Fetal breathing and development of control of breathing ARNO H. JANSEN AND VICTOR CHERNICK Perinatal Physiology Laboratory, Department of Pediatrics, University of Manitoba, Winnipeg, Manitoba R3E OW3, Canada JANSEN, ARNO H., AND VICTOR C~~~~~~~.Fetulbreathingund development of control of breathing. J. Appl. Physiol. 70(4): 1431-1446, 1991.Technical advances during the last several decades have greatly facilitated research into fetal physiology and behavior, specifically fetal breathing (FB). Breathing movements have been demonstrated in the fetuses of every mammalian species investigated and appear to be part of normal fetal development. In this review we focus on the methods of measuring FB and on some of the problems associated with these measurements and their interpretation. We also review fetal behavior, the role of the peripheral and central chemoreceptors in spontaneous FB, the fetal respiratory response to hypercapnia and hypoxia, and the transition to continuous breathing at birth. It is clear that in many ways the control of breathing movements in utero differs from that after birth. In particular, inhibitory influences are much more prominent before than after birth. Possibly this is due to the unique fetal situation, in which conservation of energy may be more important than any advantage breathing activity imparts to the fetus. carotid

body; peripheral

chemoreceptor;

REPORTS of fetal breathing (FB) in animals and humans have appeared from time to time since the latter part of the 18th century (see Ref. 31 for review), but this topic was not studied in a systematic way until the pioneering work of Barcroft (lo), Snyder and Rosenfeld (166, l74), and Windle and colleagues (183) in the 1930s and 1940s. Although these early studies were limited by the available technology at the time, the impetus they gave to the study of fetal physiology has been of unquestionable importance. More recently, the study of FB has greatly benefited from two technical developments. The first was the introduction of the chronic fetal sheep preparation by Meschia et al. (129) in 1965, which made longitudinal studies on fetuses possible during the last third of gestation in near-normal conditions. The second was the development of ultrasound, which allowed noninvasive monitoring of fetal behavior in the human. The “modern era” of the study of the control of FB began in 1970 with the preliminary reports of spontaneous FB activity in normal chronically prepared fetal lambs by Merlet et al. (128) and Dawes et al. (47) followed by a detailed study in 1972 (48). This was a major breakthrough, because it finally settled the longstanding ANECDOTAL

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central

chemoreceptor;

birth

controversy of whether the fetus normally makes breathing movements in utero before birth. During the last several decades, FB has been extensively studied, although most reports have been of a descriptive nature. In this review we focus on the methods used to measure FB and on specific areas that are still unresolved and controversial. The role of various drugs and putative neurotransmitters in the control of FB has recently been reviewed by Moss and Inman (137) and is not covered in detail here. Methods of Assessing Fetal Breathing Tracheal pressure deflections. Tracheal pressure deflections have been used as a simple and convenient method of assessingbreathing movements in fetal sheep. Because of the viscosity of the lung liquid and the high frequency of FB, very little liquid (~1 ml) is moved in the fetal trachea during breathing activity (48, 122), so in effect tracheal pressure changes fairly accurately reflect the respiratory efforts of the fetus. This is particularly true during stimulated FB, e.g., during hypercapnia, when all the respiratory muscles are involved (49). In this situation, tracheal pressure deflections represent a more

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accurate reflection of fetal respira tory output than the integrate d diaphragmatic activity. Tracheal pressure deflections are less reliable during weak or very rapid breathing (49), and for this reason relyin go nly on trac heal pressure measurements will result in an underestimate of the incidence of normal FB activity. A further precaution concerns the nature of tracheal pressure measurements. In a liquid-filled system, as is the case in utero, any pressure is faithfully transmitted. Therefore, to avoid artifacts, the amniotic pressure has to be measured simultaneously and electronically subtracted from the tracheal pressure (34). Furthermore, obstructing the trachea (2) or opening the trachea to the amniotic fluid (57) has been shown to alter lung development. Hence, in chronic experiments, care must be taken to implant the tracheal catheter in a manner that does not impede the normal flow of the tracheal fluid. Diaphragmatic and intercostal electromyography. Recording the diaphragmatic electromyogram (EMG) (122) has become a popular way to monitor FB activity. The diaphragmatic EMG provides a stable and reliable record of FB, especially at low breathing activity, and when appropriately filtered and integrated lends itself readily to computer analysis. The inspiratory diaphragmatic bursts are often fragmented, which may result in an overestimate of the frequency of breathing. The overestimate depends to some degree on the time constant of integration and can be partially corrected by setting limits to what constitutes a breath, e.g., any EMG activity 0.1-1.5 s in duration. However, in some instances, especially in younger fetuses during control conditions, the rejected activity can be a substantial portion of the total activity. The EMG of the internal and external intercostal muscles of the fourth to eighth intercostal spaces has been studied in fetal sheep (49), but intercostal activity is not generally used as an indicator of FB behavior. The intercostal EMG is susceptible to postural changes and appears to have a higher activation threshold than the diaphragmatic EMG (49, 69), which makes it unreliable for monitoring FB during control (unstimulated) periods. Phrenic nerue activity. Phrenic nerve activity has been used successfully as an index of breathing in acute experiments on adult animals (54, 55). Bahoric and Chernick (6) were able to record phrenic activity chronically with a cuff electrode in fetal sheep, but the technical problems remain formidable. In addition, it is very difficult to recognize contamination from muscle activity. This technique, therefore, does not lend itself to chronic monitoring of FB. Ultrasound. Since 1970 a variety of ultrasound methods including A-mode, M-mode, and pulsed and continuous-wave Doppler detection have been used to monitor FB movements in the human. However, by the mid1970s these techniques were supplanted by real-time two-dimensional B-mode ultrasound images of the fetus, because setting the transducer was much less critical and the scans could be videotaped for later review (for a recent review of these techniques, see Ref. 126). The development of ultrasound techniques constitutes a significant technical advance that allows the fetus to be

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monitored and visualized well before birth. FB movements first described in the human in 1888 are now routinely monitored with ultrasound and constitute an important addition to the biophysical profile of fetal evaluation (125). The obvious advantage of ultrasound is that the technique is noninvasive, but because it is at best semiquantitative, it is not we11 suited for more rigorous animal experimentation. Fetal State Th .e near- term fetal lamb regularly cycles between two main states in ro ughly equal proportion and characterized by a high-voltage slow (HVS) and low-voltage fast (LVF) electrocorticogram (ECoG). The HVS state resembles quiet or non-rap id-ey ,e-movement (NREM) sleep postnatally, and the LVF state has characteristics of REM sleep, i.e., REMs, twitching, and lack of muscle tone. There is general agreement regarding these two states, but there is still no consensus regarding wakefulness prenatally. Brief episodes (generally 20 Torr. However, most FB occurs at rates ~100 breaths/min and at tracheal pressure deflections 132 days gestation. Because of the nature of the experiments. it is not clear whether

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the stimulus is hyperoxemia per se or whether lung distension is a prerequisite for this effect. This question could possibly be answered by raising the fetal PaOnin a hyperbaric chamber (5,135) or via extracorporeal perfusion. Glucose. Spontaneous FB is reduced or absent during episodes of hypoglycemia, but normal FB resumes when the hypoglycemia is corrected (23, 159). In light of the fetal situation, this is not totally surprising, but more surprising is the fact that in the human FB is increased during hyperglycemia after bolus injections of glucose into the maternal circulation or after ingestion of a meal by the mother (61,64,147,148,151,152). Considering the rapid growth and development of the fetus, it is not reasonable to assume that the fetus is normally substrate deficient for much of the time. The problem is complicated by the ability of the fetus to use fuels other than glucose (11) and the lack of identification of a site of action of glucose. At present, therefore, it is not at all clear how glucose stimulates FB. Possibly glucose (or lack of it) affects primarily REM sleep and FB secondarily (159), or alternatively glucose metabolism may lead to an increase in [H+] in the vicinity of the central chemosensitive cells, which then leads to increased FB (147, 148, 157). Clearly, more work has to be done to unravel this puzzle, but practical implications of the fetal response to hypo- and hyperglycemia are already evident, particularly when human FB is assessedby ultrasound. Respiratory-related reflexes. Several respiratory-related reflexes have been investigated and found to function well before birth. The effectiveness of the HeringBreuer inflation and deflation reflexes in fetal lambs and their dependence on intact vagi were first demonstrated in acute experiments (43) and subsequently verified in chronically prepared fetuses (123). Similarly the laryngeal chemoreflex is well developed before birth; water (but not saline) instilled into the region of the larynx will result in prompt arrest of FB (94). Although these reflexes can be demonstrated experimentally, it is doubtful whether they have a significant role in the control of FB. Vagotomy, which eliminates the pulmonary stretch receptors, does not appear to affect FB (24), possibly because the displacement of fluid, and hence change in lung volume, is small (48, 122) and the laryngeal reflex is not triggered by amniotic fluid in newborn lambs (103).

maneuver will stimulate respiration within minutes after clamping of the umbilical cord (76). Similarly, hypercapnia will stimulate breathing within moments after birth in sinoaortic-denervated lambs (76). Similar responses have been reported for the newborn lamb (76), guinea pig, rabbit (Ml), and rat (68). In addition, hypercapnia recently has been shown to stimulate FB in fetal lambs deprived of peripheral chemoreceptor function (115). Individually these were not exhaustive studies, but together they provide fairly strong evidence of functional and responsive central chemoreceptors before birth. More direct proof was provided by Hohimer et al. (78), who were able to selectively stimulate or depress FB in chronically prepared fetal lambs by altering the bicarbonate concentration of the fetal cerebrospinal fluid. Demonstrating responsiveness of central chemoreceptors before birth, however, does not prove that these receptors are providing the main drive to spontaneous FB. In fact, the great variability and general pattern of FB suggest that they do not. Carotid bodies. In histological terms, the carotid bodies of several mammalian species studied were found to be fully differentiated and mature at birth (12,29, 165), but the level of functional maturity has been difficult to determine (see Ref. 65 for review). A major reason is their relative inaccessibility and the need to use anesthesia and the exteriorized fetus to study direct chemoreceptor firing. Anesthesia may alter chemoreceptor discharge directly or secondarily to vascular changes (16), but the main drawback of using anesthesia in fetuses is the total suppression of breathing activity, which makes it impossible to correlate chemoreceptor discharge with respiratory output. Cross and Malcolm (41) were the first to report carotid body chemoreceptor activity in a whole sinus nerve of an exteriorized fetal lamb, although the blood gas status was not indicated. Subsequently, Harned et al. (71) also recorded from the whole sinus nerve of fetal lambs and found little chemoreceptor activity until the umbilical cord was clamped. Again, blood gaseswere not measured. It should be noted that evaluation of whole sinus nerve discharge is complicated by the presence of powerful baroreceptor activity, especially in situations of increased blood pressure. Ideally only single- or few-fiber preparations should be used. In a more detailed study on fetal lambs, Biscoe et al. (17) found irregular activity in the sinus nerve to be Chemoreceptors sparse and largely unresponsive to physiological and Central chemoreceptors. The central chemoreceptors pharmacological stimulation. However, this activity inare believed to be responsive to [H+] and to mediate the creased during electrical stimulation of the sympathetic respiratory drive to CO, that cannot be accounted for by nerve to the carotid body or after clamping of the umbilithe peripheral chemoreceptors. There is still consider- cal cord, which incidently also increased sympathetic activity. They concluded that the carotid chemoreceptors able controversy regarding the specific stimulus, extracellular fluid pH or CO, or cerebrospinal fluid pH or CO,, were insensitive during fetal life and required sympaand the actual site and nature of these receptors (see thetic stimulation for activation at or shortly after birth. Refs. 131 and 172 for review). In postnatal animals, su- A subsequent study in the same laboratory (101) did not perfusion of discreet areas of the ventral medullary sur- verify the earlier findings (17) and also did not substanface with acid solutions has been shown to stimulate tiate the pivotal role of sympathetic stimulation in actibreathing whereas alkaline solutions depressed breathvating the chemoreceptors at birth. In this study, howing. However, in the exteriorized anesthetized fetal lamb, ever, it was again found that spontaneous chemoreceptor superfusion of the ventral medulla with acidic mock cere- activity was sparse in the fetus in vivo (normally rebrospinal fluid will not initiate FB (76,102), but the same sponding chemoreceptors were found in only 8 of 20 fe-

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tuses) but was much more plentiful in a superfused preparation in vitro. More recently, the problem of fetal peripheral chemoreceptor sensitivity has again been studied by Blanc0 et al. (19). In this study, spontaneous and normally responding chemoreceptor activity was found in all 14 fetuses studied but not in newborn lambs. They concluded that the carotid chemoreceptors are active during fetal life but become silent after birth until they have reset to a higher 0, level. The mechanism of this resetting is also not understood but appears to be 0, dependent, because 30 h of fetal hyperoxia have been shown to shift the chemoreceptor response to the right (21). On reading the recent literature, one senses a relief that the issue of fetal carotid body chemosensitivity has finally been settled. Or has it? The experimental evidence is not compelling. Jansen et al. (101) commented on the likelihood of recruitment of chemoreceptors and suggested that in the fetus many chemoreceptors are normally below threshold. Recruitment of chemoreceptors is also indicated in Fig. 2 of Ref. 19. These investigators state that the fetal condition had no bearing on the ease of finding spontaneous chemoreceptor activity, but their published figures indicate a substantially raised fetal Pacoz. Hypercapnia and hypoxia [as is possibly the case in the in vitro preparation (lOl)] could conceivably activate many normally silent receptors and thus increase the likelihood of their detection. Furthermore the dose of cyanide required to stimulate the chemoreceptors in the fetal lamb is -10 times greater than that required in adult rabbits (53) and cats (127). Finally, it is difficult to reconcile the concept of spontaneously active chemoreceptors with the very ambiguous effect of chemoreceptor denervation on FB (see below). It is obvious from the discussion so far that spontaneous activity of fetal carotid chemoreceptors can be detected under certain conditions. The question then becomes one of quantity and effectiveness. Ideally this problem should be studied with chronically implanted electrodes, but to date this is not technically possible. Alternatively it should be reinvestigated in the exteriorized fetus but with strict adherence to a narrowly defined range of fetal blood gases. Aortic bodies.Aortic bodies are small aggregates of glomus tissue situated in the region of the aortic arch and innervated by branches of the vagus nerves. In adult animals the aortic bodies are primarily responsible for cardiovascular reflexes (42) and in the fetus also do not appear to influence FB (24). During fetal life, oxygenation is strictly a vascular function and one might expect these receptors to be well developed. This is in fact the case. In a series of elegant experiments on exteriorized fetal sheep, Dawes et al. (45, 51) demonstrated the ability of the aortic bodies to elicit vascular reflexes when stimulated. These findings have recently been confirmed in chronically prepared fetuses in which the aortic bodies were shown to be involved in selectively routing blood to the vital organs (brain, adrenal) during fetal hypoxemia (90). The latter study also showed that, in the absence of the aortic bodies, the carotid bodies and possibly also the adrenals (catecholamines) can compensate to some de-

gree. This appears to be a case of an increased safety factor in an area vital to fetal survival under stress. Other chemoreceptors. In human and animal fetuses, some of the chemoreceptor tissue in the aortic arch receives a dual blood supply, from the aorta and from the pulmonary artery (30, 79, 118). Indirect evidence of a respiratory reflex originating in the pulmonary vascular bed of young puppies was provided by Kollmeyer and Kleinman (111) using an extracorporeal oxygenation/ perfusion system. Respiration varied inversely with the level of the venous 0, tension. This response could not be detected in adult dogs. Whether these receptors have any unique role during fetal and early neonatal life or whether they merely constitute an anatomic curiosity remains to be established. Unresolved Issues in Fetal Breathing Quantification of fetal breathing. Because of the very irregular and episodic nature of FB, it has been difficult to quantitate fetal respiratory output, a problem that is exacerbated by the lack of standardization between different laboratories. The limitations of measurement of tracheal pressure deflections and of diaphragmatic activity as indexes of FB also influence the quantitative analysis of FB. Therefore, none of the approaches used to date has been totally satisfactory or universally applicable to FB. The incidence of FB either as percentage of total recorded time or as percentage of REM sleep (LVF ECoG) is a simple and the most widely used measure of FB. It lends itself readily to both human and animal studies, but because it depends on the definition of what constitutes breathing and apnea it is a difficult measure for comparison of results from different laboratories. The incidence of FB is a better measure of fetal behavior than of the respiratory output under different conditions. Moss and colleagues (136, 138,139) have used several parameters to assessFB: 1) frequency of breathing per minute; 2) maximal tracheal pressure change per breath, equivalent to tidal volume; 3) tracheal pressure 100 ms after the onset of inspiration, a measure of inspiratory drive; 4) steepest slope of the tracheal pressure deflection, a measure of inspiratory drive; and 5) sum of peak amplitudes of all the breaths per minute, the equivalent of minute ventilation. These parameters can also be derived from the integrated diaphragmatic EMG, but all have limitations as a quantitative measure of FB. Similarly attempts to adapt the instantaneous breathing analysis (or parts of it), VE = VT/TI X TI/TT (where VE is expired minute ventilation, VT is tidal volume, TI is inspiratory time, and TT is respiratory cycle) (130), to FB (83, 85, 161) also suffer from the shortcomings of breath identification. In addition, there is uncertainty whether the entire EMG burst duration (28,49,161) or the time to peak integrated diaphragmatic EMG (83, 84) best describes the inspiratory time during FB. One analysis of fetal respiratory output that goessome way in circumventing these problems is the sum of diaphragmatic activity per minute (power/min) (9,98), especially if limits are set to eliminate tonic diaphragmatic

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Fetal PaCO 2 4. Respiratory output of 2 fetal lambs (triangles and circles) expressed as mean diaphragmatic power per minute for every breathing episode in an 8-h period in relation to fetal arterial PCO, (Pa,,,) during that episode. One fetus was monitored on 2 different days, the 4th (closed circles) and 6th (open circles) days after the operation. On 4 occasions, this fetus was challenged with hypercapnia. A line is drawn between responses and respective levels of baseline breathing. Significance of this figure lies in demonstration of a great variability in level of spontaneous respiratory output per breathing episode independent of changes in fetal Pacoz. FIG.

activity that is clearly not of respiratory origin. The advantage of this analysis is that it can be done easily by a computer for any length of time required (Fig. 4). Dawes et al. (49), using both the tracheal pressure and integrated diaphragm EMG as index of FB, have done a rigorous comparison of FB during control and hypercapnia and came to the conclusion that neither alone is adequate. Tracheal pressures are not sufficiently sensitive at the lower levels of FB, and the diaphragmatic EMG, being from only one of several respiratory muscles, reaches a plateau during stimulated breathing and may underestimate fetal respiratory output. It is, therefore, important to limit the diaphragmatic EMG analysis to low or moderately stimulated FB. Because neither tracheal pressure deflection nor diaphragmatic EMG is freely comparable between fetuses, the values are generally normalized, e.g., percent change from baseline, with every fetus serving as its own control. It is obvious that when this is done the magnitude of the response is to a large degree dependent on the baseline or control recording. What to use as a control can be a problem. For very short experiments one can compare a finite number of breaths before the stimulus with an equal number of breaths or length of time after the stimulus (140). In long experiments one can compare the incidence or total respiratory output over many respiratory cycles before an intervention with that during an equal length of time during or after an intervention (24, 28, 115). For some experiments, neither approach is practical, but because FB is so variable it is advisable to use the baseline and the test recording within the same breathing episode (Fig. 4). Of course, FB is variable even within one breathing cycle and apparent stimulation may be observed by chance. Therefore, adequate control experiments are imperative, with the significance of a test response being determined statistically (9, 97). Role of carotid bodies during fetal life. The study of ca-

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rotid body function using chronically prepared sheep fetuses in utero has generally been indirect insofar as spontaneous FB or respiratory and cardiovascular reflexes in intact fetuses were compared with the behavior and responses in fetuses deprived of chemoreceptor function. Jansen et al. (99) denervated the carotid bodies in fetal lambs and could not detect a difference in FB after the first several days following the operation. However, because the aortic bodies were left intact, it is possible that those receptors compensated for the loss of the carotid bodies. Subsequently these experiments have been repeated in several laboratories on totally “chemodenervated” fetuses (115,134, 160). The general finding was a reduction in the incidence and amplitude of FB for several days after the operation with recovery and normal breathing activity thereafter, suggesting that the peripheral chemoreceptors are not essential or do not contribute significantly to FB. In contrast, Murai et al. (141) found the recovery to be incomplete in both incidence of FB and the amplitude of tracheal pressure deflections. They concluded that the carotid bodies are active during fetal life and participate in the control of FB. It should be pointed out that in the latter study a total of 1,840 h over 13 days of recording were analyzed, much more than in any of the other studies, which would give this study greater credence. However, a contribution of the carotid bodies to FB that is so subtle that it can be detected statistically only by analyzing hundreds of hours of recording raises the question of physiological relevance. At the present time there is no definitive answer as to the role of the carotid body in FB, but at best it appears to be minimal. The role of the carotid bodies in the control of the cardiovascular system during fetal life has been studied in the acute and chronic situation (see Ref. 66 for review). Intrauterine sinoaortic denervation does not significantly alter the fetal blood pressure, but it does result in greater variability (89, 184). This is probably not the result of the elimination of the chemoreceptors but of the baroreceptors, which have been shown to be active and responsive long before full term (20, 173). From their acute studies on exteriorized fetal sheep, Dawes et al. (45, 46, 51) concluded that the fetal circulation was primarily under the control of the aortic bodies but that, during severe hypoxia, the carotid bodies could be stimulated and participated in the response. Recently this question has been reinvestigated on chronically prepared fetuses (90) by use of the isotope-labeled microsphere technique of blood flow determination (169). This study essentially verified the previous findings that during normoxia there was no discernible difference in organ perfusion between groups of intact, vagotomized, and sinoaortic-denervated fetuses. In addition, during hypoxemia the carotid bodies could to some degree compensate for the loss of the aortic bodies in the redistribution of the fetal cardiac output (90). It should be pointed out, however, that from the latter study it is not clear whether the fetus has the inherent ability to compensate for the loss of either the aortic or carotid bodies or whether this capacity develops over several days. Definitive answers to this question would require a study design of reversible

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1440 Blood Pressure

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1

Ala Nasi EMG Tracheal Pressure

10 torr I------1

Diaphragm 2oo( PV 1 EMG

--

I

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FIG. 5. Direct recording from a near-term fetal lamb with chronic transection of cervical spinal cord at C,. Note typical irregular fetal breathing evident on ala nasi EMG tracing and “apnea” on tracheal pressure and diaphragmatic EMG traces. This experiment demonstrates central origin of spontaneous fetal breathing.

blocking or indirectly denervating the respective chemoreceptors in a chronic preparation. In summary, the importance of the carotid bodies during fetal life is not yet clear. Experimental evidence indicates that they can be stimu lated and may partic ipate in respi ratory an .d cardiovasc ular reflexes under certain circumstances but that otherwise they are not essential to the well-bei ng of the fetus. Even durin g birth, when one might expect a major role for the carotid bodies in the initiation of air breathing, these receptors are not essential (99, 160). Origin of fetal respiratory rhythmogenesis. The respiratory rhythm in postnatal animals has long been believed to originate in the medulla oblongata, although secondary rhythms may also be found in the pons and spinal cord (see Ref. 80 for review). It is important to emphasize that FB is also of medullary origin, becau se it persists after transection of the brain stem at the level of the pons activity and tracheal pressure (50) 9 but diaphragmatic deflections are abolished by transection of the spinal cord at C, (unpublished observations) (Fig. 5). At the present time we do not know precisely where the respiratory rhythm originates or how it is maintained. The fetus may be a suitable model to study this question, because FB may represent central respiratory rhythm in its purest form unmodulated by peripheral feedback. Alternatively, because of weak or absent reflex modulation, FB may be more su sceptible to intrinsic factors such as sleep states, which may be responsible for the erratic breathing pattern observed in the fetus. Because of technical difficulties the central control of FB has remained largely unstudied. Classical stimulation (35) and recording techniques (32) on exteriorized fetal lambs, as well a s chronically i .mplanted “floating” electrodes into the fetal medulla (83, hav fe demonstrated that FB can be initiated by central stimulation and that inspiratory and expiratory neurons are firing prenatally in phase with tracheal pressure deflections. However, none of these approaches was totally satisfactory , and more recently we have had more success with a two- stage approach (86). Briefly, this involves complete instrumentation of the fetus for recording of FB and sleep states as well as making a chronic “window” to the dorsal surface of the medulla and fixing metal screws to the

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fetal skull for easy attachment to a stereotaxic frame. After several days of recovery, the fetus is exteriorized under maternal spinal anesthesia and placed in a warm saline bath. In successful preparations the fetus breathes and cycles normally between sleep states, and the medulla can be extensively probed for many hours. This study has shown that the sa.me types of respiratory neurons firing postnatally can also be encountered in the fetal medulla during FB. Furthermore, some neurons continue to fire phasically during periods of diaphragmatic silence in both REM and NREM sleep; others stop firing or become tonic. This approach can be easily adapted to lesioning, stimulation, and iontophoretic studies of putative neurotransmitters important in the generation of the respiratory rhythm in the fetus. Why does the fetus make breathing movements in utero? Because the placenta acts as the organ of gas exchange for the fetus, the question arises Wh .at benefit does the fetus derive from the seemingly fu .tile breathing activity? This has been a difficult question to answer, because in a complex developing system any intervention has multiple effects. On purely teleological grounds it has been suggested that FB represents prenatal practi .ce of the respiratory system, because effecti ve and sustained breathing is so vital for survival after bi rth (4 4 ). It seems self-eviden t that practice is necessary for the normal development of th e respiratory muscul ature, but experimental evidence that this is in fact true is not yet available. Perhaps FB is an essential prerequisite for normal development of the central nervous control system. Again, there are no experimental data relating specifitally to this point, but considering the changing breathing pattern during the last half of gestation and the problems encountered in premature human infants with periodic breathing and apneic spells and possibly even sudden infant death syndrom e, it is a reasonable hypothesis. Recently it has been demonstrated that FB significantly increases fetal cardiac output and blood flow to a number of vital organs including heart, brain, and placenta (90). This raises the interesting possibility that a major function of FB is its influence on the distribution of the cardiac output and thus indirect facilitation of organ development. Again, this notion is conjectural at present. Attempts have been made to determine the contribution of FB to fetal development indirectly by eliminating FB and then assessing the deviation from normal development. Unfortunately many of the experimental procedures that prevent FB, such as phrenectomy (3,58,143), also lead to a reduction of the intrathoracic space because of enc roachment by the abdominal viscera, and this has long been recognized to lead to pulmonary hypoplasia (see Ref. 108 for review). This has made interpretation of such experiments difficult. However, pulmonary hypoplasia also occurs in fetal rabbits ( 182) and lambs (120) with high cervical cordotomy, whi .ch eliminates FB but m .aintains diaphragmatic tone; in fetal rats kept paralyzed with curare (132); by maternal ingestion of alcohol (81), which has been shown to depress FB (60, 178); and in association with certain teratological anoma-

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lies and clinical situations that prevent or reduce FB (108). Liggins et al. (121) studied this question by leaving the neuraxis intact but diminishing the negative pressures generated during FB by replacing part of the fetal chest wall with a silicon membrane. This procedure also resulted in fetal pulmonary hypoplasia. Conversely, increasing FB by giving pregnant rabbits 8% CO, in air to breathe during late gestation accelerated fetal lung development (142). Although these studies are not definitive by themselves, the weight of evidence suggeststhat FB is necessary for normal development of the fetal lung. Why is breathing activity episodic in the fetus but continuous after birth? It has become axiomatic that FB is episodic and, in the lamb at least, occurs only during REM sleep. During NREM sleep, breathing activity is inhibited by a suprapontine mechanism that somehow becomes inactivated at birth to permit continuous breathing in any state. The nature of this inhibition and its lifting at birth is one of the great unsolved puzzles in the control of breathing. In the fetal lamb the REM sleep dependence of breathing activity can be broken in a number of ways. FB can be induced during NREM sleep by perfusing the cerebral ventricles with mock cerebrospinal fluid containing a low bicarbonate concentration (78), pretreatment with large doses of 5hydroxytryptophan (59, X8), bolus injections of the y-aminobutyric acid antagonist picrotoxin (105), and intracerebroventricular administration of thyrotropin-releasing hormone (13, 177) or corticotrophin-releasing factor (14). Whether and how these factors are involved in the change to continuous breathing at birth remain to be determined. The most dramatic continuous intrauterine FB can be elicited by prolonged infusion of large dosesof the prostaglandin synthase inhibitors meclofenamate and indomethacin (110). Conversely, prostaglandin E, (PGE,) depresses FB (see Ref. 109 for review). The postnataltype P attern of FB after in hibition of p rostaglandin synthesis and the coincident observation of raised plasma levels of PGE, and reduced FB in the days before birth (33, 155), as well as the reduced plasma levels of PGE, and increased breathing postnatally (33), suggest that the prostaglandins may be involved in the transition from periodic fetal to continuous postnatal respiration. The site of action of PGE, (and prostaglandin synthase inhibition) has been roughly localized to the central nervous system between the lower pons and T, (95,112), but the mechanism by which prostaglandinsaffect FB remains to be elucidated. It does not appear to be a direct action 9however, because during prolonged depression of prostaglandin synthesis the stimulation of FB is not maintained (154) and FB is reduced before birth despite continued very low levels of PGE, (180). Furthermore, Lee et al. (119) have recently shown that although fetal breathing activity in utero is inversely related to the circulating fetal PGE, levels, the normal PGE, levels at the onset of continuous breathing at birth are approximately three times the fetal levels. At best, therefore, prostaglandins can be ascribed only a secondary or modulatory role in the control of FB and probably no role in the establishment of continuous breathing at birth. Numerous attempts have been made to mimic birth in

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utero and to identify the critical factor for the stimulation of continuous breathing, e.g., thermal or sensory stimulation, asphyxia followed by hyperoxia, and release from a presumed placental inhibitor. To a varying degree, birth involves all these factors. Sensory, mechanical, or electrical stimulation of the skin or peripheral nerves (37, 171) can be a powerful stimulus to breathing but is to some degree subject to the arousal state of the fetus (87). Similarly cooling of the fetal skin, but not the core (62), as well as raising the core temperature of the fetus (179) will stimulate powerful continuous breathing in fetuses with normal blood gases. Conversely, fetal asphyxia produced by umbilical cord occlusion will initiate continuous postnatal-type breathing in utero in the absence of other sensory stimulation, if the fetus has access to air (1). Whether the establishment of continuous breathing at birth is due to the sudden release from a placental inhibitor to breathing has been debated for a long time. Recently a number of provocative papers have again raised interest in this question, but the results and conclusions are still controversial. Pagtakhan et al. (150) in 1971 studied the initiation of respiration at birth using anesthetized exteriorized near-term fetal lambs that were crossperfused with newborn lambs of similar size. In this preparation, clamping the umbilical cord per se did not stimulate breathing, and the investigators concluded that the placenta does not provide an inhibitor to breathing in utero. A similar conclusion was reached by Faber et al. (56), who found that lung distension and ventilation of chronically prepared fetal lambs with or without umbilical cord occlusion had an unpredictable effect on FB. The same fetuses always started to breathe after delivery, even at the same range of blood gases.Other investigators (1), however, found that umbilical cord occlusion will initiate continuous and prolonged breathing in nearterm fetuses in any sleep state and that this breathing is reversible on reperfusion of the placenta. The latter experiments suggest that a placental factor inhibitory to breathing is present in utero and that its elimination is critical in the transition to continuous breathing at birth. The presence of an inhibitory placental factor was also indicated in the experiments of Baier et al. (7), who distended the fetal lungs with different concentrations of 0, and maintained fetal oxygenation with high-frequency oscillatory ventilation with or without concomitant umbilical cord occlusion. In this situation, however, the more important factor in stimulating and maintaining continuous breathing appeared to be high Paoz, because the response occurred even in the absence of cord occlusion. Conversely, breathing was markedly reduced and became episodic again at fetal levels of Pa,, , despite continuous cord occlusion (4). It may be significant that the fetal 0, levels achieved with this technique are much in excess of those likely to be encountered at birth. The situation is complicated further: the response does not require the carotid bodies (74) but occurs only in fetuses with intact vagi (73) and >132 days gestation (full term 147 days) (72), although in the latter case it is not clear whether it is due to the young age or difficulty in achieving sufficiently high fetal 0, levels. Many investigators have commented on the arousal and agitation that fre-

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quently accompany the onset of continuous breathing, but whether arousal is a side effect or a prerequisite is not known. The experimental observations have to be contrasted to the normal situation in which premature human newborns maintain breathing despite immaturity and poor oxygenation. As can be seen from this brief discussion, birth presents a very complex situation, and the transition from episodic FB to continuous postnatal breathing probably depends on many factors, any one of which can assume a dominant role in a given situation. Summary

Remarks

FB differs in several fundamental ways from the breathing after birth. Spontaneous FB is rapid, very irregular, and episodic and is highly state dependent: it occurs only during REM sleep. During NREM sleep the breathing movements are inhibited by a mechanism situated in the midbrain and lateral pons. The fetus does show a positive respiratory response to increased Pa,, , although by postnatal standards the sensitivity to cd, is low. During acute hypoxemia the fetus demonstrates a paradoxical inhibition of breathing activity. Peripheral and central chemoreflexes as well as vagal afferent reflexes can be demonstrated in the fetus, but their role in spontaneous FB appears to be minimal. Birth and the associated transition from episodic FB to continuous postnatal breathing are still poorly understood phenomena that so far have defied a simple explanation. Much descriptive work about FB has been published, but there is a dearth of information regarding the central respiratory rhythmogenesis in the fetus. Ablation and lesion experiments on chronically prepared unanesthetized fetuses have provided valuable indirect evidence, but in the future more direct neuronal recording will be required to advance our knowledge significantly in this field. New techniques of recording neuronal activity and studying the effect of iontophoretically applied neurotransmitters in unanesthetized fetal sheep are promising. We are grateful to Shirley Alton for typing the manuscript. This study was supported by the Medical Research Council of Canada and the Children’s Hospital of Winnipeg Research Foundation Inc. Address for reprint requests: A. H. Jansen, Perinatal Physiology Laboratory, Dept. of Pediatrics, University of Manitoba, P216, 770 Bannatyne Ave., Winnipeg, Manitoba R3E 043, Canada. REFERENCES 1. ADAMSON, S. L., B. S. RICHARDSON, AND J. HOMAN. Initiation of pulmonary gas exchange by fetal sheep in utero. J. Appl. Physiol. 62: 989-998, 1987. 2. ALCORN, D., T. M. ADAMSON, T. F. LAMBERT, J. E. MALONEY, B. C. RITCHIE, AND P. M. ROBINSON. Morphological effects of chronic tracheal ligation and drainage in the fetal lamb lung. J. Anat. 123: 649-660, 1977. 3. ALCORN, D., T. M. ADAMSON, J. E. MALONEY, AND P. M. ROBINSON. Morphological effects of chronic bilateral phrenectomy or vagotomy in the fetal lamb lung. J. Anat. 130: 683-695, 1980. 4. ALVAREZ, J., R. J. BAIER, C. FAJARDO, B. NOWACZYK, D. CATES, AND H. RIGATTO. The effect of hypoxia on the continuous breathing induced by 0, or 0, plus cord occlusion in the fetal sheep (Abstract). Federation Proc. 4: A1179, 1990. 5. ASSALI, N. S., T. H. KIRSCHBAUM, AND P. V. DILTS, JR. Effects of hyperbaric oxygen on uteroplacental and fetal circulation. Circ. Res, 22: 573-588, 1968.

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Fetal breathing and development of control of breathing.

Technical advances during the last several decades have greatly facilitated research into fetal physiology and behavior, specifically fetal breathing ...
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