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Fetal heart rate accelerations and late decelerations during the course of intrauterine death in chronically catheterized rhesus monkeys
Fetal heart rate accelerations and late decelerations during the course of intrauterine death in chronically catheterized rhesus monkeys YUJI
MURATA,
CHESTER
B.
M.D. MARTIN,
TSUYOMU
IKENOUE,
TADASHI
HASHIMOTO,
SHOZO
TAIRA,
TADASHI
SAKATA,
Orange,
M.D.
M.D.
M.D.
SAGAWA,
HISAEI
JR., M.D.
M.D. M.D.
Calijomia
The appearance of late decelerations and the disappearance of accelerations in the fetal heart rate were observed during the days that preceded intrauterine fetal death in nine chronically instrumented rhesus monkeys. All nine animals had recovered satisfactorily from the initial surgical procedure, as evidenced by normal biophysical and biochemical parameters. After recovery, all the fetuses had shown accelerations and no late decelerations with spontaneous uterine contractions. The mean duration of the preparations was 16.1 days. The duration of the preterminal observation period varied from 3 to 13 days, during which time no experiments were performed. The fetuses died during labor at a mean gestational age of 143 days. Late decelerations were the first sign of fetal deterioration and occurred with a slight but significant decrease in fetal Pao2 without changes in pH, whereas accelerations in fetal heart rate were still present. The loss of accelerations in fetal heart rate was a later phenomenon and was associated with significant reductions in fetal pH and Pao,.
(AM.
J. OBSTET.
GYNECOL.
144218,
1982.)
ANTEPARTUM monitoring of the fetal heart rate in order to reduce perinatal mortality and morbidity is supported in most of the recent literature.‘, * Two currently popular techniques which are used for anteparturn surveillance of the fetus are nonstress testing and contraction stress testing of the fetal heart rate. The clinical application of these techniques, however, varies from one institution to another, and still
From the Division of Maternal and Fetal Medicine, Department of Obstetrics and Gynecology, University Calijmia, Irvine, School of Medicine.
of
Presented in part at the Twenty-eighth Annual Meeting the Society for Gynecologk Investigation, St. Louis, Missouri, March 18-21, 1981. Received for publication Revised
May
Accepted May
December
30, 1981.
12, 1982. 25, 1982.
Reprint requests: Yuji Murata, M.D., South, Orange, Calfornia 92886.
218
of
101 The City Drive
leaves unanswered the critical question of which one should be the primary test. At present, more institutions seem to apply the nonstress test as the primary test and use the contraction stress test when the result of the former is nonreactive. This protocol, if applied properly, appears to have reduced perinatal mortality and morbidity significantly.2-” Obvious advantages of this approach are that it is simpler and less expensive, requires less time, and is applicable to more patients without any contraindications. Besides a high incidence of false positive results (nonreactive record from a normal fetus), however, some reports indicate limitations of this approach and describe cases in which intrauterine fetal death occurred within a week after a reactive nonstress test.@* 7 On the other hand, the contraction stress test, even with its technical difficulties in application, has been used as a primary test for antepartum surveillance of the fetus in postterm pregnant women with an excellent perinatal outcome.s The reliability of the contraction 0002-9378/82/180218+06$00.60/0
0
1982
The
C. V. Mosby
Co.
Volume Number
FHR during course of intrauterine death
144 2
stress test has been substantiated in a recent multicenter study conducted by Freeman and associates.“* 9b They reported a large prospective comparison of two groups in which the nonstress test and contraction stress test were used separately as primary tests for antepartum surveillance of the fetus. The results indicated a statistically significant decrease in antepartum mortality in the group in which the contraction stress test was used as a primary test. Although practicality plays an important role in clinical medicine, the more important question at present seems to be which is a more sensitive indicator of fetal compromise: the appearance of late decelerations or the disappearance of accelerations. In this study, an attempt was made to answer this question by observing the natural course of intrauterine fetal death in nine chronically catheterized rhesus monkey fetuses.
Material and methods The records from nine chronically catheterized rhesus monkey fetuses were chosen to observe changes in the pattern of the fetal heart rate during the course of fetal deterioration preceding intrauterine fetal death. The surgical procedure for creation of the chronic preparation was performed between 116 and 139 days’ gestation (mean, 127 days; normal term gestation, 165 days). At operation, the catheters were inserted into a fetal carotid artery, jugular vein, and trachea, as well as a maternal femoral artery and vein. An additional open-end catheter was left inside the intrauterine cavity for the recording of amniotic fluid pressure. Electrocardiographic electrodes were attached to the fetal chest. More detailed information in regard to the surgical technique was published previously.‘” Continuous recordings of fetal heart rate, blood pressure, breathing activity, and intrauterine pressure, along with the maternal arterial blood pressure and heart rate, commenced immediately after operation and continued until intrauterine fetal death occurred. The pregnant animals were placed in a restraining chair postoperatively until the pregnancy was terminated. All nine fetuses, as well as the mothers, exhibited complete recovery from the operation and anesthesia within 24 hours, as judged by their biochemical and biophysical profiles. All nine fetuses were subjected to physiologic or pharmacologic experiments of various types, but recovery from the last experiment was documented in each case. The mother and fetus remained undisturbed thereafter for the duration of the preparation, except for periodic samplings of blood to determine fetal well-being. The fetal heart rate was obtained from the fetal elec-
Table
I. Fetal arterial
PH Pa0, (mm Hg) ho, (mm Hg)
7.37 (7.3 l-7.43) 27.6 (23.0-31.8) 29.8 (26.6-32.0)
blood
219
gas and nH values
7.32 (7.20-7.37) 23.9t (21.8-27.5) 33.9 (28.2-40.5)
7.22* (7.20-7.25) 18.7$ (15.0-25.4) 38.8 (26.0-49.5)
*P = 0.002 versus control; p = 0.048 versus appearance of late deceleration. tp = 0.041 versus control; p = 0.021 versus disappearance of acceleration. $p = 0.009 versus control; p = 0.021 versus appearance of late deceleration. trocardiogram through an instantaneous cardiotachometer. The fetal and maternal vascular catheters, and the fetal tracheal and intra-amniotic catheters were connected to the appropriate pressure transducers. All signals were continuously displayed on a multichannel strip chart recorder (Beckman Model RB Dynograph) and recorded simultaneously on magnetic tape. Samples of maternal and fetal arterial blood were drawn anaerobically into heparinized syringes. Determinations of pH, Pa,, and Pa,, were made by means of microelectrodes (Radiometer Model BMS-3) at a temperature of 38” C. Observations were carried out retrospectively, starting at the point at which both mother and fetus were physiologic and stable, as confirmed by normal blood pressures, a normal range of fetal and maternal baseline heart rates, the presence of fetal breathing movements, and the presence of accelerations and the absence of decelerations in fetal heart rate. All nine mothers showed periodic uterine activity, particularly at night. For purposes of analysis, increases in intrauterine pressure of less than 10 mm Hg intensity were not regarded as uterine contractions. Six preparations showed a typical pattern of uterine contractions that appeared approximately at 1900 hours and disappeared approximately at 0800 hours the next morning, with minimal or no activity during the daytime. In two additional cases, episodes of uterine contractions also occurred during the daytime. The other animal exhibited continuous uterine contractions during the period of observation, regardless of the time of day or night. The intensity of the uterine contractions exceeded 30 mm Hg, and the frequency became approximately three contractions per 10 minutes during periods of maximum activity. All nine fetuses died during labor. None of the animals received any tocolytic agents during the period of observation.
220
Murata et al.
September Am. J. Obstet.
15. 1982 Gynerol.
Fig. 1. A sample of the record at the beginning of the observation period from a chronically catheterized rhesus monkey fetus. From the top: Time code, Signals which were generated every I! minutes. MABP, Maternal femoral arterial blood pressure. MHR, Maternal heart rate calculated from maternal blood pressure. Fetal tracheal /n~~urr. IUP. Intrauterine pressure. FHR, Fetal heart rate obtained from fetal electrocardiogram. FABP, Fetal carotid arterial blood pressure. FE%, Fetal electrocardiogram. Accelerations in the fetal heart rate are indicated by arrows. There are no late decelerations despite spontaneous uterine contractions. The blood pressure tracing was interrupted by sampling of blood, the result of which is indicated on the FABP channel. Periods of observation differed in the individual preparations, ranging from 3 to 13 days with both the mean and median durations being 6 days. The patterns of fetal heart rate were reviewed during each 24minute epoch until fetal death. This epoch corresponded to one page of the strip chart recording. Acceleration was defined as an increase in heart rate of 12 beats per minute or more from the baseline for a period of 10 seconds or more, because these were equivalent to the smallest vertical and horizontal scales which could be read reliably from the recordings. If there were two or more accelerations with or without evidence of fetal movement, the 24-minute epoch was classified as reactive. Late deceleration was defined as a decrease in the fetal heart rate of 12 beats per minute or more from the baseline for 30 seconds or more, beginning 20 seconds or more after the onset of uterine contraction and ending after the contraction disappeared.
Results Fetal arterial blood gas and pH values obtained at the beginning of the observations were all within normal limits, as shown in Table I. At this point, all fetuses showed two or more accelerations in 24 minutes and no late decelerations despite uterine contractions (Fig. 1). During the 24-hour period in which the control sample of blood was obtained, the fetal heart rate was reactive in 94.5% of the 24-minute epochs.
Even the fetus with the shortest postoperative survival (4 days) had exhibited an evident recovery from the surgical procedure. At the beginning of the observation, pH, Pa,, and PacoL were 7.32, 24 mm Hg, and 30.3 mm Hg, respectively, and the pattern of fetal heart rate was clearly reactive. Regardless of the cause of death, all nine fetuses experienced a relatively gradual course of deterioration with progressive metabolic acidosis. After the control period, two of the fetuses went through a phase (that lasted 4 hours for one and 6 hours for the other) in which late decelerations were transiently and intermittently present but did not recur consistently with successive contractions of equivalent intensity and duration. During this phase in these two fetuses, 14% of the 24-minute epochs contained late decelerations and 96% showed reactive patterm of fetal heart rate. In the other seven fetuses, late decelerations, when they did appear, tended to recur with equivalent contractions. In all nine fetuses, accelerations were present at the time of appearance of repetitive late decelerations (Fig. 2). The fetal PaoP values that were measured at approximately the time at which persistent late deceleration appeared averaged 3.7 mm Hg lower than the control values, and exhibited a statistically significant reduction (p = 0.041 by Mann-Whitney c’ test). The changes in pH and Pacoz did not approach significance (Table I). The coexistence of late decelerations and ac-
Volume Number
FHR
144 2
during
course
of intrauterine
death
221
Fig. 2. Late record from the monkey shown in Fig. 1. At this stage, the fetus is exhibiting repetitive late decelerations in the heart rate but accelerations remain. Abbreviations are the same as in Fig. I.
Fig. 3. Still later record from the same fetus as in Figs. 1 and 2, obtained immediately prior to intrauterine fetal death. Each uterine contraction is associated with a late deceleration, and no typical accelerations are present.
celerations was a consistent finding in all of the animals studied in this series, and this phase lasted from 12 to 234 hours (mean, 80.3 hours; median, 84.8 hours). During this phase, late decelerations appeared in 66.3% of all the epochs. The proportion of reactive epochs decreased somewhat to 86.2%. Complete absence of accelerations in the fetal heart rate with persistent late decelerations was observed during the phase prior to intrauterine fetal death (Fig. 3). The beginning of this phase was associated with fetal arterial pH and Pa,, values significantly lower than
those of either the control period (p = 0.002 and p = 0.009, respectively, by Mann-Whitney U test) or the time when the late decelerations appeared (p = 0.048 and p = 0.021, respectively, by Mann-Whitney U test) (Table I). The period between the time that accelerations disappeared and fetal death occurred varied among the individual fetuses, with a range of from 4.8 to 54.4 hours (mean, 36.6 hours; median, 22.4 hours). Late decelerations were present in a total of 84% of all epochs during this period, and there were no reactive epochs.
222
Murata
et al.
September Am. J. Obstet.
Comment These observations demonstrate that, during the course of progressive hypoxia that led to fetal death over the period of 2 to 13 days, the fetuses uniformly exhibited late decelerations of fetal heart rate before the development of significant acidosis and at a time when accelerations of fetal heart rate, which generally are assumed to demonstrate absence of significant depression of function of the central nervous system, were still present. This course of events can best be explained by postulating that transient, contractionrelated periods of hypoxemia sufficient to produce reflexly mediated decelerations of fetal heart rate occurred while fetal oxygenation between contractions was adequate to maintain normal function of the central nervous system and acid-base balance. Ikenoue and associates,” using chronically catheterized rhesus monkey fetuses under physiologic conditions, reported that an acute reduction in Pao, without acidemia resulted in a decrease in baseline fetal heart rate and an increase in both the long-term and shortterm variability of fetal heart rate. They also demonstrated that pretreatment with atropine significantly modified these responses of the heart rate. The authors suggested an important role for a vagal reflex via chemoreceptors in the responses of the heart rate. Druzin and associates,‘” using a similar pregnant monkey preparation, demonstrated that the fetal baroreceptors were also involved in this response. Martin and coworkersI produced late decelerations in chronically instrumented fetal lambs by periodic occlusion of the maternal common hypogastric artery. Using a systematic approach with various autonomic blocking agents, they clearly demonstrated the important involvement of reflex mechanisms in late decelerations of the fetal heart rate in the earlier stages of hypoxemia. Advanced hypoxia associated with acidosis caused direct myocardial depression which was responsible for the late decelerations in the later stages of fetal compromise.
REFERENCES
OBSTET.
Theobservationscitedabovedemonstrated that,when oxygenation is acutely lowered, sufficiently to stimulate the fetal chemoreceptors, deceleration of the fetal heart rate can be created even in a previously uncompromised fetus. Clinical experience also has shown that an exceedingly intense or prolonged (tetanic) contraction can produce late deceleration in a healthy fetus. According to the report by Ikenoue and associates.” this
critical
GYNECOL.
156:81,
1980.
level
of
fetal
PaoP appears
to be approxi-
mately 20 mm Hg in rhesus monkey fetuses under physiologic conditions. Uterine contractions reduce the supply of oxygen to the fetus through well-known mechanisms. A late deceleration can result if either oxygen reduction is severe, as seen with tetanic contractions, or, with “normal” prelabor contractions, the fetal oxygenation is in a suboptimal state. In the present study, the mean fetal arterial Pao,! at the time of appearance of late decelerations was slightly but significantly lower than that at the beginning of the observation period. At this time, however, the level of oxygenation was sufficient to prevent the development of metabolic acidosis and, apparently, to maintain relatively normal function of the central nervous system. The mean fetal Paoz between contractions at the time of the first occurrence of late decelerations was, however, not far above the level shown by Ikenoue and associates” to activate reflex cardiac deceleration ing
in fetal
uterine
monkeys.
Thus,
contractions
decelerations
could
a small
be expected
decrease
dur-
to produce
of the fetal heart rate.
Therefore,
fetuses
with
suboptimal
oxygenation,
though showing normal biochemical and biophysical parameters under otherwise stable conditions, may exhibit late decelerations when uterine contractions even
appear. The the appearance
logical of
disappearance earlier
sign
deterioration
5. Phelan,
Schifrin, B. S., Foye, G., Amato, J., Kates, R., and MacKenna, J.: Routine fetal heart rate monitoring in the antepartum period, Obstet. Gynecol. 54:21, 1979. Freeman, R. K.: The use of the oxytocin challenge test for antepartum clinical evaluation of uteroplacental respiratory function, AM. J. OBSTET. GYNECOL. 121:481, 1975. Keegan, K. A., and Paul, R. H.: Antepartum fetal heart rate testing. IV. The nonstress, test as a primary appreach, AM. J. OBSTET. GYNECOL. 1.36:75, 1980. Keegan, K. A., Paul, R. H., Broussard, P. M., McCart, D., and Smith, M. A.: Antepartum fetal heart rate testing. V. The nonstress test-An outpatient approach, AM. J.
15. 1982 Gynecol.
conclusion, therefore, may be that late decelerations rather than the
of accelerations of
fetal seen
compromise in this
J. P.: The
of fetal heart rate is the at the
rate
of
fetal
stud).
test: A review of 3,000 tests, 139:7, 1980. Schmidt, P. L., Thorneycroft, I. M., and Goeblesmann, U.: Fetal distress following a reactive nonstress test, AM. J. OBSTET. GYNECOL. 136:960, 1980. Barrett, J. M.. Salyer, S. L., and Boem, F. H.: The nonstress test: An evaluation of 1,000 patients, AM. J. OBSTET. GYNECOL. 141:153, 1981. Freeman, R. K., Garite, T. J., Modanlou, H., Dorchester, W., Rommal, C., and Dovancy, M.: Postdate pregnancy: Utilization of contraction stress testing for primary fetal surveillance, AM. J. OBSTET. GYNECOL. 140:128, 1981. 9a. Freeman, R. K., Anderson, G., and Dorchester, W.: Prospective multi-institutional study of antepartum fetal AM. J. OBSTET.
nonstress
GYNECOL.
Volume Number
FHR
144 2
heart rate monitoring. I. Risk of perinatal mortality and morbidity according to antepartum fetal heart rate test results, AM. J. OBSTET. GYNECOL. 143:771, 1982. 9b. Freeman, R. K., Anderson, G., and Dorchester, W.: Prospective multi-institutional study of antepartum fetal heart rate monitoring. 11. Contraction stress test versus nonstress test for primary surveillance, AM. J. OBSTET. GYNECOL. 143:778, 1982. 10. Martin, C. B., Jr., Murata, Y., and Parer, J. T.: A method for obtaining biochemical and biophysical measurements from rhesus monkey fetuses for prolonged periods, AM. J. OBSTET.
Il.
GYNECOL.
Ikenoue, T., Martin, and Lu. P. S.: Effect
117:126,
1973.
C. B., Jr., Murata, of acute hypoxemia
Y., Ettinger, B., and respiratory
acidosis
during
course
of intrauterine
death
223
on the fetal heart rate in rhesus monkeys, AM. J. GYNECOL. 141:797, 1981. 12. Druzin, M., Ikenoue, T., Murata, Y., Socol, M., and Martin, C. B., Jr.: A possible mechanism for the increase in fetal heart rate variability following hypoxemia, in Scientific Abstracts, Twenty-sixth Annual Meeting of the Society for Gynecologic Investigation, San Diego, California, March 21-24, 1979. (Abst. 149.) 13. Martin, C. B., Jr., deHaan, J., van der Wildt, B., Jongsma, H. W., Dieleman, A., and Arts, T. H. M.: Mechanisms of late decelerations in the fetal heart rate. A study with autonomic blocking agents in fetal lambs, Eur. J. Obstet. Gynaecol. Reprod. Biol. 9:361, 1979. OBSTET.
MURATA,
CHESTER
B.
M.D. MARTIN,
TSUYOMU
IKENOUE,
TADASHI
HASHIMOTO,
SHOZO
TAIRA,
TADASHI
SAKATA,
Orange,
M.D.
M.D.
M.D.
SAGAWA,
HISAEI
JR., M.D.
M.D. M.D.
Calijomia
The appearance of late decelerations and the disappearance of accelerations in the fetal heart rate were observed during the days that preceded intrauterine fetal death in nine chronically instrumented rhesus monkeys. All nine animals had recovered satisfactorily from the initial surgical procedure, as evidenced by normal biophysical and biochemical parameters. After recovery, all the fetuses had shown accelerations and no late decelerations with spontaneous uterine contractions. The mean duration of the preparations was 16.1 days. The duration of the preterminal observation period varied from 3 to 13 days, during which time no experiments were performed. The fetuses died during labor at a mean gestational age of 143 days. Late decelerations were the first sign of fetal deterioration and occurred with a slight but significant decrease in fetal Pao2 without changes in pH, whereas accelerations in fetal heart rate were still present. The loss of accelerations in fetal heart rate was a later phenomenon and was associated with significant reductions in fetal pH and Pao,.
(AM.
J. OBSTET.
GYNECOL.
144218,
1982.)
ANTEPARTUM monitoring of the fetal heart rate in order to reduce perinatal mortality and morbidity is supported in most of the recent literature.‘, * Two currently popular techniques which are used for anteparturn surveillance of the fetus are nonstress testing and contraction stress testing of the fetal heart rate. The clinical application of these techniques, however, varies from one institution to another, and still
From the Division of Maternal and Fetal Medicine, Department of Obstetrics and Gynecology, University Calijmia, Irvine, School of Medicine.
of
Presented in part at the Twenty-eighth Annual Meeting the Society for Gynecologk Investigation, St. Louis, Missouri, March 18-21, 1981. Received for publication Revised
May
Accepted May
December
30, 1981.
12, 1982. 25, 1982.
Reprint requests: Yuji Murata, M.D., South, Orange, Calfornia 92886.
218
of
101 The City Drive
leaves unanswered the critical question of which one should be the primary test. At present, more institutions seem to apply the nonstress test as the primary test and use the contraction stress test when the result of the former is nonreactive. This protocol, if applied properly, appears to have reduced perinatal mortality and morbidity significantly.2-” Obvious advantages of this approach are that it is simpler and less expensive, requires less time, and is applicable to more patients without any contraindications. Besides a high incidence of false positive results (nonreactive record from a normal fetus), however, some reports indicate limitations of this approach and describe cases in which intrauterine fetal death occurred within a week after a reactive nonstress test.@* 7 On the other hand, the contraction stress test, even with its technical difficulties in application, has been used as a primary test for antepartum surveillance of the fetus in postterm pregnant women with an excellent perinatal outcome.s The reliability of the contraction 0002-9378/82/180218+06$00.60/0
0
1982
The
C. V. Mosby
Co.
Volume Number
FHR during course of intrauterine death
144 2
stress test has been substantiated in a recent multicenter study conducted by Freeman and associates.“* 9b They reported a large prospective comparison of two groups in which the nonstress test and contraction stress test were used separately as primary tests for antepartum surveillance of the fetus. The results indicated a statistically significant decrease in antepartum mortality in the group in which the contraction stress test was used as a primary test. Although practicality plays an important role in clinical medicine, the more important question at present seems to be which is a more sensitive indicator of fetal compromise: the appearance of late decelerations or the disappearance of accelerations. In this study, an attempt was made to answer this question by observing the natural course of intrauterine fetal death in nine chronically catheterized rhesus monkey fetuses.
Material and methods The records from nine chronically catheterized rhesus monkey fetuses were chosen to observe changes in the pattern of the fetal heart rate during the course of fetal deterioration preceding intrauterine fetal death. The surgical procedure for creation of the chronic preparation was performed between 116 and 139 days’ gestation (mean, 127 days; normal term gestation, 165 days). At operation, the catheters were inserted into a fetal carotid artery, jugular vein, and trachea, as well as a maternal femoral artery and vein. An additional open-end catheter was left inside the intrauterine cavity for the recording of amniotic fluid pressure. Electrocardiographic electrodes were attached to the fetal chest. More detailed information in regard to the surgical technique was published previously.‘” Continuous recordings of fetal heart rate, blood pressure, breathing activity, and intrauterine pressure, along with the maternal arterial blood pressure and heart rate, commenced immediately after operation and continued until intrauterine fetal death occurred. The pregnant animals were placed in a restraining chair postoperatively until the pregnancy was terminated. All nine fetuses, as well as the mothers, exhibited complete recovery from the operation and anesthesia within 24 hours, as judged by their biochemical and biophysical profiles. All nine fetuses were subjected to physiologic or pharmacologic experiments of various types, but recovery from the last experiment was documented in each case. The mother and fetus remained undisturbed thereafter for the duration of the preparation, except for periodic samplings of blood to determine fetal well-being. The fetal heart rate was obtained from the fetal elec-
Table
I. Fetal arterial
PH Pa0, (mm Hg) ho, (mm Hg)
7.37 (7.3 l-7.43) 27.6 (23.0-31.8) 29.8 (26.6-32.0)
blood
219
gas and nH values
7.32 (7.20-7.37) 23.9t (21.8-27.5) 33.9 (28.2-40.5)
7.22* (7.20-7.25) 18.7$ (15.0-25.4) 38.8 (26.0-49.5)
*P = 0.002 versus control; p = 0.048 versus appearance of late deceleration. tp = 0.041 versus control; p = 0.021 versus disappearance of acceleration. $p = 0.009 versus control; p = 0.021 versus appearance of late deceleration. trocardiogram through an instantaneous cardiotachometer. The fetal and maternal vascular catheters, and the fetal tracheal and intra-amniotic catheters were connected to the appropriate pressure transducers. All signals were continuously displayed on a multichannel strip chart recorder (Beckman Model RB Dynograph) and recorded simultaneously on magnetic tape. Samples of maternal and fetal arterial blood were drawn anaerobically into heparinized syringes. Determinations of pH, Pa,, and Pa,, were made by means of microelectrodes (Radiometer Model BMS-3) at a temperature of 38” C. Observations were carried out retrospectively, starting at the point at which both mother and fetus were physiologic and stable, as confirmed by normal blood pressures, a normal range of fetal and maternal baseline heart rates, the presence of fetal breathing movements, and the presence of accelerations and the absence of decelerations in fetal heart rate. All nine mothers showed periodic uterine activity, particularly at night. For purposes of analysis, increases in intrauterine pressure of less than 10 mm Hg intensity were not regarded as uterine contractions. Six preparations showed a typical pattern of uterine contractions that appeared approximately at 1900 hours and disappeared approximately at 0800 hours the next morning, with minimal or no activity during the daytime. In two additional cases, episodes of uterine contractions also occurred during the daytime. The other animal exhibited continuous uterine contractions during the period of observation, regardless of the time of day or night. The intensity of the uterine contractions exceeded 30 mm Hg, and the frequency became approximately three contractions per 10 minutes during periods of maximum activity. All nine fetuses died during labor. None of the animals received any tocolytic agents during the period of observation.
220
Murata et al.
September Am. J. Obstet.
15. 1982 Gynerol.
Fig. 1. A sample of the record at the beginning of the observation period from a chronically catheterized rhesus monkey fetus. From the top: Time code, Signals which were generated every I! minutes. MABP, Maternal femoral arterial blood pressure. MHR, Maternal heart rate calculated from maternal blood pressure. Fetal tracheal /n~~urr. IUP. Intrauterine pressure. FHR, Fetal heart rate obtained from fetal electrocardiogram. FABP, Fetal carotid arterial blood pressure. FE%, Fetal electrocardiogram. Accelerations in the fetal heart rate are indicated by arrows. There are no late decelerations despite spontaneous uterine contractions. The blood pressure tracing was interrupted by sampling of blood, the result of which is indicated on the FABP channel. Periods of observation differed in the individual preparations, ranging from 3 to 13 days with both the mean and median durations being 6 days. The patterns of fetal heart rate were reviewed during each 24minute epoch until fetal death. This epoch corresponded to one page of the strip chart recording. Acceleration was defined as an increase in heart rate of 12 beats per minute or more from the baseline for a period of 10 seconds or more, because these were equivalent to the smallest vertical and horizontal scales which could be read reliably from the recordings. If there were two or more accelerations with or without evidence of fetal movement, the 24-minute epoch was classified as reactive. Late deceleration was defined as a decrease in the fetal heart rate of 12 beats per minute or more from the baseline for 30 seconds or more, beginning 20 seconds or more after the onset of uterine contraction and ending after the contraction disappeared.
Results Fetal arterial blood gas and pH values obtained at the beginning of the observations were all within normal limits, as shown in Table I. At this point, all fetuses showed two or more accelerations in 24 minutes and no late decelerations despite uterine contractions (Fig. 1). During the 24-hour period in which the control sample of blood was obtained, the fetal heart rate was reactive in 94.5% of the 24-minute epochs.
Even the fetus with the shortest postoperative survival (4 days) had exhibited an evident recovery from the surgical procedure. At the beginning of the observation, pH, Pa,, and PacoL were 7.32, 24 mm Hg, and 30.3 mm Hg, respectively, and the pattern of fetal heart rate was clearly reactive. Regardless of the cause of death, all nine fetuses experienced a relatively gradual course of deterioration with progressive metabolic acidosis. After the control period, two of the fetuses went through a phase (that lasted 4 hours for one and 6 hours for the other) in which late decelerations were transiently and intermittently present but did not recur consistently with successive contractions of equivalent intensity and duration. During this phase in these two fetuses, 14% of the 24-minute epochs contained late decelerations and 96% showed reactive patterm of fetal heart rate. In the other seven fetuses, late decelerations, when they did appear, tended to recur with equivalent contractions. In all nine fetuses, accelerations were present at the time of appearance of repetitive late decelerations (Fig. 2). The fetal PaoP values that were measured at approximately the time at which persistent late deceleration appeared averaged 3.7 mm Hg lower than the control values, and exhibited a statistically significant reduction (p = 0.041 by Mann-Whitney c’ test). The changes in pH and Pacoz did not approach significance (Table I). The coexistence of late decelerations and ac-
Volume Number
FHR
144 2
during
course
of intrauterine
death
221
Fig. 2. Late record from the monkey shown in Fig. 1. At this stage, the fetus is exhibiting repetitive late decelerations in the heart rate but accelerations remain. Abbreviations are the same as in Fig. I.
Fig. 3. Still later record from the same fetus as in Figs. 1 and 2, obtained immediately prior to intrauterine fetal death. Each uterine contraction is associated with a late deceleration, and no typical accelerations are present.
celerations was a consistent finding in all of the animals studied in this series, and this phase lasted from 12 to 234 hours (mean, 80.3 hours; median, 84.8 hours). During this phase, late decelerations appeared in 66.3% of all the epochs. The proportion of reactive epochs decreased somewhat to 86.2%. Complete absence of accelerations in the fetal heart rate with persistent late decelerations was observed during the phase prior to intrauterine fetal death (Fig. 3). The beginning of this phase was associated with fetal arterial pH and Pa,, values significantly lower than
those of either the control period (p = 0.002 and p = 0.009, respectively, by Mann-Whitney U test) or the time when the late decelerations appeared (p = 0.048 and p = 0.021, respectively, by Mann-Whitney U test) (Table I). The period between the time that accelerations disappeared and fetal death occurred varied among the individual fetuses, with a range of from 4.8 to 54.4 hours (mean, 36.6 hours; median, 22.4 hours). Late decelerations were present in a total of 84% of all epochs during this period, and there were no reactive epochs.
222
Murata
et al.
September Am. J. Obstet.
Comment These observations demonstrate that, during the course of progressive hypoxia that led to fetal death over the period of 2 to 13 days, the fetuses uniformly exhibited late decelerations of fetal heart rate before the development of significant acidosis and at a time when accelerations of fetal heart rate, which generally are assumed to demonstrate absence of significant depression of function of the central nervous system, were still present. This course of events can best be explained by postulating that transient, contractionrelated periods of hypoxemia sufficient to produce reflexly mediated decelerations of fetal heart rate occurred while fetal oxygenation between contractions was adequate to maintain normal function of the central nervous system and acid-base balance. Ikenoue and associates,” using chronically catheterized rhesus monkey fetuses under physiologic conditions, reported that an acute reduction in Pao, without acidemia resulted in a decrease in baseline fetal heart rate and an increase in both the long-term and shortterm variability of fetal heart rate. They also demonstrated that pretreatment with atropine significantly modified these responses of the heart rate. The authors suggested an important role for a vagal reflex via chemoreceptors in the responses of the heart rate. Druzin and associates,‘” using a similar pregnant monkey preparation, demonstrated that the fetal baroreceptors were also involved in this response. Martin and coworkersI produced late decelerations in chronically instrumented fetal lambs by periodic occlusion of the maternal common hypogastric artery. Using a systematic approach with various autonomic blocking agents, they clearly demonstrated the important involvement of reflex mechanisms in late decelerations of the fetal heart rate in the earlier stages of hypoxemia. Advanced hypoxia associated with acidosis caused direct myocardial depression which was responsible for the late decelerations in the later stages of fetal compromise.
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GYNECOL.
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level
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