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The Physiological Laboratory, University of Cambridge, Cambridge, United Kingdom CB2 3EG
Address all correspondence and requests for reprints to: Dr. Dino A. Giussani, The Physiological Laboratory, University of Cambridge, Downing Street, Cambridge, United Kingdom CB2 3EG. E-mail: dag26{at}cam.ac.uk
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Abstract |
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145 days), 12 sheep fetuses were instrumented under
halothane anesthesia with an occluder cuff around the umbilical cord,
amniotic and vascular catheters, and a transit-time flow probe around
an umbilical artery. In 6 of the fetuses at 125 days, umbilical blood
flow was reduced by about 30% from baseline for 3 days (UCC), after
which the occluder was deflated. The remaining 6 fetuses acted as
sham-operated controls in which the occluder was not inflated. All
fetuses were then subsequently subjected to 2 periods of acute
hypoxemia, elicited by reducing the maternal inspired fraction of
oxygen (FiO2) at 2 ± 1 and 5 ± 2 days
after the end of cord compression or sham compression. In addition, 4
fetuses from each group were subjected to an ACTH challenge 1–2 days
after the final episode of acute hypoxemia. Maternal and fetal arterial
blood samples were taken at appropriate intervals during cord
compression, acute hypoxemia, and ACTH challenge for analyses of blood
gases, pH, and plasma ACTH and cortisol concentrations. Partial
compression of the umbilical cord produced reversible mild fetal
asphyxia, a transient increase in fetal plasma ACTH, and a progressive
increase in fetal plasma cortisol. At 5 ± 2 days after the end of
compression, despite similar blood gas status between the groups, basal
plasma cortisol, but not ACTH, concentrations were significantly
greater in compressed fetuses relative to sham controls. However, this
dissociation did not affect a similar increment in fetal plasma ACTH
and cortisol concentrations during acute hypoxemia or in the fetal
plasma cortisol response to the ACTH challenge in either group. An
increase in adrenocortical mass occurred in fetuses preexposed to
partial compression of the umbilical cord relative to sham controls.
The data suggest that fetal exposure to a reversible period of adverse
intrauterine conditions produced by partial compression of the
umbilical cord does not affect the magnitude of the fetal
hypothalamic-pituitary-adrenal axis response to subsequent acute
hypoxemia, but it leads to resetting of basal
hypothalamic-pituitary-adrenal axis function in the fetus. The
mechanism for this resetting may include an increase in adrenocortical
steroidogenic synthetic capacity, but it is not due to a change in
adrenocortical sensitivity to ACTH. Inappropriate fetal glucocorticoid
exposure after reversible periods of adverse intrauterine conditions
has important implications for fetal and postnatal development. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The aims of the present study were therefore to determine the fetal plasma ACTH and cortisol responses to acute hypoxemia after exposure of the fetus to a reversible period of adverse intrauterine conditions produced by controlled, partial compression of the umbilical cord in sheep during late gestation. In addition, to address possible mechanisms mediating any alteration in these endocrine responses, control and compressed fetuses were subjected to an ACTH challenge, and the adrenal glands from both groups of fetuses were harvested for histological analysis.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Surgery was performed under aseptic conditions at 118 ± 2 days
gestation (dGA; term is 145 dGA). Anesthesia was induced with sodium
thiopentone (20 mg/kg, iv; Intraval Sodium, Rhone Mérieux,
Dublin, Ireland) and was maintained with 1–2% halothane in
O2/N2O (50:50). In brief,
after midline abdominal and uterine incisions, the fetal head was
exteriorized for insertion of carotid artery and jugular vein catheters
(id, 0.86 mm; od, 1.52 mm; Critchly Electrical Products, Auburn, NSW,
Australia) with the tips of the catheters extended to the
ascending aorta and superior vena cava, respectively. The catheters
were plugged with sterile brass pins, and the uterine incision was
closed in layers. The fetal hindlimbs were subsequently exteriorized
through a second uterine incision for insertion of femoral artery (id,
0.86 mm; od, 1.52 mm) and femoral vein (id, 0.56 mm; od, 0.96 mm)
catheters, which were extended into the descending aorta and inferior
vena cava, respectively. A further catheter was anchored onto the fetal
hindlimb in the amniotic cavity for recording of the reference
pressure. A transit-time flow transducer (Transonics, Inc., Ithaca, NY)
was placed around an umbilical artery (4RS) within the fetal abdominal
cavity as previously described (14). In addition, an
inflatable occluder cuff (OC20HD, In Vivo Metrics, CA) was positioned
around the proximal end of the umbilical cord and anchored to the fetal
abdominal wall so as to avoid contact with the cord when not inflated
(14). The second uterine incision was closed in layers. A
Teflon catheter was placed in the maternal femoral artery and extended
to the descending aorta. Antibiotics were administered to the fetus
through the femoral vein (300 mg ampicillin; Penbritin,
SmithKline Beecham Animal Health, Surrey, UK) and amniotic
catheters (300 mg ampicillin). All catheters were filled with
heparinized saline (80 IU heparin/ml in 0.9% NaCl), plugged with brass
pins. Then, together with the flow probes and occluder leads, the
catheters were exteriorized through an incision in the maternal flank
and housed in a pouch sutured to the maternal skin.
Postoperative care
Animals were housed in individual pens with access to hay and
water ad libitum. Concentrates were fed twice daily (100 g;
Sheep Nuts no. 6, H&C Beart Ltd., Kings Lynn, UK). All ewes received
antibiotics (0.20–0.25 mg/kg, im; Depocillin, Mycofarm, Cambridge, UK)
and analgesia (10–20 mg/kg, orally, phenylbutazone; Equipalozone
Paste, Arnolds Veterinary Products Ltd., Shropshire, UK) immediately
after surgery and daily for 3 days. The patency of fetal vascular
catheters was maintained by a slow continuous infusion of heparinized
saline (25 IU heparin/ml at 0.1 ml/h in 0.9% NaCl) containing
antibiotic (1 mg/ml benzylpenicillin; Crystapen, Schering-Plough Corp., Welwyn Garden City, UK).
Experimental procedure
At least 5 days after surgery, at 124 ± 0.5 dGA, baseline
mean unilateral umbilical blood flow was determined over a 24-h period
in all fetuses. The animals were then divided randomly into two
experimental groups. In six fetuses the occluder cuff was inflated to
reduce umbilical blood flow by about 30% from the predetermined
baseline for 3 days (Fig. 1
). Compression
of the umbilical cord was achieved either by manual inflation of the
occluder cuff with saline (n = 2) or by an automated
servo-controlled system that inflated or deflated the occluder cuff
according to the umbilical blood flow reading (n = 4)
(15). After 3 days of compression the occluder cuff was
deflated, allowing return of umbilical blood flow to baseline. In the
remaining six fetuses the occluder cuff remained deflated throughout
the duration of the experimental procedure. These animals were
designated sham-operated control animals.
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Measurements and biochemical analyses
Daily maternal descending aortic and fetal carotid blood samples
(0.4 ml) were drawn into sterile syringes and analyzed for arterial
blood gases, percent saturation of O2 in
hemoglobin (% Sat Hb), hemoglobin concentration, and acid/base status
using an ABL5 blood gas analyzer and OSM2 hemoximeter (Radiometer,
Copenhagen, Denmark). Measurements in maternal and fetal blood were
corrected to 38 and 39.5 C, respectively. In addition, maternal and
fetal arterial blood samples (4 ml) were taken simultaneously before
umbilical cord compression at -1 day and -1 h; during umbilical cord
compression at +1 h, +8 h, +1 day, +2 days, and +3 days; and
subsequently at 1 day after deflation of the occluder cuff for
measurement of blood gases, acid/base status and hormone
concentrations. During the hypoxemia protocol, paired maternal and
fetal arterial blood samples (4 ml) were collected at 15 and 45 min of
normoxia, after 15 and 45 min of hypoxemia, and after 45 min of
recovery for measurement of blood gases, acid/base status, and
hormones. Fetal arterial blood samples (2 ml) were also taken during
the ACTH challenge at -15 and -5 min and subsequently at 5, 15, and
30 min after injection. This blood-sampling regimen did not
significantly affect fetal hemoglobin concentration over the period of
study in either group. All blood samples for hormone analysis were
collected into K+/EDTA-treated tubes, kept on
ice, and centrifuged at 4000 rpm for 4 min at 4 C. Plasma samples were
stored at -70 C until analyses.
Hormone analyses
All hormone measurements were performed within 2 months of
sample collection. Plasma ACTH and cortisol concentrations were
determined by RIA validated for use in ovine plasma.
ACTH. Maternal and fetal plasma ACTH concentrations were
measured using a commercially available double antibody
125I RIA kit (INCSTAR Corp.,
Wokingham, UK). The lower limit of detection for the assay was between
10–25 pg/ml. The intraassay coefficients of variation for two plasma
pools (37 and 150 pg/ml) were 3.6% and 4.1%, respectively. The
interassay coefficient of variation was 8.4%. The cross-reactivities
for the assay were less than 0.01% for 
MSH, ß-endorphin,
ß-lipotropin, leucine enkephalin, methionine enkephalin, bombesin,
calcitonin, PTH, FSH, arginine vasopressin, oxytocin, and substance
P.
Cortisol. Maternal and fetal plasma cortisol concentrations were measured by RIA validated for use in ovine plasma, as described previously (18). The lower limit of detection for the assay was 1.0–1.5 ng/ml. The intra- and interassay coefficients of variations were 5.3% and 7.8%, respectively. The cross-reactivities of the antiserum at 50% binding with other cortisol-related compounds were 0.5% cortisone, 2.3% corticosterone, 0.3% progesterone, and 4.6% deoxycortisol.
Microscopy
At least 1 day after the ACTH challenge, between 136–137 dGA,
all ewes were injected iv with a terminal anesthetic (20 mg/kg sodium
pentobarbitone), and the fetal body and adrenal weights were
determined. In addition, an adrenal gland was fixed in 10%
formaldehyde and, within 2 days, embedded in paraffin wax for
sectioning (UCC fetuses, n = 5; sham control fetuses, n = 3).
Adrenal glands from an additional two age-matched control fetuses
without hormone measurements were also fixed, embedded, and included in
the analyses for adrenal morphology. Each adrenal gland was cut in half
along its longitudinal axis, and a total of 6 x 7-µm sections
from the midline were taken with a microtome, mounted on individual
slides, and stained with hemalum. Total adrenal, adrenocortical, and
adrenomedullary widths were determined with a calibrated eye-piece
graticule under low power (x4) light microscopy. At least six
measurements were taken from each of the adrenal sections.
Data collection and analyses
Analog signals for calibrated umbilical blood flow were recorded
continuously in control and UCC fetuses for 1 day before umbilical cord
compression, during the 3 days of compression, and for 1 day after
deflation of the occluder cuff using a data acquisition system. The
signal was digitized, displayed, and subsequently stored at 8-sec
intervals on disk by custom software (NI-DAQ, National Instruments,
Austin, TX) running on a personal computer. Files were subsequently
analyzed using Microsoft Corp. Excel spreadsheets.
Unilateral umbilical blood flow was measured on a T201 or T206 flow box
(Transonic).
Statistical analyses
Values for all variables are expressed as the mean ±
SEM unless otherwise stated. All measured variables were
first analyzed for normality of distribution. All data obtained were
parametric and were analyzed using two-way ANOVA with repeated measures
(Sigma-Stat, SPSS, Inc., Chicago, IL) followed by an
appropriate post-hoc test. A comparison between the slopes
and intercepts of regression curves was conducted according to Armitage
and Berry (19). For all comparisons, statistical
significance was accepted when P < 0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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). After umbilical cord compression, unilateral umbilical blood
flow returned to a level significantly greater than that measured
during baseline (Fig. 1).
Arterial blood gas and metabolic status.
Fetal: Baseline arterial blood gas and acid/base status
were similar in sham control and UCC fetuses (Table 1). Arterial blood gas status remained
unchanged from baseline throughout the experimental protocol in sham
control fetuses. In UCC fetuses, umbilical cord compression, to reduce
umbilical blood flow by approximately 30% of baseline, caused falls in
pHa,
PaO2, and %SatHb
and an immediate rise in
PaCO2. These changes were
maintained until the end of the 3-day compression period (Table 1).
After umbilical cord compression, arterial blood gas values and
acid/base status returned to baseline conditions by 1 day recovery in
UCC fetuses (Table 1).
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Plasma ACTH and cortisol.
Fetal: Before umbilical cord compression, baseline ACTH
and cortisol concentrations were similar in control and UCC fetuses
(Fig. 2). In control fetuses, both ACTH
and cortisol concentrations remained unaltered from baseline for the
duration of the sham compression period. In contrast, umbilical cord
compression elicited an immediate increase in plasma ACTH
concentration; however, the effect was transient, with values returning
toward baseline concentrations 1 day after compression (Fig. 2). In
contrast, plasma cortisol concentrations increased progressively during
the period of compression, with values remaining significantly higher
than baseline 3 days after the onset of umbilical cord compression.
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Effect of acute hypoxemia after the period of reversible adverse
intrauterine conditions on arterial blood gas and acid/base status and
ACTH and cortisol concentrations
Arterial blood gas and acid/base status during acute
hypoxemia.
Fetal: Baseline arterial blood gas and acid/base status
were similar in sham control and UCC fetuses during both acute
hypoxemia protocols (Table 2). A similar
reduction in PaO2, %SatHb,
pHa and acid-base excess (ABE) occurred in
sham control and UCC fetuses during both hypoxemia I and II (Table 2).
These changes generally occurred without any alteration in
PaCO2 from baseline in
either group of fetuses; however, a mild hypercapnia developed in
control fetuses early during the first hypoxemic challenge (Table 2).
Arterial blood gas status returned to baseline levels during recovery;
however, both groups of fetuses remained mildly acidic by the end of
each of the hypoxemic protocols (Table 2).
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). Similar falls in maternal
PaO2 and %SatHb and
increases in hemoglobin concentration occurred during each of the
hypoxemia protocols in both groups of ewes. These changes occurred
without any alteration in
PaCO2 from baseline.
After each of the hypoxemia protocols, arterial blood gas status
returned to baseline levels by the end of recovery period in both
groups of ewes (Table 3).
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. Basal plasma ACTH and cortisol
concentrations were similar in sham control and UCC fetuses during
hypoxemia I. However, in the hypoxemia II protocol, basal plasma
cortisol, but not ACTH, concentrations were elevated in UCC fetuses
relative to those in sham controls. Despite the elevated basal plasma
cortisol values in the UCC fetuses produced by hypoxemia II,
significant increases in fetal plasma ACTH and cortisol occurred in
both groups of fetuses during each acute hypoxemia experiment. During
recovery after hypoxemia I and II, plasma ACTH and cortisol remained
elevated relative to baseline in both groups of fetuses. However,
plasma cortisol, but not ACTH, concentrations remained elevated in UCC
relative to those in sham control fetuses during recovery after
hypoxemia II. Correlation of paired plasma ACTH and cortisol
concentrations showed that both the slope and intercept of the
relationship were similar for control and UCC fetuses during hypoxemia
I (Fig. 4). However, a significant change
in the intercept, but not the slope, of the relationship between plasma
ACTH and cortisol occurred in UCC fetuses during hypoxemia II (Fig. 4).
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Plasma cortisol during the ACTH challenge. Before the ACTH
challenge, plasma ACTH concentrations were similar in control and UCC
fetuses (54.2 ± 8.4 vs. 50.7 ± 8.7 pg/ml).
Concentrations of plasma cortisol were 39% greater in UCC fetuses
relative to controls (35.5 ± 10.0 vs. 49.5 ±
13.0 ng/ml), although this difference fell outside statistical
significance. A similar increment in plasma cortisol occurred after the
ACTH challenge in control and UCC fetuses (Fig. 5).
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). However, the adrenal
glands were larger in UCC than in sham control fetuses when expressed
in absolute terms or relative to body weight (P <
0.05). The width of the adrenal cortex was greater, and the width of
the adrenal medulla narrower, in UCC fetuses relative to sham controls
(P < 0.05). Consequently, when expressed as a
proportion of total adrenal width, the percentage of the adrenal
occupied by the adrenal cortex was significantly greater, and that
occupied by the adrenal medulla was significantly lower, in UCC fetuses
relative to sham controls (P < 0.05).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The present study reports that the magnitude of the fetal plasma ACTH and cortisol responses to 1 h of acute hypoxemia after a 3-day period of adverse intrauterine conditions produced by partial compression of the umbilical cord is not altered relative to that in sham control fetuses. However, after adverse intrauterine conditions, the basal plasma cortisol, but not ACTH, concentration becomes elevated. This suggests that in contrast to the effects of acute-on-chronic stress on the fetal HPA axis, fetal adrenocortical sensitivity is unaltered, but a resetting of the HPA axis occurs during acute-after-chronic stress. Factors affecting the set-point and sensitivity of the axis are, therefore, differentially modified by the timing, duration, and degree of fetal exposure to adverse intrauterine conditions.
A sustained elevation in basal fetal plasma cortisol despite unaltered ACTH levels is a feature of many experimental models that produces prolonged adverse intrauterine conditions. For example, in sheep, sustained fetal hypercortisolemia with only transient elevations in fetal plasma ACTH concentration occur after carunclectomy (20), feto-placental embolization (7, 21), and reduced utero-placental blood flow (22). The mechanism(s) mediating sustained elevations in fetal plasma cortisol in the absence of significant elevations in fetal plasma ACTH during or after adverse intrauterine conditions remains unclear, but may involve increased adrenocortical steroidogenic capacity or sensitivity to ACTH, altered trans-placental cortisol passage, decreased negative feedback at the level of the adrenal, an increase in the activity or concentration of ACTH-independent steroidogenic factor, or changes in the ratio of bioactive/immunoreactive ACTH.
To address the first possibility, cord-compressed and control fetuses were subjected to an ACTH challenge, and at the end of all experiments, their adrenals were harvested and prepared for histological analysis. Cord compression induced a marked increase in adrenal weight, which was predominantly due to an increase in adrenocortical mass, suggesting a greater potential for increased adrenocortical steroidogenic capacity. Maintained adrenal growth against a declining rate of growth of the fetal body during chronic adverse intrauterine conditions may be achieved through a specific redistribution of the fetal circulation favoring cerebral, myocardial, and adrenal perfusion (23). Larger adrenal glands may reflect an increase in cell number (hyperplasia) or cell size (hypertrophy); however, only adrenal hypertrophy was reported in response to reductions in utero-placental blood flow for 48 h in fetal sheep at a similar gestational age (24), suggesting that increased cell size, rather than number, may explain the increase in adrenocortical mass in UCC fetuses. However, although the results of the ACTH challenge show that the adrenocortical response in compressed fetuses is not sensitized to ACTH under basal conditions, they do not exclude the possibility that the adrenal cortex in cord-compressed relative to sham control fetuses may be sensitized to ACTH under stimulated conditions. Neural innervation of the adrenal gland by the splanchnic nerve comprises one of the components mediating adrenocortical sensitivity to ACTH. Stimulation of the splanchnic innervation to the adrenal gland potentiates adrenocortical steroidogenesis in response to an exogenous infusion of ACTH (25). In addition, studies in fetal and adult animals have provided clear evidence that tonic activity in the splanchnic nerve maintains the sensitivity of the adrenal cortex to ACTH. In calves (25), lambs (26), and fetal sheep (27), section of the splanchnic nerve reduces the sensitivity of ACTH-induced cortisol output from the adrenal cortex. Therefore, it is possible that fetal exposure to umbilical cord compression may increase sympathetic outflow, thereby increasing adrenocortical sensitivity to circulating ACTH. However, as only the intercept, not the slope, of the relationship between ACTH and cortisol was altered by cord compression, the data suggest that a change in the setting, but not the sensitivity, of the adrenal cortex to ACTH mediates sustained elevations in fetal plasma cortisol after preexposure to umbilical cord compression.
Although the extent to which chronic elevations of fetal plasma cortisol concentration reflect greater materno-fetal trans-placental passage cannot be determined in the present study, the potential for this mechanism to maintain higher circulating fetal plasma cortisol concentrations is negligible, because maternal plasma cortisol concentrations remained unaltered from baseline during cord compression and the majority of circulating cortisol in fetuses greater than 120 dGA is of fetal origin (28). Indeed, in sheep, such a scenario is actively prevented by the placental enzyme complex 11ß-hydroxysteroid dehydrogenase, which metabolizes bioactive cortisol to its inactive, stable metabolite cortisone (29).
It is possible that enhanced fetal cortisol output after preexposure to umbilical cord compression may be due to a reduction in adrenocortical sensitivity to negative feedback by cortisol. Potentially, the level of cortisol-induced negative feedback to the adrenal is highest during late gestation in fetal sheep, as the adrenocortical density of glucocorticoid receptor (GR) is highest at this time (30). A down-regulation of fetal adrenocortical GR can be promoted in late gestation under certain circumstances, for example, after 2-day exposure to dexamethasone (31). However, dexamethasone is a potent synthetic glucocorticoid, and whether a down-regulation of adrenocortical GR occurs after exposure to high concentrations of endogenous glucocorticoid remains to be determined.
Increased action of an ACTH-independent steroidogenic factor during cord compression could in part account for potentiation of cortisol output from the adrenal cortex. Possible candidates include several neuropeptides, such as vasoactive intestinal peptide, CRH, and the eicosanoid PGE2, as all have been shown to promote steroidogenesis in the absence of changes in circulating ACTH (32, 33, 34). Of these factors, PGE2 is the most likely candidate in fetal sheep, because fetal plasma PGE2 concentrations increase in parallel with plasma cortisol when plasma ACTH is depressed during chronic adverse intrauterine conditions, such as those produced by embolization (11, 35, 36) and reduced utero-placental blood flow (35).
Alternatively the possibility remains that hypothalamic processing of ACTH is altered by umbilical cord compression. ACTH is cosecreted from the fetal sheep pituitary with higher mol wt precursor forms of ACTH, such as pro-ACTH and POMC, which may also exhibit a degree of ACTH-like biological activity (37). The processing of POMC is gestational age dependent (38) and can be affected by fetal stress (39). Therefore, it is possible that fetal exposure to umbilical cord compression may have led to a change in the ratio of bioactive/immunoreactive ACTH in our study, leading to greater adrenocortical stimulation of cortisol output despite lower measured concentrations of ACTH.
Finally, in sheep, an ontogenic increase in fetal plasma cortisol
occurs toward term that induces maturation of fetal organ systems in
preparation for postnatal life and initiates labor and delivery
(40). In the present study the concentrations of fetal
plasma cortisol measured 7 days after umbilical cord compression
(135 dGA) are commensurate with the concentrations of fetal plasma
cortisol at approximately 2–3 days before term (141–142 dGA) in
control sheep fetuses of the same breed as those used in the present
study (40). This may suggest a forward shift in the
mechanisms that account for the normal prepartum increment in plasma
cortisol in cord-compressed fetuses. However, in the present study this
was insufficient to initiate labor, as determined by intrauterine
pressure fluctuations, by the end of the experimental protocol.
In conclusion, the data reported in this study show that partial compression of the umbilical cord for 3 days in late gestation fetal sheep elevates basal fetal plasma cortisol, but not ACTH, concentrations and does not affect the magnitude of the pituitary-adrenal response to a subsequent period of acute hypoxemia. Additional analysis of the data suggests that the mechanism mediating maintained elevations in fetal plasma cortisol, in the absence of increased ACTH concentrations, is a change in the set-point of the HPA axis and/or increased adrenal steroidogenic capacity, rather than an increase in adrenocortical sensitivity to ACTH. These findings imply that acute stress after, rather than superimposed during, a period of adverse intrauterine conditions has a differential effect on the HPA axis. Sustained elevations of circulating cortisol in the fetus have important implications not only for fetal development (41), but also for adult health, as inappropriate glucocorticoid overexposure in fetal life has been associated with hypertension and insulin resistance in adult life (42, 43).
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Acknowledgments |
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Footnotes |
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Received August 18, 2000.
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 B.-L. Giles, H. Suliman, L. B. Mamo, C. A. Piantadosi, T. D. Oury, and E. Nozik-Grayck Prenatal hypoxia decreases lung extracellular superoxide dismutase expression and activity Am J Physiol Lung Cell Mol Physiol, September 1, 2002; 283(3): L549 - L554. [Abstract] [Full Text] [PDF]
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D S Gardner, A J W Fletcher, M R Bloomfield, A L Fowden, and D A Giussani Effects of prevailing hypoxaemia, acidaemia or hypoglycaemia upon the cardiovascular, endocrine and metabolic responses to acute hypoxaemia in the ovine fetus J. Physiol., April 1, 2002; 540(1): 351 - 366. [Abstract] [Full Text] [PDF]
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D S Gardner, A J W Fletcher, A L Fowden, and D A Giussani A novel method for controlled and reversible long term compression of the umbilical cord in fetal sheep J. Physiol., August 15, 2001; 535(1): 217 - 229. [Abstract] [Full Text] [PDF]
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D S Gardner, A J W Fletcher, M R Bloomfield, A L Fowden, and D A Giussani Effects of prevailing hypoxaemia, acidaemia or hypoglycaemia upon the cardiovascular, endocrine and metabolic responses to acute hypoxaemia in the ovine fetus J. Physiol., April 1, 2002; 540(1): 351 - 366. [Abstract] [Full Text] [PDF]
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umb,
Umbilical blood flow.
; n = 6) and UCC (•; n = 6) fetuses. Fetal
blood samples were collected for measurement of ACTH and cortisol
during the baseline period at -1 day and -1 h; at +1 h, +8 h, +1 day,
+2 days, and +3 days during umbilical cord compression or sham
compression (bar); and at +1 day of recovery after
umbilical cord compression or sham compression. a,
P < 0.05, baseline vs. umbilical
cord compression; b, P < 0.05, control
vs. UCC fetuses.
; n = 6) and UCC (
; n = 6)
fetuses. a, P < 0.05, baseline vs.
hypoxemia or recovery; b, control vs. UCC fetuses.
