Effects of moderate hypoxia on fetal electrocortical activity, eye movements, and breathing activity in sheep

Isocapnic hypoxaemia (delta PaO2 = -8.0 +/- 0.5 mmHg; delta CaO2 = -2.86 +/- 0.20 ml/dl) was produced in fetal sheep by having the ewe breathe for one hour a gas mixture (v/v) of 10.5% O2 and 1.5% CO2 in N2. Mean fetal heart rate, blood pressure, and incidence of low voltage electrocortical activity were not affected. However, the incidence of rapid-eye-movements and breathing activity was reduced by about 40%. Breathing movements during hypoxaemia had a mean inspiratory time, breath interval, and tracheal pressure amplitude which did not differ significantly from those during control experiments in which the ewe breathed air from the plastic bag. These observations suggest that hypoxia decreases the incidence of breathing movements but does not affect the amplitude or pattern of breathing activity and that it may reduce the incidence of eye movements and breathing activity through a common mechanism.     

Effects of naloxone on breathing movements during hypercapnia in the fetal lamb

To determine whether endogenous opioids influence the fetal breathing response to CO2 we have investigated the effect of the opiate antagonist, naloxone on the incidence, rate, and amplitude of breathing movements during hypercapnia in fetal lambs in utero. In 20 experiments in six pregnant sheep (130-145 days gestation) hypercapnia was induced by giving the ewe 4-6% CO2-18% O2 in N2 to breathe for 60 min. After 30 min of hypercapnia either naloxone (13 experiments) or saline (7 experiments) was infused intravenously for the remaining 30 min. During hypercapnia breath amplitude increased from 5.8 +/- 0.5 to 9.1 +/- 1.2 mmHg (P less than 0.001), and infusion of naloxone was associated with a further significant increase to 15.7 +/- 1.2 mmHg (P less than 0.001). Naloxone had no effect on the incidence or rate of breathing movements during hypercapnia. After hypercapnia there was a significant decrease in the incidence of fetal breathing movements in the naloxone group (14.7 +/- 3.2%). Infusion of saline during hypercapnia had no effect on incidence, rate, or amplitude of fetal breathing movements. These results suggest that endogenous opioids act to suppress or limit breath amplitude during hypercapnia but do not affect rate or incidence of breathing movements.     

Effect of hypoxia on the excitability of two cranial reflexes in unanaesthetized fetal sheep

In fetal sheep acute hypoxia causes a decreased incidence of breathing movements and motor activity, and the excitability of polysynaptic reflexes in the hindlimbs is depressed. To determine whether this inhibitory effect extends to other areas in the fetal CNS, we have studied the effect of hypoxia on two reflexes with cranial pathways. The digastric (jaw opening) reflex was elicited by stimulation of the dental nerve through a pair of stainless steel electrodes implanted into the mandible (4 fetuses). The thyroarytenoid muscle of the larynx was reflexly activated by stimulation of the superior laryngeal nerve by a cuff electrode (4 fetuses). Low level stimulation at 1.5-2 X threshold was repeated at approximately 2 min intervals for 3-4 h; the stimulation did not alter the pattern of electrocortical activity, breathing movements, or cause arousal. The amplitude of the digastric reflex was greatest during low voltage electrocortical activity; conversely, the amplitude of the thyroarytenoid reflex was greatest during high voltage electrocortical activity. Isocapnic hypoxia lasting 30-60 min (16 trials), in which the PaO2 was reduced to 12-14 mmHg, did not reduce the amplitude of either reflex. The reduction of thyroarytenoid reflex amplitude which normally occurred during low voltage electrocortical activity was not present during hypoxia. These experiments show that the inhibitory effects of hypoxia on spinal reflexes, breathing movements and motor activity do not include these cranial pathways.     

Induction of premature delivery in sheep following infusion of cortisol to the fetus. I. The effect of maternal administration of progestagens

Premature induction of delivery in fetuses infused with graded doses of cortisol was brought about in 123.5 +/- 7.7 h (mean +/- SEM, n = 6) after the start of cortisol infusion. This treatment caused a rise in fetal plasma cortisol similar to that observed at normal delivery. Maternal and fetal progesterone and 20 alpha-dihydroprogesterone concentrations decreased to basal levels during infusion of cortisol to the fetus. Induction of premature delivery was delayed or prevented by concomitant treatment of the ewe with progestagen. Maternal intramuscular injection of 100 mg progesterone, 2 times daily, prevented delivery in four of four ewes treated during the time that cortisol was infused into the fetus (11-13 days). Maternal plasma progesterone and 20 alpha-dihydroprogesterone concentrations were maintained during this period, but fetal plasma progesterone concentrations decreased to the same extent as in the fetuses infused with cortisol alone. A single intramuscular injection of 250 mg of medroxyprogesterone acetate to ewes on the day before commencement of infusion of cortisol to the fetus prevented delivery in four of six ewes during the time that cortisol was infused for 9, 13, 14, and 15 days, respectively. One ewe delivered a live lamb at 133.5 h and another at 147.7 h after the start of infusion of cortisol to the fetus. Maternal and fetal plasma cortisol, progesterone, and 20 alpha-dihydroprogesterone concentrations were similar to those observed during infusion of cortisol alone to the fetus. Although fetal cortisol concentrations rose in a similar fashion, and to a similar extent, in all three groups during infusion of cortisol to the fetus, fetal 11-desoxycortisol concentrations only rose above basal levels close to the time of delivery in cortisol-infused fetuses or, in the progestagen-treated groups, when the fetus showed signs of being stressed.     

Naloxone reduces decrease in ventilation induced by hypoxia in newborn infants

The mechanism responsible for the decrease in ventilation during breathing of low fractional concentration of inspired O2 in the newborn infant is poorly understood. The present study tested the hypothesis that endogenous opiates account for this ventilatory decrease. Eleven healthy newborn infants breathed 15% O2, balance N2 for 5 min following an injection of saline and following an injection of naloxone. Neither injection caused a change in minute ventilation (VE) or ventilatory pattern when the infants were breathing room air. However, the decreased ventilation during hypoxia following naloxone was significantly less than that following saline. VE dropped about 14% following saline but only about 4% following naloxone. However, the adult ventilatory response to hypoxemia, i.e., a relatively sustained increase in VE, was not attained. Naloxone had no influence on the occurrence of periodic breathing during hypoxemia. Thus in the healthy full-term newborn infant, endogenous opiates account only for a part of the decreased ventilation during hypoxemia.     

Effect of acutely-induced lactic acidemia on fetal breathing movements, heart rate, blood pressure, ACTH and cortisol in sheep.

Experiments were conducted in 8 chronically-catheterized fetal sheep at 125-135 days gestation in order to determine the effect of exogenously administered lactic acid to the fetus on fetal heart rate, blood pressure, breathing movements (FBM), electrocortical activity (ECOG), plasma immunoreactive (IR-ACTH) and cortisol concentrations. When fetal arterial pH decreased from 7.37 +/- 0.01 during the control period to 7.20 +/- 0.01, there was an initial bradycardia followed by tachycardia but no change in blood pressure. The amplitude of FBM increased 2-fold initially in association with an increase in PCO2 from 47.9 +/- 2.1 mmHg to 58.8 +/- 3.6 mmHg at 5 min into the lactate infusion. There was no change in the incidence of FBM or low-voltage ECOG and there was no change in the plasma concentrations of IR-ACTH and cortisol with the infusion of lactate. We conclude that the major effects of acutely elevating circulatory lactate concentrations in fetal sheep are to increase the amplitude of FBM and to cause an initial bradycardia followed by a tachycardia.     

Effect of beta-endorphin on fetal breathing movements in sheep

It has been suggested that endogenous opioids, such as beta-endorphin (beta-EP), act to depress respiration in the fetus and newborn. We have investigated the effect of infusing beta-EP either intravenously or into a lateral cerebral ventricle on breathing movements and electrocortical activity in eight fetal lambs between 116 and 133 days gestation. Intravenous infusion of beta-EP (200 or 500 micrograms over 1 h) increased plasma beta-EP concentrations 2- to 230-fold and was associated with a small decrease in the percent time spent breathing, from 57.8 +/- 9.1 to 51.3 +/- 8.2%/h (n = 6 exp). There was no change in the amount of high- or low-voltage electrocortical activity. Intracerebroventricular beta-EP infusion (1 or 2 micrograms beta-EP/min for 120 min) was not associated with any change of breathing movements (n = 5 exp) during the period of the infusion. However, in four experiments, in the 6-h period after the end of the beta-EP infusion there were episodes of 2-4 h when the percent time per hour spent breathing exceeded 70%. Electrocortical activity increased in amplitude and distinct episodes of high- and low-voltage activity were sometimes lost in these experiments. We conclude that high concentrations of beta-EP in plasma or cerebrospinal fluid do not totally suppress fetal breathing directly in the fetal lamb.     

The central effects of morphine on fetal breathing movements in the fetal sheep

The fetal respiratory and electrocortical effects of 0.6 microgram to 600 micrograms of morphine, administered into the lateral cerebral ventricle, have been studied in chronically catheterised, unanaesthetized fetal sheep at 115-135 days gestation. Morphine at 0.6 microgram had no effect on breathing movements or electrocorticographic activity, and at 6 micrograms induced a period of apnoea (43-122 min) but had no effect on electrocortical activity. Intravenous naloxone (2 mg bolus and infusion of 2 mg/kg/h for 2 h) to the fetus had no effect on this apnoea. Morphine at 60 micrograms induced an initial period of apnoea (30-65 min) followed by episodic but significantly deep breathing movements with no effect on electrocortical activity and at 600 micrograms induced an initial period of apnoea (22-95 min) which was followed by deep, irregular and continuous (126-302 min) breathing movements. During the apnoea electrocortical activity initially remained cyclic, but as apnoea progressed there was a gradual reduction in the voltage of the electrocorticogram to a low voltage state. Intravenous naloxone (2 mg bolus and infusion of 2 mg/kg/h for 2 h) reversed both the respiratory and electrocortical effects. The hyperventilation was also inhibited by hypoxia. Naloxone alone had no effect on fetal breathing activity.     

Studies on experimental growth retardation in sheep. The effects of maternal hypoxaemia

Intrauterine growth retardation in fetal sheep was caused by removal of endometrial caruncles prior to conception. Such fetuses are chronically hypoxaemic and to establish their ability to withstand additional episodes of hypoxia, the effects of administration of 9% O2 to the pregnant ewe was investigated. Fetuses were studied at 135-140 days. During maternal hypoxia the small fetuses showed a greater tendency to further hypoxaemia and acidaemia, but the differences compared with controls were not large. Whilst the initial response to hypoxaemia was a fall in heart rate in the small fetuses, unlike the controls, the heart rate returned to normal within 15 min. Metabolite responses to hypoxia in the small fetuses were less than normal and the changes in plasma insulin concentrations were uncommonly small. In contrast the plasma cortisol and ACTH responses to hypoxia were larger than normal in the small fetus. The results are discussed in relation to the altered physiological state of the growth-retarded fetal sheep.     

Role of plasma adenosine in breathing responses to hypoxia in fetal sheep.

The importance of plasma adenosine in hypoxic inhibition of breathing movements was determined in chronically catheterized fetal sheep (greater than 0.8 term). Preductal arterial blood for adenosine measurements was withdrawn using a double lumen catheter to mix blood entering the catheter with a solution to stop adenosine metabolism. In 6 fetuses, isocapnic hypoxia (delta PaO2 congruent to -10 Torr) increased the average plasma adenosine concentration from 1.1 +/- 0.2 (SEM) to 2.0 to +/- 0.4 microM. During hypoxia, plasma levels of adenosine were inversely related to preductal arterial O2 content (CaO2) with values ranging between 1.6 and 4.0 microM when CaO2 was less than 3 ml/dl. Hypoxia also significantly reduced the incidence of fetal breathing and rapid eye movements. In other experiments, adenosine (0.36 +/- 0.03 mg/min/kg) was infused for one hour into the inferior vena cava of 5 fetuses. During this infusion, mean plasma concentration of adenosine was 2.8 +/- 0.3 microM, a value about 2.5 times the control average. Adenosine also significantly reduced the incidence of low voltage electrocortical activity, rapid eye movements and breathing activity. We conclude that hypoxic inhibition of fetal breathing most likely arises from an increase in central adenosine production, although during severe O2 deprivation (CaO2 less than 3 ml/dl) blood-borne adenosine could also contribute.     

Cortisol inhibits ACTH but not the AVP response to hypoxaemia in fetal lambs at days 123-128 of gestation

During acute hypoxemia in fetal sheep the elevation in ACTH concentration in the fetal circulation at days 125-129 is greater than that at term, but similar rises in AVP occur at both times. To examine whether the diminished ACTH response is due to elevated endogenous cortisol, and if there is differential control of ACTH and AVP release in hypoxemia, we infused either vehicle or cortisol (5 micrograms/min) into fetal sheep at days 123-128 for 5 h before and then during a 2-h period of acute hypoxemia (mean PaO2 decrease 8.2 mmHg) without acidemia. During cortisol infusion, plasma cortisol rose to 40-50 ng/ml, similar to values in term fetuses. In vehicle-infused fetuses, cortisol rose from 2.1 to 7.0 ng/ml at +1 to +2 h of hypoxemia. ACTH rose significantly during hypoxemia in the vehicle-infused fetuses, and this response was attenuated by cortisol infusion. In contrast, fetal AVP rose significantly during hypoxemia both in the presence and absence of cortisol infusion. Fetal breathing movements, and electroocular activity decreased during hypoxemia, and these responses were not altered by cortisol. We conclude that cortisol exerts differential negative feedback on ACTH but not on AVP release during hypoxemia. The maintained AVP response may facilitate cardiovascular adjustments of the fetus to hypoxemia even when endogenous cortisol is elevated, such as near term.     

The incidence of breathing movements of fetal sheep in normoxia and hypoxia after peripheral chemodenervation and brain-stem transection

The incidence of fetal breathing movements and low voltage electrocortical activity was measured in three groups of fetal sheep, at 123-137 days gestation. The first group (transected & denervated) had the brainstem transected at the level of the colliculi and also had peripheral arterial chemodenervation. The second group (denervated) had a sham brain-stem transection and peripheral arterial chemodenervation. The third group (sham-operated) had sham brain-stem transection and sham peripheral chemodenervation. No differences were observed in the incidence of fetal breathing movements or low voltage electrocortical activity between the sham-operated and the denervated groups in normoxia, or in hypoxia when all these fetuses became apnoeic. There were however differences between these 2 groups and the transected & denervated group, in which fetal breathing movements where dissociated from electrocortical activity and which in some fetuses were continuous. During isocapnic hypoxia 3 of 8 transected & denervated fetuses made fetal breathing movements. We discuss the problems of interpreting data from brain-stem transected fetuses, but conclude that the evidence reveals no tonic influence of the peripheral arterial chemoreceptors on fetal breathing movements.     

Fetal breathing and behavior measured through a double-wall Plexiglas window in sheep

The inability to see the fetus makes the assessment of fetal behavior difficult. To circumvent this problem we implanted a Plexiglas window in the left flank of the ewe. Fetuses were instrumented for measurements of sleep, breathing, and swallowing. Ten fetal sheep were studied on 32 occasions. Six fetuses were delivered through the window at term, and postnatal behavior was compared with intrauterine behavior. Fetuses observed during resting conditions alternated between periods of quiet sleep [high-voltage electrocortical activity (ECoG)] and active or rapid-eye-movement sleep (low-voltage ECoG). In quiet sleep, movements were absent except for periodic generalized electromyographic discharges. Eye and breathing movements were rare or absent. Swallowing was also absent. In active sleep, movements were increased with powerful breathing and swallowing activity. Fetal wakefulness defined by open eyes and purposeful movements of the head was never seen in utero but was clearly observed after delivery. We conclude that fetal wakefulness as defined postnatally was not able to be demonstrated in utero.     

Antenatal glucocorticoids reset the level of baseline and hypoxemia-induced pituitary-adrenal activity in the sheep fetus during late gestation

This study examined the effects of dexamethasone treatment on basal hypothalamo-pituitary-adrenal (HPA) axis function and HPA responses to subsequent acute hypoxemia in the ovine fetus during late gestation. Between 117 and 120 days (term: approximately 145 days), 12 fetal sheep and their mothers were catheterized under halothane anesthesia. From 124 days, 6 fetuses were continuously infused intravenously with dexamethasone (1.80 +/- 0.15 microg.kg(-1).h(-1) in 0.9% saline at 0.5 ml/h) for 48 h, while the remaining 6 fetuses received saline at the same rate. Two days after infusion, when dexamethasone had cleared from the fetal circulation, acute hypoxemia was induced in both groups for 1 h by reducing the maternal fraction of inspired O2. Fetal dexamethasone treatment transiently lowered fetal basal plasma cortisol, but not ACTH, concentrations. However, 2 days after treatment, fetal basal plasma cortisol concentration was elevated without changes in basal ACTH concentration. Despite elevated basal plasma cortisol concentration, the ACTH response to acute hypoxemia was enhanced, and the increment in plasma cortisol levels was maintained, in dexamethasone-treated fetuses. Correlation of fetal plasma ACTH and cortisol concentrations indicated enhanced cortisol output without a change in adrenocortical sensitivity. The enhancements in basal cortisol concentration and the HPA axis responses to acute hypoxemia after dexamethasone treatment were associated with reductions in pituitary and adrenal glucocorticoid receptor mRNA contents, which persisted at 3-4 days after the end of treatment. These data show that prenatal glucocorticoids alter the basal set point of the HPA axis and enhance HPA axis responses to acute stress in the ovine fetus during late gestation.     

Fetal breathing, sleep state, and cardiovascular responses to adenosine in sheep

The possibility that adenosine mediates hypoxic inhibition of fetal breathing and eye movements was tested in nine chronically catheterized fetal sheep (0.8 term). Intracarotid infusion of adenosine (0.25 +/- 0.03 mg.min-1.kg-1) for 1 h to the fetus increased heart rate and hemoglobin concentration but did not significantly affect mean arterial pressure or blood gases. As with hypoxia, adenosine decreased the incidence of rapid eye movements by 55% and the incidence of breathing by 77% without significantly affecting the incidence of low-voltage electrocortical activity. However, with longer (9 h) administration, the incidence of breathing and eye movements returned to normal during the adenosine infusion. Intravenous infusion of theophylline, an adenosine receptor antagonist, prevented most of the reduction in the incidence of breathing and eye movements normally seen during severe hypoxia (delta arterial PO2 = -10 Torr). It is concluded that 1) adenosine likely depresses fetal breathing and eye movements during hypoxia and 2) downregulation of adenosine receptors may contribute to the adaptation of breathing and eye movements during prolonged hypoxia.     

Denervation of peripheral chemoreceptors decreases breathing movements in fetal sheep

The role of the peripheral chemoreceptors in the control of fetal breathing movements has not been fully defined. To determine whether denervation of the peripheral chemoreceptors affects fetal breathing movements, we studied 14 chronically catheterized fetal sheep from 120 to 138 days of gestation. In seven fetuses the chemoreceptors were denervated by bilateral section of the vagus and carotid sinus nerves; in seven others, sham operations were performed. We compared several variables during two study periods: 0-5 and 6-13 days after operation. In the denervated fetuses there were significant decreases in the incidence and amplitude of fetal breathing movements during both study periods. There were no differences between the two groups in incidence of low-voltage electrocortical activity, arterial pH and blood gas tensions, fetal heart rate, mean arterial blood pressure, or duration of survival after operation or birth weight. We conclude that denervation of the peripheral chemoreceptors decreases fetal breathing movements. These results indicate that the peripheral chemoreceptors are active during fetal life and participate in the control of fetal breathing movements.     

Effects of hyperthermia on fetal breathing movements

High environmental temperature is known to impair fetal growth and development. We now report long lasting changes in fetal breathing activity following the exposure of pregnant ewes to an ambient temperature of 43 degrees C for 8 h. In 16 trials in 10 ewes (119-138 days gestation) heat exposure increased maternal and fetal core temperatures 1.5-2.0 degrees C, and the hyperventilation by the ewe produced a fall in fetal PaCO2 from 53.5 +/- 1.3 to 34.8 +/- 5.3 mmHg (P less than 0.05). Fetal breathing movements decreased in incidence during the hyperthermia but remained episodic (present during low-voltage electrocortical activity) with occasional brief episodes of breathing at high rates (greater than 4 breaths/s). However, 1-2 h after the end of heating, when maternal and fetal core temperature and PaCO2 had returned to normal, fetal breathing movements became continuous, and were augmented 30-100% in amplitude. Fetal breathing movements occurred during both low- and high-voltage electrocortical activity. The results show that a heat load similar to that experienced by sheep in sub-tropical regions in the summer months cause prolonged changes in the central regulation of fetal breathing.     

Changes to metabolite concentration in fetal sheep subjected to prolonged hypobaric hypoxia

The effect of hypobaric hypoxaemia on the concentration of metabolic substrates in the ovine fetus and pregnant ewe with implanted vascular catheters, was investigated. At 120 to 141 days of gestation sheep were subjected to hypobaria (mean fetal carotid PO2 12.7 +/- 0.7 torr; n = 9) or normobaria (mean fetal carotid PO2 22.7 +/- 0.7 torr; n = 11; P less than 0.001). At 141 days gestation mean fetal weight was 3.46 +/- 0.72 kg in the hypobaric group compared to 4.15 +/- 0.51 in the normobaric group (P less than 0.05). Concentrations of glucose in maternal and fetal plasma and fructose in fetal plasma were similar in hypobaric and normobaric fetuses. The concentration of lactate in fetal plasma rose from 1.68 +/- 1.34 to 8.79 +/- 5.8 mmol/l (P less than 0.001) within 24 h of onset of hypoxia, but fell to 3.36 +/- 1.13 mmol/l by day 3 of treatment, though still significantly above the concentration of lactate in the control fetuses (1.47 +/- 0.47; P less than 0.001). There was no significant effect of hypoxia on the concentration of lactate or alanine in maternal plasma. Alanine concentration in the plasma of fetuses subjected to hypoxia significantly increased within 24 h of exposure (0.28 +/- 0.10 vs 0.58 +/- 0.39 mmol/l; P less than 0.01) and remained elevated for the duration of the study. There was no significant effect of gestational age on the concentration of metabolic substrates in either the control or experimental groups. Hypoxia is associated with a sustained rise in the concentration of plasma lactate and alanine in the fetus.(ABSTRACT TRUNCATED AT 250 WORDS)     

Restriction of placental function alters heart development in the sheep fetus

Placental insufficiency, resulting in restriction of fetal substrate supply, is a major cause of intrauterine growth restriction (IUGR) and increased neonatal morbidity. Fetal adaptations to placental restriction maintain the growth of key organs, including the heart, but the impact of these adaptations on individual cardiomyocytes is unknown. Placental and hence fetal growth restriction was induced in fetal sheep by removing the majority of caruncles in the ewe before mating (placental restriction, PR). Vascular surgery was performed on 13 control and 11 PR fetuses at 110-125 days of gestation (term: 150 +/- 3 days). PR fetuses with a mean gestational Po(2) < 17 mmHg were defined as hypoxic. At postmortem (<135 or >135 days), fetal hearts were collected, and cardiomyocytes were isolated and fixed. Proliferating cardiomyocytes were counted by immunohistochemistry of Ki67 protein. Cardiomyocytes were stained with methylene blue to visualize the nuclei, and the proportion of mononucleated cells and length and width of cardiomyocytes were measured. PR resulted in chronic fetal hypoxia, IUGR, and elevated plasma cortisol concentrations. Although there was no difference in relative heart weights between control and PR fetuses, there was an increase in the proportion of mononucleated cardiomyocytes in PR fetuses. Whereas mononucleated and binucleated cardiomyocytes were smaller, the relative size of cardiomyocytes when expressed relative to heart weight was larger in PR compared with control fetuses. The increase in the relative proportion of mononucleated cardiomyocytes and the relative sparing of the growth of individual cardiomyocytes in the growth-restricted fetus are adaptations that may have long-term consequences for heart development in postnatal life.     

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.