Acta pbysiol. scand. 1975. 93. 59-66 From the Department of Physiology and t h e Department of Pediatrics I. University

of Goteborg. Sweden

Changes in the Fetal Heart Rate and ECG during Hypoxia BY

K. G. R O S ~ AND N I. KJELLMER Received 25 May 1974

Abstract R O S ~ NK. G. and I. KJELLMER. Changes in the fetal heart rate and ECG during hypoxia. Acta physiol. scand. 1975. 93. 59-66. Previous reports on the fetal hypoxic bradycardia in animals have indicated, that there is a vagal influence, especially when asphyxia is induced by umbilical cord occlusion. In the present study hypoxia was induced oia the mother, thus keeping the fetal circulation intact. The experiments were conducted on mature fetuses of three different species, namely 20 guinea-pig, 3 cat and 3 lamb fetuses. The ECG was recorded continuously and used for measuring the fetal heart rate. The vagal influence on the fetal hypoxic bradycardia was tested by comparing the time for the onset of the bradycardia with or without v a p l activity. There was no indication of any vagal component in the fetal hypoxic bradycardia, which is therefore to be regarded rather as a sign of myocardial hypoxia and failing fetal circulation. The ECG recordings showed that the fetal bradycardia initially is an AV-block, type 11, and that there are progressive changes in the S-T interval as an early sign of hypoxia.

Continuous fetal heart rate (FHR) monitoring is today the most used way to study the fetal situation during labour. Clinical investigations by e.g. Caldeyro-Barcia et a]. (1966) and Hon (1959) have shown that when the fetus reacts with intense bradycardia, this response is well correlated to the degree of fetal hypoxia and acidosis. It is, however, remarkable that, in spite of its great clinical importance, the mechanism behind this fetal bradycardia is still incompletely known. Several studies on the vagal influence on FHR in different animals have been performed. Thus, Barcroft (1946) demonstrated that the fetal lamb reacted with a rapidly developing, vagally mediated bradycardia during occlusion of the umbilical cord. The mechanism behind was supposed to be a baroreceptor reflex because of the increase in arterial blood pressure associated with the bradycardia. After bilateral vagotomy the lamb fetus reacted with a more slowly developing anoxic type of bradycardia. By selective occlusions of the umbilical artery and vein in the lamb fetus Reynolds (1954) showed that occlusion of the umbilical vein led to a rapidly developing bradycardia in spite of a decrease in blood pressure, while he observed the same response as Barcroft (1946) on selective occlusion of the umbilical artery. The findings were essentially the same after bilateral 59


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vagotomy though with a more delayed slowing of the heart in connection with the development of anoxia. Fetal rabbits were studied by Bauer (1938), observing a non-vagal bradycardia during umbilical cord occlusion and that asphyxia led to vagal bradycardia first when the newborn rabbit was about 10 days of age. This would indicate that the degree of neurological maturity is one factor which could explain the difference in vagal activity. The results of Barcroft (1946) and Reynolds (1954), mentioned above indicate that umbilical cord occlusion, with interruption of the circulation over the placenta which receives over 50 per cent of cardiac output, leads to extensive redistributions of blood flow to other vascular beds. Accordingly, marked changes in arterial and venous pressures are also induced, activating arterial, venous and/or cardiac mechanoreceptors leading to a reflex in which vagal bradycardia is one component. Therefore, the umbilical circulation must be kept intact in case adequate studies on the fetal circulatory regulation during graded hypoxia are to be performed. Moreover, during umbilical cord occlusion hypoxia is inevitably accompanied by an increase in the CO, tension of the fetal blood. This means that hypoxia has to be induced via the mother, for instance by letting her breathe a gas mixture with a low oxygen concentration. This approach was used by Reynolds (1958) in fetal lambs, showing that the fetus exhibited an increased tendency to react with bradycardia when the ewe was given gas mixtures with low oxygen tension and atropine given during the bradycardia resulted in some increase in FHR. One mechanism behind such a vagal hypoxic bradycardia could be a stimulation of left ventricular distension receptors, studied by Thorkn (1972) in adult cats. These receptors are activated also by severe asphyxia causing ventricular dilatation leading to reflex vagal bradycardia among other things. The purpose of the present investigation was to explore in more detail to what extent vagal activation contributed to the fetal bradycardia when hypoxia was induced during intact umbilical circulation.

Methods The experiments were conducted on 3 different animal species, namely guinea-pig, lamb and cat fetuses. 18 pregnant guinea-pigs with 20 fetuses were the main experimental material. The gestational age ranged from 55 to 64 days (term about 65 days). This was estimated from the weight of the mother (over I 100 g) and the mean fetal weight, using standard curves from Draper (1920). The neurological maturity could roughly be tested by watching the strong fetal movements as a response to mechanical stimulation. The guinea-pig mother was anesthetized with ether as an induction and then tracheotomized. After cannulation of a carotid artery, anesthesia was maintained with urethane (200 mg/ml) in small doses (at a total of 1.0 g/kg). Maternal blood pressure was measured from one carotid artery and recorded on a Grass polygraph 7 A recorder by means of a Statham pressure transducer. From the same artery blood gas samples were taken during the hypoxic periods. The fetus was taken out by a midline cesarean incision, placed on a disc and immediately covered with pads soaked in warm saline. The temperature was kept at about 38°C by radiation. To prevent the fetus from breathing a rubber bag was placed firmly over its nose. During the entire experiment great care was taken to prevent tension upon the umbilical cord. Both vagal nerves were dissected free and, in most experiments, placed on small probes which could be cooled down to 0°C by perfusing them with a mixture of ice-water and alcohol. In this way reversible vagal block could be induced. In some cases bilateral cervical vagotomy was performed instead. In only a few



experiments it was possible to cannulate the right carotid artery allowing a direct recording of fetal blood pressure. The fetal heart rate was monitored from the ECG, which was recorded as a precordial lead with crocodile clips placed on the left part of the chest and on both right legs. The ECG impulses were recorded o n a Grass polygraph 7 A recorder. The guinea-pig mother was artificially ventilated throughout the experiment. Blood gas analyses were made in order to control the respiratory status. Gas mixtures with an oxygen concentration of 3 to 10 per cent were given to the mother via a ventilator. The ECG was recorded every 15 s during a period of 5 s. After 60 to 90 s of hypoxia arterial blood gas samples were taken and analyses for blood gas tensions and p H were immediately made at 38°C with a Radiometer pHM27GM. using standard Por and PCO,electrodes. The hypoxic period was stopped after 3 to 5 min, or when there was a marked decrease in FHR. A control period of 10-15 min was inserted between the hypoxic periods. The fetuses were randomly exposed to hypoxia with o r without vagal block. Parallel experiments were performed also on 3 mature cat fetuses and 3 lamb fetuses (120-130 days of gestation, term at 145-150 days). The anesthesia and preparation methods of the lamb experiments have been described in a previous report by Kjellmer er al. (1974). ECG recordings were also made during the lamb experiments. In the cat and lamb experiments, FHR was measured on the Polygraph recorder by a tachograph, that was triggered by the arterial pressure.

Results The duration of the hypoxic periods varied between 3 to 5 min and hypoxia was stopped when a marked bradycardia could be seen, which was usually quite sudden in onset rather than gradual. A total number of 23 equivalent hypoxic periods were recorded, with or without intact vagal control. The vagal effect on the fetal hypoxic bradycardia was tested by comparing the time for the onset of the bradycardia when the vagal nerves were intact or not. The maximal range on time difference was 45 s and when calculating the mean time difference there was no difference to be seen, neither was there any increased reduction of the FHR with or without intact vagal control. Maternal arterial bloodgasanalysis were made in order to measure the extent of fetal hypoxic stress. However, when comparing the time for the onset of fetal bradycardia with the maternal blood gas values, there was no regular correlation between them. The ECG recordings then provided more information than the mere recording of heart rate alone and the different ECG components could usually be clearly identified. Fig. 1 shows an example of a moderate hypoxic period recorded in a mature guinea-pig fetus. There is a slight decrease in heart rate and blood pressure, but no more intense bradycardia was obtained. However, progressive changes in the ECG were quite obvious in the form of an increased T-wave amplitude and an elevation of the S-T segment, the latter phenomenon being regularly observed. In some experiments, negative T-wave changes could be recorded instead. As can be seen in Fig. 1, these ECG changes are normalized during the recovery period. Fig. 2 shows ECG recordings from three guinea-pig fetuses where the abrupt onset of bradycardia is obvious. The figure demonstrates that the fetuses reacted with an AV-block, type 11, during the initial phase of bradycardia. The hypoxic T-wave changes are also demonstrated. No differences were observed in the occurrence of these ECG changes when vagotomy was performed. Dropped beats could be seen as an early sign of hypoxia.



beat8 l mRATE HEART ln

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i ' t ; ' 3' ' " 4 '

Maternal blobd gar aomple at lmin 458sc of hypoxia; Pgl=37,=to.-P ,

5 38, p H x 7 . 3 4

Fig. I . Effect of moderate hypoxia in a mature guinea-pig fetus. Note the progressive changes in the configuration of the ECG.

As previously stated, the hypoxic S-T elevation was a constant finding, and in Fig. 3 some examples of the time relationship between the onset of these changes and the fetal

bradycardia are shown. In moderate degrees of hypoxia, (i.e. pH 2 7.26 and PaO, > 30 mm Hg) no bradycardia occurred in spite of marked changes in the S-T interval. When the fetal hypoxic stress was increased at still more lowered maternal pH and PaO,, the S-T changes remained an earlier sign of fetal hypoxia than bradycardia. In some cases hypoxic S-T changes could be seen already at the beginning of the hypoxic period. These fetuses had previously been exposed to a hypoxic period. In those cases where arterial blood pressure could be measured (10 hypoxic periods), the fetus reacted with a marked pressure fall in association with the bradycardia. No consistent changes in blood pressure could be obtained w k n only S-T changes were recorded. In Fig. 4 recordings in a mature lamb fetus during grave hypoxia (7% 0,) is shown, still without any signs of a vagally mediated bradyc?rdia. Instead it seems as if the vagal blockade leads to a fall in blood pressure in association with a bradycardia response. With

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FETUS 60 DAYS, 6 % 0, Moternol blood gos sample


Pao,= 36, Paco,=41,










p H = 7.14

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FETUS 56 DAYS, 69/00: Molernal blood gos sample ; Pao,=27, Poco,= 51, p H = 7.16



FETUS 6 4 DAYS, 3%0, Maternal blood gos sample;





bol; 17, poco,= 38, p~ = 727

Fin. - 2. Recordinas - of the abruot onset of the bradycardia in three guinea-pig fetuses. The AV-block, type 11, is demonstrated together with hypoxic T-wave changes.






Fig. 3. Figure showing the time relationship between the onset of the hypoxic S-T changes and the fetal bradycardia compared with the maternal pH values.











I Minutes 2of hypoxia




Time for earliest changes in the ST-period 0 Tlme for bradycardia

intact vagal function the fetus reacts with initial increases in blood pressure and heart rate, followed by a gradual decrease in blood pressure here associated with a tachycardia, which eventually turns abruptly into a marked bradycardia. Also in the lamb experiments the hypoxic S-T changes can be easily and clearly recorded. AV-block, type 11, has also been recorded during the initial bradycardia. 3 pregnant cats were also investigated. Fig. 5 shows one experiment where the fetuses after preparation were replaced in the uterus. The carotid artery was cannulated, and blood pressure and heart rate were recorded. In fetus I the vagal nerves were kept intact, while they were cut in fetus 11. Simultaneously with the onset of bradycardia there

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- - - 1"




HEART RATE beats l m i n





Fig. 4. Effect of grave hypoxia in a mature lamb fetus with or without vagal activity. Note the vagal effect on the FHR and blood pressure during the initial phase of the hypoxic periods.



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7% 02 TIME. I min






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BP mm Hg






MOTHER 300 HR beats/mln

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40 1


300 1



6 % 02 TIME,lmin

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Fig. 5. Effect of hypoxia during intrauterine conditions in two cat fetuses. In fetus I the vagal nerves were kept intact, while in fetus I1 they were cut.

is a fall in blood pressure which then is kept at a fairly constant level until the mother is given air for breathing. No vagally mediated contribution to the bradycardia response to hypoxia could be seen. The bradycardia was here more marked and appeared about 30 s earlier during 3 % 0 2 hypoxia compared with 6% 02.

Discussion The main purpose of the present study was to test whether maternally induced fetal hypoxia gives rise to any vagally mediated bradycardia or not. For these purposes three different species of animals were investigated. Both the lamb and the guinea-pig fetus can be regarded as neurologically mature, while the cat fetus is in this respect more immature at term. The degree of neurological maturity is one factor that may strongly influence the fetal circulatory response to hypoxic stress. However, in none of these species were there any signs of a vagally mediated component in the bradycardia response elicited by a maternally induced hypoxia. It is, on the other hand, clearly demonstrated in earlier studies (Barcroft 1947, Reynolds 1954), that the lamb fetus has an ability to react with an increased vagal activity, leading to a bradycardia when hypoxia is induced by umbilical cord occlusion. Thus, the degree of neurological maturity could not explain why no vagal bradycardia was observed in the present experiments. It has previously been stated by Sholander (1960), that the fetal bradycardia may be



considered as a form of a diving reflex. This reflex is, among other things, a vagal reflex in association with intense neurogenic vasoconstriction, which enables diving animals like seals to reduce and redistribute their cardiac output to favour only the vitally most important organs, the heart and the brain, leading to the most beneficial utilization of the large quantity of oxygen stored in the lungs and the blood. However, the fetus has no such oxygen stores available and must instead utilize anaerobic glycolysis as its main energy source. It has been demonstrated by Dawes et al. (1963) that a correlation exists between survival time and myocardial glycogen stores, and it has also been reported by Su and Friedman (1973) that the fetal heart is more capable of, and dependent on, glycolytic than aerobic metabolism during hypoxia as compared to the adult heart. Thus there is not the same need for oxygen conserving reflex adjustments in the fetus, where a high blood flow to the vital organs may be more important in terms of eliminating anaerobic waste products, like lactate. If so the non vagal fetal bradycardia should be a sign of myocardial hypoxia and failing fetal circulation. Thus, no vagal component could be recorded in any of the three species of animals investigated, and it seems as if the vagal bradycardia previously recorded during umbilical cord occlusion rather implies a reflex brought about by haemodynamic changes, and not by hypoxia alone. Activation of the left ventricular distension receptors could be one mechanism behind this type of bradycardia but they d o not seem to be activated when hypoxia is induced viu the mothcr and the fetal circulation kept intact. The lamb experiments suggest the presence of vagal afferent impulses, blocked by cervical vagotomy, which induced stimulation of the vasomotor center during grave hypoxia, resulting in reflex tachycardia and increased blood pressure. Activated aortic chemoreceptors are likely to be the cause of this effect. The fetal hypoxic bradycardia was, as mentioned, essentially the result of AV-block, type 11. The mechanism behind this could be that the atrial myocardium has a higher tolerance against hypoxic stress than the ventricular myocardium. Su and Friedman (1973) showed that an isolated spontaneously beating SA node-right atrial strip had a greater ability to withstand profound hypoxia compared with a ventricular myocardial strip tested, under the same conditions for generating contractile force. The AV-block could also be explained by a low hypoxic tolerance of the AV-node. The continuous fetal ECG recordings made during the experiments gave also another interesting item of information, namely the progressive hypoxic changes in the S-T interval occurring well in advance of any bradycardia and fairly well reflecting the degree of hypoxia. The S-T interval represents the repolarization of the myocardium, which is regarded as an active process. T-wave variations may be of two basic typzs: The first type depends upon accompanying variations in the sequence of ventricular depolarization, represented in the QRS complex. The other o x o c w s independmtly of QRS and is mainly the result of haemodynamic, metabolic, electrolyte or other functional abnormalities. The hypoxic S-T changes are to be assigned to this latter group and, judging from the very marked increase in T-wave amplitude, a rise in plasma potassium may be one of the underlying mechanisms. Since the pattern of ECG changes was unaffected by vagotomy a vagal component of these changes can be ruled out. 5 - 755871


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In conclusion This investigation on guinea-pig, lamb and cat fetuses has shown that no sign of any vagal component was present in the bradycardia response to hypoxia, when induced via the mother thus leaving the umbilical cord intact. Continuous fetal ECG recordings during hypoxia showed that the fetal bradycardia, usually abrupt in onset, is due to an AV-block, type 11, and that there are progressive changes in the S-T interval which can serve as the most early sign of hypoxia in the fetus. This study was supported by a grant from the Medical Faculty, Goteborg and from the Swedish Medical Research Council No 19X-259 I.

References BARCROFT, J., Researches on prenatal life. Oxford: Blackwell Scientific Publ. 1946. BAUER,D. J., The effect of asphyxia upon the heart rate of rabbits at different ages. J. fhysiol. (Lond.) 1938. 93. 90-103. CALDEYRO-BARCIA, R., C. M~NDEZ-BAUER, J. J. POSEIRO, L. A. ESCARCENA, S. V. Pos~,J. BIENIARZ, I. ARNT,L. G U L I Nand 0. ALTHABE, Control of human fetal heart rate during labor. In Cassels, D. E. (ed.): The Heart and Circulation in the Newborn and Infant. New York: Grune & Stratton, Inc. 1966. 7-36.

DAWES,G. S., H. N. JAKOBSON, J. C. MOTT,H. J. SHELLEY and A. STAFFORD, The treatment of asphyxiated mature foetal lambs and rhesus monkeys with intravenous glucose and sodium carbonate. J. fhysiol. (Lond.) 1963. 169. 167-184. DRAPER,R. L., The prenatal growth of the guinea-pig. Anat. Rec. 1920. 13. 369-392. HON,E. H.,Observations on “pathologic” fetal bradycardia. Amer. J. Obsiei. Gynec. 1959. 77. 1084-1092. KJELLMER. I., K. KARLSSON, T. OLSSONand K. G. R O S ~ N Cerebral , reactions during intra-uterine asphyxia in the sheep. 1. Circulation and oxygen consumption in the fetal brain Pediarr. Res. 1974. 8. 50-57. S. R. M., Bradycardia in the lamb fetus in responsetocirculatory distress. Amer. J. fh.vsio1. 1954. REYNOLD;, 176. 169-174. R E Y N O L ~S.S ,R. M. and W. M. PAUL,Relation of bradycardia and blood pressure of the fetal lamb in utero to mild and severe hypoxia. Amer. J. fhysiol. 1958. 193. 249-256. SCHOLAYDER, P. F., Experimental studies on asphyxia in animals. In J. Walker and A. C. Turnbull (eds.). Oxygen Supply to the Foetus. 1960. 267-274.

Su, J. Y. and W. F. FRIEDMAN, Comparison of the responses of fetal and adult cardiac muscle to hypoxia. Atner. J . fhysiol. 1973. 224. 1249-1253. THOR~N P.,, Left ventricular receptors activated by severe asphyxia and by coronary artery occlusion. Acta physiol. srand. 1972. 85. 455-163.

Changes in the fetal heart rate and ECG during hypoxia.

Previous reports on the fetal hypoxic bradycardia in animals have indicated, that there is vagal influence, especially when asphyxia is induced by umb...
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