181
Early Human Development. 21 (1990) 181-191 Elsevier
Scientific
Publishers
Ireland
Ltd.
EHD 01031
The fetal breath cycle* Brian J. Trudinger and Colleen M. Cook The Fetal Welfare Laboratory, The University of Sydney at Westmead Hospital, Westmead. N.S. W. 2 I45 (Australia) Accepted
for publication
30 October
1989
Summary
Fetal breathing movements may be timed precisely from the umbilical vein flow velocity profile recorded using Doppler ultrasound. Serial studies were performed on eight normal fetuses from 28 weeks pregnancy until delivery. Measurements were made of the inspiratory time, total breath time and breath amplitude. There was a clear change in the pattern of fetal breathing with advancing gestation. The inspiratory time lengthened and the amplitude of each breath increased. The variability of these measures decreased. The timing equation fi/ftota, lengthened. The area of change in the umbilical vein sonogram was calculated as a measure of respiratory work and this increased with gestation. It is suggested that the changing pattern of fetal breathing movements reflects changes in central control of breathing in the fetus and parallels observations in the newborn. fetal breathing; doppler; umbilical vein; fetus; respiratory movements.
Introduction
Fetal breathing movements have been associated with active or rapid eye movement sleep [6] and regarded as essential for the development of the respiratory apparatus. Most studies of fetal breathing movements have been directed at recording their presence and periodicity [2]. In this paper our aim was to study the individual breath, the units which sum temporally to an epoch of breathing. Since each breath results from the interaction of the CNS controller and the respiratory apparatus, *This work was supported
Correspondence to: Assoc. University
by the National Health and Medical Research Council Professor B. Trudinger, Department of Obstetrics
of Sydney at Westmead
0378-3782/90/$03.50 Published and Printed
Hospital,
Westmead,
0 1990 Elsevier Scientific in Ireland
N.S.W.
Publishers
2145, Australia.
Ireland
Ltd.
of Australia. and Gynaecology,
The
182
such studies should provide information about the fetal respiratory cycle and its regulation [14,19]. Breathing movements modulate blood flow in the great veins of the fetus. A simple continuous wave Doppler ultrasound system may be used to record this. A precise measure of the duration of the movements of inspiration and expiration of the fetal respiratory cycle [23] may be obtained from the umbilical vein sonogram. In the present study the timing components of the fetal breath cycle were examined in relation to gestational age using this method. Patients and methods
Patients Eight normal primiparous patients were studied serially at two-week intervals from 28 weeks. In all patients gestational age had been confirmed by early ultrasound scan. All pregnancies remained uncomplicated and labour commenced spontaneously. Birthweight of all infants was greater than the tenth centile. Patients were studied in the morning. Patients had fasted before attending the laboratory. Studies were carried out to record fetal breathing movements for at least 20 min. All patients, whether fetal breathing had been observed or not, were then given a 50-grams glucose load. The study was then repeated after an interval of 30 min.
Methods A real-time ultrasound scan was carried out to determine fetal lie, observe fetal breathing activity and locate a loop of the umbilical cord. A ~-MHZ continuous wave directional Doppler blood flow velocimeter was then used. The pencil transducer was directed to record from the umbilical vein. This signal was generally recorded along with the umbilical artery waveform. The sonogram was displayed after real time frequency spectrum analysis. Recognition of recording from the umbilical vessels was readily achieved by both auditory and visual display of the sonogram and the transducer angle could be adjusted to optimise the signal. In other studies we confirmed the origin of this signal from the umbilical vein using a pulsed Doppler system which allowed location of a small sample window over the umbilical vein identified from the simultaneously displayed B-mode image. The umbilical vein flow velocity profile was recorded onto light-sensitive paper using an oscilloscope recorder (paper speed 10 cm/s) and measurements were made from this record. Thirty breath cycles were measured for each study. The timing components of the breath cycle were measured. Inspiratory movement time (tJ occurred during the period of decreasing umbilical vein flow velocity from its beginning to its lowest value. Expiratory time (t) was measured over the period from the end inspiratory point to the onset of the next inspiratory movement. This included the period during which the umbilical vein flow velocity returned to its baseline value and the period of steady flow before the next breath. Total breath time (ttota,)was the sum of inspiratory and expiratory time. If this exceeded 2 s the fetus was regarded as not breathing. This value (2 s) was chosen as it was just greater
183
than the sum of the mean and two standard deviations of the longest total breath time observed at any gestational age. The baseline umbilical vein velocity was given a single unit value. This allowed comparison from one record to another without knowledge of the angle of incidence of ultrasound beam to flow direction. It has been shown that umbilical vein flow velocity does not vary with gestational age over the latter half of human pregnancy [8]. It is rising intra-abdominal pressure produced by the inspiratory diaphragmatic contraction which retards flow in the umbilical vein in the cord external to the fetus during the inspiratory movement. A number of indices were calculated. The fractional change (Av/v) in umbilical vein flow velocity was measured to provide an index of the change in intra-abdominal pressure produced by the diaphragmatic contraction. Slowing of umbilical vein blood flow during the inspiratory movement is the result of the positive pressure in the fetal abdomen produced by the contraction of the diaphragm and balanced against the elasticity of the abdominal wall. The decrease in umbilical vein flow velocity integrated over the inspiratory time (area of decrease of umbilical vein sonogram) was calculated to represent a measurement of respiratory muscle work, tension time or energy consumption by the contracting diaphragm. Statistical analysis. For each parameter the mean and 95% confidence intervals were determined at each gestational period. Analysis of variance was used to determine the significance of changes with gestational age. These studies were carried out with the approval of our hospital research and ethics committee. Results Very little fetal breathing activity was recorded during the fasting studies. In only 7 of the patient fasting studies was this activity recorded. In 5 patients fetal breathing activity at 28 weeks was not seen after the glucose load, but all studies were satisfactory after this gestational age. Two patients delivered spontaneously between 38 and 40 weeks. Analysis was therefore carried out in the non-fasted state when breathing movements were present in all fetuses. The breath pattern after glucose did not differ from that seen before glucose when present. The pattern of fetal breathing changed very clearly with gestational age. Representative records from one patient are shown (Fig. 1). The results have been tabulated (Table I). Inspiratory movement time ti (Fig. 2a) increased with gestational age, but expiratory movement time remained relativly constant. The increase in total breath time was related to the changing inspiratory time. The timing equation ti/ttota, also increased (Fig. 3). The coefficient of variation of the duration of the movement of inspiration did not differ from 28 to 36 weeks but was significantly less at 38 and 40 weeks (Fig. 2b). This indicates a more regular, less variable pattern of total breath times in the last four weeks of pregnancy. The amplitude or depth of each breath was measured as the fractional change in umbilical vein flow velocity during the movement of inspiration. There was a significant increase with gestational age (Fig. 4a) from 28 to 38 weeks. Breaths were shallower at 40 weeks than 38 weeks. The coefficient of variation of this parameter
184
28wks
30wks
32wks
34tiks
40wks
Fig. 1. Representative records of the umbilical vein flow velocity profile at differing gestational ages illustrating the changing pattern of fetal breathing movements.
decreased with gestational age, indicating a more regular depth of breathing movements (Fig. 4b). The area of change in the umbilical vein velocity profile during inspiration increased with gestational age (Fig. 5). Discussion
This study shows a clear change in the character of the fetal breath cycle with advancing gestational age. The total breath time or breath-to-breath interval increases with advancing gestation, and on closer analysis this is seen to be accounted for by an increase in the duration of the inspiratory movement. The inspiratory duty cycle (t/&J also increases with gestational age. In the newborn the pattern of breathing has been studied to gain insight into the maturation of control of breathing [25]. It is suggested that the onset of inspiration is determined centrally in the respiratory controller [3,24]. Two mechanisms seem to control inspiratory time in the newborn. There appears to be a bulbopontine pacemaker responsible for tonic vagal impulses acting to end inspiration unrelated to lung inflation. The second component is the Hering-Breuer inflation reflex and this provides a phasic control
28 30 32 34 36 38 40
Gestational
0.26 0.27 0.33 0.35 0.51 0.54 0.57
t.
f + 2 + f f f
0.03 0.02 0.03 0.03 0.02 0.02 0.03
Insp. time
40.3 34.9 36.6 35.8 33.8 22.9 20.5 + + + f + f +
6.4 3.9 5.1 4.0 2.0 1.6 1.5
Coeff. variation insp. time COfVf
0.60 0.67 0.70 0.58 0.78 0.76 0.70
+ 2 + f f f +
0.12 0.09 0.08 0.06 0.05 0.04 0.05
Exp. time
0.85 0.95 1.02 0.93 1.29 1.29 1.26
+ + + + + + 2
0.15 0.10 0.10 0.09 0.06 0.05 0.07
Total breath time t,o,
Measurements of fetal breathing parameters for each gestational age (mean + S.E.M.).
TABLE I
11.7 25.3 27.8 32.1 31.8 36.8 28.6
V
E%
f f + f f + f
Breath amp.
0.9 2.1 3.3 5.2 4.4 4.3 4.3
Coeff. variation
1.5
f 4.3 +1 3.3 f 4.0 f 4.5 f 2.7 f 3.6 19.0 f
34.6 31.0 28.0 33.8 23.5 22.0
breath amp. CofV AV -% V
2 2 f k f k
0.64 1.1 1.7 2.6 3.0 2.5 12.9 + 1.6
5.1 8.3 10.3 13.0 15.7 18.7
Breath area AV -XI v 2
E
186
(a1
y = 2.946x - 59.75
60 1
Rl - ,932 p=
26
bl
28
Gnol
3.0
4.0
42.5
i h 37.5. P v) 35. c '= ._ 32.5. ;
30.
;
27.5
0
25 22.5 / 20 26
28
38
? 40
Fig. 2. The mean duration of the inspiratory movement (rJ (Fig. 2a) and its coefficient of variation (C of Vri) (Fig. 2b) plotted against gestational age. The equation for linear regression and its significance is shown.
terminating inspiration. Although both mechanisms are present in term and preterm infants the phasic component is less important in the infant delivered at full term in comparison to preterm [lo]. In the newborn there is a close correlation between inspiratory period and total respiratory period so the mechanism that determines inspiratory time also indirectly determines respiratory rate [ 161. Hence, the inflation reflex operates to increase respiratory rate in the premature infant. Our results concerning inspiratory time in the fetus are quite consistent with the operation of these mechanisms of control in the fetus and a shift with gestational age away from the phasic control towards the tonic control.
187
46~ 44. 42. 40. 38. 36. 34. 32. 30.
, 2'6
'
2i
'
3'0
.
3'2
Gestational
.
3'4
.
S-6
.
3iI
4'0
Age (wks)
Fig. 3. The mean of the timing equation inspiratory movement time (t,)/total breath time (f,,,,,) plotted for each gestational age period. The equation for linear regression and its significance is shown.
In the present study we observed that there was a change in the variability during inspiration of both time and depth. In the fetal lamb, episodes of rapid irregular breathing are seen in association with high voltage electrocorticogram rapid eye movement sleep (state 2 sleep), but not in quiet or state 1 sleep. During active sleep, there is tonic inhibition of the intercostal muscles so that the diaphragm distorts the rib cage, and paradoxical movements of the chest wall and abdomen are observed in animals [9] and humans. Knill and Bryan [ 1l] have demonstrated the existence of an intercostal-phrenic inhibitory reflex originating most probably from the spindles of the intercostal muscles and activated by chest wall deformation. Rib cage distortion is permitted by the inactive intercostal muscles during active sleep and the operation of this reflex will act to terminate inspiration prematurely. The effect of this reflex is to decrease tidal volume and ventilation when rates of rib cage retraction are high. The high variability seen in both the duration and depth of inspiratory movements in our studies before 36 weeks are consistent with the operation of this reflex. An examination of respiratory load compensation [ 121in the newborn demonstrated the disadvantage of this inefficient breathing control should there occur a requirement for increased ventilation during active sleep. Although this is not relevant to the fetus it is of importance if premature delivery occurs and the infant attempts to cope with surfactant deficiency by tachypnoea. Fetal breathing movements have been considered as practice for extra-uterine existence. The premature infant will benefit from a fast respiratory rate. The high rate may be beneficial in not allowing time for passive expiration to functional residual capacity, at which point there is a danger of instability and collapse of the ter-
188
.& c b
37.52 35. 32.5.
I
, ;
20, 2;
.
2'8
3b
'
3-2
Gestational
.
3'4
3'6
3-6
.
4'0
Age (wks)
Fig. 4. The mean breath amplitude, calculated as the percentage change in the maximum umbilical vein flow velocity at the end of inspiration, is plotted against gestational age (Fig. 4a) along with the coefficient of variation (Fig. 4b) of this measure.
mitral air spaces deficient in surfactant. The Hering-Breuer reflex will act to increase respiratory rate. However, the paradoxical breathing movements and the operation of the intercostal phrenic reflex are not helpful. Whilst surfactant deficiency underlies the respiratory distress syndrome, we can speculate that a relative deficiency may be overcome if the fetus is able to maintain a fast rate without premature termination of inspiration (i.e. maturation of respiratory control beyond intercostal phrenic reflex dominance in active sleep). It remains possible that the pattern of breathing may also be important in the production and release of surfactant in the lungs. The precise method of study of human fetal breathing in this paper confirms ear-
189 y=.886x-18.114
201 18.
p= .0181
16. m * 5 14.
a. r 12. z a 2 10. m I 8. 6. 44 26
.
X 28
38
I40
Fig. 5. The breath area calculated as the total variation in the umbilical vein sonogram produced by the fetal breath and assuming a unit value for maximum velocity plotted against gestation. The equation for linear regression and its significance is shown.
lier findings relying on less precise methods of recording fetal breathing activity. In a study of human fetal breathing movements a finger-operated event recorder was used to time breath-to-breath intervals and assess variability. A lengthening of the breath time and a reduction in variability was noted with advancing gestational age [22]. The same observation has been made in the fetal lamb using the diaphragmatic EMG as the event marker [4]. Glucose has been previously reported as having no effect on frequency or variabiliy of fetal breathing [l] measured with an ultrasonic tracking device. Using an M-mode recording system the amplitude of the thoracic and abdominal movement was measured in a standard scanning plane [15] and reported to increase with gestation. This is in agreement with our observation of an increasing depth of retardation of umbilical vein flow during the inspiratory movement. The presence of fetal breathing movements has been used as a measure of fetal health [l&20], but long study periods are required if normal apnoea is to be distinguished from that associated with fetal compromise. In fetal lambs before fetal demise a pattern of very regular movements may be seen [5,17]. A pattern of less variability of breathing movements has also been reported in human fetal compromise [21], but there is no information about the components of the individual breath and fetal welfare. Information about the normal fetus available from our study is necessary before any consideration of pathological pregnancy. The use of Doppler ultrasound recordings of umbilical vein flow velocity profile make it possible to study changes in timing of the fetal breath cycle. This has not
190
been possible using other methods to study human fetal breathing movements. An increase in the maximum tension that the respiratory musculature can exert is the likely reason for an increasing intra-abdominal pressure reflected in the increase in extent to which the umbilical vein blood flow velocity is retarded or slowed. This tension is developed against the compliance of the lungs and chest wall. The tension time (the area of change in umbilical vein flow velocity over inspiration) increases with gestational age and suggests an increase in work carried out by the respiratory apparatus. In the light of experiments in fetal sheep showing impairment of breathing movements can arrest lung growth, there has been a call [7] for better methods of quantification of fetal breathing movements, and especially movements of the diaphragm rather than the chest wall. The studies reported in this paper may provide such a method. References 1
2 3
4
5 6 7 8
9 10
11 12 13 14 15 16
Adamson, S.L., Backing, A., Cousin, A.J., Rapopart, I. and Patrick, J.E. (1983): Ultrasonic measurement of rate and depth of human fetal breathing: Effect of glucose. Am. J. Obstet. Gynecol., 147,288-295. Body, K. and Dawes, G.S. (1975): Fetal breathing. Br. Med. Bull., 3 1,3-7. Bradley, G.W. (1977): Control of the breathing pattern. In: International Review of Physiology, Respiratory Physiology II, 14, pp. 185-217. Editor: J.G. Widdicombe, University Park Press, Baltimore. M.H. and Maloney, J.E. Bowes, G., Adamson, T.M., Ritchie, B.C., Dowling, M,. Wilkinson, (1981): Development of patterns of respiratory activity in unanaesthetised fetal sheep in utero. J. Appl. Physiol., 50,693-700. Chapman, R.L.K., Dawes, G.S., Rurak, D.W. and Wilds, P.L. (1978): Intermittent breathing before death in fetal lambs, Am. J. Obstet. Gynecol., 131, 894-898. Dawes, G.S., Fox, H.E., Leduc, B.M., Liggins, G.C. and Richards, R.T. (1972): Respiratory movements and rapid eye movement sleep in the foetal lamb. J. Physiol., 220, 119-143. Editorial: (1989): Breath of Life. Lancet i, 305-306. Gill, R.W., Trudinger, B.J., Garrett, W.J., Kossoff, G. and Warren, P.S. (1981): Fetal umbilical venous flow measured in utero by pulsed Doppler and B-mode ultrasound. 1. Normal pregnancies. Am. J. Obstet. Gynecol., 139,720-725. Harding, R., Johnson, P. and McClelland, M.E. (1980): Respiratory function of the larynx in developing sheep and the influence of sleep state. Respir. Physiol., 40, 165-179. Kirkpatrick, S.M.L., Olinsky, A., Bryan, M.H. and Bryan, A.C. (1976): Effect of premature delivery on the maturation of the Hering-Breuer inspiratory inhibitory reflex in human infants. J. Pediatr., 88, 1010-1014. Knill, R. and Bryan, A.C. (1976): An intercostal-phrenic inhibitory reflex in human newborn infants. J. Appl. Physiol., 40,352-356. Knill, R., Andrews, W., Bryan, A.C. and Bryan, M.H. (1976): Respiratory load compensation in infants. J. Appl. Physiol., 40, 357-361. Manning, F.A. (1977): Fetal breathing movements as a reflection of fetal status. Postgrad. Med., 61, 116-122. Milic-Emili, J., Siafakas, N.M. and Gautier, H. (1979): A new approach for clinical assessment of control of breathing. Bull. Europ. Physiopath. Respir., 15, 17-26. Neldam, S. (1982): Fetal respiratory movements: A nomagram for fetal thoracic and abdominal respiratory movements. Am. J. Obstet. Gynecol., 142,867-869. Olinsky, A., Bryan, M.H. and Bryan, A.C. (1974): Influence of lung inflation on respiratory control in neonates. J. Appl. Physiol., 36.426-429.
191 17 18 19 20 21 22 23 24 25
Patrick, J.E., Dalton, K.J. and Dawes, G.S. (1976): Breathing patterns before death in fetal lambs. Am. J. Obstet. Gynecol., 12573-78. Platt, L.D., Manning, F.A., Le May, M. and Sipos, L. (1978): Human fetal breathing: Relationship to fetal condition. Am. J. Obstet. Gynecol., 132.542-551. Remmers, J.E. (1970): Analysis of ventilatory response. Chest, 70 (Suppl.), 134-137. Trudinger, B.J., Lewis, P.J., Mangez, J. and O’Connor, E. (1978): Fetal breathing movements in high-risk pregnancy. Br. J. Obstet. Gynaecol, 85,662-667. Trudinger, B.J., Lewis, P.J., Petit, B. (1979): Fetal breathing patterns in intrauterine growth retardation. Br. J. Obstet. Gynaecol., 86,432-436. Trudinger, B.J. and Knight, P.C. (1980): Fetal age and patterns of human fetal breathing movements. Am. J. Obstet. Gynecol., 137,724-728. Trudinger, B.J. and Cook, C.M. (1989): Fetal breathing movements - a comparison of hard copy records produced by M-mode and Doppler ultrasound. Early Hum. Dev., 20,247-253. Wyman, R.J. (1977): Neural generation of the breathing rhythm. Annu. Rev. Physiol., 39, 417448. Wyszogrodski, I., Thach, B.T. and Milic-Emili, J. (1978): Maturation of respiratory control in unanesthetized newborn rabbits. J. Appl. Physiol., 44, 304-310.
Early Human Development. 21 (1990) 181-191 Elsevier
Scientific
Publishers
Ireland
Ltd.
EHD 01031
The fetal breath cycle* Brian J. Trudinger and Colleen M. Cook The Fetal Welfare Laboratory, The University of Sydney at Westmead Hospital, Westmead. N.S. W. 2 I45 (Australia) Accepted
for publication
30 October
1989
Summary
Fetal breathing movements may be timed precisely from the umbilical vein flow velocity profile recorded using Doppler ultrasound. Serial studies were performed on eight normal fetuses from 28 weeks pregnancy until delivery. Measurements were made of the inspiratory time, total breath time and breath amplitude. There was a clear change in the pattern of fetal breathing with advancing gestation. The inspiratory time lengthened and the amplitude of each breath increased. The variability of these measures decreased. The timing equation fi/ftota, lengthened. The area of change in the umbilical vein sonogram was calculated as a measure of respiratory work and this increased with gestation. It is suggested that the changing pattern of fetal breathing movements reflects changes in central control of breathing in the fetus and parallels observations in the newborn. fetal breathing; doppler; umbilical vein; fetus; respiratory movements.
Introduction
Fetal breathing movements have been associated with active or rapid eye movement sleep [6] and regarded as essential for the development of the respiratory apparatus. Most studies of fetal breathing movements have been directed at recording their presence and periodicity [2]. In this paper our aim was to study the individual breath, the units which sum temporally to an epoch of breathing. Since each breath results from the interaction of the CNS controller and the respiratory apparatus, *This work was supported
Correspondence to: Assoc. University
by the National Health and Medical Research Council Professor B. Trudinger, Department of Obstetrics
of Sydney at Westmead
0378-3782/90/$03.50 Published and Printed
Hospital,
Westmead,
0 1990 Elsevier Scientific in Ireland
N.S.W.
Publishers
2145, Australia.
Ireland
Ltd.
of Australia. and Gynaecology,
The
182
such studies should provide information about the fetal respiratory cycle and its regulation [14,19]. Breathing movements modulate blood flow in the great veins of the fetus. A simple continuous wave Doppler ultrasound system may be used to record this. A precise measure of the duration of the movements of inspiration and expiration of the fetal respiratory cycle [23] may be obtained from the umbilical vein sonogram. In the present study the timing components of the fetal breath cycle were examined in relation to gestational age using this method. Patients and methods
Patients Eight normal primiparous patients were studied serially at two-week intervals from 28 weeks. In all patients gestational age had been confirmed by early ultrasound scan. All pregnancies remained uncomplicated and labour commenced spontaneously. Birthweight of all infants was greater than the tenth centile. Patients were studied in the morning. Patients had fasted before attending the laboratory. Studies were carried out to record fetal breathing movements for at least 20 min. All patients, whether fetal breathing had been observed or not, were then given a 50-grams glucose load. The study was then repeated after an interval of 30 min.
Methods A real-time ultrasound scan was carried out to determine fetal lie, observe fetal breathing activity and locate a loop of the umbilical cord. A ~-MHZ continuous wave directional Doppler blood flow velocimeter was then used. The pencil transducer was directed to record from the umbilical vein. This signal was generally recorded along with the umbilical artery waveform. The sonogram was displayed after real time frequency spectrum analysis. Recognition of recording from the umbilical vessels was readily achieved by both auditory and visual display of the sonogram and the transducer angle could be adjusted to optimise the signal. In other studies we confirmed the origin of this signal from the umbilical vein using a pulsed Doppler system which allowed location of a small sample window over the umbilical vein identified from the simultaneously displayed B-mode image. The umbilical vein flow velocity profile was recorded onto light-sensitive paper using an oscilloscope recorder (paper speed 10 cm/s) and measurements were made from this record. Thirty breath cycles were measured for each study. The timing components of the breath cycle were measured. Inspiratory movement time (tJ occurred during the period of decreasing umbilical vein flow velocity from its beginning to its lowest value. Expiratory time (t) was measured over the period from the end inspiratory point to the onset of the next inspiratory movement. This included the period during which the umbilical vein flow velocity returned to its baseline value and the period of steady flow before the next breath. Total breath time (ttota,)was the sum of inspiratory and expiratory time. If this exceeded 2 s the fetus was regarded as not breathing. This value (2 s) was chosen as it was just greater
183
than the sum of the mean and two standard deviations of the longest total breath time observed at any gestational age. The baseline umbilical vein velocity was given a single unit value. This allowed comparison from one record to another without knowledge of the angle of incidence of ultrasound beam to flow direction. It has been shown that umbilical vein flow velocity does not vary with gestational age over the latter half of human pregnancy [8]. It is rising intra-abdominal pressure produced by the inspiratory diaphragmatic contraction which retards flow in the umbilical vein in the cord external to the fetus during the inspiratory movement. A number of indices were calculated. The fractional change (Av/v) in umbilical vein flow velocity was measured to provide an index of the change in intra-abdominal pressure produced by the diaphragmatic contraction. Slowing of umbilical vein blood flow during the inspiratory movement is the result of the positive pressure in the fetal abdomen produced by the contraction of the diaphragm and balanced against the elasticity of the abdominal wall. The decrease in umbilical vein flow velocity integrated over the inspiratory time (area of decrease of umbilical vein sonogram) was calculated to represent a measurement of respiratory muscle work, tension time or energy consumption by the contracting diaphragm. Statistical analysis. For each parameter the mean and 95% confidence intervals were determined at each gestational period. Analysis of variance was used to determine the significance of changes with gestational age. These studies were carried out with the approval of our hospital research and ethics committee. Results Very little fetal breathing activity was recorded during the fasting studies. In only 7 of the patient fasting studies was this activity recorded. In 5 patients fetal breathing activity at 28 weeks was not seen after the glucose load, but all studies were satisfactory after this gestational age. Two patients delivered spontaneously between 38 and 40 weeks. Analysis was therefore carried out in the non-fasted state when breathing movements were present in all fetuses. The breath pattern after glucose did not differ from that seen before glucose when present. The pattern of fetal breathing changed very clearly with gestational age. Representative records from one patient are shown (Fig. 1). The results have been tabulated (Table I). Inspiratory movement time ti (Fig. 2a) increased with gestational age, but expiratory movement time remained relativly constant. The increase in total breath time was related to the changing inspiratory time. The timing equation ti/ttota, also increased (Fig. 3). The coefficient of variation of the duration of the movement of inspiration did not differ from 28 to 36 weeks but was significantly less at 38 and 40 weeks (Fig. 2b). This indicates a more regular, less variable pattern of total breath times in the last four weeks of pregnancy. The amplitude or depth of each breath was measured as the fractional change in umbilical vein flow velocity during the movement of inspiration. There was a significant increase with gestational age (Fig. 4a) from 28 to 38 weeks. Breaths were shallower at 40 weeks than 38 weeks. The coefficient of variation of this parameter
184
28wks
30wks
32wks
34tiks
40wks
Fig. 1. Representative records of the umbilical vein flow velocity profile at differing gestational ages illustrating the changing pattern of fetal breathing movements.
decreased with gestational age, indicating a more regular depth of breathing movements (Fig. 4b). The area of change in the umbilical vein velocity profile during inspiration increased with gestational age (Fig. 5). Discussion
This study shows a clear change in the character of the fetal breath cycle with advancing gestational age. The total breath time or breath-to-breath interval increases with advancing gestation, and on closer analysis this is seen to be accounted for by an increase in the duration of the inspiratory movement. The inspiratory duty cycle (t/&J also increases with gestational age. In the newborn the pattern of breathing has been studied to gain insight into the maturation of control of breathing [25]. It is suggested that the onset of inspiration is determined centrally in the respiratory controller [3,24]. Two mechanisms seem to control inspiratory time in the newborn. There appears to be a bulbopontine pacemaker responsible for tonic vagal impulses acting to end inspiration unrelated to lung inflation. The second component is the Hering-Breuer inflation reflex and this provides a phasic control
28 30 32 34 36 38 40
Gestational
0.26 0.27 0.33 0.35 0.51 0.54 0.57
t.
f + 2 + f f f
0.03 0.02 0.03 0.03 0.02 0.02 0.03
Insp. time
40.3 34.9 36.6 35.8 33.8 22.9 20.5 + + + f + f +
6.4 3.9 5.1 4.0 2.0 1.6 1.5
Coeff. variation insp. time COfVf
0.60 0.67 0.70 0.58 0.78 0.76 0.70
+ 2 + f f f +
0.12 0.09 0.08 0.06 0.05 0.04 0.05
Exp. time
0.85 0.95 1.02 0.93 1.29 1.29 1.26
+ + + + + + 2
0.15 0.10 0.10 0.09 0.06 0.05 0.07
Total breath time t,o,
Measurements of fetal breathing parameters for each gestational age (mean + S.E.M.).
TABLE I
11.7 25.3 27.8 32.1 31.8 36.8 28.6
V
E%
f f + f f + f
Breath amp.
0.9 2.1 3.3 5.2 4.4 4.3 4.3
Coeff. variation
1.5
f 4.3 +1 3.3 f 4.0 f 4.5 f 2.7 f 3.6 19.0 f
34.6 31.0 28.0 33.8 23.5 22.0
breath amp. CofV AV -% V
2 2 f k f k
0.64 1.1 1.7 2.6 3.0 2.5 12.9 + 1.6
5.1 8.3 10.3 13.0 15.7 18.7
Breath area AV -XI v 2
E
186
(a1
y = 2.946x - 59.75
60 1
Rl - ,932 p=
26
bl
28
Gnol
3.0
4.0
42.5
i h 37.5. P v) 35. c '= ._ 32.5. ;
30.
;
27.5
0
25 22.5 / 20 26
28
38
? 40
Fig. 2. The mean duration of the inspiratory movement (rJ (Fig. 2a) and its coefficient of variation (C of Vri) (Fig. 2b) plotted against gestational age. The equation for linear regression and its significance is shown.
terminating inspiration. Although both mechanisms are present in term and preterm infants the phasic component is less important in the infant delivered at full term in comparison to preterm [lo]. In the newborn there is a close correlation between inspiratory period and total respiratory period so the mechanism that determines inspiratory time also indirectly determines respiratory rate [ 161. Hence, the inflation reflex operates to increase respiratory rate in the premature infant. Our results concerning inspiratory time in the fetus are quite consistent with the operation of these mechanisms of control in the fetus and a shift with gestational age away from the phasic control towards the tonic control.
187
46~ 44. 42. 40. 38. 36. 34. 32. 30.
, 2'6
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.
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.
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.
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.
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Age (wks)
Fig. 3. The mean of the timing equation inspiratory movement time (t,)/total breath time (f,,,,,) plotted for each gestational age period. The equation for linear regression and its significance is shown.
In the present study we observed that there was a change in the variability during inspiration of both time and depth. In the fetal lamb, episodes of rapid irregular breathing are seen in association with high voltage electrocorticogram rapid eye movement sleep (state 2 sleep), but not in quiet or state 1 sleep. During active sleep, there is tonic inhibition of the intercostal muscles so that the diaphragm distorts the rib cage, and paradoxical movements of the chest wall and abdomen are observed in animals [9] and humans. Knill and Bryan [ 1l] have demonstrated the existence of an intercostal-phrenic inhibitory reflex originating most probably from the spindles of the intercostal muscles and activated by chest wall deformation. Rib cage distortion is permitted by the inactive intercostal muscles during active sleep and the operation of this reflex will act to terminate inspiration prematurely. The effect of this reflex is to decrease tidal volume and ventilation when rates of rib cage retraction are high. The high variability seen in both the duration and depth of inspiratory movements in our studies before 36 weeks are consistent with the operation of this reflex. An examination of respiratory load compensation [ 121in the newborn demonstrated the disadvantage of this inefficient breathing control should there occur a requirement for increased ventilation during active sleep. Although this is not relevant to the fetus it is of importance if premature delivery occurs and the infant attempts to cope with surfactant deficiency by tachypnoea. Fetal breathing movements have been considered as practice for extra-uterine existence. The premature infant will benefit from a fast respiratory rate. The high rate may be beneficial in not allowing time for passive expiration to functional residual capacity, at which point there is a danger of instability and collapse of the ter-
188
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.
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.
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.
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Fig. 4. The mean breath amplitude, calculated as the percentage change in the maximum umbilical vein flow velocity at the end of inspiration, is plotted against gestational age (Fig. 4a) along with the coefficient of variation (Fig. 4b) of this measure.
mitral air spaces deficient in surfactant. The Hering-Breuer reflex will act to increase respiratory rate. However, the paradoxical breathing movements and the operation of the intercostal phrenic reflex are not helpful. Whilst surfactant deficiency underlies the respiratory distress syndrome, we can speculate that a relative deficiency may be overcome if the fetus is able to maintain a fast rate without premature termination of inspiration (i.e. maturation of respiratory control beyond intercostal phrenic reflex dominance in active sleep). It remains possible that the pattern of breathing may also be important in the production and release of surfactant in the lungs. The precise method of study of human fetal breathing in this paper confirms ear-
189 y=.886x-18.114
201 18.
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16. m * 5 14.
a. r 12. z a 2 10. m I 8. 6. 44 26
.
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38
I40
Fig. 5. The breath area calculated as the total variation in the umbilical vein sonogram produced by the fetal breath and assuming a unit value for maximum velocity plotted against gestation. The equation for linear regression and its significance is shown.
lier findings relying on less precise methods of recording fetal breathing activity. In a study of human fetal breathing movements a finger-operated event recorder was used to time breath-to-breath intervals and assess variability. A lengthening of the breath time and a reduction in variability was noted with advancing gestational age [22]. The same observation has been made in the fetal lamb using the diaphragmatic EMG as the event marker [4]. Glucose has been previously reported as having no effect on frequency or variabiliy of fetal breathing [l] measured with an ultrasonic tracking device. Using an M-mode recording system the amplitude of the thoracic and abdominal movement was measured in a standard scanning plane [15] and reported to increase with gestation. This is in agreement with our observation of an increasing depth of retardation of umbilical vein flow during the inspiratory movement. The presence of fetal breathing movements has been used as a measure of fetal health [l&20], but long study periods are required if normal apnoea is to be distinguished from that associated with fetal compromise. In fetal lambs before fetal demise a pattern of very regular movements may be seen [5,17]. A pattern of less variability of breathing movements has also been reported in human fetal compromise [21], but there is no information about the components of the individual breath and fetal welfare. Information about the normal fetus available from our study is necessary before any consideration of pathological pregnancy. The use of Doppler ultrasound recordings of umbilical vein flow velocity profile make it possible to study changes in timing of the fetal breath cycle. This has not
190
been possible using other methods to study human fetal breathing movements. An increase in the maximum tension that the respiratory musculature can exert is the likely reason for an increasing intra-abdominal pressure reflected in the increase in extent to which the umbilical vein blood flow velocity is retarded or slowed. This tension is developed against the compliance of the lungs and chest wall. The tension time (the area of change in umbilical vein flow velocity over inspiration) increases with gestational age and suggests an increase in work carried out by the respiratory apparatus. In the light of experiments in fetal sheep showing impairment of breathing movements can arrest lung growth, there has been a call [7] for better methods of quantification of fetal breathing movements, and especially movements of the diaphragm rather than the chest wall. The studies reported in this paper may provide such a method. References 1
2 3
4
5 6 7 8
9 10
11 12 13 14 15 16
Adamson, S.L., Backing, A., Cousin, A.J., Rapopart, I. and Patrick, J.E. (1983): Ultrasonic measurement of rate and depth of human fetal breathing: Effect of glucose. Am. J. Obstet. Gynecol., 147,288-295. Body, K. and Dawes, G.S. (1975): Fetal breathing. Br. Med. Bull., 3 1,3-7. Bradley, G.W. (1977): Control of the breathing pattern. In: International Review of Physiology, Respiratory Physiology II, 14, pp. 185-217. Editor: J.G. Widdicombe, University Park Press, Baltimore. M.H. and Maloney, J.E. Bowes, G., Adamson, T.M., Ritchie, B.C., Dowling, M,. Wilkinson, (1981): Development of patterns of respiratory activity in unanaesthetised fetal sheep in utero. J. Appl. Physiol., 50,693-700. Chapman, R.L.K., Dawes, G.S., Rurak, D.W. and Wilds, P.L. (1978): Intermittent breathing before death in fetal lambs, Am. J. Obstet. Gynecol., 131, 894-898. Dawes, G.S., Fox, H.E., Leduc, B.M., Liggins, G.C. and Richards, R.T. (1972): Respiratory movements and rapid eye movement sleep in the foetal lamb. J. Physiol., 220, 119-143. Editorial: (1989): Breath of Life. Lancet i, 305-306. Gill, R.W., Trudinger, B.J., Garrett, W.J., Kossoff, G. and Warren, P.S. (1981): Fetal umbilical venous flow measured in utero by pulsed Doppler and B-mode ultrasound. 1. Normal pregnancies. Am. J. Obstet. Gynecol., 139,720-725. Harding, R., Johnson, P. and McClelland, M.E. (1980): Respiratory function of the larynx in developing sheep and the influence of sleep state. Respir. Physiol., 40, 165-179. Kirkpatrick, S.M.L., Olinsky, A., Bryan, M.H. and Bryan, A.C. (1976): Effect of premature delivery on the maturation of the Hering-Breuer inspiratory inhibitory reflex in human infants. J. Pediatr., 88, 1010-1014. Knill, R. and Bryan, A.C. (1976): An intercostal-phrenic inhibitory reflex in human newborn infants. J. Appl. Physiol., 40,352-356. Knill, R., Andrews, W., Bryan, A.C. and Bryan, M.H. (1976): Respiratory load compensation in infants. J. Appl. Physiol., 40, 357-361. Manning, F.A. (1977): Fetal breathing movements as a reflection of fetal status. Postgrad. Med., 61, 116-122. Milic-Emili, J., Siafakas, N.M. and Gautier, H. (1979): A new approach for clinical assessment of control of breathing. Bull. Europ. Physiopath. Respir., 15, 17-26. Neldam, S. (1982): Fetal respiratory movements: A nomagram for fetal thoracic and abdominal respiratory movements. Am. J. Obstet. Gynecol., 142,867-869. Olinsky, A., Bryan, M.H. and Bryan, A.C. (1974): Influence of lung inflation on respiratory control in neonates. J. Appl. Physiol., 36.426-429.
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Patrick, J.E., Dalton, K.J. and Dawes, G.S. (1976): Breathing patterns before death in fetal lambs. Am. J. Obstet. Gynecol., 12573-78. Platt, L.D., Manning, F.A., Le May, M. and Sipos, L. (1978): Human fetal breathing: Relationship to fetal condition. Am. J. Obstet. Gynecol., 132.542-551. Remmers, J.E. (1970): Analysis of ventilatory response. Chest, 70 (Suppl.), 134-137. Trudinger, B.J., Lewis, P.J., Mangez, J. and O’Connor, E. (1978): Fetal breathing movements in high-risk pregnancy. Br. J. Obstet. Gynaecol, 85,662-667. Trudinger, B.J., Lewis, P.J., Petit, B. (1979): Fetal breathing patterns in intrauterine growth retardation. Br. J. Obstet. Gynaecol., 86,432-436. Trudinger, B.J. and Knight, P.C. (1980): Fetal age and patterns of human fetal breathing movements. Am. J. Obstet. Gynecol., 137,724-728. Trudinger, B.J. and Cook, C.M. (1989): Fetal breathing movements - a comparison of hard copy records produced by M-mode and Doppler ultrasound. Early Hum. Dev., 20,247-253. Wyman, R.J. (1977): Neural generation of the breathing rhythm. Annu. Rev. Physiol., 39, 417448. Wyszogrodski, I., Thach, B.T. and Milic-Emili, J. (1978): Maturation of respiratory control in unanesthetized newborn rabbits. J. Appl. Physiol., 44, 304-310.
