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Fetal heart rate response to sustained recreational exercise
Tekay and Jouppila
the uteroplacental circulation in early pregnancy. Obstet Gynecol 1991;77:365-9. 15. Campbell S, Pearce jMF, Hackett G, Cohen-Overbeek T, Hernandez C. Qualitative assessment of uteroplacental blood flow: early screening test for high-risk pregnancies. Obstet Gynecol 1986;68:649-53. 16. Anderson WR, Davis J. Placental site involution. AM j OBSTET GYNECOL 1968;102:23-33. 17. Monheit AG, Cousins L, Resnik R. The puerperium:
January 1993 Am J Obstet Gynecol
anatomic and physiologic readjustments. Clin Obstet Gynecol 1980;23:973-83. 18. Fuchs A-R. Endocrinology of lactation. In: Fuchs F, K1opper A, eds. Endocrinology of pregnancy. 3rd ed. Philadelphia: Harper & Row, 1983:271-87. 19. Hertzberg Bj, Bowie jD. Ultrasound of the postpartum uterus: prediction of retained placental tissue. j Ultrasound Med 1991;10:451-6.
Fetal heart rate response to sustained recreational exercise James F. Clapp III, MD: Kathleen D. Little, PhD: and Eleanor L. Capeless, MDb
Cleveland, Ohio, and Burlington, Vermont OBJECTIVE: We aimed to test the hypotheses that fetal heart rate increases during and after sustained exercise and that the magnitude of the increase is related to gestational age and the duration, intensity, and type of exercise. STUDY DESIGN: Maternal oxygen uptake and fetal heart rate were monitored in 120 regularly exerCising women in association with routine 20-minute workouts between 16 and 39 weeks' gestation. RESULTS: In 97% of the studies fetal heart rate increased during and after exercise. This was significant at all gestational ages and with all forms of exercise with an overall increase of 15 ± 11 beats· min -, at 60% ± 12% of maximal aerobic capacity (mean ± SO). The magnitude increased with gestational age (10 ± 8 to 20 ± 11 beats' min-'), exercise intensity (8 ± 7 to 21 ± 13 beats· min-'), and exercise duration (8 ± 4 to 16 ± 7 beats· min-'). CONCLUSION: We concluded that the hypothesis is correct and speculate that these changes represent a maturing fetal response to a reduction in P02 • (AM J OBSTET GVNECOL 1993;168:198-206.)
Key words: Pregnancy, sustained exercise, fetal heart rate In recent years the fetal heart rate (FHR) response to maternal exercise has been examined by more than 20 investigators with mixed results. ' -' A number of investigators have noted that FHR is increased by 5 to 20 minutes of various types of exercise at work rates up to 75% of maximum capacity whereas others have noted no change after similar types of exercise. Three studies have reported profound decreases in the FHR during low-intensity exercise, but it is likely that the majority of these findings really represented foot strike or pedal
From the Departments of Reprodudive Biology and Obstetrics and Gynecology, MetroHealth Medical Center and Case Western Reserve School of Mediczne: and The Umversity of Vermont College of Medicine. b Supported in part by NatIOnal Institutes of Health grant HD21268 and funds from MetroHealth Medical Center. ReceIVed for publicatIOn October 8, 1991; reVISed April 13, 1992; accepted May 21, 1992. Reprint requests: James F. Clapp III, MD, Department of Obstetrics and Gynecology, MetroHealth Medical Center, 2500 MetroHealth Dr., Cleveland, OH 44109-1998. 6/1/39538
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artifact. 5 However, postexercise fetal bradycardia has been observed in pregnancies complicated by hypertension and growth retardation' and one recent study reported a 16% incidence of ultrasonography-confirmed, transient fetal bradycardia during or immediately after short periods of cycle ergometry when it was performed at maximal or near-maximal capacity by untrained women. 6 The diversity of these findings suggests that multiple confounding variables are influencing the fetal response, which makes it difficult to understand the mechanisms involved. Accordingly, the current study was designed to control for likely confounding maternal, fetal, and exercise variables. Maternal variables included position at the time the measurements were obtained, fitness level, and exercise habits. Fetal variables included a clinically normal singleton pregnancy, normal growth, unengaged presentation, fetal quiescence, and gestational age at the time the measurements were obtained. Exercise variables included exercise type, intensity, and duration. 0002-9378/93 $1.00
+ 0.20
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The study was designed to test two hypotheses. The first hypothesis states that the FHR increases during and after sustained exercise. The second hypothesis states that the magnitude of the increase is related to gestational age and the duration, intensity, and type of exercise. These were based on the physiologic supposition that exercise in the human is associated with a reduction in placental blood flow 7 • 8 and the observations that the duration and intensity of the stimulus and the degree of maturation of the fetal autonomic nervous system alter the magnitude of the FHR response to a variety of stimuli. 9 . 13 Material and methods
Mter informed consent was obtained in accord with institutional guidelines, 120 healthy, physically active women with accurately dated, clinically normal, singleton pregnancies were enrolled. Sixty-seven percent were primigravid, 30% were secundigravid, and 3% were experiencing their third or fourth pregnancy. Although overall exercise performance varied widely between subjects, all met our minimal standard for a "recreational" athlete. This standard required that the subject had been performing a sustained type of exercise regularly (three or more sessions each week and a minimum of 20 minutes per session) for at least 6 months before conception at an intensity in excess of 50% of maximal capacity. This assessment of overall exercise performance was routinely confirmed before and during pregnancy by laboratory determination of oxygen uptake during exercise coupled with continuous heart rate monitoring during each field exercise se~~ion and a weekly exercise log.14.lb The subjects performed a variety of exercise at a variety of levels. Forty-two subjects were regular runners, 38 either taught or performed aerobics, 23 performed several forms of biking (touring, mountain biking, wind trainers, and stationary cycle ergometry), 13 swam, and 4 used various stair-climbing machines. Their exercise was largely unsupervised and individually regulated for personal pleasure and fitness or as a means of income. Thirty-nine percent of the subjects had been members of a high school team or a college team. However, except for occasional local road races and club swim meets, the subject's routine exercise was non-competitive. The range of exercise performance encountered was wide and much the same as that detailed earlier in a similar populace. 16 All the women were fit as evidenced by their maximal oxygen uptake values before conception (mean ± SD 53 ± 7 mi, kg-I. min-I, range 39 to 67 mi, kg-I. min-I), which were determined by means ofa constantspeed, progressive-grade treadmill protocol. 15 Furthermore, all continued their chosen forms of exercise during pregnancy and maintained their weekly exercise
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volumes (the product of duration and intensity) above 60% of preconceptional levels through the time points of study.'6 All subjects exercised at time relative to food intake that coincided with their usual schedules (90 to 240 minutes after meals). Thirty women were studied once between the thirtyfirst and thirty-eighth gestational weeks during a 20minute, intensity-controlled workout on a cycle ergometer or on a treadmill with a 4% to 10% uphill grade. Ten of the women rode a cycle ergometer at a work rate that required an oxygen uptake equal to 60% ± 3% of their preconceptional maximal uptake values, 10 walked uphill at a work rate that required 40% ± 3% of their preconceptional maximal uptake values. and 10 walked uphill at a work rate that required 60% ± 3% of their preconceptional maximal uptake values. In these studies the FHR was recorded for a minimum of 20 seconds three times before, every 5 minutes dt:ring, and in the first, fifth, and tenth minutes of recovery by imaging the fetal heart with real-time ultrasonography.5. 6 During cycle ergometry all measurements of FHR were obtained with the subject seated on the ergometer. During treadmill exercise all measurements were obtained with the subject in the upright position. Although fetal quiescence could not be adequately assessed during exercise, the rest and recovery measurements were always obtained when fetal breathing and body movements were visually absent. Maternal oxygen uptake was measured for the last 10 minutes of the exercise to confirm the exercise intensity,15"8 and maternal heart rate was continuously monitored with a portable telemetry system. '4
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The remaining 90 women were studied between the sixteenth and thirty-ninth gestational weeks during two or more routine 20-minute workouts at the usual exercise intensity for that t:me point in pregnancy (235 total studies). In this group the FHR was measured in duplicate over I5-second intervals by the standard Doppler technique in the position of exercise. Measurements were obtained after a rest period before exercise and within the first minute after the cessation of exercise. Observer palpation coupled with the woman's subjective sensation was used to rule out the potential confounding effect of fetal motion on the heart rate response. To confirm the reliability of this approach, real-time ultrasonography was used 37 times to simultaneously visualize fetal activity and heart rate and, except for one instance, the fetus was visually quiescent for the initial minute after exercise. On that occasion both the subject and the examiner were aware cf the fetal motion. With the exception of the swimmers, maternal oxygen uptake was measured for the last 10 minutes of the exercise period. The average value obtained was used to calculate exercise intensity, which was expressed as a
200
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TIME (min) Fig. 1. Effect of 20 minutes of cycle ergometry at 60% ± 3% of preconceptional maximal oxygen uptake on FHR in 10 well-conditioned women studied between thirty-third and thirty-eighth gestational weeks. Solid circles, Mean group rate at sitting rest and at 5, 10, 15, and 20 minutes of exercise, as well as first, fifth, and tenth minutes of recovery. Error bars, Standard deviation.
percentage of each individual's preconceptional maximal aerobic capacity, which appears to be unchanged by pregnancy.15 The swimmers were studied in their local pools; Borg's index of perceived exertion (a 15-point subjective rating scale that gives a valid estimate of exercise intensity)'9 was recorded, and the subject's oxygen uptake was measured in the laboratory during an alternate form of exercise at the same perceived level of exertion. This value was used to estimate exercise intensity during the swim. All subjects wore a rectal thermistor and a portable heart rate monitor, and with the exception of the swimmers, all had maternal glucose and catecholamine levels measured before and after the exercise. The raw data were examined for statistical relationships with repeated measures analysis of variance, the Kruskal-Wallis one-way analysis of variance, the unpaired t test, and linear regression. Significance was set at the p = 0.05 level.
Results Real-time ultrasonographic findings during exercise. The results of the 30 intensity-controlled exercise sessions, conducted at a mean gestational age of 36.5 ± 1.8 weeks, are presented in Figs. 1 and 2. In each one of these studies an increase in FHR was visually documented by the tenth minute of exercise and persisted throughout at least the fifth minute of recovery. These changes were significant at the p = 0.001 level. However, there was no significant difference between the fetal heart rates obtained in the last minute of exercise and those observed in the first minute of recovery (152 ± 11 vs 155 ± 12 beats
min - I). Spontaneous fetal breathing and body movements were not observed in the first minute of recovery but were observed in a minority of cases (n = 7) by the fifth minute. During cycle ergometry at 60% of preconceptional maximal oxygen uptake the mean FHR increased from 138 beats' min - I at rest to 144 beats' min - I after 5 minutes of exercise. After 10 minutes of exercise the mean FHR had increased to 151 beats . min - I and was maintained at that level through the fifth minute of recovery for a maximal mean ± SD increase of 13 ± 6 beats . min - I, which was significantly greater than the increase of 6 ± 4 beats' min - I noted in the fifth minute. During uphill treadmill exercise at 40% ± 3% of preconceptional maximal oxygen uptake the time course and magnitude of the changes in FHR were similar to those observed during cycle ergometry at 60% ± 3% of preconceptional maximal uptake. After 5 minutes of exercise the FHR had increased 7 ± 4 beats' min - I and continued to rise thereafter with a maximum increase of 12 ± 8 beats' min- ' in the twentieth minute. During more intense treadmill exercise at 60% ± 3% of preconceptional maximal oxygen uptake, the time course of the changes was similar but the magnitude of the increase in FHR was significantly (p < 0.05) greater than that seen during either the lower-intensity treadmill exercise or cycle ergometry at the same intensity. At 5 minutes the FHR had increased 10 ± 3 beats' min - I. At 10 minutes the increase was 15 ± 4 beats' min- ' and, in the twentieth minute the FHR was 20 ± 6 beats' min - I above that observed at rest.
Volume 168 Number I. Part I
FHA response to exercise
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TIME (min) Fig. 2. Effect of uphill treadmill walking at 40% ± 3% (_) and 60% ± 3 %(0) of preconceptional maximal oxygen uptake in 20 well-conditioned women (10 in each group) between 31 and 37 weeks' gestation. Data are expressed as group mean ± SD at each time point. Between-group differences were significant at p = 0.05 level at tenth, fifteenth, and twentieth minutes of exercise and in the first and fifth minutes of recovery. Sampling times are same as in Fig. 1.
Doppler findings before and immediately after ex· ercise. Fig. 3 illustrates the relationship between exercise intensity and the change in FHR observed in association with 235 spontaneous 20-minute workouts in the 90 women between the sixteenth and thirty-ninth weeks of gestation. Note that the spontaneous level of exercise intensity ranged between 40% and 84% of maximal aerobic capacity with changes in FHR ranging between - 10 and + 54 beats' min - J and that the FHR rose after exercise 96% of the time. The overall mean ± SD increase was 15 ± 11 beats' min - J at an intensity equal to 60% ± 12% of individual preconceptional maximal oxygen uptake. This was significant at the p = 0.001 level. Linear regression of the raw data indicated that approximately 15% of the variability in the FHR response was due to differences in exercise intensity (r = 0.3885). The relationship was best described by the equation .:1FHR = - 8 + 004 X Percent maximal capacity, indicating that on average FHR rose 8 beats' min - J after 20 minutes of exercise at 40% of preconceptional maximal oxygen uptake and increased an additional 8 beats' min - J for every 20% increase in exercise intensity over that level. Fig. 4 illustrates the effects of differences in gestational age on the relationship between exercise intensity and the change in FHR. The raw data have been divided into three arbitrary groups, which may reflect differences in the functional maturity of the fetal autonomic nervous system: 16 to 25 , 26 to 33, and 34 to 39 weeks. Before the twenty-sixth week the strength of relationship between exercise intensity and heart rate response is similar to that seen in the overall data (r = 0.3880)
However, the slope is flatter (.:1FHR = - 5 + 0.24 . percent of maximal oxygen uptake), indicating that in early gestation the FHR rose only an average of 5 beats' min - J after 20 minutes of exercise at 40% of maximal oxygen uptake with a further small increase of 5 beats' min - J for each 20% increase in exercise intensity above that level. Between the twenty-sixth and thirty-third weeks the relationship strengthened (r = 0.4642) with exercise intensity explaining 21 % of the variability in the change in FHR. The slope also steepened (.:1FHR = -13 + 0049· percent maximal oxygen uptake), indicating that FHR rose an average of 7 beats' min - J after 20 minutes of exercise at 40% of maximal oxygen uptake with a further increase of 10 beats' min - 1 for every 20% increase in exercise intensity above that level. From the thirty-fourth week onward the relationship strengthened further (r = 0.5264) with exercise intensity now explaining 27% of the variability in the FHR response. The slope remained steep (.:1FHR = -12 + 0.54 · percent maximal oxygen uptake) with the FHR increasing an average of 10 beats' min - J after 20 minutes of exercise at 40% of maximal oxygen uptake with further increases of 11 beats' min - J for each 20% increase in exercise intensity above that level. Thus the magnitude of the mean FHR response observed increased significantly as gestation advanced. At a mean ± SD gestational age of 22.5 ± 1.8 weeks the FHR rose an average of 10 ± 8 beats' min - J at an average intensity of 61 % ± 12% of maximal oxygen uptake. At 29.0 ±_ 1Aweeks' gestation the mean increase was 16 ± 10 beats' min - J at an average intensity of 61 % ± 11 % of maximal oxygen uptake, and at 36 ± 104 weeks it increased 20 ± 11 beats' min - 1 at
202 Clapp, Little, and Capeless
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an average exercise intensity of 58% ± 11% of maximal oxygen uptake. The change from before to after the beginning of the twenty-sixth week is significant at the p = 0.01 level, and that from the thirty-fourth week onward is also significant (p < 0.05) when corrected for the 3% decrease in mean exercise intensity in late pregnancy. Additional observations. There was no effect of exercise type on the magnitude of the FHR response to 20 minutes of exercise before the twenty-sixth week. After the twenty-sixth week the FHR responses to 20 minutes of running (with the four stairclimbers included), aerobics, and swimming were indistinguishable (increases of 18 to 20 beats' min-I), but the FHR response to biking was significantly less than that observed after the other forms of exercise (14 ± 8 beats' min -1 at 62% ± 10% of maximal oxygen uptake vs 19 ± 11 beats' min -1 at 59% ± 12% of maximal oxygen uptake). Maternal heart rate responses at any given exercise intensity were quite variable and did not accurately reflect individual exercise intensity. For example, at currently recommended exercise intensities « 50% of maximal oxygen uptake) average maternal heart rates ranged between 105 and 170 beats' min - 1 with different types of exercise at different time points in gestation. As anticipated, average heart rates were lowest during swimming and highest during aerobics, reflecting the effects of immersion and upper-extremity involvement on exercise heart rate. 20 • 21 In addition, when exercise type (running, aerobics, or cycling) was controlled for, the range of average maternal heart rates between subjects performing the same type of exercise within a 5% range of exercise intensity was 2: 30
beats . min - lover the exercise intensity range between 40% and 80% of maximum aerobic capacity. These findings are similar to those reported earlier I6 and suggest that without knowledge of the relationship between heart rate and oxygen consumption for an individual, heart rate is a poor index of exercise intensity during pregnancy. The Borg scale of perceived exertion was a better index of exercise intensity with a rating of 14 describing exercise at 45% to 55% of maximal oxygen uptake, 15 indicating exercise at 55% to 65% of maximal oxygen uptake, and 16, 17, and 18 reflecting intensities of 65% to 75%, 75% to 80%, and > 80% of maximal oxygen uptake, respectively. The increase in the magnitude of the FHR response with advancing gestation could not be attributed to a change in the thermal response because the rise in maternal rectal temperature decreased as pregnancy progressed. Between 16 and 25 weeks the average increase was 0.53° ± 0.19° C, falling to 0.38° ± 0.13° C between the twenty-sixth and thirty-third weeks and to 0.27° ± 0.09° C after the thirty-fourth week. These changes were much less than those seen in the nonpregnant state and, within any 19% range in exercise intensity, were unrelated to the change in FHR at all gestational ages. I7. 22 At all gestational ages studied mean maternal glucose concentrations fell during the 20-minute exercise session by approximately 0.5 mmol . L -1 and the exercise-associated change in maternal norepinephrine decreased significantly (20% to 30%) at intensities above 50% of maximal oxygen uptake in late pregnancy. Again, although both the maternal norepinephrine and the FHR responses increased with increasing exercise intensity, there was no relationship between the rise in maternal norepineph-
Volume 168 Number 1. Part 1
FHR response to exercise
rine and the rise in FHR within a 10% range of exercise intensity despite a wide range in both the FHR and the norepinephrine response. These results have been reported earlier l7 • 18 for most of the subjects and therefore are not further detailed here.
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Comment The results of these experiments support the hypothesis that the direction and magnitude of the FHR response to exercise are influenced by gestational age and exercise intensity, duration, and type. They also indicate that the variety of responses reported in the literature reflect differences in these and other variables mentioned earlier. We attempted to exclude the effects of other potential confounding variables, such as peripheral venous pooling as a result of maternal position and fetal motion. We always obtained our measurements with the subjects in the exercise position before, during, and after the exercise, and the real-time ultrasonographic information suggests that the data obtained were not biased to any great extent by fetal motion in the immediate postexercise period. We limited the study to well-conditioned, regularly exercising women without pregnancy complications so that the response we observed was consistently superimposed only on the physiologic adaptations to regular exercise. We avoided studying women after clinical engagement of the fetal vertex to minimize the potential of head compression artifact, and although not directly measured, no palpable or subjective increase in uterine tone was noted immediately after exercise. This is consistent with the experience of others. 2 • With a standard, moderate-duration exercise session and an exercise intensity > 40% of maximal oxygen uptake, the FHR increased in all except 3% of the trials and the magnitude of the change increased with advancing gestation. This indicates that the mechanism of the heart rate response is influenced by functional maturation, which is clearly the case in animal models.9 - 1• A direct relationship between exercise intensity and the magnitude of the FHR response was also observed within each gestational age group, indicating that the strength of the stimulus probably varies directly with exercise intensity with an apparent threshold between 35% and 40% of maximal oxygen uptake in the third trimester. The most likely stimulus known to be directly related to exercise intensity is the flow redistribution requirement. 3 During pregnancy, it is probable that this requirement is partially met by a progressive reduction in uterine blood flow, which should result in a temporary decrease in fetal P0 2 : ' 8 In the current experiments the type and duration of exercise also influenced the magnitude of the response. Cycle ergometry was associated with a decrease in the
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EXERCISE INTENSITY (~max) Fig. 4. Relationship between exercise intensity and change in FHR after 20 minutes of exercise between sixteenth and twenty-fifth (top panel), twenty-sixth and thirty-third (middle panel). and thirty-fourth and thirty-ninth (bottom panel) weeks of pregnancy. 0, Single experiment; linear regressIOn lines are superimposed on raw data. See text for details.
magnitude of the response when compared with that seen with running, aerobics, and swimming. This is consistent with the concept that the underlying stimulus for the change in FHR is a decrease in uterine perfusion because the flow redistribution requirement for the splanchnic bed is lower at any given exercise intensity during cycle ergometry than during the other types of exercise. This difference is due to the use of a smaller
204 Clapp, Little, and Capeless
percentage of an individual's total muscle mass during cycle ergometry versus the other types of exercise!3 As the duration of the intensity-controlled exercise in the last trimester increased, there was a consistent increase in the magnitude of the FHR response through at least the tenth minute. With this relatively low-intensity exercise « 65% of maximal oxygen uptake) it appeared that the exercise stimulus was present for > 5 minutes before it elicited a consistent FHR response . The data discussed suggest that this time requirement should increase when the exercise is performed at an earlier gestational age, when it is performed at a lower exercise intensity, and when the exercise uses a small percentage of an individual's total muscle mass. This interpretation explains much of the discrepant data because many of the reported studies used cycle ergometry for short periods of time at ill-defined intensities. 1-4 We were unable to obtain measurements of FHR during exercise at the higher exercise intensities for technical reasons. First, in our hands standard Doppler techniques were consistently associated with either foot stroke, motion, or pedal artifact.'· 5 Second, we were unable to image the fetal heart for sufficient time to obtain a reliable rate at higher workloads. During higher-intensity cycle ergometry there were problems with transducer motion at the skin interphase as a result of trunk motion. Likewise, the inevitable movement of the uterus and its tissue contents within the abdomen during high-intensity running and ballistic aerobic motion made reliable recording impossible. However, information obtained from five recently studied subjects, not included in the data presented here, indicates that the same progressive increase in FHR occurs during exercise at intensities in excess of 70% of maximal oxygen uptake. In these cases the subjects stopped exercise for 20 seconds at 5-minute intervals during their exercise sessions while we imaged the fetal heart. In each instance the increase in FHR did not stabilize until the fifteenth minute of the exercise routine. Given the nature of these experiments, we were unable to precisely define the underlying mechanism responsible for the observed increase in FHR. However, as discussed, its relationship to gestational age and the type, duration, and intensity of the exercise suggest that the stimulus is an exercise-induced fall in uterine blood flow and that there is maturation of the mechanism underlying the fetal response. In the absence of additional data we speculate that a decrease in uterine blood flow results in a decrease in fetal P0 2 and that the integrated fetal response, which has chemoreceptor, baroreceptor, and adrenal components, is a rise in heart rate. Additional support for this interpretation and a discussion of other potential explanations follow. To date, direct measurement of the exercise-induced
January 1993 Am J Obstel Gynecol
changes in uterine blood flow and its distribution have not been possible in the pregnant human. However, the well-known exercise-induced decrease in splanchnic blood flow in the nonpregnant human, coupled with inferential human and conclusive animal data during pregnancy, indicate that it is likely that uterine blood flow falls during exercise in pregnancy.'· 7. 8 Likewise, both animal data and transcutaneous P0 2 and scalp blood measurements in the human fetus clearly indicate that fetal P0 2 falls during decreases in uterine blood flow!··26 The FHR response to a fall in P0 2 is complex as it reflects the integrated output from both peripheral and central chemoreceptor responses, neural activation of adrenal medullary catecholamine release, and baroreceptor-mediated vagal responses initiated by the concomitant changes in arterial pressure. g.". 26·28 Whereas the integrated response to acute hypoxic challenge in the fetal lamb usually results in bradycardia and hypertension, this is not always the case, especially when there is a minimal fall in P0 2 ,10. 27. 28 the fetus is immature, or the stimulus is prolonged. g ·,,· 26 Experiments that use autonomic blockade demonstrate that the different responses can be partially explained by a change in the integrated autonomic response with advancing gestation. g • 11·13 Likewise, measurement ofmedullary and peripheral catecholamine release during hypoxic challenge demonstrates a threshold for both catecholamine secretion and the bradycardiac response and documents that adrenal medullary catecholamine release is altered with prolonged hypoxia .27. 28 Unfortunately, the issue of different heart rate responses with different degrees of fetal hypoxia has not been directly addressed in the experimental animal. However, there is one clinical observation and several experiments in pregnant women suggesting that the integrated output to minor decremental changes in fetal P0 2 is a rise in FHR!5. 29·31 The clinical example is the well-known rise in baseline FHR of the otherwise healthy fetus to an iatrogenic increase in baseline uterine tone, which also produces minor decremental changes in fetal transcutaneous Po 2 • The human experiments have four relevant findings. First, the usual heart rate response of the normal fetus to a reduction in maternal fraction of inspired oxygen to 15% is an increase. In addition, FHR always remained within ± 15 beats· min - 1 of control and differences in response appeared related to differences in placental function. Second, vasoactive maternal stimuli produce a similar response. Third, baseline FHR usually rises when fetal transcutaneous P0 2 falls and falls when fetal transcutaneous P0 2 increases in response to changes in maternal inspired oxygen concentration. Fourth, uterine contractions are associated with increased sympathetic tone and a fall in fetal transcutaneous Po 2 , which may be associated with a rise in fetal heart rate. These data are
Volume 168 Number I, Part 1
consistent with the mechanistic interpretation presented earlier. If this interpretation is correct, then the exercises performed by the women in this study produced only minimal changes in fetal P02 whereas the transient bradycardias reported by others in response to near-maximal or maximal exercise in uncomplicated pregnancies or at lower intensities in pregnancies with potential fetal compromise 4 • 6 represent the response to a greater fall in fetal P0 2 !5. 29. 31 Other possible contributors to the observed intensitydependent increase in FHR include the following: direct physical stimulation of the fetus and/or a concomitant change in fetal behavioral state, placental transfer of maternal catecholamines and/or fetal catecholamine secretion, and an exercise-induced rise in fetal temperature. Whereas direct physical stimulation and/or a change in state may occasionally play a role, we could not substantiate that this was consistently the case. We specifically used real-time ultrasonography in the 30 intensity-controlled experiments and in an additional 37 instances at varied exercise intensities to rule out this possibility. Placental transfer of maternal catecholamines may well contribute and fetal catecholamine secretion has been shown to contribute to the fetal cardiovascular response to hypoxia!7. 28. 31 However, high fetal levels should produce bradycardia!7. 28 and placental transfer in active form appears quite limited. 32 In addition, we were unable to demonstrate a relationship between the maternal catecholamine response and the FHR response within a reasonable range of exercise intensity, and maternal blood levels were actually lower at high intensities in late gestation when the FHR response was maximal. 18 It is also clear that the FHR increases approximately 15 beats' min - I for each degree rise in temperature during labor," and it is likely that the temperature of the human fetus rises passively during maternal exercise. However, the exercise-associated rise in maternal temperature actually decreased with increasing gestation while the heart rate response increased. In addition, we have been unable to demonstrate a relationship between the magnitude of the rise in maternal temperature and the magnitude of the change in heart rate in both this and an earlier study!2 In all probability this is due to the change in the thermal response to exercise during pregnancy, which progressively reduces the thermal stress of high-intensity exercise with advancing gestation. l7 Thus, whereas these factors may well contribute to the overall FHR response, the magnitude of their contribution is below the limits of detection of the method used in this study. In summary, these experiments indicate that recreational exercise, performed by well-conditioned women at or above a baseline conditioning level in mid and late pregnancy, is normally associated with an increase in FHR. The magnitude of the increase is influenced by
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gestational age and the intensity, type, and duration of the exercise. On the basis of this information and the known physiologic responses to exercise, we speculate that the underlying stimulus is a decrease in placental perfusion, resulting in a small decrease in fetal P0 2 • One portion of the integrated fetal response to this change in P0 2 is an increase in heart rate. REFERENCES 1. Wolfe LA, Otake PJ, Mottola MF, McGrath MJ. Physiological interactions between pregnancy and aerobic exercise. Exerc Sports Sci Rev 1989;17:295-351. 2. Sady SP, Carpenter MW. Aerobic exercise during pregnancy. Sports Med 1989;7:357-75. 3. Clapp JF. Exercise in pregnancy: a brief clinical review. Fetal Med Rev 1990;2:89-101. 4. Artal RM, Posner MD. Fetal responses to maternal exercise. In: Artal RM, Wiswell RA, Drinkwater BL, eds. Exercise in pregnancy. Baltimore: Williams & Wilkins, 1991: 213-24. 5. Palone AM, Shangold M, Paul D, Minnitti J, Weiner S. Fetal heart rate measurement during maternal exerciseavoidance of artifact. Med Sci Sports Exerc 1987;19:605. 6. Carpenter MW, Sady SP, Hoegsbert B, Sady MA, Haydon B, Coustan DR. Fetal heart rate response to maternal exertion. JAMA 1988;259:3006-9. 7. Lotgering FK, Gilbert RD, Longo LD. Maternal and fetal responses to exercise during pregnancy. Physiol Rev 1985; 65:1-36. 8. Clapp JF. The effects of exercise on uteroplacental blood flow. In: Rosenfeld CR, ed. The uterine circulation. Ithaca, New York: Perinatology Press, 1989:299-310. 9. Walker AM, Cannata J, Ritchie BC, Maloney JE. Hypotension in fetal and newborn lambs; different patterns of reflex heart rate control revealed by autonomic blockade. Bioi Neonate 1983;44:358-65. 10. Boddy K, Dawes GS, Fisher R, Pinter S, Robinson JS. Foetal respiratory movements, electrocortical and cardiovascular responses to hypoxaemia and hypercapnia in sheep. J Physiol 1974;243:599-618. 11. Walker AM, Cannata JP, Dowling MH, Ritchie BC, Maloney JE. Age-dependent pattern of autonomic heart rate control during hypoxia in fetal and newborn lambs. Bioi Neonate 1979;35: 198-208. 12. Walker AM, Cannata J, Dowling MH, Ritchie B, Malone JE. Sympathetic and parasympathetic control of heart rate in unanaesthetized fetal and newborn lambs. Bioi Neonate 1978;33: 135-43. 13. Rudolph AH, Heymann MA. Fetal and neonatal circulation and respiration. Am Rev Physiol 1974;36:187-207. 14. Seaward BL, Sleamaker RH, McAuliffe T, Clapp JF. The precision and accuracy of a portable heart rate monitor. Biomed Inst Technol 1990;24:37-41. 15. Clapp JF. The V02 max of recreational athletes before and after pregnancy. Med Sci Sports Exerc 1991;23: 1128-33. 16. Clapp JF. The course of labor after endurance exercise during pregnancy. AM J OBSTET GYNECOL 1990; 163: 1799805. 17. Clapp JF. The changing thermal response to endurance exercise during pregnancy. AM J OBSTET GYNECOL 1991; 165:1684-90. 18. Clapp JF, Capeless EL. The changing glycemic response to exercise during pregnancy. AM J OBSTET GYNECOL 1991; 165:1678-83. 19. Borg GAV. Psychophysical bases of perceived exertion. Med Sci Sports Exerc 1982;14:377-81. 20. NcArdle WD, Glaser RM, Magel JR. Metabolic and cardiorespiratory response during free swimming and treadmill walking-. J Appl Physiol 1971;30:733-8.
Clapp, Little, and Capeless
21. Vokac Z, Bell H], Bautz-Holter E, Rodhal K. Oxygen uptake/heart rate relationship in leg and arm exercise, sitting and standing.] Appl Physiol 1975;39:54-9. 22. Clapp ]F. Fetal heart rate response to running in midpregnancy and late pregnancy. AM] OSSTET GYNECOL 1985; 153:251-2. 23. Vielle ]C, Hohimer AR, Buny K, Speroff L. The effect of exercise on uterine activity in the last 8 weeks of pregnancy. AM] OBSTET GYNECOL 1985;151:729-33. 24. Clapp ]F. The relationship between blood flow and oxygen consumption in the uterine and umbilical circulations. AM] OBSTET GYNECOL 1978;132:410-3. 25. Huch A, Huch R, Schneider H, Rooth G. Continuous transcutaneous monitoring of fetal oxygen tension during labor. Br] Obstet Gynaecol 1977;84(suppl 1): 1-39. 26. Bocking AD, Gagnon R, White SE, Homan], Milne KM, Richardson BS. Circulatory responses to prolonged hypoxemia in fetal sheep. AM] OBSTET GYNECOL 1988;159: 1418-24. 27. Cohen WR, Piasecki G], Jackson BT. Plasma catechol-
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28. 29.
30. 31. 32.
33.
amines during hypoxemia in the fetal lamb. Am] Physiol 1982;243:R520-5. Cohen WR, Piasecki G], Cohn HE, Young]B,]ackson BT. Adrenal secretion of catecholamines during hypoxemia in fetal lambs. Endocrinology 1984; 114:383-90. Walker A, Maddern L, Day E, Renou P, Talbot], Wood C. Fetal scalp tissue oxygen tension measurements in relation to maternal dermal oxygen tension and fetal heart rate. ] Obstet Gynaecol Br Commonw 1971;78:1-12. Renou P, Newman W, Wood C. Autonomic control of fetal heart rate. AM] OBSTET GYNECOL 1969;105:949-53. Copher DE, Huber CPo Heart rate response of the human fetus to induced hypoxia. AM] OBSTET GYNECOL 1967;98: 320-35. Sodha R], Proegler M, Schneider H. Transfer and metabolism of norepinephrine studied from maternal-to-fetal and fetal-to-maternal sides in the in vitro perfused human placental lobe. AM] OBSTET GYNECOL 1984;148:474-81. Walker D, Walker A, Wood C. Temperature of the human fetus.] Obstet Gynaecol Br Commonw 1969;76:503-11.
Induction of endothelial cell tissue factor activity by sera from patients with antiphospholipid syndrome: A possible mechanism of thrombosis D. Ware Branch, MD," and George M. Rodgers, MD, PhDb
Salt Lake City, Utah OBJECTIVE: The hypothesis of our study is that antiphospholipid antibodies predispose to thrombosis by inducing endothelial cell tissue factor expression. STUDY DESIGN: Monolayers of cultured human umbilical vein endothelial cells were incubated for 8 hours in a medium containing 20% serum obtained either from patients with anti phospholipid antibodies (n = 11) or normal subjects (n = 8). Similar incubations were performed with immunoglobulin G fractions from either patients with anti phospholipid antibodies (n = 3) or normal subjects (n = 3). Endothelial cell tissue factor expression was measured with a tissue factor-specific chromogenic substrate assay. The results were analyzed with a two-tailed t test. RESULTS: The mean endothelial cell tissue factor expression induced by anti phospholipid sera was significantly greater than the controls (p < 0.02). Immunoglobulin experiments indicated that the factor(s) responsible for the induction of tissue factor expression resides in the immunoglobulin G fraction of the sera (p < 0.01). CONCLUSIONS: Endothelial cell tissue factor expression is induced by anti phospholipid sera, with activity residing at least in part in the immunoglobulin fraction. The induction of tissue factor by anti phospholipid sera may playa role in the thrombotic tendency Observed in patients with antiphospholipid syndrome. (AM J OBSTET GVNECOL 1993; 168:206-1 0.)
Key words: Antiphospholipid antibodies, tissue factor, thrombosis, fetal loss
From the Departments of Obstetrtcs and Gynecology, a Medicine, b and Pathology, b Unzverstty of Utah and Salt Lake Veterans Administration Medical Center. Supported In part by a grant from the Veterans AdministratIOn and a Bwmedlcal Research Support Crant from the Unzverslty of Utah (C.M.R.).
206
ReceIVed for publicatIOn October 17, 1991; revised June 3, 1992; accepted June 16, 1992. Reprint requests: D. Ware Branch, MD, Room 2B200, Medical Center, 50 North Medical Dr., Salt Lake CIty, UT 84132. 6/1/40268
the uteroplacental circulation in early pregnancy. Obstet Gynecol 1991;77:365-9. 15. Campbell S, Pearce jMF, Hackett G, Cohen-Overbeek T, Hernandez C. Qualitative assessment of uteroplacental blood flow: early screening test for high-risk pregnancies. Obstet Gynecol 1986;68:649-53. 16. Anderson WR, Davis J. Placental site involution. AM j OBSTET GYNECOL 1968;102:23-33. 17. Monheit AG, Cousins L, Resnik R. The puerperium:
January 1993 Am J Obstet Gynecol
anatomic and physiologic readjustments. Clin Obstet Gynecol 1980;23:973-83. 18. Fuchs A-R. Endocrinology of lactation. In: Fuchs F, K1opper A, eds. Endocrinology of pregnancy. 3rd ed. Philadelphia: Harper & Row, 1983:271-87. 19. Hertzberg Bj, Bowie jD. Ultrasound of the postpartum uterus: prediction of retained placental tissue. j Ultrasound Med 1991;10:451-6.
Fetal heart rate response to sustained recreational exercise James F. Clapp III, MD: Kathleen D. Little, PhD: and Eleanor L. Capeless, MDb
Cleveland, Ohio, and Burlington, Vermont OBJECTIVE: We aimed to test the hypotheses that fetal heart rate increases during and after sustained exercise and that the magnitude of the increase is related to gestational age and the duration, intensity, and type of exercise. STUDY DESIGN: Maternal oxygen uptake and fetal heart rate were monitored in 120 regularly exerCising women in association with routine 20-minute workouts between 16 and 39 weeks' gestation. RESULTS: In 97% of the studies fetal heart rate increased during and after exercise. This was significant at all gestational ages and with all forms of exercise with an overall increase of 15 ± 11 beats· min -, at 60% ± 12% of maximal aerobic capacity (mean ± SO). The magnitude increased with gestational age (10 ± 8 to 20 ± 11 beats' min-'), exercise intensity (8 ± 7 to 21 ± 13 beats· min-'), and exercise duration (8 ± 4 to 16 ± 7 beats· min-'). CONCLUSION: We concluded that the hypothesis is correct and speculate that these changes represent a maturing fetal response to a reduction in P02 • (AM J OBSTET GVNECOL 1993;168:198-206.)
Key words: Pregnancy, sustained exercise, fetal heart rate In recent years the fetal heart rate (FHR) response to maternal exercise has been examined by more than 20 investigators with mixed results. ' -' A number of investigators have noted that FHR is increased by 5 to 20 minutes of various types of exercise at work rates up to 75% of maximum capacity whereas others have noted no change after similar types of exercise. Three studies have reported profound decreases in the FHR during low-intensity exercise, but it is likely that the majority of these findings really represented foot strike or pedal
From the Departments of Reprodudive Biology and Obstetrics and Gynecology, MetroHealth Medical Center and Case Western Reserve School of Mediczne: and The Umversity of Vermont College of Medicine. b Supported in part by NatIOnal Institutes of Health grant HD21268 and funds from MetroHealth Medical Center. ReceIVed for publicatIOn October 8, 1991; reVISed April 13, 1992; accepted May 21, 1992. Reprint requests: James F. Clapp III, MD, Department of Obstetrics and Gynecology, MetroHealth Medical Center, 2500 MetroHealth Dr., Cleveland, OH 44109-1998. 6/1/39538
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artifact. 5 However, postexercise fetal bradycardia has been observed in pregnancies complicated by hypertension and growth retardation' and one recent study reported a 16% incidence of ultrasonography-confirmed, transient fetal bradycardia during or immediately after short periods of cycle ergometry when it was performed at maximal or near-maximal capacity by untrained women. 6 The diversity of these findings suggests that multiple confounding variables are influencing the fetal response, which makes it difficult to understand the mechanisms involved. Accordingly, the current study was designed to control for likely confounding maternal, fetal, and exercise variables. Maternal variables included position at the time the measurements were obtained, fitness level, and exercise habits. Fetal variables included a clinically normal singleton pregnancy, normal growth, unengaged presentation, fetal quiescence, and gestational age at the time the measurements were obtained. Exercise variables included exercise type, intensity, and duration. 0002-9378/93 $1.00
+ 0.20
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The study was designed to test two hypotheses. The first hypothesis states that the FHR increases during and after sustained exercise. The second hypothesis states that the magnitude of the increase is related to gestational age and the duration, intensity, and type of exercise. These were based on the physiologic supposition that exercise in the human is associated with a reduction in placental blood flow 7 • 8 and the observations that the duration and intensity of the stimulus and the degree of maturation of the fetal autonomic nervous system alter the magnitude of the FHR response to a variety of stimuli. 9 . 13 Material and methods
Mter informed consent was obtained in accord with institutional guidelines, 120 healthy, physically active women with accurately dated, clinically normal, singleton pregnancies were enrolled. Sixty-seven percent were primigravid, 30% were secundigravid, and 3% were experiencing their third or fourth pregnancy. Although overall exercise performance varied widely between subjects, all met our minimal standard for a "recreational" athlete. This standard required that the subject had been performing a sustained type of exercise regularly (three or more sessions each week and a minimum of 20 minutes per session) for at least 6 months before conception at an intensity in excess of 50% of maximal capacity. This assessment of overall exercise performance was routinely confirmed before and during pregnancy by laboratory determination of oxygen uptake during exercise coupled with continuous heart rate monitoring during each field exercise se~~ion and a weekly exercise log.14.lb The subjects performed a variety of exercise at a variety of levels. Forty-two subjects were regular runners, 38 either taught or performed aerobics, 23 performed several forms of biking (touring, mountain biking, wind trainers, and stationary cycle ergometry), 13 swam, and 4 used various stair-climbing machines. Their exercise was largely unsupervised and individually regulated for personal pleasure and fitness or as a means of income. Thirty-nine percent of the subjects had been members of a high school team or a college team. However, except for occasional local road races and club swim meets, the subject's routine exercise was non-competitive. The range of exercise performance encountered was wide and much the same as that detailed earlier in a similar populace. 16 All the women were fit as evidenced by their maximal oxygen uptake values before conception (mean ± SD 53 ± 7 mi, kg-I. min-I, range 39 to 67 mi, kg-I. min-I), which were determined by means ofa constantspeed, progressive-grade treadmill protocol. 15 Furthermore, all continued their chosen forms of exercise during pregnancy and maintained their weekly exercise
FHR response to exercise
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volumes (the product of duration and intensity) above 60% of preconceptional levels through the time points of study.'6 All subjects exercised at time relative to food intake that coincided with their usual schedules (90 to 240 minutes after meals). Thirty women were studied once between the thirtyfirst and thirty-eighth gestational weeks during a 20minute, intensity-controlled workout on a cycle ergometer or on a treadmill with a 4% to 10% uphill grade. Ten of the women rode a cycle ergometer at a work rate that required an oxygen uptake equal to 60% ± 3% of their preconceptional maximal uptake values, 10 walked uphill at a work rate that required 40% ± 3% of their preconceptional maximal uptake values. and 10 walked uphill at a work rate that required 60% ± 3% of their preconceptional maximal uptake values. In these studies the FHR was recorded for a minimum of 20 seconds three times before, every 5 minutes dt:ring, and in the first, fifth, and tenth minutes of recovery by imaging the fetal heart with real-time ultrasonography.5. 6 During cycle ergometry all measurements of FHR were obtained with the subject seated on the ergometer. During treadmill exercise all measurements were obtained with the subject in the upright position. Although fetal quiescence could not be adequately assessed during exercise, the rest and recovery measurements were always obtained when fetal breathing and body movements were visually absent. Maternal oxygen uptake was measured for the last 10 minutes of the exercise to confirm the exercise intensity,15"8 and maternal heart rate was continuously monitored with a portable telemetry system. '4
a
The remaining 90 women were studied between the sixteenth and thirty-ninth gestational weeks during two or more routine 20-minute workouts at the usual exercise intensity for that t:me point in pregnancy (235 total studies). In this group the FHR was measured in duplicate over I5-second intervals by the standard Doppler technique in the position of exercise. Measurements were obtained after a rest period before exercise and within the first minute after the cessation of exercise. Observer palpation coupled with the woman's subjective sensation was used to rule out the potential confounding effect of fetal motion on the heart rate response. To confirm the reliability of this approach, real-time ultrasonography was used 37 times to simultaneously visualize fetal activity and heart rate and, except for one instance, the fetus was visually quiescent for the initial minute after exercise. On that occasion both the subject and the examiner were aware cf the fetal motion. With the exception of the swimmers, maternal oxygen uptake was measured for the last 10 minutes of the exercise period. The average value obtained was used to calculate exercise intensity, which was expressed as a
200
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TIME (min) Fig. 1. Effect of 20 minutes of cycle ergometry at 60% ± 3% of preconceptional maximal oxygen uptake on FHR in 10 well-conditioned women studied between thirty-third and thirty-eighth gestational weeks. Solid circles, Mean group rate at sitting rest and at 5, 10, 15, and 20 minutes of exercise, as well as first, fifth, and tenth minutes of recovery. Error bars, Standard deviation.
percentage of each individual's preconceptional maximal aerobic capacity, which appears to be unchanged by pregnancy.15 The swimmers were studied in their local pools; Borg's index of perceived exertion (a 15-point subjective rating scale that gives a valid estimate of exercise intensity)'9 was recorded, and the subject's oxygen uptake was measured in the laboratory during an alternate form of exercise at the same perceived level of exertion. This value was used to estimate exercise intensity during the swim. All subjects wore a rectal thermistor and a portable heart rate monitor, and with the exception of the swimmers, all had maternal glucose and catecholamine levels measured before and after the exercise. The raw data were examined for statistical relationships with repeated measures analysis of variance, the Kruskal-Wallis one-way analysis of variance, the unpaired t test, and linear regression. Significance was set at the p = 0.05 level.
Results Real-time ultrasonographic findings during exercise. The results of the 30 intensity-controlled exercise sessions, conducted at a mean gestational age of 36.5 ± 1.8 weeks, are presented in Figs. 1 and 2. In each one of these studies an increase in FHR was visually documented by the tenth minute of exercise and persisted throughout at least the fifth minute of recovery. These changes were significant at the p = 0.001 level. However, there was no significant difference between the fetal heart rates obtained in the last minute of exercise and those observed in the first minute of recovery (152 ± 11 vs 155 ± 12 beats
min - I). Spontaneous fetal breathing and body movements were not observed in the first minute of recovery but were observed in a minority of cases (n = 7) by the fifth minute. During cycle ergometry at 60% of preconceptional maximal oxygen uptake the mean FHR increased from 138 beats' min - I at rest to 144 beats' min - I after 5 minutes of exercise. After 10 minutes of exercise the mean FHR had increased to 151 beats . min - I and was maintained at that level through the fifth minute of recovery for a maximal mean ± SD increase of 13 ± 6 beats . min - I, which was significantly greater than the increase of 6 ± 4 beats' min - I noted in the fifth minute. During uphill treadmill exercise at 40% ± 3% of preconceptional maximal oxygen uptake the time course and magnitude of the changes in FHR were similar to those observed during cycle ergometry at 60% ± 3% of preconceptional maximal uptake. After 5 minutes of exercise the FHR had increased 7 ± 4 beats' min - I and continued to rise thereafter with a maximum increase of 12 ± 8 beats' min- ' in the twentieth minute. During more intense treadmill exercise at 60% ± 3% of preconceptional maximal oxygen uptake, the time course of the changes was similar but the magnitude of the increase in FHR was significantly (p < 0.05) greater than that seen during either the lower-intensity treadmill exercise or cycle ergometry at the same intensity. At 5 minutes the FHR had increased 10 ± 3 beats' min - I. At 10 minutes the increase was 15 ± 4 beats' min- ' and, in the twentieth minute the FHR was 20 ± 6 beats' min - I above that observed at rest.
Volume 168 Number I. Part I
FHA response to exercise
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TIME (min) Fig. 2. Effect of uphill treadmill walking at 40% ± 3% (_) and 60% ± 3 %(0) of preconceptional maximal oxygen uptake in 20 well-conditioned women (10 in each group) between 31 and 37 weeks' gestation. Data are expressed as group mean ± SD at each time point. Between-group differences were significant at p = 0.05 level at tenth, fifteenth, and twentieth minutes of exercise and in the first and fifth minutes of recovery. Sampling times are same as in Fig. 1.
Doppler findings before and immediately after ex· ercise. Fig. 3 illustrates the relationship between exercise intensity and the change in FHR observed in association with 235 spontaneous 20-minute workouts in the 90 women between the sixteenth and thirty-ninth weeks of gestation. Note that the spontaneous level of exercise intensity ranged between 40% and 84% of maximal aerobic capacity with changes in FHR ranging between - 10 and + 54 beats' min - J and that the FHR rose after exercise 96% of the time. The overall mean ± SD increase was 15 ± 11 beats' min - J at an intensity equal to 60% ± 12% of individual preconceptional maximal oxygen uptake. This was significant at the p = 0.001 level. Linear regression of the raw data indicated that approximately 15% of the variability in the FHR response was due to differences in exercise intensity (r = 0.3885). The relationship was best described by the equation .:1FHR = - 8 + 004 X Percent maximal capacity, indicating that on average FHR rose 8 beats' min - J after 20 minutes of exercise at 40% of preconceptional maximal oxygen uptake and increased an additional 8 beats' min - J for every 20% increase in exercise intensity over that level. Fig. 4 illustrates the effects of differences in gestational age on the relationship between exercise intensity and the change in FHR. The raw data have been divided into three arbitrary groups, which may reflect differences in the functional maturity of the fetal autonomic nervous system: 16 to 25 , 26 to 33, and 34 to 39 weeks. Before the twenty-sixth week the strength of relationship between exercise intensity and heart rate response is similar to that seen in the overall data (r = 0.3880)
However, the slope is flatter (.:1FHR = - 5 + 0.24 . percent of maximal oxygen uptake), indicating that in early gestation the FHR rose only an average of 5 beats' min - J after 20 minutes of exercise at 40% of maximal oxygen uptake with a further small increase of 5 beats' min - J for each 20% increase in exercise intensity above that level. Between the twenty-sixth and thirty-third weeks the relationship strengthened (r = 0.4642) with exercise intensity explaining 21 % of the variability in the change in FHR. The slope also steepened (.:1FHR = -13 + 0049· percent maximal oxygen uptake), indicating that FHR rose an average of 7 beats' min - J after 20 minutes of exercise at 40% of maximal oxygen uptake with a further increase of 10 beats' min - 1 for every 20% increase in exercise intensity above that level. From the thirty-fourth week onward the relationship strengthened further (r = 0.5264) with exercise intensity now explaining 27% of the variability in the FHR response. The slope remained steep (.:1FHR = -12 + 0.54 · percent maximal oxygen uptake) with the FHR increasing an average of 10 beats' min - J after 20 minutes of exercise at 40% of maximal oxygen uptake with further increases of 11 beats' min - J for each 20% increase in exercise intensity above that level. Thus the magnitude of the mean FHR response observed increased significantly as gestation advanced. At a mean ± SD gestational age of 22.5 ± 1.8 weeks the FHR rose an average of 10 ± 8 beats' min - J at an average intensity of 61 % ± 12% of maximal oxygen uptake. At 29.0 ±_ 1Aweeks' gestation the mean increase was 16 ± 10 beats' min - J at an average intensity of 61 % ± 11 % of maximal oxygen uptake, and at 36 ± 104 weeks it increased 20 ± 11 beats' min - 1 at
202 Clapp, Little, and Capeless
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an average exercise intensity of 58% ± 11% of maximal oxygen uptake. The change from before to after the beginning of the twenty-sixth week is significant at the p = 0.01 level, and that from the thirty-fourth week onward is also significant (p < 0.05) when corrected for the 3% decrease in mean exercise intensity in late pregnancy. Additional observations. There was no effect of exercise type on the magnitude of the FHR response to 20 minutes of exercise before the twenty-sixth week. After the twenty-sixth week the FHR responses to 20 minutes of running (with the four stairclimbers included), aerobics, and swimming were indistinguishable (increases of 18 to 20 beats' min-I), but the FHR response to biking was significantly less than that observed after the other forms of exercise (14 ± 8 beats' min -1 at 62% ± 10% of maximal oxygen uptake vs 19 ± 11 beats' min -1 at 59% ± 12% of maximal oxygen uptake). Maternal heart rate responses at any given exercise intensity were quite variable and did not accurately reflect individual exercise intensity. For example, at currently recommended exercise intensities « 50% of maximal oxygen uptake) average maternal heart rates ranged between 105 and 170 beats' min - 1 with different types of exercise at different time points in gestation. As anticipated, average heart rates were lowest during swimming and highest during aerobics, reflecting the effects of immersion and upper-extremity involvement on exercise heart rate. 20 • 21 In addition, when exercise type (running, aerobics, or cycling) was controlled for, the range of average maternal heart rates between subjects performing the same type of exercise within a 5% range of exercise intensity was 2: 30
beats . min - lover the exercise intensity range between 40% and 80% of maximum aerobic capacity. These findings are similar to those reported earlier I6 and suggest that without knowledge of the relationship between heart rate and oxygen consumption for an individual, heart rate is a poor index of exercise intensity during pregnancy. The Borg scale of perceived exertion was a better index of exercise intensity with a rating of 14 describing exercise at 45% to 55% of maximal oxygen uptake, 15 indicating exercise at 55% to 65% of maximal oxygen uptake, and 16, 17, and 18 reflecting intensities of 65% to 75%, 75% to 80%, and > 80% of maximal oxygen uptake, respectively. The increase in the magnitude of the FHR response with advancing gestation could not be attributed to a change in the thermal response because the rise in maternal rectal temperature decreased as pregnancy progressed. Between 16 and 25 weeks the average increase was 0.53° ± 0.19° C, falling to 0.38° ± 0.13° C between the twenty-sixth and thirty-third weeks and to 0.27° ± 0.09° C after the thirty-fourth week. These changes were much less than those seen in the nonpregnant state and, within any 19% range in exercise intensity, were unrelated to the change in FHR at all gestational ages. I7. 22 At all gestational ages studied mean maternal glucose concentrations fell during the 20-minute exercise session by approximately 0.5 mmol . L -1 and the exercise-associated change in maternal norepinephrine decreased significantly (20% to 30%) at intensities above 50% of maximal oxygen uptake in late pregnancy. Again, although both the maternal norepinephrine and the FHR responses increased with increasing exercise intensity, there was no relationship between the rise in maternal norepineph-
Volume 168 Number 1. Part 1
FHR response to exercise
rine and the rise in FHR within a 10% range of exercise intensity despite a wide range in both the FHR and the norepinephrine response. These results have been reported earlier l7 • 18 for most of the subjects and therefore are not further detailed here.
203
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Comment The results of these experiments support the hypothesis that the direction and magnitude of the FHR response to exercise are influenced by gestational age and exercise intensity, duration, and type. They also indicate that the variety of responses reported in the literature reflect differences in these and other variables mentioned earlier. We attempted to exclude the effects of other potential confounding variables, such as peripheral venous pooling as a result of maternal position and fetal motion. We always obtained our measurements with the subjects in the exercise position before, during, and after the exercise, and the real-time ultrasonographic information suggests that the data obtained were not biased to any great extent by fetal motion in the immediate postexercise period. We limited the study to well-conditioned, regularly exercising women without pregnancy complications so that the response we observed was consistently superimposed only on the physiologic adaptations to regular exercise. We avoided studying women after clinical engagement of the fetal vertex to minimize the potential of head compression artifact, and although not directly measured, no palpable or subjective increase in uterine tone was noted immediately after exercise. This is consistent with the experience of others. 2 • With a standard, moderate-duration exercise session and an exercise intensity > 40% of maximal oxygen uptake, the FHR increased in all except 3% of the trials and the magnitude of the change increased with advancing gestation. This indicates that the mechanism of the heart rate response is influenced by functional maturation, which is clearly the case in animal models.9 - 1• A direct relationship between exercise intensity and the magnitude of the FHR response was also observed within each gestational age group, indicating that the strength of the stimulus probably varies directly with exercise intensity with an apparent threshold between 35% and 40% of maximal oxygen uptake in the third trimester. The most likely stimulus known to be directly related to exercise intensity is the flow redistribution requirement. 3 During pregnancy, it is probable that this requirement is partially met by a progressive reduction in uterine blood flow, which should result in a temporary decrease in fetal P0 2 : ' 8 In the current experiments the type and duration of exercise also influenced the magnitude of the response. Cycle ergometry was associated with a decrease in the
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EXERCISE INTENSITY (~max) Fig. 4. Relationship between exercise intensity and change in FHR after 20 minutes of exercise between sixteenth and twenty-fifth (top panel), twenty-sixth and thirty-third (middle panel). and thirty-fourth and thirty-ninth (bottom panel) weeks of pregnancy. 0, Single experiment; linear regressIOn lines are superimposed on raw data. See text for details.
magnitude of the response when compared with that seen with running, aerobics, and swimming. This is consistent with the concept that the underlying stimulus for the change in FHR is a decrease in uterine perfusion because the flow redistribution requirement for the splanchnic bed is lower at any given exercise intensity during cycle ergometry than during the other types of exercise. This difference is due to the use of a smaller
204 Clapp, Little, and Capeless
percentage of an individual's total muscle mass during cycle ergometry versus the other types of exercise!3 As the duration of the intensity-controlled exercise in the last trimester increased, there was a consistent increase in the magnitude of the FHR response through at least the tenth minute. With this relatively low-intensity exercise « 65% of maximal oxygen uptake) it appeared that the exercise stimulus was present for > 5 minutes before it elicited a consistent FHR response . The data discussed suggest that this time requirement should increase when the exercise is performed at an earlier gestational age, when it is performed at a lower exercise intensity, and when the exercise uses a small percentage of an individual's total muscle mass. This interpretation explains much of the discrepant data because many of the reported studies used cycle ergometry for short periods of time at ill-defined intensities. 1-4 We were unable to obtain measurements of FHR during exercise at the higher exercise intensities for technical reasons. First, in our hands standard Doppler techniques were consistently associated with either foot stroke, motion, or pedal artifact.'· 5 Second, we were unable to image the fetal heart for sufficient time to obtain a reliable rate at higher workloads. During higher-intensity cycle ergometry there were problems with transducer motion at the skin interphase as a result of trunk motion. Likewise, the inevitable movement of the uterus and its tissue contents within the abdomen during high-intensity running and ballistic aerobic motion made reliable recording impossible. However, information obtained from five recently studied subjects, not included in the data presented here, indicates that the same progressive increase in FHR occurs during exercise at intensities in excess of 70% of maximal oxygen uptake. In these cases the subjects stopped exercise for 20 seconds at 5-minute intervals during their exercise sessions while we imaged the fetal heart. In each instance the increase in FHR did not stabilize until the fifteenth minute of the exercise routine. Given the nature of these experiments, we were unable to precisely define the underlying mechanism responsible for the observed increase in FHR. However, as discussed, its relationship to gestational age and the type, duration, and intensity of the exercise suggest that the stimulus is an exercise-induced fall in uterine blood flow and that there is maturation of the mechanism underlying the fetal response. In the absence of additional data we speculate that a decrease in uterine blood flow results in a decrease in fetal P0 2 and that the integrated fetal response, which has chemoreceptor, baroreceptor, and adrenal components, is a rise in heart rate. Additional support for this interpretation and a discussion of other potential explanations follow. To date, direct measurement of the exercise-induced
January 1993 Am J Obstel Gynecol
changes in uterine blood flow and its distribution have not been possible in the pregnant human. However, the well-known exercise-induced decrease in splanchnic blood flow in the nonpregnant human, coupled with inferential human and conclusive animal data during pregnancy, indicate that it is likely that uterine blood flow falls during exercise in pregnancy.'· 7. 8 Likewise, both animal data and transcutaneous P0 2 and scalp blood measurements in the human fetus clearly indicate that fetal P0 2 falls during decreases in uterine blood flow!··26 The FHR response to a fall in P0 2 is complex as it reflects the integrated output from both peripheral and central chemoreceptor responses, neural activation of adrenal medullary catecholamine release, and baroreceptor-mediated vagal responses initiated by the concomitant changes in arterial pressure. g.". 26·28 Whereas the integrated response to acute hypoxic challenge in the fetal lamb usually results in bradycardia and hypertension, this is not always the case, especially when there is a minimal fall in P0 2 ,10. 27. 28 the fetus is immature, or the stimulus is prolonged. g ·,,· 26 Experiments that use autonomic blockade demonstrate that the different responses can be partially explained by a change in the integrated autonomic response with advancing gestation. g • 11·13 Likewise, measurement ofmedullary and peripheral catecholamine release during hypoxic challenge demonstrates a threshold for both catecholamine secretion and the bradycardiac response and documents that adrenal medullary catecholamine release is altered with prolonged hypoxia .27. 28 Unfortunately, the issue of different heart rate responses with different degrees of fetal hypoxia has not been directly addressed in the experimental animal. However, there is one clinical observation and several experiments in pregnant women suggesting that the integrated output to minor decremental changes in fetal P0 2 is a rise in FHR!5. 29·31 The clinical example is the well-known rise in baseline FHR of the otherwise healthy fetus to an iatrogenic increase in baseline uterine tone, which also produces minor decremental changes in fetal transcutaneous Po 2 • The human experiments have four relevant findings. First, the usual heart rate response of the normal fetus to a reduction in maternal fraction of inspired oxygen to 15% is an increase. In addition, FHR always remained within ± 15 beats· min - 1 of control and differences in response appeared related to differences in placental function. Second, vasoactive maternal stimuli produce a similar response. Third, baseline FHR usually rises when fetal transcutaneous P0 2 falls and falls when fetal transcutaneous P0 2 increases in response to changes in maternal inspired oxygen concentration. Fourth, uterine contractions are associated with increased sympathetic tone and a fall in fetal transcutaneous Po 2 , which may be associated with a rise in fetal heart rate. These data are
Volume 168 Number I, Part 1
consistent with the mechanistic interpretation presented earlier. If this interpretation is correct, then the exercises performed by the women in this study produced only minimal changes in fetal P02 whereas the transient bradycardias reported by others in response to near-maximal or maximal exercise in uncomplicated pregnancies or at lower intensities in pregnancies with potential fetal compromise 4 • 6 represent the response to a greater fall in fetal P0 2 !5. 29. 31 Other possible contributors to the observed intensitydependent increase in FHR include the following: direct physical stimulation of the fetus and/or a concomitant change in fetal behavioral state, placental transfer of maternal catecholamines and/or fetal catecholamine secretion, and an exercise-induced rise in fetal temperature. Whereas direct physical stimulation and/or a change in state may occasionally play a role, we could not substantiate that this was consistently the case. We specifically used real-time ultrasonography in the 30 intensity-controlled experiments and in an additional 37 instances at varied exercise intensities to rule out this possibility. Placental transfer of maternal catecholamines may well contribute and fetal catecholamine secretion has been shown to contribute to the fetal cardiovascular response to hypoxia!7. 28. 31 However, high fetal levels should produce bradycardia!7. 28 and placental transfer in active form appears quite limited. 32 In addition, we were unable to demonstrate a relationship between the maternal catecholamine response and the FHR response within a reasonable range of exercise intensity, and maternal blood levels were actually lower at high intensities in late gestation when the FHR response was maximal. 18 It is also clear that the FHR increases approximately 15 beats' min - I for each degree rise in temperature during labor," and it is likely that the temperature of the human fetus rises passively during maternal exercise. However, the exercise-associated rise in maternal temperature actually decreased with increasing gestation while the heart rate response increased. In addition, we have been unable to demonstrate a relationship between the magnitude of the rise in maternal temperature and the magnitude of the change in heart rate in both this and an earlier study!2 In all probability this is due to the change in the thermal response to exercise during pregnancy, which progressively reduces the thermal stress of high-intensity exercise with advancing gestation. l7 Thus, whereas these factors may well contribute to the overall FHR response, the magnitude of their contribution is below the limits of detection of the method used in this study. In summary, these experiments indicate that recreational exercise, performed by well-conditioned women at or above a baseline conditioning level in mid and late pregnancy, is normally associated with an increase in FHR. The magnitude of the increase is influenced by
FHR response to exercise
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gestational age and the intensity, type, and duration of the exercise. On the basis of this information and the known physiologic responses to exercise, we speculate that the underlying stimulus is a decrease in placental perfusion, resulting in a small decrease in fetal P0 2 • One portion of the integrated fetal response to this change in P0 2 is an increase in heart rate. REFERENCES 1. Wolfe LA, Otake PJ, Mottola MF, McGrath MJ. Physiological interactions between pregnancy and aerobic exercise. Exerc Sports Sci Rev 1989;17:295-351. 2. Sady SP, Carpenter MW. Aerobic exercise during pregnancy. Sports Med 1989;7:357-75. 3. Clapp JF. Exercise in pregnancy: a brief clinical review. Fetal Med Rev 1990;2:89-101. 4. Artal RM, Posner MD. Fetal responses to maternal exercise. In: Artal RM, Wiswell RA, Drinkwater BL, eds. Exercise in pregnancy. Baltimore: Williams & Wilkins, 1991: 213-24. 5. Palone AM, Shangold M, Paul D, Minnitti J, Weiner S. Fetal heart rate measurement during maternal exerciseavoidance of artifact. Med Sci Sports Exerc 1987;19:605. 6. Carpenter MW, Sady SP, Hoegsbert B, Sady MA, Haydon B, Coustan DR. Fetal heart rate response to maternal exertion. JAMA 1988;259:3006-9. 7. Lotgering FK, Gilbert RD, Longo LD. Maternal and fetal responses to exercise during pregnancy. Physiol Rev 1985; 65:1-36. 8. Clapp JF. The effects of exercise on uteroplacental blood flow. In: Rosenfeld CR, ed. The uterine circulation. Ithaca, New York: Perinatology Press, 1989:299-310. 9. Walker AM, Cannata J, Ritchie BC, Maloney JE. Hypotension in fetal and newborn lambs; different patterns of reflex heart rate control revealed by autonomic blockade. Bioi Neonate 1983;44:358-65. 10. Boddy K, Dawes GS, Fisher R, Pinter S, Robinson JS. Foetal respiratory movements, electrocortical and cardiovascular responses to hypoxaemia and hypercapnia in sheep. J Physiol 1974;243:599-618. 11. Walker AM, Cannata JP, Dowling MH, Ritchie BC, Maloney JE. Age-dependent pattern of autonomic heart rate control during hypoxia in fetal and newborn lambs. Bioi Neonate 1979;35: 198-208. 12. Walker AM, Cannata J, Dowling MH, Ritchie B, Malone JE. Sympathetic and parasympathetic control of heart rate in unanaesthetized fetal and newborn lambs. Bioi Neonate 1978;33: 135-43. 13. Rudolph AH, Heymann MA. Fetal and neonatal circulation and respiration. Am Rev Physiol 1974;36:187-207. 14. Seaward BL, Sleamaker RH, McAuliffe T, Clapp JF. The precision and accuracy of a portable heart rate monitor. Biomed Inst Technol 1990;24:37-41. 15. Clapp JF. The V02 max of recreational athletes before and after pregnancy. Med Sci Sports Exerc 1991;23: 1128-33. 16. Clapp JF. The course of labor after endurance exercise during pregnancy. AM J OBSTET GYNECOL 1990; 163: 1799805. 17. Clapp JF. The changing thermal response to endurance exercise during pregnancy. AM J OBSTET GYNECOL 1991; 165:1684-90. 18. Clapp JF, Capeless EL. The changing glycemic response to exercise during pregnancy. AM J OBSTET GYNECOL 1991; 165:1678-83. 19. Borg GAV. Psychophysical bases of perceived exertion. Med Sci Sports Exerc 1982;14:377-81. 20. NcArdle WD, Glaser RM, Magel JR. Metabolic and cardiorespiratory response during free swimming and treadmill walking-. J Appl Physiol 1971;30:733-8.
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21. Vokac Z, Bell H], Bautz-Holter E, Rodhal K. Oxygen uptake/heart rate relationship in leg and arm exercise, sitting and standing.] Appl Physiol 1975;39:54-9. 22. Clapp ]F. Fetal heart rate response to running in midpregnancy and late pregnancy. AM] OSSTET GYNECOL 1985; 153:251-2. 23. Vielle ]C, Hohimer AR, Buny K, Speroff L. The effect of exercise on uterine activity in the last 8 weeks of pregnancy. AM] OBSTET GYNECOL 1985;151:729-33. 24. Clapp ]F. The relationship between blood flow and oxygen consumption in the uterine and umbilical circulations. AM] OBSTET GYNECOL 1978;132:410-3. 25. Huch A, Huch R, Schneider H, Rooth G. Continuous transcutaneous monitoring of fetal oxygen tension during labor. Br] Obstet Gynaecol 1977;84(suppl 1): 1-39. 26. Bocking AD, Gagnon R, White SE, Homan], Milne KM, Richardson BS. Circulatory responses to prolonged hypoxemia in fetal sheep. AM] OBSTET GYNECOL 1988;159: 1418-24. 27. Cohen WR, Piasecki G], Jackson BT. Plasma catechol-
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28. 29.
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amines during hypoxemia in the fetal lamb. Am] Physiol 1982;243:R520-5. Cohen WR, Piasecki G], Cohn HE, Young]B,]ackson BT. Adrenal secretion of catecholamines during hypoxemia in fetal lambs. Endocrinology 1984; 114:383-90. Walker A, Maddern L, Day E, Renou P, Talbot], Wood C. Fetal scalp tissue oxygen tension measurements in relation to maternal dermal oxygen tension and fetal heart rate. ] Obstet Gynaecol Br Commonw 1971;78:1-12. Renou P, Newman W, Wood C. Autonomic control of fetal heart rate. AM] OBSTET GYNECOL 1969;105:949-53. Copher DE, Huber CPo Heart rate response of the human fetus to induced hypoxia. AM] OBSTET GYNECOL 1967;98: 320-35. Sodha R], Proegler M, Schneider H. Transfer and metabolism of norepinephrine studied from maternal-to-fetal and fetal-to-maternal sides in the in vitro perfused human placental lobe. AM] OBSTET GYNECOL 1984;148:474-81. Walker D, Walker A, Wood C. Temperature of the human fetus.] Obstet Gynaecol Br Commonw 1969;76:503-11.
Induction of endothelial cell tissue factor activity by sera from patients with antiphospholipid syndrome: A possible mechanism of thrombosis D. Ware Branch, MD," and George M. Rodgers, MD, PhDb
Salt Lake City, Utah OBJECTIVE: The hypothesis of our study is that antiphospholipid antibodies predispose to thrombosis by inducing endothelial cell tissue factor expression. STUDY DESIGN: Monolayers of cultured human umbilical vein endothelial cells were incubated for 8 hours in a medium containing 20% serum obtained either from patients with anti phospholipid antibodies (n = 11) or normal subjects (n = 8). Similar incubations were performed with immunoglobulin G fractions from either patients with anti phospholipid antibodies (n = 3) or normal subjects (n = 3). Endothelial cell tissue factor expression was measured with a tissue factor-specific chromogenic substrate assay. The results were analyzed with a two-tailed t test. RESULTS: The mean endothelial cell tissue factor expression induced by anti phospholipid sera was significantly greater than the controls (p < 0.02). Immunoglobulin experiments indicated that the factor(s) responsible for the induction of tissue factor expression resides in the immunoglobulin G fraction of the sera (p < 0.01). CONCLUSIONS: Endothelial cell tissue factor expression is induced by anti phospholipid sera, with activity residing at least in part in the immunoglobulin fraction. The induction of tissue factor by anti phospholipid sera may playa role in the thrombotic tendency Observed in patients with antiphospholipid syndrome. (AM J OBSTET GVNECOL 1993; 168:206-1 0.)
Key words: Antiphospholipid antibodies, tissue factor, thrombosis, fetal loss
From the Departments of Obstetrtcs and Gynecology, a Medicine, b and Pathology, b Unzverstty of Utah and Salt Lake Veterans Administration Medical Center. Supported In part by a grant from the Veterans AdministratIOn and a Bwmedlcal Research Support Crant from the Unzverslty of Utah (C.M.R.).
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ReceIVed for publicatIOn October 17, 1991; revised June 3, 1992; accepted June 16, 1992. Reprint requests: D. Ware Branch, MD, Room 2B200, Medical Center, 50 North Medical Dr., Salt Lake CIty, UT 84132. 6/1/40268