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Journal of Physiology (2001), 535.3, pp. 879-888
© Copyright 2001 The Physiological Society
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ABSTRACT |
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FHR: control, 34.6 ± 3.6 beats min-1; occlusion, 36.9 ± 2.7 beats min-1) and MAP increased (MAP: control, 3.1 ± 1.7 mmHg; occlusion, 5.2 ± 2.1 mmHg) to a similar extent in control and occlusion groups between days 1 and 21 of the study. There was a small decline in FHR variation over the 21 day study in occlusion, but not control, group fetuses.
FHR to MAP on days 9 and 18 compared to day 1, there was no difference between control and occlusion groups in baroreflex sensitivity. However FHR/PO2, an index of chemoreceptor sensitivity, had decreased by day 9 and 18 compared to day 1.
FHR/MAP, which does not involve changes in baroreflex sensitivity, but may involve changes in chemoreceptor sensitivity. However, repeated umbilical cord occlusion appears to have no impact on baseline cardiovascular control since there was no change in the normal maturational decrease in FHR and rise in MAP.
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INTRODUCTION |
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Large variable-type fetal heart rate (FHR) decelerations (V- or U-shaped dips in FHR) are observed in ~5 % of FHR monitoring traces made in humans near term (Dawes et al. 1993). The decelerations are associated with an increased risk of low Apgar scores (assessment of an infant's condition based on evaluation of heart rate, respiration, muscle tone, response to a pharyngeal catheter and colour of trunk) and neonatal acidosis, and are likely to be attributable to umbilical cord complications arising from uterine contractions (Dawes et al. 1993), oligohydramnios (Gabbe et al. 1976) or nuchal cords (umbilical cord around the neck ) (Anyaegbunam et al. 1986; Dawes et al. 1993). Nuchal cords are present in ~25 % of pregnancies at the time of delivery, have been detected as early as 20 weeks of gestation and can persist after diagnosis until delivery (Collins, 1995). Recently, we observed that babies born with a nuchal cord are smaller relative to the size of the placenta (Osak et al. 1997). This could be due to chronic or intermittent interruption of umbilical blood flow and oxygen/nutrient delivery to the fetus, and could be mediated either by a direct action at the tissue level, via endocrine/growth hormones, or indirectly via a redistribution of blood flow in favour of vital organs.
The cardiovascular responses of the late gestation ovine fetus to sustained hypoxaemia have been well characterized and include a rapid initial fall in FHR and a variable rise in mean arterial pressure (MAP) and subsequent sustained tachycardia (Rurak et al. 1990 Bocking et al. 1992). Furthermore, repeated embolization of the fetal side of the ovine placental circulation over 21 days decreased fetal arterial oxygen content by 40-50 % and increased arterial blood pressure (Murotsuki et al. 1997). Umbilical cord occlusion produces a fall in FHR by chemoreflex and baroreflex mechanisms, a fall in peripheral blood flow and a rise in MAP (Itskovitz et al. 1983; Giussani et al. 1997; Green et al. 1999). Dependent upon the severity and frequency of insult, repetitive umbilical cord occlusion over a period of hours modifies the FHR and peripheral vascular resistance response to subsequent insults (Lewis et al. 1984; Giussani et al. 1997; Westgate et al. 1999). Moreover, increased frequency of uterine contractures (long-lasting, low-amplitude epochs of myometrial activity) during late gestation accelerates the normal maturational changes in FHR and MAP (Shinozuka et al. 2000). Recently we have demonstrated that repeated umbilical cord occlusion over a period of 4 days in the preterm ovine fetus alters the FHR response to subsequent stress, possibly via altered chemoreflex mechanisms (Green et al. 1999) although the contribution of altered baroreflex mechanisms was not assessed. Disruption of these reflex mechanisms could have important consequences for later cardiovascular function, e.g. during birth or postnatally (Hanson, 1988). We hypothesized that repeated umbilical cord occlusion over several weeks in the latter part of gestation would alter fetal cardiovascular control and development, mediated in part by altered chemo- and baroreceptor mechanisms.
The aim of this study was to examine the effect of repeated umbilical cord occlusion in the latter part of gestation on fetal cardiovascular development and control. We have used a model of umbilical cord occlusion to produce intermittent reversible hypoxic insults, without fetal acidosis and therefore avoiding fetal demise. Our objectives were to determine the effect of this repeated insult over a 21 day period on the normal maturation of FHR, MAP and the responses to subsequent umbilical cord occlusion, and to assess the contribution of baroreflex mechanisms. In addition we have measured FHR variation, as an index of fetal behavioural state (Richardson, 1994).
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METHODS |
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Surgical preparation
Pregnant mixed Western ewes (6 control group and 9 occlusion group) were instrumented using sterile techniques at 108.6 ± 0.3 days of gestation (term= 147 days) under general anaesthesia (1 g thiopental sodium in solution intravenously (I.V.), for induction (Abbott Laboratories Ltd, Montreal, Canada) followed by 1-1.5 % halothane in O2 for maintenance). A midline incision was made in the lower abdominal wall, and the uterus was palpated to determine the fetal number and position. The fetal head, chest, and proximal portion of the umbilical cord were exteriorized through an incision in the uterine wall. Polyvinyl catheters filled with heparinized saline were placed in the left and right brachial arteries, a brachial vein, and the amniotic cavity. Stainless steel electrodes were sewn onto the fetal chest to monitor electrocardiogram (ECG). An inflatable occluder cuff (OCHD16; In Vivo Metric, Healdsburg, CA, USA) was positioned around the proximal portion of the umbilical cord and secured to the abdominal skin. The volume required for complete occluder cuff inflation was determined at surgery. The uterine and abdominal incisions were closed, and the catheters and electrodes were exteriorized through the maternal flank and secured to the ewe's back in a plastic pouch. A catheter was placed in a maternal femoral vein for administration of fluids and collection of maternal blood for transfusion to the fetus. Ewes received broad-spectrum, long-acting antiobiotic immediately before surgery (1.2 g oxytetracycline, intramuscularly (I.M.); LA-200, Rogar, STB Inc., London, Canada).
Following surgery, ewes were administered analgesic (75 mg flunixin I.M., Schering, Pointe-Claire, Canada) and fluids (500-1000 ml saline I.V.). Fetal and maternal catheters were filled with heparinized saline and were flushed daily to maintain their patency. A 3 day postoperative recovery period was allowed prior to experimentation during which daily antibiotic treatment was given to the fetus (1 million i.u. penicillin G sodium I.V., Novopharm Ltd, Toronto, Canada) and into the amniotic cavity (1 million i.u. penicillin G sodium), and fetal arterial blood was collected for blood gas analysis.
Surgery and experiments were conducted in accordance with Canadian Council on Animal Care regulations.
Experimental procedure
Fetuses were studied on 21 successive days between 113.0 ± 0.2 and 132.9 ± 0.3 days of gestation. Baseline measurements of FHR, arterial pressure and amniotic pressure were made in control and occlusion group fetuses between 9.00 to 10.00 am each day, and between 1.00 and 2.00 pm following the last occlusion on days 1, 9 and 18. In occluded fetuses, umbilical cord occlusions were carried out each day by complete inflation of the occluder cuff (about 3 ml saline) for 90 s every 30 min (Fig. 1). The occlusion regimen was chosen to induce severe but reversible intermittent hypoxic insults to the fetus but without inducing a fetal acidosis over the 21 day study. For the purpose of comparison within the study and with previous observations (Green et al. 1999; Kawagoe et al. 1999a,b) and to facilitate more extensive blood sampling, the protocol on days 1, 9 and 18 was the same and consisted of only seven umbilical cord occlusions. Fetal arterial blood was sampled 5 min before the first and seventh umbilical cord occlusions (4 ml, blood gas, glucose, lactate and hormone analysis), 60 s into the occlusions (approximately the nadir of the FHR response; 1 ml, blood gas, glucose and lactate analysis), and 5 min after the final occlusion (3 ml, blood gas, glucose, lactate and hormone analysis) (Fig. 1). On intervening days 2-4, 7, 8, 10, 11 and 14-17, nine umbilical cord occlusions were carried out and blood sampling (1 ml, blood gas, glucose and lactate analysis) was restricted to the control hour. On the remaining days (days 5, 6, 12, 13, 19 and 20) a blood sample for blood gas analysis (1 ml, blood gas, glucose and lactate analysis) and three occlusions only were performed. Fetal heart rate (triggered off pulse pressure or ECG waveform), arterial pressure and amniotic pressure were recorded continuously during the period of study each day using strain gauge manometers (Statham Model P-23ID; Gould, Oxnard, CA, USA) and a strip-chart recorder (model 78D; Grass, Quincy, MA, USA). Blood pressure measurements were corrected for amniotic pressure. In control fetuses no cord occlusions were carried out, but they were subject to the same blood sampling and cardiovascular monitoring procedure as the experimental group.
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Figure 1. Twenty-one day umbilical cord occlusion protocol Each segment represents 1 h and the shaded region denotes the time period over which 90 s umbilical cord occlusions ( | ||
In addition FHR was monitored as described by Guzman & Vintzileos (1997) during control hours in control and experimental groups. Fetal heart rate signals from ECG leads were acquired by a fetal monitor (Cardiotocograph 8040A, Hewlett-Packard, Boeblingen, Germany) and digitized, and the fetal pulse interval (milliseconds) and autocorrelation function, which discriminate between background noise and a valid FHR signal, were analysed by computer software (System 8000 Rev. 2.15, Oxford Sonicaid Ltd, Oxford, UK). Both long-term and short-term measures of FHR variation were calculated excluding decelerations. Because of technical limitations, the System 8000 calculates the mean length of beat-to-beat intervals over a 3.75 s epoch and then calculates short-term FHR variation as the mean of differences between successive epoch means. Long-term FHR variation is expressed as mean minute range (milliseconds) and is calculated as the average of differences between minimum and maximum pulse intervals in each minute. However, if all pulse intervals are less than baseline FHR, then the range is measured from baseline. When mean minute range (long-term FHR variations) exceeded 32 ms or fell below 30 ms for 5 of 6 consecutive minutes, a period of high or low FHR variation, respectively, was defined. Accelerations are defined as deviations in FHR above the baseline of more than 10 beats min-1 for at least 15 s and decelerations as deviations in FHR below the baseline of more than 20 beats min-1 for at least 30 s.
On days 1, 9 and 18 the volume of fetal blood taken was replaced with an equal volume of maternal venous blood at the end of study each day. Fetal arterial blood samples were stored briefly on ice and then analysed for blood gas composition (ABL 500 and OSM 3, Radiometer, Copenhagen, Denmark), glucose and lactate (2300 Stat Plus, YSI Inc., Yellow Springs, OH, USA), or immediately spun at 4 °C (10 min, 2000 g, Beckman TJ-6, CA, USA), and the plasma decanted and stored at -20 °C for subsequent analysis.
On day 21, following collection of a blood sample for blood gas and hormone analysis, ewes and fetuses were killed by an overdose of barbiturate (30 mg sodium pentobarbital I.V., MTC Pharmaceuticals, Cambridge, ON, Canada) prior to delivery of the fetus. At this time the location and function of the umbilical occluder cuff was confirmed.
Baroreflex responses
At the end of days 1 and 18, 75-100 µg boluses of phenylephrine (phenylephrine hydrochloride, 10 mg ml-1, Sabex Inc., Boucherville, Quebec, Canada) were administered I.V. to fetuses in 2 ml saline and flushed in with saline. Chart speed was adjusted to 25 mm s-1 prior to phenylephrine administration and arterial pressure and ECG waveform was recorded continuously until ca 1 min post-drug administration.
Data analysis
Baseline cardiovascular chart recordings were made at 10 mm min-1 but chart speed was adjusted to 50 mm min-1 during umbilical cord occlusions to allow the profile of the responses to be accurately recorded. Baseline MAP and FHR measurements are reported (Fig. 2) as a single summary measurement composed of five 30 s interval measurements made every 15 min during the initial control hour. In the occlusion group, the 1st and 7th occlusions on days 1, 9 and 18 were focused on for analysis. Fetal heart rate and MAP were measured 5 min before occlusion onset (at five consecutive 30 s time points), every 5 s for the duration of the 90 s occlusion, and 5 min post-occlusion (at five consecutive 30 s time points).
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Figure 2. Ontogeny of mean arterial pressure and fetal heart rate Mean (± S.E.M.) values of mean arterial pressure (MAP, upper panel) and fetal heart rate (FHR, lower panel) during 1 h control periods on days 1, 4, 9, 14, 18 and 21 of study in control ( | ||
Baroreflex curves were created by plotting R-R intervals from adjacent QRS complexes of the ECG waveform against the corresponding systolic pressure measured at 2-10 s intervals following administration of the phenylephrine dose. Baroreflex sensitivity in individual fetuses was measured as the slope of the linear portion of these curves (s mmHg-1). The start of the linear portion was defined as the R-R interval preceding the R-R interval which showed the first increase, and the end of the linear portion was defined as the R-R interval preceding the R-R interval which showed no further increase (Ismay et al. 1979).
Data are expressed as means ± S.E.M. Two-way analysis of variance (ANOVA) followed by a post-hoc Student's t test with Bonferroni correction was used to compare between groups and over time. Statistical significance was accepted when P < 0.05.
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RESULTS |
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Fetal arterial blood measurements
Changes in fetal arterial PO2, PCO2, pH, glucose and lactate have been reported elsewhere (Czikk et al. 2000). Briefly, and for the purpose of characterizing the insult used in the current study, 90 s umbilical cord occlusion resulted in a fall in fetal arterial partial pressure of oxygen (Pa,O2) (26.7 ± 0.4 to 7.9 ± 0.4 mmHg, P < 0.01), pH (7.37 ± 0.01 to 7.32 ± 0.01, P < 0.01) and glucose (0.92 ± 0.06 to 0.63 ± 0.04 mM, P < 0.01), and a rise in PCO2 (50.4 ± 0.5 to 58.7 ± 0.9 mmHg, P < 0.01) to a similar extent on days 1, 9 and 18. Individual umbilical cord occlusions produced a variable rise (~1.5-fold) in blood lactate and a cumulative rise over successive daily occlusions to a greater extent on days 9 and 18 than on day 1.
In addition, umbilical cord occlusion produced a marked fall in saturation of haemoglobin with oxygen (Sa,O2; from 69.2 ± 1.2 to 10.2 ± 1.0 %, P < 0.01), blood oxygen content (from 4.3 ± 0.1 to 0.6 ± 0.1 mM, P < 0.01) and a slight, but significant, fall in blood haemoglobin (from 10.9 ± 0.2 to 10.7 ± 0.2 g dl-1, P < 0.05), but with no change in haematocrit. Baseline Sa,O2 declined over the study period in control (day 1 vs. day 18: 70.1 ± 3.0 vs. 60.1 ± 2.2 %, P < 0.05) and occlusion (day 1: 76.8 ± 1.4 % vs. day 9: 68.0 ± 2.7 %, P < 0.01 and vs. day 18: 62.5 ± 2.6 %, P < 0.01) groups, but with no change in O2 content (control day 1: 4.2 ± 0.3 mM; occlusion day 1: 4.4 ± 0.2 mM). In occlusion, but not control, group fetuses this change in Sa,O2 was coupled to a rise in haemoglobin (day 1: 9.7 ± 0.4 g dl-1 vs. day 9: 11.5 ± 0.5 g dl-1, P < 0.05 and vs. day 18: 11.8 ± 0.6 g dl-1, P < 0.05), with no change in haematocrit (control day 1: 33.0 ± 1.8 %; occlusion day 1: 32.3 ± 1.5 %).
Blood pressure and heart rate
Daily baseline measurements of FHR declined over the 21 day study in control and occlusion groups, so that FHR was significantly reduced compared to day 1 FHR by day 14 (Fig. 2). On days 14 and 18, daily baseline MAP measurements were significantly elevated compared to day 1 in occlusion, but not control, group fetuses (Fig. 2). There was no difference between control and occlusion groups in baseline FHR or MAP measurements over the 21 day study.
On days 1, 9 and 18, MAP increased and FHR and decreased over the course of 90 s umbilical cord occlusion (Fig. 3; 1st and 7th occlusions). On day 1, but not thereafter, the time to reach the nadir of the FHR response was significantly greater during the last occlusion of the day (7th occlusion) compared to the 1st occlusion (52.2 ± 3.7 vs. 41.7 ± 2.9 s, P < 0.05). In addition, the overall time to reach the FHR nadir (1st and 7th occlusions combined) was greater on days 9 (62.8 ± 3.3 s, P < 0.01) and 18 (59.4 ± 4.3 s, P < 0.05) compared to day 1 (46.9 ± 2.7 s). MAP returned towards baseline 5 min after the release of the occluder cuff. Throughout the study, a pronounced bradycardia was still in evidence 5 min after the 1st daily occlusion, but following successive daily occlusions (by the 7th occlusion) a post-occlusion rebound tachycardia had developed (Fig. 3).
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Figure 3. Profile of mean arterial and fetal heart rate responses to umbilical cord occlusion Values are means ± S.E.M., n = 9 fetuses. Measurements of mean arterial and fetal heart rate responses at 5 s intervals for the 1st and 7th 90 s umbilical cord occlusion ( | ||
There was no change in the magnitude of the FHR or MAP response to umbilical cord occlusion over the course of successive occlusions each day (i.e. 1st occlusion vs. 7th occlusion; see Fig. 3). However, the overall (1st and 7th occlusions together) magnitude of the change in FHR, assessed at the nadir of the FHR response, in response to umbilical cord occlusion was significantly reduced by day 9 compared to day 1 of study, and remained lower when determined again on day 18 (Fig. 4). Furthermore, the overall magnitude of the change in MAP in response to umbilical cord occlusion, measured at the nadir of the FHR response, was significantly elevated on days 9 and 18 compared to day 1 (Fig. 4).
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Figure 4. Magnitude of the mean arterial pressure (MAP) and fetal heart rate (FHR) responses to umbilical cord occlusion Values are means ± S.E.M. The FHR response was reduced and the MAP response was enhanced by day 9 and 18 of study. n = 9 fetuses. **P < 0.01, significantly different from day 1. | ||
The ratio of the magnitude of the change in FHR to magnitude of the change in MAP in response to umbilical cord occlusion was lower on day 9 and 18 compared to day 1 (Fig. 5, P < 0.05). This relationship was suggestive of attenuated baroreflex mechanisms. However, when we examined this relationship further by assessment of the baroreflex responses, there was no difference between day 1 and day 18, or between control and occluded groups, in baroreflex sensitivity (Fig. 6). The FHR response to umbilical cord occlusion when expressed in terms of the fall in arterial PO2 (Fig. 5) or the time to reach the nadir of the response (day 1: 3.1 ± 0.3 beats min-1 s-1; vs. day 9: 1.9 ± 0.2 beats min-1 s-1, P < 0.01; vs. day 18: 1.8 ± 0.2 beats min-1 s-1, P < 0.01) was significantly reduced on days 9 and 18 compared to day 1.
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Figure 5. The ratio of the change in fetal heart rate (FHR) to the change in mean arterial pressure (MAP) and arterial PO2 Values are means ± S.E.M. For a given change in Pa,O2 or MAP the size of the change in FHR was significantly less on days 9 and 19 than on day 1. n = 9 fetuses. *P < 0.05 and **P < 0.01, significantly different from day 1. | ||
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Figure 6. Baroreflex curves following repetitive umbilical cord occlusion Values are means ± S.E.M. A, control group (upper panel, n = 5 fetuses), B, occlusion group (lower panel, n = 6 fetuses). There was no difference in baroreflex sensitivity, as determined from the slope of the linear portion of the curve, between day 1 and 18 in control or occluded fetuses. | ||
Fetal heart rate variation
There was no difference in the number of baseline FHR accelerations or decelerations between control and occluded groups, or over the course of the study period (Table 1). Baseline episodes of high FHR variation were lower on day 1 in the occluded group than in the control group. Episodes of high FHR variation were more numerous on days 9 and 18 compared to day 1 in occluded, but not control, fetuses. There was no change in episodes of low FHR variation. There was a small but significant increase in long-term variation by day 18 compared to day 1 in occluded, but not control, fetuses and no change in short term FHR variation.
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DISCUSSION |
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We have used a model of intermittent umbilical cord occlusion to induce acute severe but reversible hypoxaemia, without development of a cumulative acidosis. Previously we established that repeated hypoxaemia attenuates the FHR and metabolic responses over a period of days (Green et al. 1999). In the present study we have demonstrated that the attenuation of FHR response to repeated hypoxaemia persists when the study period is extended to 3 weeks in the latter part of gestation, and is coupled to an enhanced MAP response. The possible mechanisms contributing to the altered cardiovascular control over the 3 week study are discussed.
Blood pressure and heart rate development
In the present study, repetitive umbilical cord occlusion over 3 weeks appears to have no effect on baseline cardiovascular control since there was no difference between control and occlusion groups in the normal maturational decrease in FHR and rise in MAP. These findings concur with, and extend those of, our previous study in which the same cardiovascular variables were recorded over a period of time equivalent to the first 4 days of the current study (Green et al. 1999). Other studies in the ovine fetus using more moderate continuous (PO2 to ~19 mmHg; Kitanaka et al. 1989) or daily 1 h (PO2 to ~13 mmHg; Steyn & Hanson, 1998) hypoxaemic challenges, by alteration of maternal inspired gases, for 2-3 weeks from ~110 days of gestation have also shown that MAP and FHR developmental trajectories are unaltered. In contrast, Shinozuka et al. (2000) have recently observed that an increased frequency of myometrial contractures in ewes, induced by pulsed oxytocin administration, over the last 50 days of gestation results in higher fetal arterial blood pressure and lower FHR, possibly mediated by fetal hypoxia or stimulation of endocrine axes such as the hypothalamic-pituitary-adrenal (HPA) axis. Embolization of the fetal side of the placenta in sheep produces a rise in fetal MAP when carried out repeatedly over 21, but not 8-10, days in the latter half of gestation (Block et al. 1989; Gagnon et al. 1994). Aside from obvious differences between these studies in experimental technique, it is interesting that altered baseline MAP in the embolization studies was coupled to a decrease in fetal arterial oxygen content by 40-50 % from the beginning to the end of the study whereas in the present study, and that of Steyn & Hanson (1998), arterial oxygenation was maintained.
We have found no difference between control and experimental fetuses in the maturational changes in blood pressure and heart rate during fetal life. The placenta receives ~40 % of the fetal combined ventricular output (Rudolph & Heymann, 1970) and therefore must determine to a large degree fetal arterial blood pressure (Hanson, 1993). From the present study we cannot rule out the possibility that cardiovascular control, e.g. heart structure, and fetal or placental vascular structure were altered by repetitive interruption of blood flow from the placenta. Differences between control and experimental fetuses in blood pressure and heart rate might only become apparent postnatally when the placental contribution to fetal blood pressure has been removed (see Hanson, 1993).
Fetal heart rate variation
Indices of FHR variation in the present study are comparable to those of our previous study (Green et al. 1999) and to values that are considered normal for the human fetus (Dawes et al. 1992). We have found a significant increase in baseline long-term FHR variation and episodes of high FHR variation in occluded fetuses over the 3 week study period. Episodes of high FHR variation were lower in occluded group fetuses on day 1, before any occlusions had been carried out. We did not measure behavioural state in these fetuses and therefore we were not able to control for the influence of state on FHR variation measurements, since high-voltage electrocortical activity is associated with a decline in FHR variation (Dalton et al. 1977). While electrocorticogram patterns are not well defined at this age the influence of fetal breathing movements and body movements cannot be ruled out (Dawes et al. 1981). However, we have previously shown in near-term ovine fetuses exposed to a 4 day occlusion regimen (Kawagoe et al. 1999b) that during non-occlusion hours the time spent in low-voltage electrocorticogram activity and electrocular activity were similar in occluded and control fetuses. Clinically, FHR variation indices are positively correlated to blood pH (see Guzman & Vintzileous, 1997). During sustained fetal hypoxaemia in sheep, achieved by alteration of maternal inspired gases or reduced uterine blood flow (Bocking et al. 1989), there is an initial increase in FHR variation (Parer et al. 1980). However, in the current study, fetal oxygenation was well maintained and we found no cumulative change in arterial pH over the 21 days to explain an increased long-term or high FHR variation. Other possible mechanisms include changes in circulating plasma hormones, such as catecholamines.
Cardiovascular responses to umbilical cord occlusion
On the first day of study (~113 days of gestation) we observed a similar magnitude of change in FHR and MAP as in our previous 4 day study. Umbilical cord occlusion can trigger fetal cardiovascular responses by two mechanisms: first, by separation of the placental vascular bed from the fetal systemic circulation and subsequent increase in peripheral vascular resistance, and second, by impaired placental gas exchange and subsequent transient hypoxic insults to the fetus. A redistribution of blood flow in favour of vital organs such as the brain and at the expense of the periphery has been characterized in response to umbilical cord occlusion in the sheep fetus (Richardson et al. 1996; Giussani et al. 1997). A rise in peripheral vascular resistance is likely to contribute to the rise in MAP observed during each umbilical cord occlusion in the present study. In the absence of umbilical blood flow measurements, insults were standardized over the course of the 21 day study by carrying out maximal inflation of the occluder cuff for each occlusion. Furthermore, changes in arterial oxygenation in response to occlusion were similar when measured on days 1, 9 and 18. The intense bradycardia observed in the current study, and other rapid cardiovascular responses such as the peripheral vasoconstriction observed by others (Giussani et al. 1997), induced by cord occlusion is likely to be mediated via a combination of chemoreceptor and baroreceptor stimulation, as well as via a stimulation of cardiac mechanoreceptors following a decrease in venous return to the fetal heart (Siassi et al. 1979; Itskovitz et al. 1983). In addition, umbilical cord occlusion stimulates a number of hormone responses, including production of adenosine (Kubonoya & Power, 1997), ACTH/cortisol (Unno et al. 1997; Green et al. 2000), catecholamines (Lewis et al. 1984) and endothelin-1 (Takada et al. 1996), which are implicated in fetal cardiovascular control.
We observed no change in the magnitude of the FHR or MAP responses over the course of the seven consecutive cord occlusions carried out on days 1, 9 and 18, with blood gases and cardiovascular parameters returning to baseline levels between each occlusion. In contrast, in previous sheep studies using a much more intense regimen of occlusions (60 s occlusion every 2.5 min), a progressive hypotension during occlusions and a severe progressive acidaemia (Westgate et al. 1999) was produced. In common with the study of Westgate et al. (1999) we have observed the appearance of an 'overshoot' or rebound in FHR immediately following the cessation of the last occlusion which was measured throughout the 21 day study. This rebound in FHR could reflect the withdrawal of the powerful vagally mediated bradycardic mechanisms combined with the direct action of circulating catecholamines (sympathetic overflow or from the adrenal medulla) on the heart. Indeed a reproducible rise in circulating catecholamines is sustained over the course of successive umbilical cord occlusion in the late gestation sheep fetus (Lewis et al. 1984). Thus it is possible that the emergence of a rebound tachycardia by the 7th daily occlusion is due to sympathetic activation or an accumulation of circulating catecholamines.
Over the 21 day study period, the magnitude of the fetal bradycardia decreased and the hypertension and increased with repetitive daily umbilical cord occlusion, despite the fact that changes in arterial oxygenation in response to cord occlusion remained constant over the course of the study. In our previous study there was no change in the size of the MAP response over a 4 day period equivalent in gestation to the first 4 days of the present study (Green et al. 1999). The augmentation of the MAP response observed by day 9 could reflect maturation or activation of the sympathetic nervous system, or hormone systems such as the HPA axis and the renin-angiotensin system that are involved in the redistribution of blood flow. Indeed, we have reported previously that the cortisol response to umbilical cord occlusion in these fetuses is augmented following 18 days of repetitive occlusion, but with an attenuated ACTH response (Kawagoe et al. 1999a). The FHR response to umbilical cord occlusion was attenuated by day 2 of our previous study (Green et al. 1999), and this was maintained for the duration of the current 21 day study. When FHR was expressed relative to the change in arterial oxygenation, to give an index of chemoreceptor sensitivity (Baan et al. 1993), or relative to the time taken to reach the nadir of the FHR response (i.e. rate of change in FHR), our results suggest once more that the chemoreflex function has been altered, since the response was less on days 9 and 18 than on day 1. The absence of a suitable means of specific carotid body stimulation in vivo means that it was beyond the scope of the current study to pursue this finding further. Alteration of chemoreflex function could be at the level of the chemoreceptors, the brainstem or the efferent limb of the reflex arc. It is noteworthy that the reduced FHR response occurred in the face of an increased MAP response by days 9 and 18, suggesting the contribution of altered baroreflex mechanisms. However, we found no difference between control and occlusion group fetuses in baroreflex sensitivity, as assessed by measuring the change in R-R interval in response to a change in blood pressure-induced 
-adrenergic receptor antagonism. It remains possible that endocrine mechanisms such as adenosine (Kubonoya & Power, 1997), or altered mechanoreflex mechanisms could have contributed to the altered FHR response.
In conclusion, 3 weeks of intermittent umbilical cord occlusion in the latter part of gestation appears to have little influence on the normal maturational changes in FHR or MAP but resulted in a maintained attenuation of FHR response and augmented the MAP response to individual occlusions. The decrease in the ratio of magnitude of the change in FHR to the magnitude of the change in MAP does not appear to involve changes in baroreflex sensitivity, but may involve altered chemoreflex sensitivity. The effect of such alterations in fetal cardiovascular control on postnatal blood pressure, at rest or in response to stress, is not known but is of interest in the light of increasing evidence for fetal origins of postnatal cardiovascular health (Godfrey & Barker, 2000).
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REFERENCES |
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Acknowledgements
This work was supported by grants from the Medical Research Council of Canada. L.R.G. and Y.K. were funded by Postdoctoral Fellowships from the Medical Research Council of Canada and The Lawson Research Institute. B.S.R. is a member of the Medical Research Council Group in Fetal and Neonatal Health and Development and is the recipient of the Wyeth-Ayerst Canada Inc. Clinical research Chair in Women's Health for Perinatology.
Corresponding author
L. R. Green: The Centre for Fetal Origins of Adult Disease, University of Southampton, 887 F Princess Anne Hospital, Coxford Road, Southampton, SO16 5YA, UK.
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) were carried out every 30 min. The arrows denote the times at which blood was sampled for blood gas analysis only (open arrows, 1 ml) or blood gas and hormone analysis (filled arrows, 3-4 ml). Cardiovascular variables were monitored continuously. No umbilical cord occlusions were carried out in control group fetuses but the same blood sampling and monitoring regimen was followed.
, n = 6 fetuses) and occlusion (
, n = 9 fetuses) groups. *P < 0.05, **P < 0.01, significantly different from day 1.
) on days 1 (
), 9 (
) and 18 (
). There was a rise in MAP and fall in FHR over the course of the 90 s occlusion and these data are summarized in Fig. 4 for the purposes of statistical analysis. Of note is the rebound in FHR as measured 5 min after the 7th occlusion, but not the 1st occlusion, on all days of study.