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The Physiological Laboratory, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK
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Abstract |
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(Received 18 February 2004;
accepted after revision 5 April 2004;
first published online 8 April 2004)
Corresponding author D. S. Gardner: School of Human Development, Academic Division of Child Health, Queens Medical Centre, Nottingham NG7 2UH, UK. Email: david.gardner{at}nottingham.ac.uk
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Introduction |
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Many studies have indicated that increased fetal number is an independent risk factor for poor fetal adaptation to the stress of labour and thus perinatal outcome (Koivisto et al. 1975; Ghai & Vidyasagar, 1988; Kiely, 1990; Sherer, 2001). Indeed, twinning has a 6-fold greater perinatal mortality rate than singleton births (Ghai & Vidyasagar, 1988). While the majority of this increased risk may be accounted for by prematurity, low birth weight (Imaizumi, 2001) and monochorionicity (Sherer, 2001), fetal number per se increases obstetric risk when chorionicity and birth weight are matched (Kiely, 1990; Sherer, 2001). A recent study has indicated that basal function of the hypothalamic-pituitary-adrenal (HPA) axis is relatively blunted in twin fetuses, marked by a delayed preparturient increase in fetal plasma cortisol (Edwards & McMillen, 2002a). Given that twin-bearing pregnancies generally have a shorter gestation period (Imaizumi, 2001) and that cortisol, in particular, matures the fetus physiologically over the few weeks prior to birth (Fowden et al. 1998a) then relative physiological immaturity of twin fetuses may underlie their apparent susceptibility to perinatal stress and explain their poor perinatal outcome. To date, however, it is unknown whether fetal adrenocortical responsiveness, in addition to basal function, is blunted in twin fetuses, and whether there are marked differences in the cardiovascular, endocrine and metabolic defence responses to acute stress in twin relative to singleton fetuses. This study tested the hypothesis that twin relative to singleton fetuses have blunted adrenocortical responsiveness and weaker cardiovascular and metabolic defences to acute hypoxaemic stress. Blunting of fetal adrenocortical function was further assessed directly by an exogenous ACTH test.
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Methods |
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Twenty pregnant Welsh Mountain ewes of known gestational age were used in the study. Of these ewes 10 were carrying singleton fetuses and 10 twin fetuses. The numbers of males/females within each group were similar. All procedures were performed under the UK Animals (Scientific Procedures) Act 1986. For 24 h prior to surgery all food, but not water, was withdrawn from the animals. Surgery was conducted at 121 ± 3 days of gestation (dGA; term is ca 145 dGA). Anaesthesia was induced with sodium thiopentone (20 mg kg–1I.V. Intraval Sodium; Rhone Mérieux, Dublin, Ireland) and maintained with 1–2% halothane in 50: 50 O2/N2O. In brief, fetal vascular (carotid and femoral arterial, femoral venous) and an amniotic catheter were inserted into each singleton and one randomly chosen twin fetus, and a transit-time flow transducer (Transonics, NY, USA) was placed around the other femoral artery. All uterine incisions were closed in layers and a further Teflon catheter was inserted in the maternal femoral artery. Ewes received antibiotics (0.20–0.25 mg kg–1I.M. Depocillin; Mycofarm, Cambridge, UK) for 3 days postoperatively. Fetal catheter patency was maintained by a continuous infusion of heparinized saline (25 i.u. heparin ml–1 at 0.1 ml h–1 in 0.9% NaCl) containing antibiotic (1 mg ml–1 benzylpenicillin; Crystapen, Schering-Plough, Animal Health Division, Welwyn Garden City, UK). All surgical procedures and postoperative management of the ewes and fetuses has been previously described in detail (Gardner et al. 2001a; Giussani et al. 2001).
Experimental procedure
At 130 ± 2 days gestation (0.9 dGA) all fetuses were subjected to an episode of acute hypoxaemia, induced by reducing maternal FIO2. In brief, the protocol for acute fetal hypoxaemia involved a 3 h experiment consisting of 1 h of normoxia, 1 h of hypoxaemia and 1 h of recovery. A large, transparent, polyethylene bag was placed over the ewe's head into which air was passed at a rate of ca 40 l min–1 for the first 1 h. Following this normoxaemic period, fetal hypoxaemia was induced by changing the concentration of gases breathed by the ewe to 9% O2 in N2 with 1.5–2% CO2, which has been previously shown to reduce fetal carotid PO2 to ca 12 mmHg while maintaining arterial isocapnia (Giussani et al. 1993; Gardner et al. 2002b). Following the 1 h period of hypoxaemia the ewe was returned to breathing air for the 1 h recovery period. At 133 ± 2 dGA a 2.5 µg bolus dose of synthetic ACTH (Synacthen; Ciba Pharmaceuticals, UK) was injected I.V. into eight of the singleton and six of the twin fetuses to directly assess adrenocortical responsiveness to ACTH1-24. The dose of Synacthen used was based on previous studies from this laboratory (Robinson et al. 1983b; Gardner et al. 2001b). Ewes and fetuses were subsequently humanely killed using a lethal dose of sodium pentobarbitone (200 mg kg–1 Pentoject; Animal Ltd, York, UK) and the positions of the implanted catheters and the flow probe were confirmed and fetal biometry determined.
Measurements, data collection and analyses
Maternal and fetal arterial blood samples (0.4 ml) were taken daily for the monitoring of blood gases, percentage saturation of O2 in haemoglobin, haemoglobin concentration and acid/base status using an ABL5 blood gas analyser, corrected to 38°C (maternal) and 39.5°C (fetal), and an OSM2 haemoximeter (Radiometer, Copenhagen, Denmark). Maternal and fetal arterial blood glucose and lactate concentrations were measured using an automated analyser (Yellow Springs 2300 Stat Plus glucose/lactate analyser; YSI, Farnborough, UK). Additional maternal and fetal arterial blood samples (4 ml) were taken during the hypoxaemia protocol at 15 (N15) and 45 min (N45) of normoxaemia, 15 (H15) and 45 min (H45) of hypoxaemia and after 45 min (R45) of recovery for measurement of blood gases, glucose, lactate and hormone concentrations. Fetal arterial blood pressure was corrected for amniotic pressure. Fetal femoral blood flow was measured with a T201 or T206 flowmeter (Transonic Inc., NY, USA). Fetal heart rate was triggered from the flow pulsatility. The rate pressure product, which correlates with myocardial work (r2= 0.77; Hoeft et al. 1991), was calculated as mean arterial pressure x heart rate/103 (mmHg (beats min–1)). Femoral vascular resistance was calculated according to Ohm's principle by dividing arterial blood pressure (corrected for amniotic pressure) by femoral blood flow (Giussani et al. 1993). All signals were digitized, displayed and subsequently stored on disk by custom software (NI-DAQ, National Instruments, Austin, TX, USA) running on a PC. Files were subsequently analysed using Microsoft Excel spreadsheets.
Fetal arterial blood oxygen content (CaO2) and hind limb oxygen (O2del) and glucose (Gludel) deliveries were calculated according to eqns (1)–(3).
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| (1) |
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| (2) |
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Hormone analyses
Blood samples for hormone analyses were either collected into K+-EDTA-treated tubes (1.5 ml, ACTH, cortisol and vasopressin) or chilled EGTA (5.0 µmol (ml blood)–1) and glutathione (40 µmol (ml blood–1)) -treated tubes (1 ml, catecholamines) and centrifuged immediately at 4000 r.p.m. (900 g) for 4 min at 4°C. Plasma samples were stored at –70°C until analyses. All hormone analyses were completed within 2 months of plasma collection and were performed using procedures validated for use with ovine plasma.
ACTH. Maternal and fetal plasma ACTH concentrations were measured using a commercially available double antibody 125I radioimmunoassay (RIA) kit (Incstar Ltd, Wokingham, UK) as previously described (Gardner et al. 2001a). The lower limit of detection for the assay was between 10 and 25 pg ml–1 and the assay had < 0.01% cross-reactivities for a-MSH, ß-endorphin, ß-lipotrophin, leucine enkephalin, methionine enkephalin, bombesin, calcitonin, parathyroid hormone (PTH), follicle-stimulating hormone (FSH), arginine vasopressin, oxytocin and substance P. The intra- and interassay coefficients of variation were 4% and <10%, respectively.
Cortisol. Maternal and fetal plasma cortisol concentrations were measured by RIA validated for use in ovine plasma, as previously described (Fowden et al. 1993). The lower limit of detection for the assay was 1.0–1.5 ng ml–1 and cross-reactivity of the anti-serum at 50% binding with other cortisol-related compounds was 0.5% for cortisone, 2.3% for corticosterone, 0.3% for progesterone and 4.6% for deoxycortisol. The intra- and interassay coefficients of variation were 5% and 8%, respectively.
Catecholamines. The plasma catecholamines, adrenaline and noradrenaline, were analysed by high performance liquid chromatography (HPLC) using electrochemical detection (Fowden et al. 1998b). The 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. The limit of sensitivity for the assay was 20 pg ml–1 for adrenaline and noradrenaline. The interassay coefficient of variation for both adrenaline and noradrenaline was <10%.
Vasopressin. Plasma vasopressin concentrations were measured using a commercially available double-antibody RIA kit (Nichols Institute Diagnostics Ltd, Saffron Walden, UK) following separation from plasma proteins by methanol extraction and chromatography as previously described in detail (Gardner et al. 2001a). The lower detection limit of the assay was 0.75 pg ml–1. The interassay coefficients of variation for two plasma samples (2.71 and 5.55 pg ml–1) were 4.1 and 9.8%, respectively (Giussani et al. 1994b).
Statistical analyses
Values for all variables are expressed as means ±S.E.M. unless otherwise stated. All measured variables were first analysed for normality of distribution. Statistical analyses were conducted on parametric or log-transformed, non-parametric data using two-way ANOVA with repeated measures (Sigma-Stat; SPSS Inc, Chicago, IL, USA). Significant effects of time, group or an interaction between time and group were isolated by the post hoc Student-Newman-Keuls test. A comparison between the slopes and intercepts of linear regression curves was conducted according to Armitage et al. (2002). Areas under the curve (AUCs) were calculated using a custom-designed Excel spreadsheet according to eqn (4):
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| (4) |
0.05. |
Results |
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The proportion of males to females in the groups of singletons and twins was 5: 5 and 6: 4, respectively. Absolute body weight in twin fetuses was significantly lower than in singleton fetuses and, as a consequence, absolute organ weights also tended to be lighter (Table 1). However, when expressed as a proportion of body weight, all organ weights measured were appropriately grown in twin fetuses, with the exception of the heart, which was significantly smaller (P= 0.04; Mann-Whitney U test, Table 1) and kidneys, which tended to be larger, relative to singletons (P= 0.07; Table 1).
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Maternal.
Values for maternal pH (7.48 ± 0.01), arterial PCO2 and PO2 (PaCO2 and PaO2; 35.5 ± 1.1 mmHg and 106 ± 5 mmHg, respectively),%SatHb (92 ± 2%), acid/base excess (ABE; 4.0 ± 0.9 mequiv l–1), arterial [Hb] ([Hb]a; 8.0 ± 0.5 g dl–1), arterial plasma [glucose] (2.69 ± 0.07 mmol l–1) and arterial plasma [lactate] (0.30 ± 0.06 mmol l–1) were not different during the baseline period in ewes bearing single or twin fetuses. During acute hypoxaemia maternal blood oxygenation status fell to similar levels in both groups of ewes (PaO2 to 
41 ± 2 mmHg and SatHb to 62 ± 4%), while [Hb]a increased to 9.4 ± 0.5 g dl–1. During recovery, all maternal variables returned to basal values.
Fetal. Baseline blood values for gases, acid/base status and hind limb metabolic data were similar in singleton and twin fetuses (Table 2). The changes in blood chemistry after induction of acute hypoxaemia were similar between singleton and twin fetuses with respect to all measured variables. Acute hypoxaemia induced significant falls in pHa, PaO2, %SatHb, ABE, CaO2, O2del, Gludel and significant increases in [Hb]a, blood glucose and lactate concentrations (Table 2). During hypoxaemia, arterial PCO2 remained unchanged from baseline levels in both groups of fetuses. At 45 min into the recovery period after hypoxaemia, all fetuses retained a mild metabolic acidosis and reduction in blood oxygen content (Table 2).
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Acute hypoxaemia. Baseline values (mean of N15 plus N45) for ACTH (39.0 ± 4.7 versus 30.7 ± 2.6 pg ml–1; Fig. 1A) were similar, but for cortisol (17.2 ± 1.4 versus 26.9 ± 3.3 pg ml–1) were significantly reduced in twins relative to singletons (Fig. 1A and B). Acute hypoxaemia provoked a significant increase in the fetal plasma concentration of ACTH in both groups of fetuses but the increment in cortisol was significantly blunted in twin, relative to singleton, fetuses (Fig. 1C). At 45 min into the recovery period values for ACTH and cortisol remained high in both groups of fetuses, although plasma cortisol remained at a lower level in twins with respect to the plasma concentration in singletons (Fig. 1A and B).
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Cardiovascular responses to acute hypoxaemia. During normoxic (baseline) conditions mean arterial blood pressure and femoral blood flow were significantly lower in twin, relative to singleton, fetuses reflecting the smaller size of twin fetuses in the current study (Fig. 2A and D). However, heart rate (Fig. 2B), the rate pressure product (Fig. 2C) and femoral vascular resistance (Fig. 2E) were all similar in the two groups of fetuses. In response to acute hypoxaemia, all fetuses demonstrated well-described increases in arterial blood pressure and femoral vascular resistance and decreases in heart rate and femoral blood flow (Fig. 2). The magnitudes of the change in each of these variables were similar in the two groups of fetuses. However, during hypoxaemia, the rate pressure product tended to increase in singleton fetuses (AUC, 31 ± 15 units) but decrease in twin fetuses (AUC, –28 ± 22 units, Fig. 2C). Consequently, over the 60 min duration of hypoxaemia, the average AUC values for the rate pressure product were significantly different (P= 0.04). During the recovery period, fetuses from both groups demonstrated similar time trends for each measured variable; the hypertension persisted and tachycardia developed producing a significant increase in the rate pressure product. In contrast, femoral blood flow and femoral vascular resistance returned towards baseline levels (Fig. 2). In twins, but not singletons, there was a significant relationship between arterial blood pressure and cortisol (P= 0.001, r2= 0.31).
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Discussion |
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The fetus is able to successfully accommodate mild to moderate chronic adverse intrauterine conditions with appropriate alterations to endocrine and metabolic status and changes in growth rate (Robinson et al. 1979; Mellor & Matheson, 1979; Robinson et al. 1980; Bocking et al. 1988; Gagnon et al. 1994; Gardner et al. 2001a). However, such chronic adaptation does influence the fetal response to a subsequent superimposed challenge (Robinson et al. 1983a; Block et al. 1984), the nature of which is heavily dependent upon the prior intrauterine experience and prevailing metabolic status of the fetus, i.e. the presence or absence of pre-existing hypoxaemia or hypoglycaemia or acidaemia (Gardner et al. 2002a).
In the present study the group of twin fetuses were not overtly compromised by the effects of intrauterine crowding, i.e. they showed normal blood gas and metabolic status. The cardiovascular and endocrine responses to the controlled and well-documented challenge of acute hypoxaemia could therefore be ascribed to the effect of twinning per se rather than any prevailing adverse intrauterine conditions. In support of previous observations (Edwards & McMillen, 2002a) this study has confirmed reduced basal adrenocortical function in twins and further shows that the effect persists in response to acute stress. This is an interesting observation given that intrauterine compromise generally results in an up-regulation of adrenocortical function, i.e. disproportionately increased basal and stimulated fetal plasma cortisol relative to ACTH concentration (Robinson et al. 1980; Gagnon et al. 1994; Murotsuki et al. 1996; Gardner et al. 2001b). The present data are therefore unique in that they show the developmental maturation of adrenocortical responsiveness to be either delayed and/or blunted as fetal number increases. Relatively delayed HPA axis development implies a ‘normal’ physiological response to a specific condition, i.e. twinning, where each twin may benefit from maximizing time in the womb. Adrenocortical blunting implies a permanent suppression of function in each twin, perhaps in response to specific environmental cues, e.g. reduced substrate availability. Nevertheless resetting of the fetal pituitary–adrenal axis, to down-regulate adrenocortical function during basal and stressful conditions, may illustrate an endocrine strategy specific to multiple pregnancies, to maintain pregnancy and delay parturition, thereby maximizing neonatal viability. The potential for such adrenocortical blunting in twins to be retained postnatally cannot be assumed from the current study but is of interest given the importance of the HPA axis in adult onset disease (Fowden et al. 1998a).
Mechanistically, and based upon previous investigations in twin fetal sheep (Schwartz & Rose, 1998; Block et al. 1999) and in singleton fetal sheep in the present laboratory (Gardner et al. 2001b, 2002a), the most likely candidate to explain the differential development of pituitary–adrenal function in singleton and twin fetal sheep is reduced adrenocortical steroidogenic capacity, rather than a decrease in the activity or concentration of an ACTH-independent steroidogenic factor, such as prostaglandin E2 in twins for example (Young et al. 1996). To address this possibility, an exogenous ACTH test was carried out which confirmed that adrenocortical responsiveness to ACTH was diminished, supporting the thesis that steroidogenic capacity is reduced in twin relative to singleton fetuses. While the gross adrenal weights were similar in the present study, this offers no indication as to the area within the adrenal gland occupied by the zona fasiculata, the predominant fetal adrenocortical zone (Webb, 1980; Robinson et al. 1983b). Preliminary data from our laboratory in a separate group of twin fetuses to those studied here suggest that twin fetuses have a greater adrenomedullary area, despite similar total adrenal area, suggesting reduced adrenocortical mass (Gardner et al. 2003).
In the one other study to have determined basal cardiovascular indices of singleton and twin fetuses, the arterial blood pressure and rate pressure product were found to be similar between the two groups (Edwards & McMillen, 2002b). In contrast, the present study shows lower basal arterial blood pressure and femoral perfusion in twin relative to singleton fetuses. The twin fetuses in the former study of Edwards & McMillen (2002b) were only 8% smaller than would be expected of their equivalent-aged singleton counterparts, compared to the 22% difference observed in the current study. This supports the notion that fetal blood pressure is body mass dependent and ‘tracks’ fetal growth. It is interesting to note that the relative weights of the hearts in twin fetuses were smaller than you would expect for body size alone but the rate pressure product, an index of cardiac work (Hoeft et al. 1991), during acute hypoxaemic stress was lower. The reduction in the rate pressure product during acute hypoxaemia in twin relative to singleton fetuses is consequent to lower values for blood pressure and heart rate during acute hypoxaemia in twin fetuses. This suggests that despite a relatively greater body mass to support, cardiac work was maintained at a moderate level in twin fetuses. This may reflect another adaptation in the physiology of the twin fetus to optimize its perinatal outcome.
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References |
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Acknowledgements |
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Author's present address
D. S. Gardner: Centre for Reproduction and Early Life, Institute for Clinical Research, University Hospital, Nottingham NG7 2UH, UK.
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[cortisol] (ng ml–1) during acute hypoxaemia. D, fetal plasma cortisol response to a 2.5 µg bolus dose of exogenous ACTH (Synacthen). Data are expressed as the change from mean baseline (combined values at –15 and –5 min) and at 5, 15 and 30 min after the synthetic ACTH bolus (time zero indicated by arrow). Statistical differences are: *P < 0.05 hypoxaemia or recovery compared to baseline; 
P < 0.05 singletons versus twins.
