FETAL BREATHING K. Boddy & G. S. Dawes

FETAL BREATHING K. BODDY* M.B. B.S. M.R.C.O.G. G. S. DAWES D.M. F.R.S. The Nuffield Institute for Medical Research University of Oxford The fetal electrccorticogram and diurnal rhythms Changes in blood gases, hypoglycaemia and parturition Development of a clinical method for measuring human fetal breathing by ultrasound Diurnal variations in human fetal breathing Clinical observations on fetal breathing in man a In labour b The high-risk fetus: antenatal monitoring c Prediction of fetal distress in labour Drug actions Breathing after birth References

episodic movements was unrelated to the fetal carotid blood gas values (Dawes, Fox, Leduc, Liggins & Richards, 1970, 1972a; Merlet, Hoerter, Dcvilkneuve & Tchobroutsky, 1970). Fetal breathing movements were accompanied by comparatively small alterations of pulmonary volume recorded from an electromagnetic flowmeter implanted in the trachea. The movements were insufficient to clear the tracheal dead space, and were therefore consistent with observations, previously made on animals and man, that introduction of radio-opaque contrast medium into the amniotic sac led to its appearance in the gastrointestinal tract but not in the lungs. Identification of the negative changes in thoracic pressure in fetal lambs in utero with movements of the thoracic cage was confirmed by the delivery of mature fetal lambs into a warm saline bath some days after implantation of the catheters. The pressure changes could then be correlated with gross movements of the chest wall observed directly; these were similar in character to those in human infants with respiratory distress. It was concluded from these observations that the respiratory movements were due to simultaneous activity in the diaphragm and the intercostal muscles. This was consistent with observations made in younger lambs, in which the thinness of the skin permitted observation of the underlying muscles and ribs. 1. The Fetal Electrocorticogram and Diurnal Rhythms

Fetal breathing movements in utero have been reported in man and animals from time to time during the last 80 years. The observations of Ahlfeld (1905) were evidently disbelieved by his contemporaries. Later accounts of breathing movements in fetuses of different species observed at Caesarean section were attributed to exposure, tactile or asphyxial stimuli (Windle, 1940), criticisms which were difficult to meet until the introduction of improved methods for measuring blood gas values and for implanting catheters chronically, in the 1960s. Nevertheless, it seemed surprising that the respiratory system, on which the mammal depends for survival after birth, should attain such postnatal competence without prenatal practice. Barcroft (1946) had concluded, from observations made on premature lambs delivered under spinal anaesthesia into a warm saline bath, that respiratory movements were not normally present between the ages of 40 days' and 60 days* gestation, but that they could be induced by application of tactile stimuli to the face. After 60 days the lambs were unresponsive; breathing movements began only after birth. In the autumn of 1969 these experiments were repeated; the fetus was delivered with intact umbilical cord into a warm saline bath, in which it was not restrained. Episodic respiratory movements were present in all fetuses, increasing in size and frequency from 40 to 100 days' gestation (term is 147 days). Using the sensitive membrane manometers that had not been available to Barcroft, it was observed that the application of tactile stimuli usually caused expiratory, not inspiratory, efforts. Asphyxia caused cessation of these episodic breathing movements and the institution of gasping (Dawes, Fox & Richards, 1972b). The next step taken was to implant catheters to record fetal intrathoracic pressures in utero. Rapid irregular respiratory movements were present for up to two-fifths of the time, and brief gasps also were seen. The appearance or cessation of these •Present addreu: Department of Obstetrics «nd Oyn«ecology, Univenity o f Edinburgh

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It was known that mature fetal lambs delivered with intact umbilical cords and restrained, either in a saline bath or on a warm table top, did not normally make breathing movements. Also, in chronically maintained fetal sheep preparations, breathing movements increased gradually during the first 48 hours after the operation for insertion of catheters. These facts suggested that the episodic character of fetal breathing movements in utero might be associated with a form of sleep or wakefulness. Observations on lambs delivered unrestrained in a warm saline bath with intact umbilical cords showed that irregular episodic breathing movements were associated with the signs of rapid eye movement (REM) sleep. And observations in utero showed that breathing movements of this character coincided with eye movements recorded from electrodes implanted in the palpebral ridge, and with the predominantly low-voltage rapid electrocortical activity recorded from electrodes implanted biparietally on the dura mater (Dawes, et al. 1972a). The electrocortical activities associated with quiet sleep and REM sleep were more readily discriminated after 125 days' gestational age. There are two types of fetal breathing movements discernible in the Iamb in utero: the rapid irregular movements that are present only during electrocortical signs of REM sleep, and episodes of slow (1-4/min) relatively deep respiratory efforts, described as gasps or sighs by analogy with such phenomena after birth. The latter type of fetal movement does not appear to be associated with any particular state of wakefulness or sleep, and is present for only about 5 % of the time. From the beginning, records of fetal breathing in chronically maintained sheep preparations had been made continuously, day and night At first there was little evidence of diurnal variation. The need for a quantitative estimate of fetal breathing movements in utero was soon appreciated. Clark & Wyatt (1969) designed a low-noise, very stable, electromagnetic flowmeter, which was implanted in the fetal trachea. Full-wave rectification and integration of the record was now used to

FETAL BREATHING give a measure of the total inflow and outflow of fluid corresponding to the minute volume of breathing after birth. At once it became apparent that there was a well-defined diurnal variation in trachea! fluid movement in fetal lambs, rising gradually throughout the day from a minimum in the early hours of the morning to a maximum shortly after dusk. The rise in minute volume from trough to peak was on average 2.8-fold. This was accompanied by a diurnal variation in the proportion of time which the fetus spent breathing, during which electrocortical activity was of the small-voltage rapid type. Subsequent observations have shown that the diurnal variation in breathing can be detected as early as 85-90 days* gestational age, i.e., just over half way through gestation. The diurnal rhythm persists when the variations in sound and the disturbances associated with feeding are reduced to a minimum, in pregnant sheep exposed to a 12-hour regulated light cycle in a temperature-controlled environment (Boddy, Dawes & Robinson, 1973). 2. Changes In Blood Gases, Hypoglycaemla and Parturition The effect of fetal hypercapnia was observed by exposing the pregnant ewe to a gas mixture whose CO2 content had been increased to 4-6%, while the oxygen content was reduced in such a way that the maternal, and hence the fetal, rise in oxygen tension (Po2) was limited in spite of maternal hyperventilation (Dawes, 1973; Boddy, Dawes & Robinson, 1974). In fact, fetal arterial oxygen tension (Pt, o2) rose by a mean value of 3 mm Hg 1 while the Pco3 was increased from 44 mm Hg to 57mmHg. During hypercapnia the proportion of time during which fetal breathing movements were present was doubled, tracheal fluid flow was increased 2.8-fold and the depth of respiratory movements was increased as judged by the intrathoracic pressure changes. In these respects there was an increase of fetal breathing, as with hypercapnia after birth. In many lambs the frequency of breathing movements was already high (circa 3Hz) and in these there was no increase; in fetuses in which the resting rate of breathing was lower, hypercapnia caused an increase. Exposure of fetal lambs to hypoxaemia, sufficient to cause a fall of mean ^Yo, from 23mmHg to 16mmHg, led to an immediate arrest of fetal breathing movements. This occurred whether or not there was a small fall of arterial pH. Recovery after an hour's hypoxaemia was slow; it usually required several hours before the proportion of time during which fetal breathing movements were present returned to normal. Increasing fetal oxygenation to a Po2»30mmHg, by raising the oxygen content of the maternal inspired gas, had no perceptible effects on fetal breathing movements. Episodes of asphyxia, during which the fetal Pm, o^ was decreased and the -Pa.coj allowed to rise, were associated not only with the cessation of normal episodic fetal breathing movements but also with the appearance of gasping efforts. Some pregnant sheep may from time to time lose their appetite, and such episodes allowed us to observe the effect of spontaneously occurring hypoglycaemia on the fetal lamb. In this species the blood glucose concentration is normally low, about 20-30mg/100ml (Shelley, 1973). As the blood glucose concentration of the fetus falls, the normal episodic irregular breathing movements are diminished in amplitude and • l m m H g M 133.3P«.—ED.

K. Boddy & G. S. Dawes frequency, though they do not disappear until the blood glucose concentration has reached less than 8mg/100ml. Two or three days before the onset of labour in sheep the proportion of time during which fetal breathing movements are present becomes significantly reduced. There is no apparent change in blood gas values or blood glucose concentration. 3. Development of a Clinical Method for Measuring Human Fetal Breathing by Ultrasound By 1971 it became apparent that measurements of fetal breathing in sheep were a useful indicator of continued health and well-being. Observations from many chronically maintained fetal sheep preparations showed that the first sign of impending disaster—whether by fetal hypoxia, hypoglycaemia or infection—was a diminution of, or alteration in, the characteristics of fetal breathing movements. There was therefore a strong incentive for developing a non-invasive method suitable for use in man. Such a method was developed, using a narrow beam of ultrasound and an A-scan display. The fetal heart echo was located; the echo from the fetal chest wall was then identified and wall movements were recorded, using an electronic "gate" (Boddy & Robinson, 1971). The method was validated by using it to detect chest wall movements of fetal sheep in which the thoracic pressure changes were recorded simultaneously from a catheter implanted some days previously. This system for recording human fetal breathing movements in utero has now been used on some 200 women in labour and on more than 500 antenatally (Boddy & Mantell, 1972, 1973; Boddy et al. 1974; Dawes, 1974; K. Boddy, K. Dalton, G. Gennser, J. Luther and E. Wyn-Pugh, unpublished observations). The fetal breathing movements have been detected as early as 11 weeks' gestation. They are easier to identify by 13-14 weeks and are then seen to be of a very irregular character (fig. 1), as in premature lambs. This irregular pattern is present up to 20 weeks' gestational age. hi many fetuses of over 36 weeks' gestational age, fetal breathing movements are regular (fig. 1), as after birth at term. From present evidence, however, the character of the fetal breathing movements cannot be relied upon as a good index of gestational age. FIG. I. Records of normal human fetal breathing movements in utero at (a) 14 weeks' and (b) 40 weeks' gestation (Boddy, Dawes & Robinson, 1974)

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FETAL BREATHING In many women, particularly multiparae near term, the fetal breathing movements can be seen occasionally on the abdominal wall as small rhythmic disturbances over a localized area, presumably transmitted by movements of the fetal limbs. However, such visible movements cannot regularly be relied upon as a measure of fetal breathing without the simultaneous use of ultrasound measurements. The incidence of fetal breathing movements is rather greater in man than in sheep. The proportion of time during which they are present is 55-90%. Recent evidence suggests that, as in sheep, the incidence falls near the onset of parturition. As in sheep, the movements are often of an episodic and irregular character; they are clearly distinguishable from hiccoughs andfrommovementsofthefetal limbs. Their normal frequency is 30-70/min. 4. Diurnal Variations in Human Fetal Breathing As in sheep, so in man there is evidence for a diurnal variation in the proportion of time during which fetal breathing movements are normally present. The proportion varies from what may be as low as 40 % in women who have gone without breakfast in preparation for a glucose tolerance test to about 90% in the late evening. Administration of glucose intravenously to a woman who has been starved overnight causes a dramatic rise, within 1 Omin, in the proportion of time during which fetal breathing is present (Boddy et al. 1974). While the most likely explanation for this phenomenon is a direct effect of the rise in maternal blood glucose concentration, and hence in the concentration of fetal blood glucose, it may be the result of a consequential hormonal or other change in the fetus. The phenomenon certainly merits further investigation, as it suggests prima facie that one aspect of metabolism, concerning breathing, might be directly dependent on blood sugar concentration. 5. Clinical Observations on Fetal Breathing in Man a. In Labour The observations so far made on fetal breathing in human infants during labour are not readily susceptible to statistical analysis because of the variability of the material. However, they are consistent with, and support, the observations made in the fetal lamb, in that they show that asphyxia—as evidenced by a reduction in scalp pH and POl, and accompanied by prolonged (type 2) falls in heart rate of slow onset—is associated with a cessation of normal breathing movements and the appearance of gasping recorded by ultrasound. Conversely, during normal labour, with no evidence of hypoxia or acidaemia, normal breathing movements may be continuously present if the fetal P2 is normal or raised; whereas if maternal and hence fetal Pco2 is reduced by maternal hyperventilation, normal fetal breathing also is reduced in incidence but there is no gasping. Hence, the absence of normal breathing movements should not be interpreted as sinister if the fetus is hypocapnic. So far as this investigation has gone, it suggests that measurements of fetal breathing movements in labour provide a good indication of health and a useful addition to the monitoring methods at present in use. It has occasionally proved a more reliable tool than measurements of fetal heart rate alone. It is too early to estimate the likelihood of its supplanting measurement of heart rate in labour.

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FlG. 2. Episodic breathing movements in utero in the fetus of a diabetic pregnancy at 26 weeks' gestation


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The regularity of respiratory movements, where present, is unusual at this age

b. The High-Risk Fetus: Antenatal Monitoring Measurements of fetal breathing movements in utero are now proving a useful clinical tool in the assessment of the high-risk fetus. i. Records have been made in 11 patients shortly before intra-uterine fetal death. In 10 the fetus was "small for dates" or the product of a high-risk pregnancy complicated by maternal hypertension, rhesus incompatibility or other factors. In these 10 fetuses there was absence of normal fetal breathing movements and the appearance of gasping movements only, approximately 24-72 hours before intra-uterine death. This pattern is consistent with fetal asphyxia, and is now used as a sinister prognostic sign to be interpreted, with other clinical data, as an indication for urgent delivery by Caesarean section. In insulin-dependent diabetic pregnancies during the last trimester, fetal breathing movements tend to become regular and episodic (fig. 2). In some fetuses the incidence of normal fetal breathing movements is reduced and gasping is present. In one fetus this pattern changed to vigorous breathing with bursts of activity at unusually high rates (100-200/min); the fetus died unexpectedly within two days. These preliminary observations suggest that fetal breathing may differ from normal in diabetic pregnancies. Further experience may provide a better indication of the circumstances which lead to intra-uterine death. ii. The continued presence of normal fetal breathing movements is a useful direct indication of good health, even when failure of the biparietal diameter to increase and persistent low oestriol excretion (at, say, 30 weeks' estimated gestational age) confirm the diagnosis of a "small-for-dates" infant which is at risk. By serial measurements of fetal breathing movements, a few weeks may be gained before a deterioration of fetal condition is evident and delivery must be expedited. In such cases a mixed breathing pattern commonly appears, in which normal breaths are interspersed with gasps, to give an early warning sign (fig. 3). A delay in delivery may be justified if it permits survival of the fetus until the development of sufficient pulmonary surfactant to ensure normal ventilation after birth. It remains to be seen whether maintenance of such fetuses in utero, when there is evidence of growth retardation, is in their best long-term interest. c. Prediction of Fetal Distress in Labour Observations on 200 antenatal patients, of 36 weeks' gestation or more, suggest that the character of fetal breathing may be a useful indicator of those fetuses which ultimately

FETAL BREATHING FIG. 3. Mixed pattern of breathing and gasping movements in a "small-for-dates5 human fetus in utero at 34 weeks' gestation

K. Boddy & G. S. Dawes observations (by K. Boddy, C. D. Mantell and E. Wyn-Pugh) have shown that administration of pethidine to the mother arrests fetal breathing. There is a wide range of possible investigations by means of which our knowledge of drug action upon the fetus may be extended by direct measurement. 7.




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•. 60 mm Hg, and the Pcoa falls from 45 mm Hg to 35 mm Hg after birth. It is possible that maintenance of continued breathing movements is dependent upon the relatively large rise in P,,^- This simple explanation alone is unlikely, because many newborn lambs have now been observed to continue breathing with a iYoj < 25 mm Hg. Secondly, at birth the fetus is expelled into a cooler environment without liquid support. It has often been suggested that this is a factor in the "onset" of breathing. While it is true that cold exposure, tactile and gravitational stimuli enhance ventilation after birth, they are not a necessary prerequisite to the establishment of maintained regular breathing. Fetal lambs of 142 days' gestational age were delivered under maternal epidural anaesthesia into a saline bath maintained at intra-uterine temperature. The fetuses were below the surface but could breathe by a tracheotomy tube brought out above the fluid. In all of seven lambs, wellmaintained regular breathing was established some minutes after tying the cord (G. S. Dawes, P. Johnson and J. S. Robinson, unpublished work). The results differ from those of Harned, Herrington & Ferreiro (1970), who immersed fetal lambs in water; these failed to survive when the cord was tied. This failure is now attributed to suppression of breathing by water receptors in the larynx (Johnson, Robinson & Salisbury, 1973). It seems likely that the establishment of maintained breathing after birth is a simple consequence of the ability of the lungs to act for thefirsttime as an organ of gaseous exchange, rather than as a result of some esoteric physiological mechanism. Thus episodic breathing movements in utero and entrainment of the activity of therespiratoryorgan with infantile metabolism may suffice to explain the maintenance of breathing after birth. What is still obscure is the postnatal rise in P,,o 2 and the fall in Pco^- This could be explained by several factors, to which the systemic arterial chemoreceptors may contribute. In summary, the "onset" of breathing at birth is probably not an enigma at all, but a consequence of the conjunction of factors now well established.

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Ahlfeld, F. (1905) Monatsschr. Geburtshilfe Gynaekol. 21, 143163 Barcroft, J. (1946) Researches on pre-natal life, vol. I. Blackwell Scientific Publications, Oxford Boddy, K., Dawes, G. S. & Robinson, J. S. (1973) In: Comline, R. S., Cross, K. W., Dawes, G. S. & Nathaniclsz, P. W., ed. Foetal and neonatal physiology* PP- 63-66 (Proceedings of The Sir Joseph Barcroft Centenary Symposium held at Cambridge, 25-27 July 1972). Cambridge University Press, London Boddy, K., Dawes, G. S. & Robinson, J. S. (1974) In: Gluck, L., ed. Modern perinatal medicine. Year Book Medical Publishers, Chicago, m. (In press) Boddy, K. & Mantel], C. D. (1972) Lancet, 2,1219-1220 Boddy, K. & Mantel], C. D. (1973) /. Physiol. (Lond.) 231,105P106P Boddy, K. & Robinson, J. S. (1971) Lancet, 2,1231-1233 Clark, D. M. & Wyatt, D. G. (1969) Med. Biol. Eng. 7, 185190 Dawes, G. S. (1973) In: Comline, R. S., Cross, K. W., Dawes, G. S. & Nathanielsz, P. W., ed. Foetal and neonatal physiology, pp. 49-62 (Proceedings of The Sir Joseph Barcroft Centenary Symposium held at Cambridge, 25-27 July 1972). Cambridge University Press, London Dawes, G. S. (1974) New Engl. J. Med. 290, 557-559

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Dawes, G. S., Fox, H. E., Leduc, B. M., Liggins, G. C. & Richards, R. T. (1970) / . Physiol. (Lond.) 210,47P-4SP Dawes, G. S., Fox, H. E., Leduc, B. M., Liggins, G. C. & Richards, R. T. (1972a) /. Physiol. (Lond.) 220,119-143 Dawes, G. S., Fox, H. E. & Richards, R. T. (1972b) Q. J. Exp. Physiol. 57,131-138 Harned, H. S., jr, Herrington, R. T. & Ferreiro, J. I. (1970) Pediatrics (Springfield) 45, 598-605 Johnson, P., Robinson, J. S. & Salisbury, D. (1973)In: Comline, R. S., Cross, K. W., Dawes, G. S. & Nathanielsz, P. W., ed. Foetal and neonatal physiology, pp. 217-221 (Proceedings of The Sir Joseph Barcroft Centenary Symposium held at Cambridge, 25-27 July 1972). Cambridge University Press, London Merlet, C , Hoerter, J., Devilleneuve, C. & Tchobroutsky, C. (1970) C. R. Hebd. Seances Acad. Sci. (Paris) (set. D) 270, 2462-2464 Shelley, H. J. (1973) In: Comline, R. S., Cross, K. W, Dawes, G. S. & Nathanielsz, P. W., ed. Foetal and neonatal physiology, pp. 360^381 (Proceedings of The Sir Joseph Barcroft Centenary Symposium held at Cambridge, 25-27 July 1972). Cambridge University Press, London Windle, W. F. (1940) Physiology of the fetus: origin and extent of function in prenatal life. Saunders, Philadelphia, Pa, & London

Fetal breathing.

FETAL BREATHING K. Boddy & G. S. Dawes FETAL BREATHING K. BODDY* M.B. B.S. M.R.C.O.G. G. S. DAWES D.M. F.R.S. The Nuffield Institute for Medical Rese...
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