The effect of a chronic maternal cortisol infusion on the late-gestation fetal sheep

Exposure of the fetus to excess maternal glucocorticoids has been postulated to alter fetal growth and development, and thus provide a possible mechanism for the link between impaired fetal growth and altered postnatal physiology. However, the effects of exposure to excess maternal glucocorticoids on fetal physiology and metabolism in utero have not been described. We therefore studied the effects of chronic maternal cortisol infusion on fetal growth, blood pressure, metabolism and endocrine status in chronically catheterised fetal sheep. We infused hydrocortisone (80 mg/day, n=6) or saline (n=8) for 10 days into the pregnant ewes beginning at 119 days of gestation. Maternal cortisol infusion reduced fetal growth rate by 30% (girth increment 2.9+/-0.3 vs 1.8+/-0.4 mm/day, P=0.03). Maternal cortisol infusion increased fetal heart weight by 15% relative to body weight and increased ventricular wall thickness by 30% in the left and 50% in the right ventricle. The weight of the spleen was reduced by 30% and placental weight reduced by 25%. Fetal blood pressure increased by approximately 10 mmHg (20%) during maternal cortisol infusion. Maternal cortisol infusion did not alter amino-nitrogen concentrations. However, maternal lactate concentrations increased by 80% and fetal lactate concentrations increased by 74% with maternal cortisol infusion, and both maternal and fetal urea concentrations increased by 40%. Circulating maternal IGF-binding protein (IGFBP)-3 levels had increased by 20% by the end of the maternal cortisol infusion. Fetal IGF-I concentrations decreased during cortisol infusion and fetal IGFBP-1 concentrations were negatively correlated with fetal weight (r=-0.76, P=0.02). We conclude that even a modest elevation of maternal cortisol levels affects fetal growth, cardiovascular function, metabolism and endocrine status which may have long-term consequences.

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Blood pressure and cardiovascular reflex development in fetal sheep. Relation to hypoxaemia, weight, and blood glucose

Reproduction Fertility and Development ◽

10.1071/rd9950553 ◽

1995 ◽

Vol 7 (3) ◽

pp. 553 ◽

Cited By ~ 19

Author(s):

C Crowe ◽

L Bennet ◽

MA Hanson

Keyword(s):

Blood Pressure ◽

Blood Glucose ◽

Blood Glucose Concentration ◽

Lactate Concentration ◽

Blood Gases ◽

Late Gestation ◽

Fetal Sheep ◽

Arterial Blood ◽

The Right ◽

Arterial O2 Saturation

We measured mean arterial blood pressure (MAP), fetal heart rate (FHR), the baroreflex, weight, blood gases, blood glucose and lactate in chronically instrumented fetal sheep for 14 days from Day 105 to Day 109 gestation, with or without daily administration of 1 h of acute isocapnic hypoxaemia (arterial O2 partial pressure, PaO2, 11-13 mm Hg; 1 mm Hg = 133 Pa). Fetuses subjected to hypoxia showed no significant differences in MAP or FHR v. control fetuses. However, examination of all fetuses together revealed that there were two distinct groups: those showing a rise in MAP over the 14 days ('pressure up' group, PU), and those in which blood pressure did not increase or showed only a slight decrease ('pressure down' group, PD). PU fetuses were proportionately larger than PD fetuses. In contrast to PU fetuses, PD fetuses had lower blood glucose concentration, arterial O2 saturation (SaO2), PaO2, total haemoglobin, haematocrit and oxygen content, and higher lactate concentration, pH and PaCO2. PU fetuses showed a shift of the baroreflex MAP/R-R interval curve to the right, however, the PD group showed a shift upwards from Day 1 to Day 14. The PD group responded to hypoxia with a greater increase in MAP than the PU group. Thus, repeated acute moderate isocapnic hypoxia does not affect development of MAP or FHR in late gestation fetal sheep. However, MAP follows different trajectories in individual fetuses, related to fetal size and the availability of oxygen and/or glucose. Cardiovascular chemoreflexes and baroreflexes are also different, depending on the MAP trajectory. These data indicate an important association between growth and blood pressure development, and also show that differences in growth are associated with changes in cardiovascular control.

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Treatment of underfed pigs with GH throughout the second quarter of pregnancy increases fetal growth

Journal of Endocrinology ◽

10.1677/joe.0.1660227 ◽

2000 ◽

Vol 166 (1) ◽

pp. 227-234 ◽

Cited By ~ 23

Author(s):

KL Gatford ◽

JA Owens ◽

RG Campbell ◽

JM Boyce ◽

PA Grant ◽

...

Keyword(s):

Fetal Growth ◽

Plasma Glucose ◽

Plasma Concentrations ◽

Amino Nitrogen ◽

Live Weight ◽

Maternal Plasma ◽

Gh Treatment ◽

Fetal Plasma ◽

Nitrogen Concentrations ◽

Ad Libitum Intake

Circulating growth hormone (GH) concentrations increase in pregnancy and administration of GH during early-mid pregnancy increases fetal growth in well-fed pigs. To determine whether increased maternal GH could promote fetal growth when feed availability is restricted, fifteen cross-bred primiparous sows (gilts) were fed at approximately 30% of ad libitum intake, from mating onwards and were injected daily i.m. with recombinant porcine GH (pGH) at doses of 0, 13.4+/-0.3 and 25.6+/-0.5 microg/kg live weight from day 25 to day 51 of pregnancy (term approximately 115 days). Treatment with pGH increased maternal backfat loss between day 25 and day 51 of pregnancy, and increased maternal plasma IGF-I concentrations measured at day 51 of pregnancy. Fetal body weight, length and skull width at day 51 of pregnancy were increased by maternal treatment with pGH. Fetal plasma glucose concentrations were increased and maternal/fetal plasma glucose concentration gradients were decreased by maternal pGH treatment at 13.4, but not 25.6 microg/kg.day. Fetal plasma concentrations of urea were decreased by both levels of pGH treatment. Overall, fetal weight was negatively correlated with fetal plasma concentrations of urea, positively correlated with maternal plasma alpha-amino nitrogen concentrations and unrelated to glucose concentrations in either maternal or fetal plasma. This suggests that the availability of amino acids, not glucose, limits fetal growth in the first half of pregnancy in underfed gilts, and that maternal GH treatment may improve amino acid delivery to the fetus.

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Exogenous GH infusion to late-gestational fetal sheep does not alter fetal growth and metabolism

Journal of Endocrinology ◽

10.1677/joe.0.1660591 ◽

2000 ◽

Vol 166 (3) ◽

pp. 591-597 ◽

Cited By ~ 11

Author(s):

MK Bauer ◽

JE Harding ◽

BH Breier ◽

PD Gluckman

Keyword(s):

Fetal Growth ◽

Growth Increment ◽

Late Gestation ◽

Placental Lactogen ◽

Maternal Weight ◽

Gh Treatment ◽

Fetal Sheep ◽

Crown Rump Length ◽

Gh Secretion ◽

Significant Difference

The role of GH in the regulation of fetal growth and metabolism in late gestation is not well defined. The aim of this study was to determine the effects of exogenous GH infusion on fetal growth and feto-placental metabolism in the normally growing late-gestation fetal sheep. Eleven fetuses received pulsatile GH infusion (3.5 mg/day) for 10 days while 12 control fetuses received vehicle. The GH infusion was given as a continuous infusion (2.5 mg/day) plus an additional pulsatile component (30 pulses equivalent to 1 mg/day) designed to mimic the natural pattern of GH secretion. Fetal GH infusion raised the circulating fetal concentrations of GH threefold, but did not change fetal concentrations of IGF-I, IGF-binding protein-3, insulin or ovine placental lactogen. GH-treated fetuses had blood urea concentrations 15% lower than controls (P<0.05) and glucose uptake 18% lower per kg fetal weig! ht (P=0.06). There were no other differences attributable to fetal GH infusion in feto-placental metabolism, placental function or placental blood flow. GH-treated fetuses were larger than controls at postmortem (weight+13%, P<0.01; girth+5%, P<0.01; crown-rump length+3%, P<0.05). However, there were no differences between groups in measures of fetal growth (increment in chest girth and hindlimb length). GH-treated fetuses had heavier mothers and when maternal weight was included as a covariate in the analysis, there was no significant difference between treatment groups that could be attributed to GH treatment. GH infusion to normal fetal sheep does not appear to have a significant effect on feto-placental metabolism or fetal growth.

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Blood pressure and heart rate in the ovine fetus: ontogenic changes and effects of fetal adrenalectomy

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1999.276.1.h248 ◽

1999 ◽

Vol 276 (1) ◽

pp. H248-H256 ◽

Cited By ~ 16

Author(s):

Nobuya Unno ◽

Chi H. Wong ◽

Susan L. Jenkins ◽

Richard A. Wentworth ◽

Xiu-Ying Ding ◽

...

Keyword(s):

Blood Pressure ◽

Heart Rate ◽

Plasma Cortisol ◽

Time Windows ◽

Late Gestation ◽

Fetal Sheep ◽

Fetal Plasma ◽

Long Term Study ◽

Arterial Blood ◽

Ovine Fetus

Ontogenic changes in baseline and 24-h rhythms of fetal arterial blood pressure (FABP) and heart rate (FHR) and their regulation by the fetal adrenal were studied in 18 fetal sheep chronically instrumented at 109–114 days gestation (GA). In the long-term study, FABP and FHR were continuously recorded from 120 days GA to spontaneous term labor (>145 days GA) in five animals. Peak times (PT) and amplitudes (Amp) of cosinor analysis were compared at 120–126, 127–133, and 134–140 days GA. Consistent, significant linear increases in FABP and linear decreases in FHR were observed in all fetuses. Significant 24-h rhythms in FABP and FHR were observed during all the time windows. In the adrenalectomy study, to test the hypothesis that fetal cortisol plays a key role in cardiovascular maturation, fetal adrenals were removed in eight animals (ADX); sham fetal adrenalectomy was performed on five animals (Con). Cortisol (4 μg/min) was infused intravenously in four ADX fetuses from day 7postsurgery for 7 days (ADX+F). No significant changes in PT and Amp in FABP and FHR were observed. Plasma cortisol levels remained low in Con and ADX fetuses (<4.9 ng/ml). Cortisol infusion increased fetal plasma cortisol to 22.3 ± 3.2 ng/ml (mean ± SE) on day 13 in ADX+F fetuses. FABP increased in control and ADX+F but not ADX fetuses; FHR decreased in control and ADX but rose in ADX+F fetuses. These results suggest that, in chronically instrumented fetal sheep at late gestation, 1) increases in FABP and decreases in FHR are maintained consistently from 120 to 140 days GA, with distinct 24-h rhythms, the PT and Amp of which remain unchanged, and 2) the physiological increase in FABP is dependent on the fetal adrenal; bilateral removal of the fetal adrenals does not prevent the ability of cortisol to produce a sustained increase in FABP.

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Insulin-like growth factor I promotes growth selectively in fetal sheep in late gestation

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1996.270.5.r1148 ◽

1996 ◽

Vol 270 (5) ◽

pp. R1148-R1155 ◽

Cited By ~ 11

Author(s):

F. Lok ◽

J. A. Owens ◽

L. Mundy ◽

J. S. Robinson ◽

P. C. Owens

Keyword(s):

Growth Factor ◽

Fetal Growth ◽

Late Gestation ◽

Skeletal Maturation ◽

Long Bones ◽

Insulin Like Growth Factor ◽

Fetal Sheep ◽

Factor I ◽

Igf I ◽

Growth Factor I

Insulin-like growth factor I (IGF-I) is required for normal fetal growth and skeletal maturation in late gestation, because null mutations of the IGF-I gene in mice reduce fetal weight and retard ossification of bones. To determine if, conversely, increased abundance of IGF-I promotes fetal growth and skeletal maturation, fetal sheep were infused intravascularly with recombinant human IGF-I (n = 7) (26 +/- 3 micrograms. h-1.kg-1) from 120 to 130 days gestation and compared with controls (n = 15). IGF-I infusion increased plasma IGF-I concentrations by 140% (P = 0.002) and weights of fetal liver, lungs, heart, kidneys, spleen, pituitary, and adrenal glands by 16-50% (P < 0.05). Weights and/or lengths of the fetus, placenta, gastrointestinal tract, individual skeletal muscles, and long bones were unchanged by IGF-I. However, IGF-I increased the percentage of proximal epiphyses of long bones present (P < 0.05) and their cross-sectional areas by 15 to 38% (P < 0.05). These results show that IGF-I promotes growth of major fetal organs, endocrine glands, and skeletal maturation in vivo, consistent with IGF-I actively controlling and not merely facilitating fetal growth. The variable response of different tissues may partly reflect tissue specificity in growth requirements for additional factors.

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The effects of ovine placental lactogen infusion on metabolites, insulin-like growth factors and binding proteins in the fetal sheep

Journal of Endocrinology ◽

10.1677/joe.0.1440333 ◽

1995 ◽

Vol 144 (2) ◽

pp. 333-338 ◽

Cited By ~ 15

Author(s):

M H Oliver ◽

J E Harding ◽

B H Breier ◽

P C Evans ◽

B W Gallaher ◽

...

Keyword(s):

Blood Glucose ◽

Binding Proteins ◽

Amino Nitrogen ◽

Late Gestation ◽

Placental Lactogen ◽

Fetal Blood ◽

Fetal Sheep ◽

Fetal Plasma ◽

Igf I ◽

Igfbp 3

Abstract It has been suggested, but not shown, that in the fetus placental lactogen (PL) may affect the regulation of the IGFs and fetal metabolism. To examine the effects of PL on the circulating concentrations of the IGFs, IGF-binding proteins (IGFBPs), glucose, free fatty acids (FFAs) and amino nitrogen (AN), we infused late gestation sheep fetuses with recombinant ovine PL (roPL). Five chronically-catheterised sheep fetuses were infused intravenously with three 24 h infusions of saline, roPL (100 μg bolus then 500 μg over 24 h) and then saline again. Fetal roPL infusion increased plasma oPL from 0·4 ± 0·1 to 3·3 ± 0·5 nm (mean ± s.e.m.; P<0·05; factorial analysis of variance and Scheffé's test). Fetal plasma IGF-I, IGF-II, insulin, FFAs and blood glucose were unaffected by the roPL infusion. Fetal plasma IGFBP-3, as measured by Western ligand blotting, decreased by 30% during fetal roPL infusion while other fetal plasma IGFBPs were unaffected. Fetal roPL infusion decreased fetal blood AN from 7·3 ± 0·5 to 6·6 ± 0·2 mm (P<0·05). Maternal plasma IGF-I, IGF-II, IGFBPs, insulin, FFAs, blood glucose and AN were unaffected by the fetal roPL infusion. Saline infusion had no effect on any parameter. The data suggest that PL is not a significant determinant of plasma IGFs in the late gestation sheep fetus although there may be an indirect effect via alterations in levels of IGFBP-3. The effect of fetal roPL infusion on fetal blood AN concentrations may suggest some role for PL in the regulation of fetal amino acid metabolism. Journal of Endocrinology (1995) 144, 333–338

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Wave intensity analysis of right ventricular and pulmonary vascular contributions to higher pulmonary than aortic blood pressure in fetal lambs

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00292.2010 ◽

2010 ◽

Vol 299 (3) ◽

pp. H890-H897 ◽

Cited By ~ 12

Author(s):

Joseph J. Smolich ◽

Jonathan P. Mynard ◽

Daniel J. Penny

Keyword(s):

Blood Pressure ◽

Right Ventricular ◽

Pressure Difference ◽

Compression Wave ◽

Wave Intensity ◽

Late Gestation ◽

Pulmonary Vasculature ◽

Fetal Sheep ◽

Time Flow ◽

Pressure Profiles

Although fetal pulmonary trunk (PT) blood pressure may exceed aortic trunk (AoT) pressure, the specific mechanism(s) underlying this pressure difference remain undefined. To evaluate the potential role of ventricular and vascular factors in the generation of a fetal PT-AoT pressure difference, nine anesthetized late-gestation fetal sheep were instrumented with PT and AoT micromanometer catheters to measure high-fidelity pressure and transit-time flow probes to obtain blood velocity. The PT-AoT instantaneous pressure difference (IPDPT-AoT) was calculated from PT and AoT pressure profiles. PT and AoT wave intensity (WI) was derived from the product of the appropriate pressure and velocity rates of change. While diastolic pressures were near identical, systolic PT pressure exceeded AoT pressure ( P < 0.001), with a maximal IPDPT-AoT of 6.5 ± 2.5 mmHg. The comparison of IPDPT-AoT with wave-related PT and AoT pressure changes indicated that 1) a greater pressure-generating effect of the PT forward-running compression wave arising from impulsive right ventricular contraction in early and midsystole accounted for 2.3 ± 2.3 mmHg (35%) of the maximal IPDPT-AoT and 2) a larger pressure-generating effect of a large midsystolic backward-running compression wave transmitted into the PT from the pulmonary vasculature contributed 4.0 ± 1.5 mmHg (∼60%) of the maximal IPDPT-AoT. These results indicate that the higher PT than AoT blood pressure observed in fetal lambs is a systolic phenomenon principally related to the combination of a relatively higher level of right ventricular pump function manifest in early and midsystole and a pressure-increasing energy wave arising from the fetal pulmonary vasculature in midsystole.

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Maternal undernutrition in late gestation increases IGF2 signalling molecules and collagen deposition in the right ventricle of the fetal sheep heart

The Journal of Physiology ◽

10.1113/jp275806 ◽

2018 ◽

Vol 596 (12) ◽

pp. 2345-2358 ◽

Cited By ~ 10

Author(s):

Jack R. T. Darby ◽

I. Caroline McMillen ◽

Janna L. Morrison

Keyword(s):

Right Ventricle ◽

Late Gestation ◽

Collagen Deposition ◽

Fetal Sheep ◽

Signalling Molecules ◽

Maternal Undernutrition ◽

The Right

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Fetal substrate uptake during increased ovine fetal cortisol concentration

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1996.271.1.e186 ◽

1996 ◽

Vol 271 (1) ◽

pp. E186-E191 ◽

Cited By ~ 2

Author(s):

J. R. Milley

Keyword(s):

Metabolic Rate ◽

Fetal Growth ◽

Amino Nitrogen ◽

Cortisol Concentration ◽

Late Gestation ◽

Substrate Uptake ◽

Corticosteroid Administration ◽

Metabolic Substrates ◽

Ovine Fetal ◽

Sheep Fetus

Corticosteroid administration adversely affects fetal growth and consequently, unless metabolic rate increases (thereby increasing the need for fetal metabolic substrates), reduces fetal need for exogenous substrates. To find whether the uptake of all or only certain metabolic substrates was affected by fetal hypercortisolemia, we measured exogenous uptake of glucose, lactate, and alpha-amino nitrogen during fetal hypercortisolemia in seven late-gestation sheep fetuses. Hydrocortisone infusion increased fetal cortisol concentrations from normal to values usually associated with late gestation (4.3 +/- 0.9 vs. 72.5 +/- 5.0 ng/ml; P < 0.001). In association with increased fetal cortisol concentration, both fetal metabolic rate and the uptakes of glucose and lactate remained constant. However, the uptake of alpha-amino nitrogen-containing substances fell (39.6 +/- 3.1 vs. 28.5 +/- 3.4 mumol.kg-1.min-1; P < 0.002) as did the proportion of metabolic rate (0.45 +/- 0.04 vs. 0.32 +/- 0.04; P < 0.002) that could be supported by metabolism of these substances. The proportion of fetal metabolic rate that could be supported by complete metabolism of all substrates taken up across the placenta decreased (1.09 +/- 0.07 vs. 0.95 +/- 0.06; P < 0.02). In conclusion, hypercortisolemia alters the composition of oxidative substrates taken up by the sheep fetus and decreases total fetal substrate uptake. These changes occur within hours of exposure to increased cortisol concentration.

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