronically hyperglycemic lamb

Pages R1262–R1269: T. S. Rosenkrantz, I. Knox, E. L. Zalneraitis, J. R. Raye, P. J. Porte, R. Cramer, R. Smoloski, and A. F. Philipps. “Cerebral metabolism and electrocortical activity in the chronically hyperglycemic lamb.” Page R1265: Several errors relating to significance of changes in arterial oxygen concentration, cerebral oxygen delivery, and cerebral oxygen uptake were introduced into Table 1 by the publisher. All of the information in the abstract and text are correct as originally printed. A corrected version of the table is reprinted below. Note that there were no changes in the fetal arterial oxygen content during any of the study periods, cerebral oxygen delivery rose during G2 ( P = 0.06), and there was a significant increase in cerebral oxygen uptake during G2 ( P &lt; 0.05). It is hoped that this clarifies conflicting information in the text and the table concerning the metabolic changes that occur in the brain of the chronically hyperglycemic fetal lamb. (See PDF)

Fetal endocrine responses to chronic placental embolization in the late-gestation ovine fetus

OBJECTIVE: The purpose of this study was to examine the effect of chronic fetal placental embolization on the fetal corticotropin, cortisol, and catecholamines concentrations and on myometrial contractility pattern. STUDY DESIGN: Fourteen fetal sheep were studied (seven embolized, seven controls) for 10 days between 0.84 and 0.91 of gestation. Daily injections of nonradioactive microspheres were performed to decrease fetal arterial oxygen content by 30% to 35% of the preembolization value. Umbilical artery Doppler flow velocity waveforms were measured daily. RESULTS: Chronic fetal placental embolization produced progressive fetal hypoxemia (p < 0.001) with changes in umbilical artery Doppler flow velocity waveforms indicative of a 25% increase in placental vascular resistance (p < 0.01). In response to chronic fetal hypoxemia there was a progressive increase in baseline fetal plasma norepinephrine concentration (p < 0.001). There was a transient fourfold to fivefold increase in baseline fetal plasma cortisol levels concomitant with a significant decrease in baseline immunoreactive corticotropin between days 7 and 9 of embolization (both p < 0.05), with a return to control values by day 10. There was a 57% increase in myometrial contracture frequency in the embolized group when compared with controls (p = 0.001). CONCLUSIONS: During repetitive chronic placental damage that led to fetal hypoxemia, the fetal endocrine environment changed with time in a direction that would prevent the onset of premature activation of the hypothalamic-pituitary-adrenal axis and premature delivery. (AM J OBSTET GYNECOL 1994;170:929-38.)

Cerebral metabolism and electrocortical activity in the chronically hyperglycemic lamb

Pages R1262–R1269: T. S. Rosenkrantz, I. Knox, E. L. Zalneraitis, J. R. Raye, P. J. Porte, R. Cramer, R. Smoloski, and A. F. Philipps. “Cerebral metabolism and electrocortical activity in the chronically hyperglycemic lamb.” Page R1265: Several errors relating to significance of changes in arterial oxygen concentration, cerebral oxygen delivery, and cerebral oxygen uptake were introduced into Table 1 by the publisher. All of the information in the abstract and text are correct as originally printed. A corrected version of the table is reprinted below. Note that there were no changes in the fetal arterial oxygen content during any of the study periods, cerebral oxygen delivery rose during G2 (P = 0.06), and there was a significant increase in cerebral oxygen uptake during G2 (P &lt; 0.05). It is hoped that this clarifies conflicting information in the text and the table concerning the metabolic changes that occur in the brain of the chronically hyperglycemic fetal lamb. (See PDF)