Placental insufficiency and fetal growth restriction lead to postnatal hypotension and altered postnatal growth in sheep

Low birth weight has been associated with elevated arterial pressure in later life but mechanisms are unknown. Our aim was to determine the effects of low birth weight resulting from intrauterine growth restriction (IUGR) on fetal and postnatal arterial pressures and the potential roles of circulating cortisol and renin. We induced IUGR by umbilico-placental embolization (UPE) in fetal sheep from 120 d of gestation until birth (approximately 147 d); postnatal lambs (8 IUGR, 8 controls) were studied for 8 wk. Fetal and postnatal arterial pressures were measured and blood samples taken for measurement of gas tensions, cortisol concentrations and renin activity. In IUGR fetuses, mean arterial pressure (MAP) initially increased with UPE, but near term was not different to values in controls. IUGR lambs weighed 33% less than controls at birth and remained lighter than controls during the 8 postnatal weeks; their growth pattern was different to that of controls. IUGR lambs had lower MAP than controls, and this relative hypotension (-4 mm Hg) persisted throughout the 8 postnatal weeks. Covariate analysis showed that the relative hypotension of IUGR lambs could have resulted from their smaller size. Plasma cortisol concentrations were not different between IUGR and control animals before or after birth. Plasma renin activity was not different in postnatal IUGR lambs compared with controls. Thus, postnatal cortisol and renin levels were not consistent with the development of hypotension or hypertension. We conclude that late gestational IUGR in sheep leads to relative hypotension in the early postnatal period, probably a result of reduced body size.     

Plasma vasopressin, renin, and catecholamines during nitroprusside-induced maternal and fetal hypotension in sheep

The release of vasopressin, renin, and catecholamines by the fetus during either maternal or fetal hypotension was examined in chronically catheterized fetal lambs. Nitroprusside was infused intravenously for 1 h into seven pregnant ewes (maternal hypotension) or nine fetal lambs (fetal hypotension); the rates were adjusted to achieve a 15 to 30% decrease in mean blood pressure. During maternal hypotension, mean +/- SE vasopressin in maternal plasma increased from 1.2 +/- 0.2 pg.ml-1 to 208 +/- 153 pg.ml-1 and plasma renin activity increased from 1.5 +/- 0.3 ng.ml-1.h-1 to 6.6 +/- 1.6 ng.ml-1.h-1. Fetal vasopressin and plasma renin activity also increased during the same interval from 1.1 +/- 0.3 to 16.9 +/- 7.5 pg.ml-1 and 3.7 +/- 1.1 to 10.5 +/- 2.85 ng.ml-1.h-1, respectively; but no changes were observed in fetal blood pressure, heart rate, or acid base status. During fetal hypotension, mean vasopressin in fetal plasma increased from 4.3 +/- 3.4 pg.ml-1 to 1054 +/- 772 pg.ml-1, plasma renin activity increased from 5.7 +/- 2.2 ng.ml-1 to 22.2 +/- 7.1 ng.ml-1.h-1, and total catecholamines from 174 +/- 58 pg.ml-1 to 810 +/- 416 pg.ml-1. There was no change in fetal heart rate, acid base status, osmolality, or sodium concentration. The fetus became and remained hypertensive for at least 1 h after the end of infusion. This prolonged hypertension was associated with elevated levels of vasopressin and plasma renin activity. Peak vasopressin levels were proportional to the total nitroprusside dose in both the ewe and fetus (maternal r = 0.796, fetus r = 0.870).(ABSTRACT TRUNCATED AT 250 WORDS)     

Analyses of factors contributing to vulnerability to antenatal periventricular leukomalacia induced by hemorrhagic hypotension in chronically instrumented fetal sheep.

Our purpose was to determine factors contributing to vulnerability to antenatal periventricular leukomalacia (PVL) induced by hemorrhagic hypotension in premature fetal sheep. Systemic hypotension was induced in 10 fetal sheep by acutely withdrawing 35% to 40% of the fetoplacental blood volume at 113 d gestation. Brains were processed for histologic analysis 6 d after the insult. Statistical comparisons of physiologic parameters between fetuses suffering from PVL (n = 5) and those without PVL (n = 5) were performed. Significant correlations were found between induction of PVL and fetal brain weight, changes in fetal mean blood pressure over time, base excess, oxygen content, hematocrit, and plasma arginine vasopressin (AVP) levels in fetal abdominal aortic blood. Brain developmental stage, the magnitude of induced systemic hypotension, and baseline blood oxygen content were important intrinsic factors in the induction of antenatal PVL by hemorrhagic hypotension in premature fetal sheep.     

Cardiovascular responses to hypoxemia in sinoaortic-denervated fetal sheep

Fetal cardiovascular response to acute hypoxemia is characterized by bradycardia, hypertension, and redistribution of cardiac output. The role of aortic and carotid chemoreceptors in mediating these responses was examined in eight sinoaortic-denervated and nine shamoperated fetal lambs. Blood gases, pH, heart rate, arterial pressure, and blood flow distribution were determined before and during hypoxemia. In intact fetuses, heart rate fell from 184 +/- 12 to 165 +/- 23 beats/min (p less than 0.01) but increased from 184 +/- 22 to 200 +/- 16 beats/min (p less than 0.05) in the sinoaortic-denervated fetuses. Intact fetuses showed an early hypertensive response to hypoxemia, whereas the sinoaortic-denervated fetuses developed a delayed, progressive rise in blood pressure. In both groups, fetal cardiac output and umbilical blood flow were maintained; cerebral, myocardial, and adrenal blood flow increased, and pulmonary blood flow decreased. Peripheral blood flow decreased 39% (p less than 0.001) in intact fetuses but was maintained in sinoaortic-denervated fetuses. Vascular responses to hypoxia in the brain, heart, adrenal, and lungs are regulated primarily by direct local effects. During hypoxemia, peripheral chemoreceptors mediate bradycardia and peripheral vasoconstriction but do not appear to be crucial for immediate fetal survival.     

Measurement of fetal responses to vibroacoustic stimuli. Habituation in fetal sheep

Electrocortical (ECoG) and integrated electromyographic (EMG) activity was recorded in 6 chronically prepared fetal sheep (132-145 days). Recording were made in fetuses prior to and during repeated vibroacoustic stimulation. In the undisturbed fetus, two patterns of ECoG activity were apparent; high (HV) and low voltage (LV). The fetus responded to this broad spectrum stimulus during both LV and HV ECoG activity. In 18 of the 20 experiments, repeated stimulation was not associated with a change in the background ECoG activity. All fetuses responded at least once to the stimulus. Habituation of the EMG response was observed during both HV and LV ECoG activity. The rate of habituation was independent of the background ECoG activity and was unchanged when experiments were repeated at intervals of more than 3 days. These results show that fetal sheep also respond to vibroacoustic stimulation and with repetition habituation occurs.     

Iron in fetal and neonatal nutrition

Both iron deficiency and iron excess during the fetal and neonatal period bode poorly for developing organ systems. Maternal conditions such as iron deficiency, diabetes mellitus, hypertension and smoking, and preterm birth are the common causes of perinatal iron deficiency. Long-term neurodevelopmental impairments and predisposition to future iron deficiency that are prevalent in infants with perinatal iron deficiency require early diagnosis, optimal treatment and adequate follow-up of infants at risk for the condition. However, due to the potential for oxidant-mediated tissue injury, iron overload should be avoided in the perinatal period, especially in preterm infants.     

Carotid baroreceptors in fetal and newborn sheep

The responses of single carotid baroreceptor afferents were determined in anaesthetized fetal lambs at 88-113 and 131-144 days gestation, and in newborn lambs 1-8 and 30-40 days old. The baroreceptors discharged in synchrony with the arterial pressure pulse and increased their discharge rate as pressure was raised by compression of the abdominal aorta. When step increases in pressure were applied to the vascularly isolated carotid sinus, baroreceptor discharge increased abruptly and then showed adaptation to a steady state level. Basal mean arterial pressure increased from 49.1 in the young fetuses to 87.5 mm Hg in the 30- to 40-day-old lambs without an accompanying increase in basal baroreceptor discharge expressed absolutely or as a function of maximum discharge for each unit. The slope of the steep portion of the stimulus-response curve decreased with gestational age from 7.89 +/- 1.57 (mean +/- SE) at 88-113 days gestation to 1.82 +/- 0.37% nerve activity.mm Hg-1 in the 30- to 49-day-old lambs. Dynamic and steady state response curves were determined using step increases in carotid sinus pressure in two fetal lambs of 135 days gestation and two lambs 8 days old. Both the dynamic and the steady state curves were less steep in the older lambs. We conclude that the sensitivity of the carotid baroreceptors is reset as arterial pressure increases throughout the last third of gestation and the first postnatal month. This resetting is seen as a shift to the right of the response curve and a decrease in its slope.(ABSTRACT TRUNCATED AT 250 WORDS)     

Renal metabolism in fetal and newborn sheep

The substrate and oxygen uptake by some organs in intact developing animals has been described, however, the kidney has not been studied. To examine substrate and oxygen uptake by the kidney, we implanted polyvinyl catheters into the renal vein, descending aorta, inferior vena cava, and urinary bladder of 11 fetal sheep (120-125 days gestation) and eight newborn lambs (1 day postnatal). Four days after surgery, blood samples were obtained simultaneously from the renal vein, aorta, and inferior vena cava for determination of oxygen content and saturation, and glucose and lactate concentrations. Renal blood flow was determined by the radionuclide-labeled microsphere method in the fetal lambs and by measuring 14C-inulin clearance in the newborn lambs. The fetal and newborn kidneys consumed oxygen at rates of 123 +/- 16 and 785 +/- 79 mumol/min/100 g kidney weight (mean +/- SEM), respectively. The increase in oxygen consumption from the fetal to the newborn period was accompanied by an increase in oxygen extraction from 25-35%, a large increase in oxygen delivery from 418 +/- 38 to 2231 +/- 127 mumol/min/100 g, and marked increases in glomerular filtration rate and sodium reabsorption (measured in six additional fetal sheep and the eight newborn lambs). This suggests that the postnatal increase in renal tubular activity is associated with an increase in oxygen consumption. Lactate was taken up by both fetal and newborn kidneys, and in nine of the 11 fetuses and in four of the eight newborns, there was net glucose release from the kidney.     

NIRS in the fetal to neonatal transition and immediate postnatal period

Near-infrared spectroscopy (NIRS) offers the non-invasive continuous monitoring of cerebral oxygenation and perfusion. Cerebral regional oxygen (crSO2) measured via NIRS represents a mixed tissue saturation value, thus enabling information on the balance of cerebral oxygen delivery and oxygen consumption. Cerebral oxygenation is influenced by pulse oximeter saturation (SpO2), hemoglobin content, and cerebral blood flow. Furthermore, cerebral oxygenation is dependent on metabolic parameters, cardio circulatory parameters, perinatal- and postnatal interventions. Reference ranges for healthy term born and late preterm infants have already been published. It is feasible to increase crSO2 values above the 10th percentile by guiding medical support during neonatal to fetal transition. Guiding oxygen supply based on NIRS monitoring in addition to SpO2 monitoring showed that a reduction of the burden of cerebral hypoxia was possible. A currently ongoing study will give further information whether additional NIRS monitoring guiding medical support during neonatal to fetal transition is effective in improving neonatal outcome.     

Cerebrovascular responses in the fetal sheep brain to low-dose endotoxin

Clinical and experimental evidence indicate that infection in pregnancy is associated with fetal brain damage. However, the inflammatory processes that compromise the fetal brain are not fully understood. In this study, we used a single, low dose of lipopolysaccharide (LPS, 0.1 microg/kg i.v.) to provoke an acute-phase response in unanesthetized fetal sheep in utero. COX-2 mRNA was increased in the cortex and cerebellum at 24 and 48 h after LPS, and immunoreactive COX-2 protein was increased in perivascular cells throughout gray and white matter at 24 h after LPS administration. Plasma albumin was observed in the parenchyma of the brain in cortex, thalamus, hypothalamus, corpus callosum, fornix, hippocampus, midbrain, subcallosal bundle, and cerebellar Purkinje cells. Large, rounded, lectin-positive cells with the appearance of macrophages were observed around blood vessels in subventricular white matter. These results indicate that blood-brain barrier permeability is increased in the fetal brain after exposure to endotoxin and suggests that cytotoxic and pro-inflammatory substances could pass from the circulation into the brain after peripheral inflammatory stimulation.     

Pulmonary venous flow from fetal to neonatal period

There are few reports about the effect of fetal or transitional circulation on the pulmonary venous flow. The purposes of this study were to investigate flow patterns of the pulmonary vein serially from fetal to neonatal period and to determine the relationship between pulmonary venous flow and other parameters from aortic and mitral valve. Pulmonary venous flow velocity was analyzed in 21 normal term human fetuses. Postnatal follow-up studies were performed at 1, 6, 24 h, 3 days, 1 week and 1 month. In each time point, pulsed Doppler echocardiography was used to interrogate right upper pulmonary vein, mitral and aortic valve. The measured parameters of pulmonary vein were heart rate, velocity time integral (VTI), and velocities at systolic peak (S), at diastolic peak (D), at nadir between S and D (O), and at nadir between D and the next S (X). E/A ratio and VTI were measured for mitral valve and peak systolic velocity and VTI for aortic valve. Pulmonary venous flow in fetus was phasic and continuous with low velocity. One hour after birth, without a change of flow pattern, all velocities increased dramatically. These high velocities showed a significant decrease during 24 h after birth. Three days after birth, the velocity decreased slightly and flow pattern changed from continuous to interrupted pattern with or without atrial reversal. No Doppler parameters from aortic or mitral valve showed any correlation with parameters from pulmonary vein. In conclusion, the flow pattern of the pulmonary vein in fetus may result from low pulmonary flow and decreased capacitance of the pulmonary venous system. Sudden increase in the pulmonary flow after birth is likely to be responsible for the highest velocities recorded immediately after birth. Left to right shunt through the ductus arteriosus may also contribute to the flow pattern observed in the first several days, as do changes in reservoir function of the pulmonary vein.     

Renal hemodynamic response to atrial natriuretic factor in fetal and newborn sheep

We have previously demonstrated that systemic atrial natriuretic factor (ANF) infusion induced a renal vasoconstrictor response in fetal and newborn sheep. The present study was designed to test the hypothesis that the fetal and neonatal renal vasculatures do, in fact, vasodilate in response to ANF but that this effect is negated by vasoconstrictor compensatory mechanisms when ANF is infused systemically. To test this hypothesis, the renal hemodynamic response to intrarenal infusion of ANF was studied in chronically instrumented fetal (125-135 d of gestation; term 145 d) and newborn (8-15 d) sheep. Intrarenal infusion of ANF (0.125 to 4.0 micrograms/kg of body wt in fetuses and 0.25 to 8.0 micrograms/kg in newborns) had no significant effect on mean arterial blood pressure and heart rate. However, ANF produced a concentration-dependent increase in renal blood flow velocity (F = 40.9, p less than 0.001) and a decrease in renal vascular resistance (F = 38.3, p less than 0.001) in both groups. The magnitude of changes in renal blood flow velocity and renal vascular resistance expressed as percentage of changes (% delta) from control values, were similar (p greater than 0.05) in both fetal and newborn sheep during intrarenal infusion of ANF. These results demonstrate that ANF exerts direct vasodilator action on the fetal and neonatal renal vasculature and that the renal vasoconstriction previously observed during systemic infusion of ANF was probably secondary to activation of compensatory mechanisms.     

Effects of ritodrine and fetal oxygenation after in utero fetal surgery in sheep

Surgical procedures which involve the pregnant uterus are associated with preterm labor contractions in the postoperative period. Because uterine contractions decrease fetal oxygen tension, we investigated the effect of maternal ritodrine infusion on fetal oxygen consumption in catheterized fetal sheep 5 h postoperatively. During ritodrine infusion, uterine activity promptly abated, but the oxygen tension in the umbilical vein and descending aorta decreased. The arterial-venous oxygen content difference, the umbilical blood flow, and consequently, fetal oxygen consumption did not change significantly. We conclude that fetal oxygenation is not improved by eliminating uterine activity with maternal ritodrine infusion in the postoperative period.