Factors affecting gas transfer across the placenta and the oxygen supply to the fetus

The factors that affect placental gas exchange are reviewed, with particular reference to recent measurements of the effect of changes in one or more of these factors on O2 delivery to the fetus and on fetal O2 uptake. Fetal or maternal placental blood flows and blood O2 capacities can be altered by 50% without any major change occurring in fetal O2 uptake: umbilical venous O2 content and fetal O2 delivery fall, but the O2 consumption of the fetus is maintained by increasing the fractional extraction of O2 from the blood. There is evidence that the fetus can also cope with a reduction in blood O2 affinity resulting from replacement of fetal with maternal blood. The critical level of O2 delivery is about 0.6 mmol.min-1.kg-1 in the fetal sheep. When O2 delivery is reduced below this level, by decreasing maternal placental blood flow, raising or lowering fetal haematocrit, decreasing maternal O2 capacity, or decreasing fetal O2 affinity, fetal O2 uptake tends to fall. The resultant tissue hypoxia and inability to maintain oxidative metabolism is reflected in a lowering of arterial blood pH and base excess. Whilst the results of short-term experiments suggest that there exists a large reserve for placental O2 transfer and fetal O2 supply, there is evidence that fetal O2 uptake is more tightly linked to O2 delivery when the latter is reduced for a period of days or weeks. In the long term, restriction of the supply of O2 and nutrients leads to a reduced rate of fetal growth and a reprogramming of tissue development.     

Relationships among Doppler-derived umbilical artery absolute velocities, cardiac function, and placental volume blood flow and resistance in fetal sheep

We hypothesized that umbilical artery (UA) absolute blood flow velocities measured by Doppler ultrasonography reflect placental volume blood flow (Q(UA)) and placental vascular resistance (R(UA)) in a late gestation fetal sheep model. In addition, we examined the relationships between umbilical artery absolute blood flow velocities and parameters of fetal cardiac function. Twenty-six sheep fetuses were instrumented at 112-132 days of gestation. After a 5-day recovery period, experiments were performed under general anesthesia in 16 normal fetuses, in 5 fetuses after maternal administration of phenylephrine, and in 5 fetuses after placental embolization. The Q(UA) and arterial blood pressures were measured using a transit-time ultrasonic flow probe and a catheter placed into the descending aorta, respectively. UA peak systolic velocity (PSV), end-diastolic velocity (EDV), time-averaged maximum velocity (TAMXV), pulsatility index (PI), mean velocity (V(mean)), fetal cardiac output, ventricular ejection forces, and the proportion of isovolumetric relaxation time (IRT%) in the cardiac cycle were measured with the use of Doppler ultrasonography. Significant positive linear correlations were found between UA EDV, TAMXV, and V(mean) versus Q(UA), whereas UA PI had a significant negative correlation with Q(UA). Significant negative correlations were shown between UA EDV, TAMXV, and V(mean) versus R(UA). A significant positive correlation was present between UA PI and R(UA). Doppler-derived UA parameters did not correlate with fetal arterial blood pressures, cardiac output, ventricular ejection forces or IRT%. In fetal sheep, Doppler-derived UA PI and absolute velocities, except PSV, are closely related to directly measured Q(UA) and R(UA), validating the use of noninvasive Doppler velocimetry in the assessment of placental circulation.     

Effect of prostaglandins E2 and F2α on umbilical blood flow and fetal hemodynamics

The hemodynamic effects of PGF_2α, PGE₂, and norepinephrine injected into the umbilical arterial circulation were compared in nine fetal lambs in utero. Umbilical blood flow was measured with radioactive microspheres and an electromagnetic flow transducer implanted on the distal aorta of the fetus after ligation of external iliac arteries and other accessible distal aortic branches.PGF_2α and norepinephrine increased fetal arterial pressure and umbilical blood flow while umbilical vascular resistance increased slightly (PGF_2α) or not at all (norepinephrine). PGE₂ increased fetal arterial pressure, decreased umbilical blood flow, and exerted a profound active vasoconstrictor effect on the fetal placental bed. Our data taken together with the observations of others suggest that prostaglandins may play a role in the circulatory adaptations of the fetus at birth and that PGE₂ in high concentrations is likely to have deleterious hemodynamic consequences in the fetus in utero.     

Exercise responses in pregnant sheep: blood gases, temperatures, and fetal cardiovascular system

In an effort to examine the effects of maternal exercise on the fetus we measured maternal and fetal temperatures and blood gases and calculated uterine O2 consumption in response to three different treadmill exercise regimens in 12 chronically catheterized near-term sheep. We also measured fetal catecholamine concentrations, heart rate, blood pressure, cardiac output, blood flow distribution, blood volume, and placental diffusing capacity. Maternal and fetal temperatures increased a mean maximum of 1.5 +/- 0.5 (SE) and 1.3 +/- 0.1 degrees C, respectively. We corrected maternal and fetal blood gas values for the temperatures in vivo. Maternal arterial partial pressure of O2 (PO2), near exhaustion during prolonged (40 min) exercise at 70% maximal O2 consumption, increased 13% to a maximum of 116.7 +/- 4.0 Torr, whereas partial pressure of CO2 (PCO2) decreased by 28% to 27.6 +/- 2.2 Torr. Fetal arterial PO2 decreased 11% to a minimum of 23.2 +/- 1.6 Torr, O2 content by 26% to 4.3 +/- 0.6 ml X dl -1, PCO2 by 8% to 49.6 +/- 3.2 Torr, but pH did not change significantly. Recovery was virtually complete within 20 min. During exercise total uterine O2 consumption was maintained despite the reduction in uterine blood flow because of hemoconcentration and increased O2 extraction. The decrease of 3 Torr in fetal arterial PO2 and 1.5 ml X dl -1 in O2 content did not result in major cardiovascular changes or catecholamine release. These findings suggest that maternal exercise does not represent a major stressful or hypoxic event to the fetus.     

Weekly intra-amniotic IGF-1 treatment increases growth of growth-restricted ovine fetuses and up-regulates placental amino acid transporters

Frequent treatment of the growth-restricted (IUGR) ovine fetus with intra-amniotic IGF-1 increases fetal growth. We aimed to determine whether increased growth was maintained with an extended dosing interval and to examine possible mechanisms. Pregnant ewes were allocated to three groups: Control, and two IUGR groups (induced by placental embolization) treated with weekly intra-amniotic injections of either saline (IUGR) or 360 μg IGF-1 (IGF1). IUGR fetuses were hypoxic, hyperuremic, hypoglycemic, and grew more slowly than controls. Placental glucose uptake and SLC2A1 (GLUT2) mRNA levels decreased in IUGR fetuses, but SLC2A3 (GLUT3) and SLC2A4 (GLUT4) levels were unaffected. IGF-1 treatment increased fetal growth rate, did not alter uterine blood flow or placental glucose uptake, and increased placental SLC2A1 and SLC2A4 (but not SLC2A3) mRNA levels compared with saline-treated IUGR animals. Following IGF-1 treatment, placental mRNA levels of isoforms of the system A, y(+), and L amino acid transporters increased 1.3 to 5.0 fold, while the ratio of phosphorylated-mTOR to total mTOR also tended to increase. Weekly intra-amniotic IGF-1 treatment provides a promising avenue for intra-uterine treatment of IUGR babies, and may act via increased fetal substrate supply, up-regulating placental transporters for neutral, cationic, and branched-chain amino acids, possibly via increased activation of the mTOR pathway.     

The blood supply to the heart and brain in the growth retarded guinea pig fetus

Blood flow to the heart and brain of 31 control and 15 growth retarded (IUGR) guinea pig fetuses was measured between 60-64 days of pregnancy by the microsphere technique. The animals were anaesthetized with diazepam and pentobarbitone. Brain weight was reduced by 11% in IUGR fetuses from 2.61 +/- 0.03 to 2.33 +/- 0.05 g and heart weight by 39% from 0.42 +/- 0.01 to 0.25 +/- 0.01 g, compared to a decrease in body weight of 42% from 83.6 +/- 2.3 to 48.2 +/- 2.2 g. The myocardial blood flow of control animals was negatively correlated to arterial O2 content (r = 0.78, P less than 0.001) and arterial pH (r = 0.68, P less than 0.001). Brain blood flow was inversely correlated to arterial O2 content in control fetuses (r = 0.79, P less than 0.001). Eight regions of the brain were examined: cerebral hemispheres, caudate nucleus, hippocampus, thalamus + hypothalamus, cerebellum, pons, and medulla. Regional blood flows were significantly correlated to fetal oxygenation in the controls. Growth retarded fetuses were characterized by poor oxygenation (arterial O2 content less than or equal to 2.5 mM) and were frequently acidaemic (pH less than 7.20). No relation could be demonstrated between the myocardial or cerebral blood flows of IUGR fetuses and arterial O2 content or pH. It is concluded that growth retarded fetuses are unable to maintain O2 delivery to the brain and myocardium by increases in blood flow. Although O2 extraction could be increased to meet the O2 requirements of the heart, IUGR fetuses had a lower rate pressure product, suggesting a decline in myocardial O2 consumption.(ABSTRACT TRUNCATED AT 250 WORDS)     

Characterization of the hemodynamic wall shear stresses in human umbilical vessels from normal and intrauterine growth restricted pregnancies

Significant reductions in blood flow and umbilical diameters were reported in pregnancies affected by intrauterine growth restriction (IUGR) from placental insufficiency. However, it is not known if IUGR umbilical blood vessels experience different hemodynamic wall shear stresses (WSS) compared to normal umbilical vessels. As WSS is known to influence vasoactivity and vascular growth and remodeling, which can regulate flow rates, it is important to study this parameter. In this study, we aim to characterize umbilical vascular WSS environment in normal and IUGR pregnancies, and evaluate correlation between WSS and vascular diameter, and gestational age. Twenty-two normal and 21 IUGR pregnancies were assessed via ultrasound between the 27th and 39th gestational week. IUGR was defined as estimated fetal weight and/or abdominal circumference below the 10th centile, with no improvement during the remainder of the pregnancy. Vascular diameter was determined by 3D ultrasound scans and image segmentation. Umbilical artery (UA) WSS was computed via computational flow simulations, while umbilical vein (UV) WSS was computed via the Poiseuille equation. Univariate multiple regression analysis was used to test for the differences between normal and IUGR cohort. UV volumetric flow rate, UA and UV diameters were significantly lower in IUGR fetuses, but flow velocities and WSS trends in UA and UV were very similar between normal and IUGR groups. In both groups, UV WSS showed a significant negative correlation with diameter, but UA WSS had no correlation with diameter, suggesting a constancy of WSS environment and the existence of WSS homeostasis in UA, but not in UV. Despite having reduced flow rate and vascular sizes, IUGR UAs had hemodynamic mechanical stress environments and trends that were similar to those in normal pregnancies. This suggested that endothelial dysfunction or abnormal mechanosensing was unlikely to be the cause of small vessels in IUGR umbilical cords.     

Effect of restriction of placental growth on fetal and utero-placental metabolism

The effect of restriction of placental growth on the supply of glucose to the gravid uterus and fetus and on fetal and utero-placental metabolism of glucose and lactate was examined in this study. Endometrial caruncles were removed from 13 sheep (caruncle sheep) prior to mating, which restricted placental growth in the subsequent pregnancy. Half the fetuses of caruncle sheep were small or growth retarded, with the remainder normal in size. After insertion of vascular catheters at 110 days gestation, the caruncle sheep, together with 16 control sheep, were studied between 121 and 130 days of gestation. Glucose delivery to and consumption by the gravid uterus and its contents, both as a total and per kg of tissue mass, was significantly lower in caruncle ewes with small fetuses, although glucose extraction was similar to that in controls. Utero-placental glucose consumption was significantly lower in caruncle ewes carrying small fetuses compared to that in control ewes, both as a total and per kg of placenta. Small caruncle fetuses were hypoxaemic and hypoglycaemic and the lactate concentration in the common umbilical vein was significantly higher than in control sheep. Glucose delivery to and consumption by the fetus was significantly lower in normal-sized and in small caruncle fetuses compared to controls. Fetal glucose consumption per kg of fetus was similar in control and caruncle sheep. Fetal glucose extraction increased as fetal weight decreased. Utero-placental production of lactate was similar in control and caruncle ewes. However, uterine output of lactate decreased as placental weight fell. Utero-placental production of lactate per kg of placenta was significantly higher in caruncle ewes compared to controls and increased as oxygen content in blood from the fetal femoral artery decreased. Fetal lactate consumption per kg of fetus increased as the concentration of lactate in blood from the common umbilical vein increased. It is concluded that intrauterine growth retardation due to restriction of placental growth is associated with a reduced supply of glucose to both the pregnant uterus and fetus and a redistribution of glucose therein to the fetus, both directly as glucose and indirectly as lactate. This reflects the disproportionate maintenance of fetal weight relative to that of the placenta, reduced utero-placental consumption of glucose per kg of placenta, conversion of a greater proportion of that glucose or other substrate(s) to lactate by the placenta and an increase in the fraction of the lactate produced by utero-placental tissues that is secreted into the fetal circulation.     

Hindlimb glucose and lactate metabolism during umbilical cord compression and acute hypoxemia in the late-gestation ovine fetus

The metabolic adaptation of the hindlimb in the fetus to a reversible period of adverse intrauterine conditions and, subsequently, to a further episode of acute hypoxemia has been examined. Sixteen sheep fetuses were chronically instrumented with vascular catheters and transit-time flow probes. In nine of these fetuses, umbilical blood flow was reversibly reduced by 30% from baseline for 3 days (umbilical cord compression), while the remaining fetuses acted as sham-operated, age-matched controls. Acute hypoxemia was subsequently induced in all fetuses by reducing maternal fractional inspired oxygen concentration for 1 h. Paired hindlimb arteriovenous blood samples were taken at appropriate intervals during cord compression and acute hypoxemia, and by using femoral blood flow and the Fick principle, substrate delivery, uptake, and output were calculated. Umbilical cord compression reduced blood oxygen content and delivery to the hindlimb and increased hindlimb oxygen extraction and blood glucose and lactate concentration in the fetus. However, hindlimb glucose and oxygen consumption were unaltered during umbilical cord compression. In contrast, hindlimb oxygen delivery and uptake were significantly reduced in all fetuses during subsequent acute hypoxemia, but glucose extraction, oxygen extraction, and hindlimb lactate output significantly increased in sham-operated control fetuses only. Preexposure of the fetus to a temporary period of adverse intrauterine conditions alters the metabolic response of the fetal hindlimb to subsequent acute stress. Additional data suggest that circulating blood lactate may be derived from sources other than the fetal hindlimb under these circumstances. The lack of hindlimb lactate output during acute hypoxemia in umbilical cord-compressed fetuses, despite a significant fall in oxygen delivery to and uptake by the hindlimb, suggests that the fetal hindlimb may not respire anaerobically after exposure to adverse intrauterine conditions. hypoxia     

Complex,coordinated and highly regulated changes in placental signaling and nutrient transport capacity in IUGR

The most common cause of intrauterine growth restriction (IUGR) in the developed world is placental insufficiency, a concept often used synonymously with reduced utero-placental and umbilical blood flows. However, placental insufficiency and IUGR are associated with complex, coordinated and highly regulated changes in placental signaling and nutrient transport including inhibition of insulin and mTOR signaling and down-regulation of specific amino acid transporters, Na⁺/K⁺-ATPase, the Na^+/H⁺-exchanger, folate and lactate transporters. In contrast, placental glucose transport capacity is unaltered and Ca²⁺-ATPase activity and the expression of proteins involved in placental lipid transport are increased in IUGR. These findings are not entirely consistent with the traditional view that the placenta is dysfunctional in IUGR, but rather suggest that the placenta adapts to reduce fetal growth in response to an inability of the mother to allocate resources to the fetus. This new model has implications for the understanding of the mechanisms underpinning IUGR and for the development of intervention strategies.     

Survival and size are differentially regulated by placental and fetal PKBalpha/AKT1 in mice

The importance of placental circulation is exemplified by the correlation of placental size and blood flow with fetal weight and survival during normal and compromised human pregnancies in such conditions as preeclampsia and intrauterine growth restriction (IUGR). Using noninvasive magnetic resonance imaging, we evaluated the role of PKBalpha/AKT1, a major mediator of angiogenesis, on placental vascular function. PKBalpha/AKT1 deficiency reduced maternal blood volume fraction without affecting the integrity of the fetomaternal blood barrier. In addition to angiogenesis, PKBalpha/AKT1 regulates additional processes related to survival and growth. In accordance with reports in adult mice, we demonstrated a role for PKBalpha/AKT1 in regulating chondrocyte organization in fetal long bones. Using tetraploid complementation experiments with PKBalpha/AKT1-expressing placentas, we found that although placental PKBalpha/AKT1 restored fetal survival, fetal PKBalpha/AKT1 regulated fetal size, because tetraploid complementation did not prevent intrauterine growth retardation. Histological examination of rescued fetuses showed reduced liver blood vessel and renal glomeruli capillary density in PKBalpha/Akt1 null fetuses, both of which were restored by tetraploid complementation. However, bone development was still impaired in tetraploid-rescued PKBalpha/Akt1 null fetuses. Although PKBalpha/AKT1-expressing placentas restored chondrocyte cell number in the hypertrophic layer of humeri, fetal PKBalpha/AKT1 was found to be necessary for chondrocyte columnar organization. Remarkably, a dose-dependent phenotype was exhibited for PKBalpha/AKT1 when examining PKBalpha/Akt1 heterozygous fetuses as well as those complemented by tetraploid placentas. The differential role of PKBalpha/AKT1 on mouse fetal survival and growth may shed light on its roles in human IUGR.     

Improving amino acid nutrition to prevent intrauterine growth restriction in mammals

Intrauterine growth restriction (IUGR) is one of the most common concerns in human obstetrics and domestic animal production. It is usually caused by placental insufficiency, which decreases fetal uptake of nutrients (especially amino acids) from the placenta. Amino acids are not only building blocks for protein but also key regulators of metabolic pathways in fetoplacental development. The enhanced demands of amino acids by the developing conceptus must be met via active transport systems across the placenta as normal pregnancy advances. Growing evidence indicates that IUGR is associated with a reduction in placental amino acid transport capacity and metabolic pathways within the embryonic/fetal development. The positive relationships between amino acid concentrations in circulating maternal blood and placental amino acid transport into fetus encourage designing new therapies to prevent or treat IUGR by enhancing amino acid availability in maternal diets or maternal circulation. Despite the positive effects of available dietary interventions, nutritional therapy for IUGR is still in its infancy. Based on understanding of the underlying mechanisms whereby amino acids promote fetal growth and of their dietary requirements by IUGR, supplementation with functional amino acids (e.g., arginine and glutamine) hold great promise for preventing fetal growth restriction and improving health and growth of IUGR offspring.     

Restriction of placental growth in sheep enhances placental metabolism of fetal beta-endorphin-like immunoreactivity

The opioid polypeptide beta-endorphin is present in fetal blood but it is not clear whether its source is the fetus or the placenta. We therefore measured beta-endorphin in extracts of fetal femoral arterial and umbilical venous blood plasma in sheep by radioimmunoassay to determine whether the fetus or the placenta is the major source of beta-endorphin in the fetal circulation. Chromatographic analysis of extracts of fetal arterial plasma showed that beta-lipotropin and other precursors of beta-endorphin made only a minor contribution to the immunoreactivity detected. Concentrations of immunoreactive beta-endorphin were higher in the femoral artery than in the umbilical vein in fetal sheep between 113 and 128 days of pregnancy. Therefore the placenta removes beta-endorphin or a closely related polypeptide of fetal origin from the umbilical circulation in sheep at this stage of gestation. Acute hypoxaemia and hypoglycaemia increase the concentrations of immunoassayable beta-endorphin in blood plasma of adult and fetal sheep, but little is known about the effects of chronic hypoxaemia or hypoglycaemia on the circulating levels of beta-endorphin and related polypeptides in the fetus. Therefore we also measured immunoreactive beta-endorphin in blood plasma from fetal sheep in which growth retardation in association with restricted placental growth was produced by removal of endometrial caruncles before mating. Intra-uterine growth retardation was accompanied by chronic hypoglycaemia and chronic hypoxaemia in the fetuses. This was not associated with higher concentrations of beta-endorphin-like immunoreactivity in fetal arterial or umbilical venous plasma, but was accompanied by significantly increased placental extraction of fetal immunoreactive beta-endorphin from the umbilical circulation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Melatonin supplementation alters uteroplacental hemodynamics and fetal development in an ovine model of intrauterine growth restriction

Using a mid- to late-gestation ovine model of intrauterine growth restriction (IUGR), we examined uteroplacental blood flow and fetal growth during melatonin supplementation as a 2 × 2 factorial design. At day 50 of gestation, 32 ewes were supplemented with 5 mg of melatonin (MEL) or no melatonin (CON) and were allocated to receive 100% [adequate; (ADQ)] or 60% [restricted (RES)] of nutrient requirements until day 130 of gestation. Umbilical artery blood flow was increased from day 60 to day 110 of gestation in MEL vs. CON dams, while umbilical artery blood flow was decreased from day 80 to day 110 of gestation in RES vs. ADQ dams. At day 130 of gestation, uteroplacental hemodynamics, measured under general anesthesia, and fetal growth were evaluated. Uterine artery blood flow was decreased in RES vs. ADQ dams, while melatonin supplementation did not affect uterine artery blood flow. Total placentome weight and placentome number were not different between treatment groups. Fetal weight was decreased by nutrient restriction. Abdominal girth and ponderal index were increased in fetuses from MEL-ADQ dams vs. all other groups. Fetal biparietal distance was decreased in CON-RES vs. CON-ADQ dams, while melatonin supplementation rescued fetal biparietal distance. Fetal kidney length and width were increased by maternal melatonin treatment. Fetal cardiomyocyte area was altered by both maternal melatonin treatment and nutritional plane. In summary, melatonin may negate the consequences of IUGR during specific abnormalities in umbilical blood flow as long as sufficient uterine blood perfusion is maintained during pregnancy.     

Studies on experimental growth retardation in sheep. The effects of a small placenta in restricting transport to and growth of the fetus

Fetal and placental growth rate in sheep has been manipulated by removal of endometrial caruncles prior to conception. This produced two groups of fetuses, one in which prenatal growth rate was similar to normal and a second group in which the fetuses were about half of the normal size. The mortality in the latter group was high, particularly after catheterisation, and there was evidence of early intra-uterine death and fetal reabsorption. Prior to 125 days the relationship between fetal and placental size was poor, but after 126 days a close correlation between the two was apparent. The small fetuses had comparably small placentas and in all cases there was a close relationship between fetal and placental weight. The experimental growth retardation was associated with hypoglycaemia, hypoxia and hypoinsulinaemia. Plasma T3, T4 and particularly prolactin were very low in the small fetuses whilst levels of cortisol and alanine were high. In contrast to the controls these fetuses showed little evidence of net glucose, alanine or lactate consumption. Infusion of 50% glucose into the pregnant ewe, sufficient to elevate maternal plasma glucose concentrations 2 to 3 fold, caused a comparable increase in the plasma concentrations of normal fetuses but only a 50% rise in the concentration in small fetuses. In contrast administration of 50% O2 to the ewes sufficient to cause a 2 to 3-fold increase in maternal PO2 caused only a small increase of arterial PO2 of normal fetuses but doubled that to normal levels in small fetuses. The results are discussed in relation to the effect of reduced placental size causing a fall in placental and transport and transport capacity and significance of this to the associated fetal growth retardation.     

A Computational Model of the Fetal Circulation to Quantify Blood Redistribution in Intrauterine Growth Restriction

Intrauterine growth restriction (IUGR) due to placental insufficiency is associated with blood flow redistribution in order to maintain delivery of oxygenated blood to the brain. Given that, in the fetus the aortic isthmus (AoI) is a key arterial connection between the cerebral and placental circulations, quantifying AoI blood flow has been proposed to assess this brain sparing effect in clinical practice. While numerous clinical studies have studied this parameter, fundamental understanding of its determinant factors and its quantitative relation with other aspects of haemodynamic remodeling has been limited. Computational models of the cardiovascular circulation have been proposed for exactly this purpose since they allow both for studying the contributions from isolated parameters as well as estimating properties that cannot be directly assessed from clinical measurements. Therefore, a computational model of the fetal circulation was developed, including the key elements related to fetal blood redistribution and using measured cardiac outflow profiles to allow personalization. The model was first calibrated using patient-specific Doppler data from a healthy fetus. Next, in order to understand the contributions of the main parameters determining blood redistribution, AoI and middle cerebral artery (MCA) flow changes were studied by variation of cerebral and peripheral-placental resistances. Finally, to study how this affects an individual fetus, the model was fitted to three IUGR cases with different degrees of severity. In conclusion, the proposed computational model provides a good approximation to assess blood flow changes in the fetal circulation. The results support that while MCA flow is mainly determined by a fall in brain resistance, the AoI is influenced by a balance between increased peripheral-placental and decreased cerebral resistances. Personalizing the model allows for quantifying the balance between cerebral and peripheral-placental remodeling, thus providing potentially novel information to aid clinical follow up.     

The effect of 10% O2 on the continuous breathing induced by O2 or O2 plus cord occlusion in the fetal sheep.

Although the administration of 100% O2 alone or combined with umbilical cord occlusion induces continuous breathing and arousal in the fetal sheep (Baier, Hasan, Cates, Hooper, Nowaczyk & Rigatto, 1990a), the individual contribution of O2 and cord occlusion to the response have not been determined. We hypothesized that if O2 is an important factor in the induction of continuous breathing, administration of O2 low enough (10%) to bring fetal arterial PO2 to about 20 torr while the fetus is breathing continuously should reverse these changes. Thus we subjected 12 chronically instrumented fetal sheep to 10% O2 for 10 minutes after the establishment of continuous breathing by O2 (4 fetuses; 137 +/- 1 days) or by O2 plus umbilical cord occlusion (8 fetuses; 134 +/- 1 days). Arterial PO2 decreased from about 250 torr to 20 torr during 10% O2. This induced a significant decrease in breathing output (EMGdi x f) related primarily to a decrease in frequency (f). In 3/5 experiments in 4 fetuses, with O2 alone, apnoea developed within 4 +/- 0.6 min; in 12/13 experiments in 8 fetuses, with added cord occlusion it developed at 5 +/- 0.6 min. With the decrease in PaO2, electrocortical activity (ECoG) switched from low to high-voltage within 6 minutes in 5/5 experiments (O2 alone) and in 11/13 (O2 plus cord occlusion). The findings suggest that umbilical cord occlusion alone is not sufficient to maintain breathing continuously and an increased PaO2 is needed. We speculate that in the fetus there is a vital link between PaO2, breathing and ECoG with low PaO2 inhibiting and high PaO2 favouring breathing and arousal.     

Acute supplementation of amino acids increases net protein accretion in IUGR fetal sheep

Placental insufficiency decreases fetal amino acid uptake from the placenta, plasma insulin concentrations, and protein accretion, thus compromising normal fetal growth trajectory. We tested whether acute supplementation of amino acids or insulin into the fetus with intrauterine growth restriction (IUGR) would increase net fetal protein accretion rates. Late-gestation IUGR and control (CON) fetal sheep received acute, 3-h infusions of amino acids (with euinsulinemia), insulin (with euglycemia and euaminoacidemia), or saline. Fetal leucine metabolism was measured under steady-state conditions followed by a fetal muscle biopsy to quantify insulin signaling. In CON, increasing amino acid delivery rates to the fetus by 100% increased leucine oxidation rates by 100%. In IUGR, amino acid infusion completely suppressed fetal protein breakdown rates but increased leucine oxidation rate by only 25%, resulting in increased protein accretion rates by 150%. Acute insulin infusion, however, had very little effect on amino acid delivery rates, fetal leucine disposal rates, or fetal protein accretion rates in CON or IUGR fetuses despite robust signaling of the fetal skeletal muscle insulin-signaling cascade. These results indicate that, when amino acids are given directly into the fetal circulation independently of changes in insulin concentrations, IUGR fetal sheep have suppressed protein breakdown rates, thus increasing net fetal protein accretion.     

Contractile Cardiac Activity in Fetuses with Intrauterine Growth Retardation: Correlations between Regional Nonuniformity, Relaxation, and Afterload

Fetuses of 24 women with normal pregnancies and 14 women with fetal intrauterine growth retardation (IUGR) were tested for shape and movement of the inner borders of the left ventricle (LV) by means of echocardiography. The LV contour was divided into 12 segments. The coefficient of variation (CV) of the movements of individual wall segments was calculated to assess regional nonuniformity of contractions of the LV wall. The ratio between the long and short LV axes was lower in the IUGR group (1.12 ± 0.12) than in the control group (1.75 ± 0.16). Nonuniformity of contractions was higher in the IUGR group (CV = 37.8 ± 17.6%) than in the control group (CV = 21.1 ± 9.9%, P < 0.01). The ratio of the early wave to the atrial wave of transmitral flow (E/A ratio) was lower in the IUGR group (0.69 ± 0.08) than in the control group (0.80 ± 0.08). A negative correlation between the CV and the global ejection fraction of the LV was observed in the fetuses of both groups. In addition, a negative correlation was demonstrated for the E/A ratio and the systolic-to-diastolic flow ratio (S/D ratio) in the umbilical artery. Changes in the shape, nonuniformity of contractions, and diastolic function of the heart in IUGR fetuses are considered to be an adaptation to increased afterload as a result of an elevated resistance of placental vessels.     

Redox ratio in the left ventricle of the growth restricted fetus is positively correlated with cardiac output

Intrauterine growth restriction (IUGR) is a result of limited substrate supply to the developing fetus in utero, and can be caused by either placental, genetic or environmental factors. Babies born IUGR can have poor long-term health outcomes, including being at higher risk of developing cardiovascular disease. Limited substrate supply in the IUGR fetus not only changes the structure of the heart but may also affect metabolism and function of the developing heart. We have utilised two imaging modalities, two-photon microscopy and phase-contrast MRI (PC-MRI), to assess alterations in cardiac metabolism and function using a sheep model of IUGR. Two-photon imaging revealed that the left ventricle of IUGR fetuses (at 140–141 d GA) had a reduced optical redox ratio, suggesting a reliance on glycolysis for ATP production. Concurrently, the use of PC-MRI to measure foetal left ventricular cardiac output (LVCO) revealed a positive correlation between LVCO and redox ratio in IUGR, but not control fetuses. These data suggest that altered heart metabolism in IUGR fetuses is indicative of reduced cardiac output, which may contribute to poor cardiac outcomes in adulthood.