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. 2002 Aug 2;545(Pt 2):649–660. doi: 10.1113/jphysiol.2001.015693

Effects of low dose dexamethasone treatment on basal cardiovascular and endocrine function in fetal sheep during late gestation

Andrew J W Fletcher *, Hugh H G McGarrigle *, C Mark B Edwards †, Abigail L Fowden *, Dino A Giussani *
PMCID: PMC2290705  PMID: 12456840

Abstract

This study investigated the effects on ovine fetal basal cardiovascular and endocrine functions of fetal intravenous dexamethasone treatment, resulting in circulating concentrations that were one-fifth of the values measured clinically in human infants following maternal antenatal glucocorticoid therapy. Between 117-120 days gestation (dGA; term: ca 145 dGA), 26 Welsh Mountain sheep fetuses were surgically prepared under general anaesthesia with vascular catheters and a Transonic flow probe positioned around a femoral artery. At 125 ± 1 dGA, fetuses were infused with dexamethasone (2.06 ± 0.13 μg kg−1 h−1i.v.; n = 13) or saline (n = 13) for 48 h. Daily fetal arterial blood samples were taken and cardiovascular data were recorded continuously (data acquisition system). Pressor, vasoconstrictor and chronotropic responses to exogenously administered doses of phenylephrine, angiotensin II and arginine vasopressin (AVP) were determined at 124 ± 1 (pre-infusion), 126 ± 1 (during infusion) and 128 ± 1 (post-infusion) dGA. Fetal cardiac baroreflex curves were constructed using peak pressor and heart rate responses to phenylephrine. Dexamethasone treatment elevated fetal mean arterial blood pressure by 8.1 ± 1.0 mmHg (P < 0.05), increased femoral vascular resistance by 0.65 ± 0.12 mmHg (ml min−1)−1 (P < 0.05), depressed plasma noradrenaline concentrations and produced a shift in set-point, but not sensitivity, of the cardiac baroreflex (P < 0.05). Elevations in fetal arterial blood pressure, but not femoral vascular resistance and the shift in baroreflex set-point, persisted at 48 h following dexamethasone treatment. By 48 h following dexamethasone infusion, basal plasma noradrenaline concentration was restored, whilst plasma adrenaline and neuropeptide Y (NPY) concentrations were enhanced, compared with controls (P < 0.05). Fetal dexamethasone treatment did not alter the fetal pressor or femoral vasoconstrictor responses to adrenergic, vasopressinergic or angiotensinergic agonists. These data show that fetal treatment with low concentrations of dexamethasone modifies fetal basal cardiovascular and endocrine functions. Depending on the variable measured, these changes may reverse, persist or become enhanced by 48 h following the cessation of treatment.

Since the pioneering experiments of Liggins & Howie (1972), synthetic glucocorticoids, such as betamethasone and dexamethasone, have been used widely in human obstetric practice for the treatment of pregnancies threatened with preterm delivery (NIH Consensus Development Conference, 1994). This prophylactic treatment aims to mimic the maturational effects of the normal endogenous, prepartum increase in fetal plasma glucocorticoid concentration that occurs close to term in humans and other species (Fowden et al. 1998). Antenatal glucocorticoid therapy has resulted in substantial reductions in the incidences of respiratory distress syndrome, intraventricular haemorrhage, necrotising enterocolitis and neonatal mortality in preterm human infants (Crowley, 1995). However, despite these clear benefits and the widespread use of synthetic glucocorticoids, current dosing regimens have been little modified since their introduction into human obstetric practice 30 years ago. Although betamethasone and dexamethasone have negligible mineralocorticoid activity, their glucocorticoid potency is approximately 25-fold that of cortisol (see Schimmer & Parker, 1996). This has prompted concern regarding the safety of potentially excessive synthetic glucocorticoid dosing regimens used in current clinical practice (Seckl & Miller, 1997; Spencer & Neales, 2000).

Treatment of fetal sheep with synthetic glucocorticoids in doses relevant to those used in clinical practice today has been shown to modify fetal basal cardiovascular and endocrine functions. When synthetic glucocorticoids are infused directly into the ovine fetus to produce circulating concentrations of synthetic glucocorticoid similar to those measured in human umbilical cord plasma collected at Caesarean section following a course of maternal antenatal glucocorticoid therapy, the treatment results in pronounced increases in fetal arterial blood pressure (Derks et al. 1997), augmented basal vascular resistance in the fetal cerebral and femoral vascular beds (Derks et al. 1997; Schwab et al. 2000), altered sensitivities of isolated fetal femoral arterial branches to vasoconstrictor and vasodilator agents (Anwar et al. 1999; Docherty et al. 2001) and suppression of fetal basal plasma catecholamine concentrations (Derks et al. 1997). Furthermore, preliminary observations suggest that the ovine fetal baroreflex set-point, but not sensitivity, may be altered by these relatively high doses of dexamethasone (Koenen et al. 2000).

Whilst it is clear that relatively high doses of dexamethasone may alter fetal basal cardiovascular and endocrine functions, it remains unknown whether similar effects occur during fetal exposure to lower concentrations of synthetic glucocorticoids. This is an important question given the current concerns regarding clinical dosing practices. In addition, little is known about whether such effects persist following the period of dexamethasone exposure and what the physiological mechanisms are that contribute to such changes. Given the glucocorticoid potency of dexamethasone, we hypothesise that lower doses of dexamethasone than those employed previously (Derks et al. 1997) have similar effects on fetal basal cardiovascular and endocrine functions and on fetal baroreflex function, and that these effects persist in the period following treatment. We also hypothesise that any pressor and vasoconstrictor effects of fetal exposure to these relatively low doses of dexamethasone are mediated by changes in circulating levels of endogenous vasoactive hormones and peripheral vascular responsiveness to them.

To address these inter-related hypotheses, the aims of the current study were to determine the effects of ovine fetal treatment with dexamethasone, resulting in circulating concentrations of dexamethasone that were one-fifth of those measured clinically in human obstetric practice (Kream et al. 1983), on: (1) fetal basal heart rate, blood pressure, femoral blood flow and femoral vascular resistance; (2) fetal basal plasma concentrations of noradrenaline, adrenaline, arginine vasopressin (AVP) and neuropeptide Y (NPY); (3) the in vivo fetal pressor and femoral vasoconstrictor responses to exogenously administered phenylephrine, angiotensin II and AVP; and (4) fetal cardiac baroreflex function measured during and after the period of dexamethasone treatment.

Methods

Surgical preparation

All surgical and experimental procedures were performed in accordance with the UK Animals (Scientific Procedures) Act 1986. Between 117 and 120 days gestation (dGA; term is ca 145 days), 26 Welsh Mountain sheep fetuses and their mothers were surgically prepared for long-term recording under general anaesthesia as described previously in detail (Fletcher et al. 2000b). In brief, following induction with 20 mg kg−1i.v. sodium thiopentone (Intraval Sodium; Rhone Mérieux, Dublin, Ireland), general anaesthesia (1.5-2.0 % halothane in 50:50 O2:N2O) was maintained using positive pressure ventilation. A Teflon catheter was inserted into a maternal femoral artery and advanced into the maternal caudal aorta. Following a midline laparotomy and hysterotomy, translucent PVC catheters (Critchly Electrical Products, NSW, Australia) were inserted into a fetal carotid artery, jugular vein and femoral artery (tip inserted 4-5 cm). An ultrasonic flow transducer (2R or 3S; Transonic Systems Inc., Ithaca, NY, USA) was positioned around the contralateral fetal femoral artery. Another catheter was anchored to the fetal hind limb for measurement of amniotic cavity pressure. The abdominal incisions were closed in layers, and the catheters were filled with heparinised saline (80 i.u. ml−1 heparin in 0.9 % NaCl). The flow probe lead and catheters were exteriorised via a small incision in the maternal flank.

Post-operative care

Ewes were housed in individual pens, had free access to water and hay, were fed concentrates twice daily (100 g; Sheep Nuts no. 6; H&C Beart Ltd, Kings Lynn, UK), and generally resumed normal feeding patterns within 24 h of surgery. The ewes received 2 days of post-operative analgesia (3 g daily oral phenylbutazone; Equipalozone Paste E-pp, Arnolds Veterinary Products Ltd, Shropshire, UK) if required. Antibiotics were administered daily to the ewe (0.20-0.25 mg kg−1i.m. Depocillin; Mycofarm, Cambridge, UK), to the fetus (150 mg kg−1i.v. ampicillin, Penbritin; SmithKline Beecham Animal Health, Surrey, UK) and into the amniotic cavity (300 mg Penbritin). During post-operative recovery, daily maternal descending aortic and fetal carotid blood samples (0.4 ml) were taken for analysis of blood gas status. Vascular catheters were maintained patent by a slow continuous infusion of heparinised saline at 0.1 ml h−1.

Pressure transducers (COBE; Argon, Texas, USA) were attached to the fetal femoral artery and amniotic cavity catheters. Mean pressure values were derived by electronic processing in the analog pressure amplifiers. Output signals from the analog pressure and flow amplifiers were channelled through a custom-built electronic switch-box (Cambridge University, Cambridge, UK) to an analog-digital Data Acquisition System (DAS) card (NIDAQ; National Instruments, Austin, Texas, USA) which sampled the signals at 500 Hz. Pulsatile analog outputs from the Transonic flow meter and pressure amplifiers were used to trigger a heart rate meter whose analog output was channelled to the DAS card. Values for fetal heart rate, mean arterial blood pressure, mean femoral blood flow and amniotic cavity pressure were logged at 8 s intervals throughout the protocol using DAS software (Cornell University, Ithaca, NY, USA) running on a PC.

Experimental procedures

Following at least 5 days of post-operative recovery, fetuses were randomly assigned to one of two experimental groups. After 48 h of baseline recording, at 125 ± 1 dGA, 13 fetuses (6 males; 7 females) were continuously infused i.v. with dexamethasone (dexamethasone sodium phosphate; Merck, Sharp, Dohme Ltd, Hertfordshire, UK) for 48 h at a rate of 2.06 ± 0.13 μg kg−1 h−1 (corrected retrospectively for fetal body weight). The remaining fetuses (n = 13; 7 males; 6 females) were infused with heparinised saline at the same rate (0.5 ml h−1) in order to act as age-matched controls. All infusions were started at 10:00 h.

Daily paired maternal and fetal arterial blood samples (1.25 ml) were taken for measurement of blood gases and plasma dexamethasone concentration. Samples were taken at 09:30 h on the 2 days before infusions began (pre-infusion; days −1 and 0), on the 2 days of infusion (infusion; days 1 and 2) and on the 2 days after the end of infusion (post-infusion; days 3 and 4). In addition, fetal arterial blood samples (4 ml) were taken at 48 h from the onset of infusion and at 48 h following cessation of infusion for measurement of plasma noradrenaline, adrenaline, NPY and AVP concentrations. Blood samples for catecholamine analysis were dispensed into chilled heparin tubes (2 ml Li+/heparin tubes; L.I.P. Ltd, Shipley, West Yorkshire, UK) containing reduced glutathione (4 nmol per tube) and EGTA (5 nmol per tube). For all other hormones, blood samples were dispensed into chilled K+/EDTA tubes (2 ml K+/EDTA tubes; L.I.P. Ltd). All tubes were immediately centrifuged at 4000 r.p.m. for 4 min at 4 °C. Aliquots of plasma were transferred to PVC tubes and were snap-frozen in liquid nitrogen. Samples for measurement of catecholamines were stored at −80 °C whilst all other samples were stored at −20 °C until required for analysis.

In some of the fetuses from each group, pressor, vasoconstrictor and chronotropic responses to exogenously administered bolus doses (1 ml) of phenylephrine (12.5, 25, 50, 100 μg via fetal jugular vein; saline: n = 5; dexamethasone: n = 5), angiotensin II (400, 800, 1200, 1600 ng via fetal femoral artery; saline: n = 4; dexamethasone: n = 4) and AVP (30, 60, 120 μg via fetal femoral artery; saline: n = 4; dexamethasone: n = 4) were determined at 124 ± 1 dGA (pre-infusion), at 126 ± 1 dGA (infusion) and at 128 ± 1 dGA (post-infusion). Prior to each bolus dose protocol, a fetal carotid arterial blood sample (0.4 ml) was taken for analysis of blood gas status. Suitable dose ranges for each agonist were derived either from pilot studies or, where possible, from previous studies reported in the literature (e.g. Maloney et al. 1977; Irion et al. 1990; Tangalakis et al. 1992). During the dose-response protocol, cardiovascular variables were recorded at 1 s intervals using the computerised DAS. Baseline values for the cardiovascular variables measured during these challenges were obtained by averaging the data for each variable over the 60 s preceding the administration of the bolus dose. Baselines for all the measured cardiovascular variables were not significantly different between doses of agonists (P > 0.05). Bolus doses were injected over 2-3 s and were administered following at least 15 min of stable baseline recording following recovery from the previous challenges.

At the end of the experimental protocol, ewes and their fetuses were killed with a lethal dose of sodium pentobarbitone (40 mg kg−1i.v. Pentoject; Animalcare Ltd, York, UK). Fetuses were delivered via an abdominal midline incision and hysterotomy. Each fetus was weighed and its sex noted. Fetal crown-rump length was recorded.

Measurements and calculations

Values for maternal and fetal arterial pH (pHa), arterial partial pressure of oxygen (Pa,O2) and arterial partial pressure of carbon dioxide (Pa,CO2) were obtained using a blood gas analyser (ABL 5; Radiometer, Copenhagen, Denmark). Measurements in maternal blood were corrected to 38 °C and those in fetal blood to 39.5 °C.

Amniotic cavity pressure was used as the pressure reference level. Fetal femoral vascular resistance was calculated by dividing supra-amniotic mean arterial blood pressure by mean fetal femoral blood flow (Fletcher et al. 2000a). Values for fetal heart rate were derived from pulsatility in arterial blood pressure or femoral blood flow signals.

Plasma hormone measurements

All measurements were made within 4 months of plasma collection.

Dexamethasone assay

Maternal and fetal plasma dexamethasone concentrations were measured by radioimmunoassay as previously described in detail (Fletcher et al. 2000b). All values were corrected for recovery (86 %). The inter-assay coefficients of variation for three control plasma pools (1.8, 5.4 and 26.7 nmol l−1) were 14.6, 9.3 and 8.2 %, respectively. The lower detection limit of the assay was 0.2 nmol l−1. The anti-dexamethasone antiserum (Bioclinical Services International, Cardiff, UK) showed a 1.6 % cross-reactivity against cortisol and cross-reactivities of less than 0.5 % against 11-deoxycortisol, corticosterone, testosterone, progesterone and oestriol.

NPY assay

Fetal plasma NPY concentrations were measured by radioimmunoassay as described previously (Fletcher et al. 2000a). All samples were assayed in duplicate at the same time. The assay used rabbit antiserum (produced in-house) and 125I-labelled porcine peptide. The animals used were humanely killed at the end of the experiment. Separation of free and bound fractions was performed with dextran-coated charcoal. The assay was validated for use in ovine plasma using stripped ovine plasma and could detect less than 1 pmol l−1 (95 % confidence interval). The inter-assay coefficient of variation was 6.8 %. There was no detectable cross-reactivity of the anti-NPY antiserum with peptide YY.

AVP assay

Fetal plasma AVP concentrations were measured using a commercially available double antibody radioimmunoassay kit (Nichols Institute Diagnostics Ltd, Saffron Walden, Essex, UK) following separation from plasma proteins by methanol extraction and chromatography. The lower detection limit of the assay was 1.3 pg ml−1. The intra-assay coefficients of variation for four control plasma pools (mean concentrations: 3.2, 9.9, 12.2 and 28.9 pg ml−1) were 10.0, 6.7, 3.7 and 4.6 %, respectively. The inter-assay coefficients of variation were 6.9 % for a mean value of 10.8 pg ml−1. The anti-AVP antiserum (Nichols Institute Diagnostics Ltd) showed cross-reactivities of less than 0.1 % with lysine vasopressin, oxytocin and vasotocin.

Catecholamine assays

Fetal plasma noradrenaline and adrenaline concentrations were measured by high pressure liquid chromatography with electrochemical detection as previously described in detail (Silver et al. 1982). Samples were prepared by absorption of 250 μl of plasma onto acid-washed alumina and 20 μl aliquots of the 100 μl perchloric acid elutes were injected onto the column. Dihydroxybenzylamine was added as the internal standard to each plasma sample before absorption. Recovery ranged from 63 to 97 % and all catecholamine values were corrected for their respective recovery. The inter-assay coefficients of variation for noradrenaline and adrenaline were 6.2 and 7.3 %, respectively, and the minimum detectable dose was 10 pg ml−1.

Data analyses

Basal fetal cardiovascular variables

Cardiovascular variables were displayed by averaging the data recorded at 8 s intervals into 1 h bins. Cardiovascular data were expressed as means ± s.e.m. of every hour for each treatment group. Absolute data and changes from mean pre-infusion baseline for daily fetal cardiovascular variables were analysed by the summary of measures method (Matthews et al. 1990). This produced mean values for fetal heart rate, arterial blood pressure, femoral blood flow, and calculated femoral vascular resistance for each consecutive 24 h period over the duration of the experimental protocol. Confounding effects of the vasoconstrictor bolus dose protocols on the 24 h cardiovascular variables study were avoided by excluding those data from the analysis.

Dose-response protocol and fetal cardiac baroreflex curves

Values for the peak fetal heart rate, pressor and femoral vasoconstrictor responses to each dose of the exogenously administered agonists were determined. Fetal cardiac baroreflex curves were constructed from the peak pressor response (i.e. the highest single blood pressure value measured) and corresponding heart rate response to the bolus doses of phenylephrine. Values for pulse interval were calculated as the reciprocal of heart rate and were expressed in milliseconds.

Statistical analyses

Values for all variables are expressed as means ± s.e.m. unless otherwise indicated. Statistical significance for comparisons between and within treatment groups was assessed using two-way ANOVA with one repeated measure and the Tukey post hoc test. For statistical analysis of the cardiac baroreflex, linear regression lines were plotted for the response of each fetus, and the individual values for slopes and intercepts compared between treatment groups using Student's t test for unpaired data. Baroreflex sensitivity was estimated as the slope of the linear relationship between arterial blood pressure and pulse interval (Ismay et al. 1979). In all cases, significance was accepted when P < 0.05.

Results

Fetal outcome

At delivery, there were no differences between treatment groups in fetal body weight (2.45 ± 0.34 vs. 2.43 ± 0.34 kg; saline vs. dexamethasone; mean ± s.d.; P > 0.05) or crown- rump length (40.3 ± 3.8 vs. 42.0 ± 2.3 cm; mean ± s.d.; P > 0.05).

Plasma dexamethasone concentrations

Throughout the experimental protocol, dexamethasone remained undetectable in the plasma from both maternal groups and from the saline-infused fetuses. Fetal dexamethasone treatment produced a significant elevation in fetal plasma dexamethasone concentration, averaging 2.73 ± 0.38 nmol l−1 over the 48 h of infusion. In the dexamethasone-treated fetuses, plasma dexamethasone was again undetectable within 48 h following the cessation of infusions.

Arterial blood gases and pHa

Values for maternal arterial blood gases and pHa remained unaltered from pre-infusion baseline throughout the infusion protocol and were similar between both groups of animals (pHa 7.48 ± 0.01 vs. 7.48 ± 0.01; Pa,CO2 35.4 ± 0.7 vs. 36.0 ± 0.6 mmHg; Pa,O2 97.4 ± 2.3 vs. 96.6 ± 2.0 mmHg; saline vs. dexamethasone; pre-infusion day −1; P > 0.05). Similarly, fetal treatment with dexamethasone had no effect on fetal carotid blood gases or pHa, and values for these variables were similar between treatment groups throughout the experimental protocol (Table 1).

Table 1.

Fetal carotid blood gases and pHa

Pre-infusion Infusion Post-infusion
Day −1 0 1 2 3 4
pHa
 Saline 7.36 ± 0.01 7.34 ± 0.01 7.35 ± 0.02 7.34 ± 0.01 7.34 ± 0.01 7.34 ± 0.01
 Dexamethasone 7.35 ± 0.01 7.35 ± 0.01 7.34 ± 0.01 7.35 ± 0.01 7.33 ± 0.01 7.32 ± 0.01
Pa,co2 (mmHg)
 Saline 51.9 ± 1.1 53.1 ± 1.0 53.6 ± 0.9 53.5 ± 0.8 54.4 ± 0.8 53.3 ± 0.8
 Dexamethasone 51.9 ± 0.9 53.0 ± 0.8 53.9 ± 0.7 52.9 ± 0.4 53.4 ± 0.8 53.3 ± 1.3
Pa,o2(mmHg)
 Saline 21.1 ± 1.0 22.0 ± 0.7 21.7 ± 1.0 22.1 ± 0.6 21.5 ± 1.2 22.0 ± 0.5
 Dexamethasone 21.1 ± 0.8 21.6 ± 0.6 21.9 ± 0.8 22.3 ± 0.7 22.7 ± 0.6 22.6 ± 0.4
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Values are means ± s.e.m. for 2 days of pre-infusion baseline (days −1 and 0), for 2 days of infusion (days 1 and 2), and for 2 days following infusion (days 3 and 4) for saline-infused (n = 13) and dexamethasone-treated (n = 13) fetuses. pHa, arterial pH;Pa,CO2, arterial CO2 partial pressure; Pa,O2 arterial O2 partial pressure.

Fetal cardiovascular variables

Data for fetal cardiovascular variables during the infusion protocol, expressed as absolute values, are shown in Fig. 1. In the saline-infused fetuses, whilst there were no significant changes in the 24 h mean values for fetal arterial blood pressure, femoral blood flow and calculated femoral vascular resistance, there was a shallow, but progressive, reduction in the 24 h mean values of fetal heart rate over the 6 days of the experimental protocol (Fig. 1). In contrast, during fetal treatment with dexamethasone there was a significant increase in fetal arterial blood pressure, a significant reduction in femoral blood flow, and hence a significant increase in calculated femoral vascular resistance (Fig. 1). During dexamethasone infusion, the magnitude of the peak increase in arterial blood pressure from mean pre-infusion baseline levels was 8.1 ± 1.0 mmHg (P < 0.05). Whilst fetal heart rate was significantly reduced from pre-infusion baseline values at 24 h of dexamethasone infusion, by 48 h following cessation of infusions heart rate was elevated compared with values for saline-infused fetuses (Fig. 1).

Figure 1. Fetal cardiovascular variables during the infusion protocol.

Figure 1

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A, absolute values of cardiovascular variables in saline-infused (n = 13) and dexamethasone-treated (n = 13) fetuses. Values are means ± s.e.m. of every hour during the infusion protocol. B, mean daily values of cardiovascular variables for saline-infused (○) and dexamethasone-treated (•) fetuses. Values are means ± s.e.m. for each 24 h epoch during the infusion protocol. Bars represent infusions. Significant differences (P < 0.05): * differences by post hoc analysis indicating a significant main effect of time compared with pre-infusion baseline; † differences by post hoc analysis indicating a significant main effect of treatment compared with saline-infused fetuses (two-way repeated measures ANOVA + Tukey test).

Plasma hormone concentrations

Basal plasma vasoconstrictor hormone concentrations in fetuses during and following saline infusion and during and following dexamethasone treatment are shown in Fig. 2. Fetal basal plasma noradrenaline concentrations were depressed at 48 h during dexamethasone infusion compared with corresponding values in saline-infused controls. In contrast, at 48 h following dexamethasone infusion, basal plasma adrenaline and NPY concentrations were enhanced compared with corresponding values in the saline-infused fetuses (Fig. 2).

Figure 2. Fetal basal arterial plasma noradrenaline, adrenaline, neuropeptide Y and arginine vasopressin concentrations.

Figure 2

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Arterial plasma concentrations of noradrenaline (NA), adrenaline (ADR), neuropeptide Y (NPY) and arginine vasopressin (AVP) for fetuses during and following saline infusion (□; n = 13), and during and following dexamethasone treatment (▪; n = 13). Values are means ± s.e.m. [X], arterial plasma concentration of X; Dur Sal, during saline infusion; Dur Dexa, during dexamethasone infusion; Foll Sal, following saline infusion; Foll Dexa, following dexamethasone infusion. * P < 0.05, dexamethasone vs. corresponding saline controls (Student's t test for unpaired data).

Fetal responses to exogenously administered vasoconstrictor agents

Phenylephrine

During the pre-infusion, infusion and post-infusion periods, administration of phenylephrine produced dose-dependent increases in fetal arterial blood pressure and reductions in fetal heart rate that were of similar magnitude in saline-infused and dexamethasone-treated fetuses (Fig. 3). Absolute peak values of arterial blood pressure attained in response to the phenylephrine doses were generally greater both during and following dexamethasone treatment compared with saline-infused controls (Fig. 3). However, when these pressor responses were expressed as absolute changes from basal fetal arterial blood pressure, values were similar between saline-infused and dexamethasone-treated fetuses during the pre-infusion, infusion and post-infusion periods (pre-infusion: 21.3 ± 1.2 vs. 26.5 ± 1.4 mmHg; during infusion: 22.4 ± 1.5 vs. 31.0 ± 4.8 mmHg; post-infusion: 23.6 ± 2.7 vs. 22.6 ± 3.7 mmHg; saline vs. dexamethasone; increment from baseline for highest dose; P > 0.05). Fetal femoral blood flow and vascular resistance responses to exogenous phenylephrine administration were not different between treatment groups during the pre-infusion, infusion or post-infusion periods, either when expressed as absolute values or as absolute changes from basal values (P > 0.05). In the dexamethasone-treated fetuses, increasing doses of phenylephrine depressed fetal femoral blood flow (pre-infusion: 25.4 ± 1.8 vs. 3.2 ± 1.3 ml min−1; during dexamethasone: 22.2 ± 2.4 vs. 1.2 ± 0.4 ml min−1; following dexamethasone: 30.2 ± 1.0 vs. 3.3 ± 0.7 ml min−1; baseline vs. maximal value at highest dose; P < 0.05) and elevated femoral vascular resistance (pre-infusion: 2.0 ± 0.1 vs. 33.0 ± 4.5 mmHg (ml min−1)−1; during dexamethasone: 3.1 ± 0.5 vs. 40.9 ± 12.8 mmHg (ml min−1)−1; following dexamethasone: 1.9 ± 0.1 vs. 28.7 ± 6.7 mmHg (ml min−1)−1; P < 0.05).

Figure 3. Absolute fetal cardiovascular variables for the phenylephrine dose-response protocol.

Figure 3

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Values are means ± s.e.m. for absolute values of fetal heart rate, arterial blood pressure, femoral blood flow and femoral vascular resistance in response to the phenylephrine dose-response protocol performed in saline-infused (○; n = 5) and dexamethasone-treated (•; n = 5) fetuses. BL, baseline value. Significant differences (P < 0.05): * differences by post hoc analysis indicating a significant main effect of dose compared with baseline; † differences by post hoc analysis indicating a significant main effect of treatment compared with saline-infused fetuses (two-way repeated measures ANOVA + Tukey test).

Angiotensin II

Fetal cardiovascular responses to exogenous angiotensin II administration are summarised in Table 2. Baseline values of fetal blood gases and cardiovascular variables prior to the administration of bolus doses were not different to values obtained during 24 h recording (P > 0.05). Responses to exogenous angiotensin II administration were not different between treatment groups during the pre-infusion, infusion or post-infusion periods, either when expressed as absolute values or as absolute changes from basal values (P > 0.05). In both groups of fetuses, administration of increasing doses of angiotensin II tended to elevate fetal arterial blood pressure and femoral vascular resistance, whilst reducing femoral blood flow and heart rate (Table 2).

Table 2.

Fetal carotid blood gases and pHa status, and absolute values of cardiovascular variables, during the angiotensin II dose-response protocol

Pre-infusion Infusion Post-infusion
Baseline Max Baseline Max Baseline Max
FHR (beats min−1)
 Saline 183.0 ± 11.5 146.6 ± 14.0 185.0 ± 15.0 110.6 ± 11.6 173.8 ± 8.3 125.0 ± 18.5
 Dexamethasone 169.2 ± 9.2 150.0 ± 8.1 164.3 ± 16.7 110.3 ± 38.3 166.0 ± 14.2 125.0 ± 15.0
FBP (mmHg)
 Saline 44.6 ± 2.8 58.5 ± 3.2* 42.5 ± 6.5 60.3 ± 2.9 * 43.5 ± 3.7 58.3 ± 2.6 *
 Dexamethasone 47.9 ± 3.2 64.8 ± 7.6* 51.8 ± 3.8 64.2 ± 10.7 51.8 ± 5.6 73.0 ± 4.0†
FBF(ml min−1)
 Saline 29.2 ± 1.6 17.7 ± 3.6* 23.5 ± 1.9 16.3 ± 7.4 30.3 ± 2.6 15.6 ± 5.6
 Dexamethasone 26.4 ± 2.0 19.9 ± 2.1 19.5 ± 1.3 11.3 ± 3.2 29.5 ± 1.3 17.5 ± 3.5*
FVR (mmHg (ml min−1)−1)
 Saline 1.52 ± 0.15 3.31 ± 0.31* 1.81 ± 0.18 3.70 ± 0.37* 1.43 ± 0.10 3.74 ± 0.46*
 Dexamethasone 1.81 ± 0.14 3.26 ± 0.67* 2.66 ± 0.23† 5.68 ± 2.24 1.75 ± 0.13 4.17 ± 1.20
pHa
 Saline 7.37 ± 0.02 — 7.37 ± 0.08 — 7.31 ± 0.01 —
 Dexamethasone 7.36 ± 0.01 — 7.34 ± 0.01 — 7.31 ± 0.02 —
Pa,co2 (mmHg)
 Saline 50.6 ± 1.8 — 52.5 ± 1.0 — 54.3 ± 0.7 —
 Dexamethasone 51.8 ± 1.1 — 51.0 ± 1.2 — 55.0 ± 1.1 —
Pa,o2(mmHg)
 Saline 21.0 ± 1.4 — 22.0 ± 1.9 — 17.7 ± 1.8 —
 Dexamethasone 23.2 ± 1.1 — 24.6 ± 1.9 — 21.3 ± 0.6 —
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Values are means ±s.e.m. for absolute values of fetal heart rate (FHR), arterial blood pressure (FBP), femoral blood flow (FBF), femoral vascular resistance (FVR), arterial pH (pHa), arterial CO2 partial pressure (Pa,co2) and arterial O2 partial pressure (Pa,o2) during the angiotensin II dose-response protocol performed in saline-infused (n =4) and dexamethasone-treated (n = 4) fetuses. Max, value at highest dose.

*

P < 0.05, Max vs. corresponding baseline (Student's t test for paired data)

†

P < 0.05, dexamethasone vs. corresponding saline controls (Student's ttest for unpaired data).

AVP

Fetal cardiovascular responses to exogenous AVP administration are shown in Table 3. Baseline values of fetal blood gases and cardiovascular variables prior to the administration of bolus doses were not different to values obtained during 24 h recording (P > 0.05). There were no differences between treatment groups in response to the AVP boluses during the pre-infusion, infusion or post-infusion periods (P > 0.05). In both groups of fetuses, increasing doses of AVP produced increases in fetal arterial blood pressure and femoral vascular resistance, whilst reducing femoral blood flow and fetal heart rate (Table 3).

Table 3.

Fetal carotid blood gases and pHa status, and absolute values ot cardiovascular variables, during the AVP dose-response protocol

Pre-infusion Infusion Post-infusion
Baseline Max Baseline Max Baseline Max
FHR (beats min−1)
 Saline 164.9 ± 3.7 135.0 ± 5.6* 161.7 ± 8.4 129.0 ± 5.6* 163.5 ± 7.6 117.6 ± 12.0*
 Dexamethasone 178.0 ± 9.3 140.5 ± 7.2* 164.0 ± 10.4 110.0 ± 15.5* 169.0 ± 7.8 128.0 ± 10.0*
FBP (mmHg)
 Saline 50.2 ± 2.5 59.0 ± 3.3 47.7 ± 4.5 58.7 ± 4.1 52.4 ± 6.6 55.5 ± 6.2
 Dexamethasone 50.8 ± 4.3 58.4 ± 4.4 50.0 ± 5.6 61.1 ± 5.2 46.0 ± 4.0 52.0 ± 5.9
FBF(ml min−1)
 Saline 29.9 ± 2.5 9.4 ± 2.3* 32.1 ± 2.2 7.7 ± 2.3* 35.1 ± 2.3 9.3 ± 1.3*
 Dexamethasone 30.2 ± 2.9 10.2 ± 0.9* 23.9 ± 2.3 7.0 ± 2.0* 32.5 ± 3.4 9.0 ± 1.0*
FVR (mmHg (ml mn−1)−1)
 Saline 1.68 ± 0.21 6.28 ± 1.28* 1.48 ± 0.35 7.62 ± 1.62* 1.49 ± 0.25 5.98 ± 1.72
 Dexamethasone 1.68 ± 0.20 5.73 ± 0.77* 2.09 ± 0.30 8.73 ± 4.58 1.42 ± 0.17 5.78 ± 1.73
pHa
 Saline 7.38 ± 0.01 — 7.33 ± 0.01 — 7.33 ± 0.01 —
 Dexamethasone 7.35 ± 0.01 — 7.33 ± 0.01 — 7.30 ± 0.02 —
Pa,co2 (mmHg)
 Saline 49.3 ± 1.7 — 52.0 ± 0.9 — 51.7 ± 2.0 —
 Dexamethasone 50.2 ± 1.1 — 50.2 ± 1.2 — 54.5 ± 2.4 —
Pa,o2(mmHg)
 Saline 22.5 ± 1.2 — 24.2 ± 0.7 — 22.7 ± 0.9 —
 Dexamethasone 24.2 ± 0.9 — 25.0 ± 1.7 — 22.0 ± 1.1 —
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Values are means ± s.e.m. for absolute values of fetal heart rate (FHR), arterial blood pressure (FBP), femoral blood flow (FBF), femoral vascular resistance (FVR), arterial pH (pHa), arterial CO2 partial pressure (Paco2) and arterial O2 partial pressure (Pa,o2) during the AVP dose-response protocol performed in saline-infused (n = 4) and dexamethasone-treated (n = 4) fetuses. Max, value at highest dose.

*

P < 0.05, Max vs. corresponding baseline (Student's ttest for paired data).

Fetal cardiac baroreflex curves

The pulse interval vs. arterial blood pressure curves derived from the phenylephrine dose-response protocol are shown in Fig. 4. Although there was no difference between responses for the two groups of fetuses in the pre-infusion period, rightward shifts in the curves occurred during and following dexamethasone treatment compared with saline infusion (Fig. 4). Whilst baseline fetal arterial blood pressure was elevated during and following dexamethasone treatment compared with saline infusion, there was no difference between treatment groups for the slopes of the pulse interval vs. fetal arterial blood pressure curves during or following infusions (P > 0.05; Student's t test for unpaired data; Fig. 4).

Figure 4. Functional baroreflex curves from the phenylephrine dose-response protocol.

Figure 4

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Values are means ± s.e.m. for pulse interval vs. fetal arterial blood pressure taken from the phenylephrine dose-response protocol performed in saline-infused (○; n = 5) and dexamethasone-treated fetuses (•; n = 5). R, regression coefficient; PI, pulse interval; ABP, fetal arterial blood pressure. * P < 0.05, comparison of intercepts for saline vs. dexamethasone (Student's t test for unpaired data).

Discussion

This study determined the effects of fetal intravenous treatment with low doses of dexamethasone on ovine fetal basal cardiovascular and endocrine functions during late gestation. In the present study, fetal plasma dexamethasone concentrations during infusion were one-fifth of the mean value measured in umbilical arterial blood samples taken from human infants at Caesarean section, 12 h after the completion of a course of maternal antenatal glucocorticoid treatment (5 mg dexamethasone intramuscularly every 12 h for 48 h; Kream et al. 1983), and approximately one-eighth of the mean value achieved previously by Derks and colleagues using direct i.v. dexamethasone infusion in fetal sheep (20 nmol l−1; Derks et al. 1997). Whilst clinical dosing regimens involve maternal intramuscular injections that expose the human fetus to initially high, but then rapidly decreasing, concentrations of synthetic steroid (Ballard & Ballard, 1995), the use of fetal i.v. administration of dexamethasone in the current study allowed assessment of the direct effects of the synthetic glucocorticoid on ovine fetal cardiovascular and endocrine variables, avoiding potential confounding influences of differences in transplacental passage between individual animals.

Several previous studies have shown that maternal antenatal glucocorticoid therapy elevates arterial blood pressure in human neonates (Kari et al. 1994), adult rats (Benediktsson et al. 1993) and in neonatal and adult sheep (Berry et al. 1997; Dodic et al. 1999a,b). In fetal sheep, administration of synthetic glucocorticoids increases fetal arterial blood pressure, whether administered directly to the fetus (Derks et al. 1997; Anwar et al. 1999) or to the mother (Bennet et al. 1999). In the current investigation, despite achieving only one-eighth of the circulating concentrations of dexamethasone measured in the study of Derks et al. (1997) and one-fifth of the concentrations measured in human infants following maternal antenatal glucocorticoid therapy (Kream et al. 1983), the magnitude of the fetal hypertension during dexamethasone infusion was similar to that observed in response to higher dexamethasone levels (Derks et al. 1997). Fetal blood pressure also remained elevated above pre-infusion baseline when dexamethasone had been cleared from the fetal circulation. These data support the hypotheses that even relatively low doses of dexamethasone have similar effects on fetal basal cardiovascular function as substantially higher doses, and that these effects persist in the period following treatment. These data emphasise the potency of synthetic glucocorticoids in modifying fetal basal physiological functions and indicate that clinical dosing regimens may be supramaximal with regard to the cardiovascular effects of dexamethasone exposure.

To date, only a few studies have addressed mechanisms accounting for glucocorticoid-induced hypertension in the sheep fetus. The study by Derks et al. (1997) showed that fetal hypertension occurring during fetal i.v. infusion with betamethasone was associated with an increase in vascular resistance in the femoral vascular bed. Similarly, the present study has demonstrated that the fetal hypertension occurring during fetal exposure to low plasma concentrations of dexamethasone was associated with increases in femoral vascular resistance which were of similar magnitude to those previously measured during betamethasone treatment (Derks et al. 1997). Increases in femoral vascular resistance have been used as good indices of more generalised increases in peripheral vascular resistance (e.g. see Giussani et al. 1996). If this assumption holds in the current study, then the elevations in fetal femoral vascular resistance may indicate that increases in total peripheral vascular resistance contribute to the fetal hypertension observed during dexamethasone treatment. Accordingly, intravenous infusion of betamethasone in fetal sheep, not only reduces femoral blood flow (Derks et al. 1997), but has also been shown to reduce cerebral blood flow and increase calculated cerebral vascular resistance at 24 h of treatment (Schwab et al. 2000).

Mechanisms accounting for these increases in fetal peripheral resistance may include changes in circulating levels of vasoconstrictor agents and changes in vascular sensitivity to them. Consistent with previous findings (Derks et al. 1997), only fetal basal plasma noradrenaline concentration was depressed during the dexamethasone infusion period. However, the present study has also demonstrated that by 48 h following dexamethasone infusion, basal plasma noradrenaline concentration was restored, whilst both basal plasma adrenaline and NPY concentrations were enhanced, compared with values in saline-infused fetuses. The enhancement of basal plasma adrenaline concentration may, at least in part, account for increased fetal heart rate and persistence of the elevated fetal arterial blood pressure in the period following dexamethasone treatment. In addition, changes in plasma NPY concentration may be a good index of sympathetic nervous activity since there is no reuptake mechanism for NPY, and NPY is known to be co-localised and co-secreted with noradrenaline at sympathetic nerve terminals (Lundberg, 1996). Therefore, the increase in basal plasma NPY concentration at 48 h following dexamethasone treatment may indicate enhanced sympathetic efferent activity to the periphery, and may contribute to the fetal hypertension at that time.

Fetal sheep are known to respond to exogenously administered angiotensin II (Ismay et al. 1979), AVP (Iwamoto et al. 1979) and α-adrenergic agonists (Ismay et al. 1979) during the last third of gestation. In the current study, there were no significant differences in responses to these exogenously administered agonists between dexamethasone-treated and saline-infused fetuses, either during or following the infusion period, even though glucocorticoid exposure may enhance α-adrenoceptor-mediated (Haigh & Jones, 1990; Liu et al. 1992) and AT1 receptor-mediated signal transduction (Sato et al. 1994). These findings are consistent with those previously reported in sheep treated with synthetic glucocorticoids. For example, Dodic et al. (1998) found that exposure to dexamethasone early in gestation had no effect on postnatal pressor responses to noradrenaline or angiotensin II in vivo. In addition, Anwar et al. (1999) removed femoral arteries from fetal sheep following 48 h of betamethasone administration during late gestation and mounted them in a small vessel wire myograph. Although betamethasone infusion enhanced sensitivity and the maximal response to depolarising K+ solutions, vasoconstrictor responses to the thromboxane mimetic U-46619 and noradrenaline were unaffected (Anwar et al. 1999). The findings of this study suggest that changes in responsiveness of the femoral vasculature to angiotensin II, AVP or adrenergic agonists in vivo do not account for the changes in fetal basal arterial blood pressure or femoral vascular resistance during the experimental protocol. However, glucocorticoid exposure may also modify vasodilator activity, for example by inhibiting prostacyclin (Axelrod, 1983) and nitric oxide synthesis (Wallerath et al. 1999). Indeed, Anwar and colleagues have recently demonstrated that pre-constricted fetal femoral arteries in vitro have enhanced sensitivity to acetylcholine but reduced sensitivities to bradykinin and forskolin following 48 h of fetal i.v. betamethasone infusion (Anwar et al. 1999). This provides evidence for possible diminished vasodilator function in mediating the increases in fetal basal blood pressure and femoral vascular resistance during synthetic glucocorticoid treatment in sheep.

Whilst Segar et al. (1998) have demonstrated that antenatal dexamethasone treatment reduces postnatal cardiac baroreflex sensitivity in preterm lambs, little is known about the effects of such treatment on the fetal cardiac baroreflex. In the sheep, baroreflexes are also known to operate during fetal life (Dawes et al. 1980), reducing short-term blood pressure and heart rate variabilities (Segar, 1997). Although sensitivity of the afferent limb of the fetal baroreflex decreases with advancing gestational age (Blanco et al. 1988), the overall gain of the baroreflex response has been shown to increase (Shinebourne et al. 1972) or remain unchanged (Maloney et al. 1977) as the fetus approaches term. In the present study, assessment of the sensitivity of the hypertensive component of the cardiac baroreflex was made using the peak heart rate and blood pressure responses at each dose of phenylephrine. The results of the present study confirm the preliminary findings of Koenen et al. (2000), who have demonstrated a shift in the cardiac baroreflex set-point (as defined by the resting arterial blood pressure), but not sensitivity, during the period of fetal dexamethasone exposure. The present study also extends these preliminary findings to show that, even with fetal exposure to lower concentrations of dexamethasone, these changes persist 48 h after the end of dexamethasone treatment. Whether the modification in fetal baroreflex function was a cause or an effect of the fetal hypertension remains unclear, but the shift in set-point would have permitted baroreflex accommodation of the fetal hypertension both during and following dexamethasone treatment.

In conclusion, this study has demonstrated that fetal infusion with dexamethasone, to produce circulating concentrations attaining one-fifth of the values achieved clinically in humans (Kream et al. 1983) and one-eighth of the values previously achieved in sheep (Derks et al. 1997), elevates fetal arterial blood pressure by a similar extent as that seen previously in response to higher dexamethasone concentrations (Derks et al. 1997). This fetal hypertension was associated with increases in femoral vascular resistance during dexamethasone treatment. Fetal hypertension during dexamethasone infusion was accommodated by a shift in the set-point, but not sensitivity, of the cardiac baroreflex. The elevation in fetal blood pressure and associated shift in baroreflex set-point persisted at 48 h following the end of the dexamethasone treatment period. These changes were not associated with alterations in the pressor or femoral vasoconstrictor responses to adrenergic, vasopressinergic or angiotensinergic agonists. Whilst fetal basal plasma noradrenaline concentration was depressed during, but not following, dexamethasone treatment, by 48 h following dexamethasone infusion both basal plasma adrenaline and NPY concentrations were enhanced, compared with values in saline-infused fetuses.

The findings of this study have important implications for the effects of dexamethasone dosing regimens used in current clinical practice on fetal arterial blood pressure and its regulation both during and following the treatment period. Persistent resetting of fetal baroreflex function has important implications for normal activity of baroreflex-regulated cardiovascular and endocrine functions during periods of acute stress in the fetus and for the long-term regulation of arterial blood pressure postnatally and into adult life. The findings of the current study reinforce the need for reassessment of the dose of glucocorticoids employed in antenatal glucocorticoid therapy in human obstetric practice today in order to maintain the beneficial maturational effects of synthetic glucocorticoids whilst minimising unwanted side-effects.

Acknowledgments

This work was funded by Tommy's - The Baby Charity, UK. The authors would like to thank Mr Malcolm Bloomfield for measuring the plasma catecholamine concentrations by HPLC; Mr Paul Hughes for his help during surgery; and Mrs Sue Nicholls and Miss Vicky Johnson for the care of the animals used in this study. Andrew Fletcher was supported by the Foster Studentship, Department of Physiology, University of Cambridge, UK.

D. A. Giussani is a Fellow of the Lister Institute for Preventive Medicine.

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