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The effects of maternal hyperoxia on fetal breathing movements in third-trimester pregnancies
The effects of maternal hyperoxia on fetal breathing movements in third-trimester pregnancies Lawrence D. Devoe, M.D., Hassan Abduljabbar, M.D., Lesley Carmichael, B.Sc., Carol Probert, B.Sc., and John Patrick, M.D. London, Ontario, Canada Fetal breathing movements and gross fetal body movements were observed before, during, and after maternal hyperoxia induced by inhalation of 50% oxygen in 14 women with normal term pregnancies. Studies were performed with real-time B-scan linear-array ultrasound and were standardized for time of day, maternal nutritional status, postprandial interval, and length of observation. Each study included a 3O-minute baseline, followed by 15 minutes of hyperoxia, and 45 minutes of continued monitoring. No significant changes occurred in the mean incidences of fetal breathing movements, gross fetal body movements, the mean breathing rate, or breath interval variability, as analyzed in 5-minute epochs. Maternal Po •. as measured by transcutaneous electrodes, increased to the maximum level after 5 minutes of hyperoxia (155% over control levels). The breathing activity of normal third-trimester fetuses appears to be stimulated maximally in the second and third postprandial hours and cannot be further increased by maternal hyperoxia. This protocol represents a possible clinical strategy for investigating fetuses at risk for intrauterine hypoxia, provided that similar experimental conditions are maintained. (AM. J. OBSTET. GVNECOL. 148:790, 1984.)
Although fetal breathing movements may reflect intrauterine conditions, extrauterine influences exert significant effects on the presence and patterns of fetal breathing activity. Animal experiments have shown that the oxygen concentration of maternal inspired air may modify the incidence of fetal breathing movements.'-4 During chronic fetal hypoxemia, brought on by maternal hypoxia, fetal breathing movements may continue, although at a reduced frequency,"' 3 whereas acute hypoxemia often results in the disappearance of fetal breathing activity" In either circumstance, maternal hyperoxia restored the incidence of fetal breathing movements to normal levels unless fetal hypoxia was prolonged or acidosis was present! In normoxemic lamb fetuses, maternal hyperoxia does not affect the incidence of fetal breathing movements.' Efforts to extend these observations to human fetuses have been problematic. Experimentally induced maternal hypoxia:; has proved to be potentially too hazardous to the fetus to be an effective study technique. Isolated case reports6 suggest that spontaneous maternal hypoxemia may lead to cessation of fetal breathing movements, which are restored by hyFrum the Departments of Obstetrics and Gynecology and of Physiology, Medical Research Council Group in Reproductive Biology, University of Western Ontario. Supported by grants frum the Canadian Medical Research Council. Receivedfor publication june 14,1983. Revised August 26, 1983. Accepted September 1,1983. Reprint requests: john Patrick, M.D., Department of Obstetrics and Gynecology, St. joseph's Hospital, 268 Grosvenor St., London, Ontario, Canada N6A 4V2.
790
peroxia. Previous studies7 • '3 of the effects of maternal hyperoxia on normal and pathologic pregnancies have failed to control for important maternal variables. Our ultimate goal was to establish normative data so that this manipulation could be considered for the investigation of fetuses at risk for intrauterine hypoxia. Material and methods Patients. Informed consent was obtained from 14 healthy pregnant women near term (37 to 40 weeks' gestation). Fetal outcomes confirmed gestational age and the good health of the fetuses studied. All infants were delivered vaginally and were appropriate for gestational age. Mean birth weight was 3,470 ± 135 gm (SEM). Mean Apgar score at 5 minutes was 9.6 ± 0.2 (SEM), with no score below 8. Mean umbilical artery pH was 7.27 ± 0.02 (SEM). All infants were discharged from the nursery in good condition. Study protocol. Mothers and their fetuses were studied in a quiet, artificially illuminated room from 0930 to 1100 hours, 90 minutes after the mothers had eaten an 800 kcal breakfast. Studies were conducted with the patients in a semi-Fowler position in bed. Smoking was not permitted during or for 12 hours preceding the studies. During the 30-minute baseline period (0930 to 1000 hours), mothers breathed room air. For the next 15 minutes, they inhaled a 50% oxygen mixture, derived from 100% oxygen and room air, mixed in an oxygen blender (Bird 3M, Palm Springs, California), and delivered via a mouthpiece connected to a one-way nonrebreathing valve, at a rate of 10 Llmin. Nasal obstruction was maintained with a standard swimmer's
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nose plug during the hyperoxia period. In seven patients, transcutaneous P02 was measured continuously beginning 15 minutes before, during, and after hyperoxia, with the use of a transcutaneous oximeter (Oxymonitor, Litton Medical Electronics) and a Hellige Transoxode P02 electrode. Mothers were instructed to breathe at a consistent rate throughout the hyperoxia phase, and this was maintained during continuous observer-to-patient monitoring and instruction. Observation and analysis of fetal breathing movements. All studies were performed with a real-time B-scanner (ADR Ultrasound, Temple, Arizona), operating at a frequency of 3.5 MHz with an average intensity of 0.045 mW/cm,2 and oriented to a sagittal section of the fetal chest and abdomen. Images were viewed on a video monitor, while individual fetal breathing movements and gross body movements were identified and coded on a Grass Polygraph (Model 7A) chart recorder. Analysis of fetal breathing movements and gross fetal body movements was performed on-line by a PDP 11/40 computer (Digital Equipment Corporation), with the use of a program developed and validated for real-time data acquisition. 14 Fetal breathing movements, gross fetal body movements, apneic episodes, and failure times were also quantified on-line to the nearest 1.0 msec. Measurements of time during which fetal breathing movements occurred did not include apneic episodes, defined as the absence of fetal breathing movements for 6 seconds or more, or gross fetal body movements, i.e., activity sufficient to prevent recognition of fetal breathing movements. Portions of the records which could not be analyzed because of failure times, i.e., technical failures or interruptions on the part of the patients, were not included in the final analysis and composed 1.42% of the total study time. Percentages of time spent making breathing movements and body movements, mean breathing rates, and breath-tobreath intervals were determined for each fetus during 5-minute epochs of the study period. Results are presented as grouped means and standard errors (SEM) for each 5-minute epoch. Unless specified otherwise, significance was determined by a t test for small samples, variance not assumed to be equal, as described by Bailey.s Results
Maternal hyperoxia. Transcutaneous Po2 1evels were measured in seven of the 14 patients (Fig. 1). Prior to maternal inhalation of the 50% oxygen mixture, mean transcutaneous P02 was 81.4 ± 0.6 (SEM) mm Hg. Significant increases in transcutaneous P02 occurred within 2 minutes, and maternal transcutaneous P02 levels above 200 mm Hg were attained by 5 minutes in all patients. Increases in transcutaneous P02 continued
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Fig. 1. Continuous measurement of maternal transcutaneous Po. (I'cPo.), in mm Hg, before, during, and after induction of maternal hypoxia. Significant increases in transcutaneous POz are achieved within 5 minutes of maternal exposure to 50% oxygen and are sustained for an additional 5 minutes after return to breathing room air.
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Fig. 2. Time incidence of fetal breathing movements during the study periods analyzed in 5-minute epochs. There were no significant changes in mean percentage of time spent breathing during or after maternal hyperoxia.
for 10 minutes but were not significant (p > 0.10, Student's t test). Maternal transcutaneous P02 returned to baseline values (83.3 ± 2.0 mm Hg) within 5 minutes of resumption of breathing room air. Fetal breathing activity and gross body movements. Figs. 2 and 3 present, respectively, grouped 5-minute incidences (mean ± SEM) of fetal breathing movements and gross fetal body movements for all 14 patients. Mean incidences of fetal breathing movements and gross fetal body movements for the entire study were 58.28% ± 3.74% and 7.22% ± 0.86%, respectively. In the 15 minutes before, during, and after hyperoxia, there were no significant changes in the incidences of fetal breathing movements or gross fetal body movements. Incidences of fetal breathing movements rose, not significantly, after the first 5-minute epoch and remained elevated until the last two 5-
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were only four with no evident breathing actIvIty (1.47%). Hiccoughs were observed in 13 or 14 fetuses studied, as characterized previously by Patrick and associates. 1o The' duration of episodes of hiccoughs was 1.5 to 7.0 minutes, and these occurred during maternal normoxemia.
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Fig. 3. Time incidence of gross fetal body movements, analyzed in 5-minute epochs. There were no significant changes in mean percentage of time spent moving during or after maternal hyperoxia.
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Fig. 4. Mean breathing rates during 5-minute epochs. There was a slight but not significant increase in mean breath rate during maternal hyperoxia.
minute epochs (85 and 90 minutes). No trends in the incidence of gross fetal body movements were observed during the study. The mean breathing rate for the entire study period was 46.32 ± 2.34 bpm. Analysis of mean 5-minute breathing rates for 15 minutes before, during, and after hyperoxia revealed a slight but not significant increase during the first 5 minutes of hyperoxia (Fig. 4). Breath-to-breath intervals and coefficients of variation (SD/mean). Table I presents the mean breath-tobreath intervals, standard deviations, and coefficients of variation for breath-to-breath intervals. The group mean of breath-to-breath intervals for the entire study was 1.34 ± 0.27 seconds, and the mean standard deviation was 0.756 ± 0.12 seconds. Hyperoxia did not produce any significant changes in the variability of breathing rates. There was also no significant alteration in variability of breath-to-breath intervals over the time of observation (r = 0.3283, p> 0.05, df = 16). During the 272 observed 5-minute epochs, there
This study has shown that the induction of maternal hyperoxia in normal term pregnancies does not result in significant alterations in fetal breathing activity, breathing rates, breath interval variability, or incidence of body movements. The overall incidence of fetal breathing movements corresponded closely to that reported by Patrick and associates1o in the second and third postprandial hours, and by Natale and associates9 105 minutes after the giving of a 50 gm bolus of glucose to normal mothers. Although blood glucose values were not determined during this study, the observation periods were initiated during a time when maximal breathing activity, associated with peak maternal levels of glucose, would be expected. Previous efforts to demonstrate the relationship between fetal breathing activity and maternal levels of oxygen were largely based on animal studies. Boddy and associates l demonstrated that maternal hyperoxia had little or no effect on normally oxygenated lamb fetuses. In chronically hypoxemic fetal lambs, fetal breathing movements may continue, although often at a reduced leveJ,2· 3 but when acidosis is present or the hypoxic insult is acute, fetal breathing movements may be totally abolished and may respond to maternal hyperoxia only after a considerable delay.3 Even normal chronic lamb preparations may exhibit apnea with P0 2 fluctuations in the hypoxic range « 16 mm Hg) unless PC02 is elevated. 11 In humans, efforts to study the effects of acute induced maternal hypoxia on fetal vital functions have produced fetal compromise5 and thus been discontinued. A case report by Manning and Platt,6 in which fetal breathing movements were abolished during acute hypoxemia and restored with hyperoxia in a patient with sickle cell crisis, suggests that human fetal breathing activity can be affected by changes in maternal P0 2 levels. The effects of induced hyperoxia on fetal heart rate patterns have been studied extensively; however, there is little direct evidence to suggest how quickly fetal P0 2 may be altered by maternal hyperoxia. Khazin and associates,12 using sampling of fetal capillary blood, demonstrated that maternal hyperoxia (Pao, > 300 mm Hg) produces small increments in fetal Po 2, on the order of 3.0 to 5.0 mm Hg. These alterations in fetal P0 2 tended to parallel maternal levels and fell rapidly after discontinuation of the enriched oxygen mixture.
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Table I. Mean breath-to-breath intervals and coefficients of variation
Time (min)
0-5 6-10 11-15 16-20 21-25 26-30 31-35 36-40 41-45 46-50 51-55 56-60 61-65 66-70 71-75 76-80 81-85 86-90
Mean breath interoal ( ± SD) (sec)
1.651 1.419 1.354 1.380 1.4 77 1.467 1.524 1.363 1.407 1.343 1.319 1.378 1.316 1.418 1.368 1.319 1.500 1.688
± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±
0.722 0,388 0,234 0.310 0.543 0.483 0,558 0.576 0,380 0,341 0,342 0,374 0.252 0.339 0,287 0.463 0,344 0.654
Marsal and colleagues13 investigated hyperoxia in nine normal third-trimester pregnant women. When transcutaneous P0 2 was raised to 70% to 100% above control levels, capillary pH and Pco2 remained constant. Fetal breathing movements decreased significantly in the first 5 minutes but subsequently returned to control levels. Ritchie and Lakhani7 reported that maternal hyperoxia, induced by 50% oxygen in 32 women with normal third-trimester pregnancies, resulted in slightly but not significantly increased incidences of fetal breathing movements. Conversely, in 16 pregnancies complicated by severe preeclampsia or intrauterine growth retardation, fetal breathing movements increased significantly, rising to normal levels during hyperoxia. Arterial P0 2 was measured intermittently in only two patients and rose by nearly 100%. Neither study controlled for maternal variables, such as time of day, meals, and gestational age. Marsal and colleagues used gated A-mode transducers, thereby introducing potential observation artifacts, whereas Ritchie and Lakhani used very short, i.e., 35-minute, observation periods. The present study differs from these earlier two studies in several major respects. The conditions under which women were studied were uniform for all subjects. Maternal hyperoxia was achieved at higher levels than in either of the other studies and was measured on a minute-to-minute basis, thus demonstrating where fetal effects should be observed. All women were in the last month of gestation, thus eliminating possible confounding effects due to gestational age. Finally, the study period was clearly long enough to complete at least one cycle of breathing activity, as evidenced by the symmetrical rise and fall of fetal breathing movements
Mean standard deviation ( ± SD) (sec)
0,817 0.791 0,678 0.728 0.706 0.654 0.686 0,585 0.773 0.683 0.637 0,691 0,718 0,749 0.737 0,801 0,809 0,829
± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±
0,343 0,247 0,190 0.357 0,283 0.300 0.238 0,255 0.230 0,236 0.159 0.233 0.212 0,333 0.251 0,186 0,228 0,328
Coefficient of variation
0.498 0,557 0.501 0.528 0.478 0.486 0.450 0.429 0.549 0.509 0.483 0.502 0.546 0.528 0.539 0.607 0.539 0.491
incidence, corresponding to the beginning and end of observations. We conclude that normal fetuses supported by adequate placentas should respond predictably to a standard carbohydrate load, as previously demonstrated by Patrick and associates. 10 Furthermore, in the absence of hypoxia or acidosis, fetal breathing activity should not be altered by the slight increase in fetal P0 2 expected with maternal hyperoxia. The cyclical nature of fetal breathing activity in normal pregnancy is unaffected by maternal hyperoxia. Therefore, the observation of fetal breathing movements in the presence of transient maternal hyperoxia may provide a means of evaluating pregnancies in which placental function is compromised, intrauterine growth retardation is suspected, or other parameters suggest that intrauterine hypoxia may exist. We wish to thank Drs. Paul Harding, Graham Chance, and Fraser Fellows for their interest in our work, and Ms. T. Clarke and Ms. V. Clemons for their excellent technical assistance.
REFERENCES 1. Boddy, K., Dawes, G. S., Fisher, R., et al.: Fetal respira-
tory movements. Electrocortical and cardiovascular responses to hypoxemia and hypercapnea in sheep, J. Physiol. (Lond.) 234:599, 1974. 2. Dawes, G. S.: Breathing and rapid-eye-movements before birth, in Comline, R, S., Gross, D, W., Dawes, G. S., and Nathanielsz, P. S., editors: Foetal and Noenatal Physiology, Cambridge, 1973, Cambridge University Press, p. 360.
3. Dalton, K. S., Dawes, G. S., and Patrick, J. E,: Diurnal, respiratory and other rhythms of fetal heart rate in lambs, AM. J. OBSTET. GYNECOL. 127:414, 1976. 4. Martin, C. B., Murata, y, U., Ikenoue, T., et al.: Effects of
Devoe et al.
5. 6. 7. 8. 9.
10.
alterations of P02 and Pco2 on fetal breathing movements in rhesus monkeys. Gynecol. Obstet. Invest. 6:74, 1975. Wood, C., Hammond, j., Lumley, j., et al.: Effect of maternal inhalation of 10% oxygen upon the human fetus, Aust. N. Z. j. Obstet. Gynecol. 11:85, 1971. Manning, F. A., and Platt, L. D.: Maternal hypoxemia and fetal breathing movements, Obstet. Gynecol. 53:758, 1979. Ritchie, j. W. K., and Lakhani, K.: Fetal breathing movements and maternal hyperoxia, Br. j. Obstet. Gynaecol. 87:1084, 1980. Bailey, N. T. j.: Statistical Methods in Biology, London, 1973, English Universities Press, p. 50. Natale, R., Patrick, j., and Richardson, B.: Effects of human maternal venous plasma glucose concentrations on fetal breathing movements. AM. j. OBSTET. GYNECOL. 132:36, 1978. Patrick, j., Campbell, K., Carmichael, L., et al.: Patterns
March 15, 1984 Am. J. Obstet. Gynecol.
II.
12. 13. 14.
of human fetal breathing in the last 10 weeks of pregnancy, Obstet. Gynecol. 56:24, 1980. Bissonnette, j. M., Hohimer, A. R., Cronan, j. Z., et al.: Effect of oxygen and of carbon dioxide tension on the incidence of apnea in fetal lambs, AM. j. OBSTET. GYNECOL. 137:575, 1980. Khazin, A. F., Hon, E. H., and Hehre, F. W.: Effects of maternal hyperoxia on the fetus. I. Oxygen tension, AM. j. OBSTET. GYNECOL. 109:628, 1971. Marsal, K., Gennser, G., and Lofgren, 0.: Effects on fetal breathing movements of maternal challenges, Acta Obstet. Gynecol. Scand. 58:335, 1979. Patrick, j., Campbell, K., Carmichael, L., Natale, R., and Richardson, B.: A definition of human fetal apnea and the distribution of fetal apneic intervals during the last 10 weeks of pregnancy, AM. j. OBSTET. GYNECOL. 136:471, 1980.
Acute effects of cigarette smoking on pregnant women and nonpregnant control subjects David E. Stetson, M.A., and Frank Andrasik, Ph.D. Albany, New York The effect of cigarette smoking on the pulse rate and carboxyhemoglobin concentration of the pregnant smoker was studied. The aim of this investigation was threefold: (1) to standardize cigarette consumption for studying short-term smoking effects in pregnant smokers, (2) to test for these effects by use of two noninvasive measures (concentration of carboxyhemoglobin in expired air and digital pulse rate), and (3) to compare the acute effects evidenced by pregnant smokers to those of a carefully matched group of nonpregnant control subjects. Increases in pulse rate and concentration of carboxyhemoglobin were found to be positively correlated with the level of intake of nicotine and concentration of inhaled mainstream smoke, respectively. The results, however, showed no evidence of significant differences between the pregnant and nonpregnant groups on either of the smoking measures. The methodologic implications of these findings are discussed. (AM. J. OBSTET. GYNECOL. 148:794, 1984.)
Increased concern about the health hazards of smoking during pregnancy has spawned several lines of investigative research. One such line of research concerns acute effects on the developing fetus,1-4 whereas another concerns acute effects on the pregnant smoker herself.5 The latter line of investigation seeks to assess whether the acute effects of smoking on a woman are compounded by the increased physiologic stress of pregnancy itself. From the State University of New York at Albany. Supported in part by funds provided by the State University of New York at Albany Benevolent Association. Receivedfor publication July 27,1982. Revised August 22,1983. Accepted October 20, 1983. Reprint requests: Frank Andrasik, Ph.D., Department of Psychology, State University of New York at Albany, 1400 Washington Ave., Albany, New York 12222.
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When one conducts investigations of acute effects of smoking, it is exceedingly important to exercise precise control over the independent variable (e.g., consumption of nicotine) and, in regards to the second area of research, to include appropriate nonpregnant control subjects. The main measure of smoking behavior used by investigators in the past was invasive and involved the collection and analysis of blood. Methodologic advances in the manipulation of the delivery of tobacco nicotine6 and the availability of an economical noninvasive method 1 , 8 of analysis of carbon monoxide afford the researcher the opportunity to observe acute physiologic changes consistent with those observed with venipuncture techniques. 6 - lo The present investigation was designed to address several of the preceding concerns and had three specific aims. The first of these was to test the adequacy of
Although fetal breathing movements may reflect intrauterine conditions, extrauterine influences exert significant effects on the presence and patterns of fetal breathing activity. Animal experiments have shown that the oxygen concentration of maternal inspired air may modify the incidence of fetal breathing movements.'-4 During chronic fetal hypoxemia, brought on by maternal hypoxia, fetal breathing movements may continue, although at a reduced frequency,"' 3 whereas acute hypoxemia often results in the disappearance of fetal breathing activity" In either circumstance, maternal hyperoxia restored the incidence of fetal breathing movements to normal levels unless fetal hypoxia was prolonged or acidosis was present! In normoxemic lamb fetuses, maternal hyperoxia does not affect the incidence of fetal breathing movements.' Efforts to extend these observations to human fetuses have been problematic. Experimentally induced maternal hypoxia:; has proved to be potentially too hazardous to the fetus to be an effective study technique. Isolated case reports6 suggest that spontaneous maternal hypoxemia may lead to cessation of fetal breathing movements, which are restored by hyFrum the Departments of Obstetrics and Gynecology and of Physiology, Medical Research Council Group in Reproductive Biology, University of Western Ontario. Supported by grants frum the Canadian Medical Research Council. Receivedfor publication june 14,1983. Revised August 26, 1983. Accepted September 1,1983. Reprint requests: john Patrick, M.D., Department of Obstetrics and Gynecology, St. joseph's Hospital, 268 Grosvenor St., London, Ontario, Canada N6A 4V2.
790
peroxia. Previous studies7 • '3 of the effects of maternal hyperoxia on normal and pathologic pregnancies have failed to control for important maternal variables. Our ultimate goal was to establish normative data so that this manipulation could be considered for the investigation of fetuses at risk for intrauterine hypoxia. Material and methods Patients. Informed consent was obtained from 14 healthy pregnant women near term (37 to 40 weeks' gestation). Fetal outcomes confirmed gestational age and the good health of the fetuses studied. All infants were delivered vaginally and were appropriate for gestational age. Mean birth weight was 3,470 ± 135 gm (SEM). Mean Apgar score at 5 minutes was 9.6 ± 0.2 (SEM), with no score below 8. Mean umbilical artery pH was 7.27 ± 0.02 (SEM). All infants were discharged from the nursery in good condition. Study protocol. Mothers and their fetuses were studied in a quiet, artificially illuminated room from 0930 to 1100 hours, 90 minutes after the mothers had eaten an 800 kcal breakfast. Studies were conducted with the patients in a semi-Fowler position in bed. Smoking was not permitted during or for 12 hours preceding the studies. During the 30-minute baseline period (0930 to 1000 hours), mothers breathed room air. For the next 15 minutes, they inhaled a 50% oxygen mixture, derived from 100% oxygen and room air, mixed in an oxygen blender (Bird 3M, Palm Springs, California), and delivered via a mouthpiece connected to a one-way nonrebreathing valve, at a rate of 10 Llmin. Nasal obstruction was maintained with a standard swimmer's
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nose plug during the hyperoxia period. In seven patients, transcutaneous P02 was measured continuously beginning 15 minutes before, during, and after hyperoxia, with the use of a transcutaneous oximeter (Oxymonitor, Litton Medical Electronics) and a Hellige Transoxode P02 electrode. Mothers were instructed to breathe at a consistent rate throughout the hyperoxia phase, and this was maintained during continuous observer-to-patient monitoring and instruction. Observation and analysis of fetal breathing movements. All studies were performed with a real-time B-scanner (ADR Ultrasound, Temple, Arizona), operating at a frequency of 3.5 MHz with an average intensity of 0.045 mW/cm,2 and oriented to a sagittal section of the fetal chest and abdomen. Images were viewed on a video monitor, while individual fetal breathing movements and gross body movements were identified and coded on a Grass Polygraph (Model 7A) chart recorder. Analysis of fetal breathing movements and gross fetal body movements was performed on-line by a PDP 11/40 computer (Digital Equipment Corporation), with the use of a program developed and validated for real-time data acquisition. 14 Fetal breathing movements, gross fetal body movements, apneic episodes, and failure times were also quantified on-line to the nearest 1.0 msec. Measurements of time during which fetal breathing movements occurred did not include apneic episodes, defined as the absence of fetal breathing movements for 6 seconds or more, or gross fetal body movements, i.e., activity sufficient to prevent recognition of fetal breathing movements. Portions of the records which could not be analyzed because of failure times, i.e., technical failures or interruptions on the part of the patients, were not included in the final analysis and composed 1.42% of the total study time. Percentages of time spent making breathing movements and body movements, mean breathing rates, and breath-tobreath intervals were determined for each fetus during 5-minute epochs of the study period. Results are presented as grouped means and standard errors (SEM) for each 5-minute epoch. Unless specified otherwise, significance was determined by a t test for small samples, variance not assumed to be equal, as described by Bailey.s Results
Maternal hyperoxia. Transcutaneous Po2 1evels were measured in seven of the 14 patients (Fig. 1). Prior to maternal inhalation of the 50% oxygen mixture, mean transcutaneous P02 was 81.4 ± 0.6 (SEM) mm Hg. Significant increases in transcutaneous P02 occurred within 2 minutes, and maternal transcutaneous P02 levels above 200 mm Hg were attained by 5 minutes in all patients. Increases in transcutaneous P02 continued
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Fig. 1. Continuous measurement of maternal transcutaneous Po. (I'cPo.), in mm Hg, before, during, and after induction of maternal hypoxia. Significant increases in transcutaneous POz are achieved within 5 minutes of maternal exposure to 50% oxygen and are sustained for an additional 5 minutes after return to breathing room air.
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Fig. 2. Time incidence of fetal breathing movements during the study periods analyzed in 5-minute epochs. There were no significant changes in mean percentage of time spent breathing during or after maternal hyperoxia.
for 10 minutes but were not significant (p > 0.10, Student's t test). Maternal transcutaneous P02 returned to baseline values (83.3 ± 2.0 mm Hg) within 5 minutes of resumption of breathing room air. Fetal breathing activity and gross body movements. Figs. 2 and 3 present, respectively, grouped 5-minute incidences (mean ± SEM) of fetal breathing movements and gross fetal body movements for all 14 patients. Mean incidences of fetal breathing movements and gross fetal body movements for the entire study were 58.28% ± 3.74% and 7.22% ± 0.86%, respectively. In the 15 minutes before, during, and after hyperoxia, there were no significant changes in the incidences of fetal breathing movements or gross fetal body movements. Incidences of fetal breathing movements rose, not significantly, after the first 5-minute epoch and remained elevated until the last two 5-
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were only four with no evident breathing actIvIty (1.47%). Hiccoughs were observed in 13 or 14 fetuses studied, as characterized previously by Patrick and associates. 1o The' duration of episodes of hiccoughs was 1.5 to 7.0 minutes, and these occurred during maternal normoxemia.
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Fig. 3. Time incidence of gross fetal body movements, analyzed in 5-minute epochs. There were no significant changes in mean percentage of time spent moving during or after maternal hyperoxia.
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Fig. 4. Mean breathing rates during 5-minute epochs. There was a slight but not significant increase in mean breath rate during maternal hyperoxia.
minute epochs (85 and 90 minutes). No trends in the incidence of gross fetal body movements were observed during the study. The mean breathing rate for the entire study period was 46.32 ± 2.34 bpm. Analysis of mean 5-minute breathing rates for 15 minutes before, during, and after hyperoxia revealed a slight but not significant increase during the first 5 minutes of hyperoxia (Fig. 4). Breath-to-breath intervals and coefficients of variation (SD/mean). Table I presents the mean breath-tobreath intervals, standard deviations, and coefficients of variation for breath-to-breath intervals. The group mean of breath-to-breath intervals for the entire study was 1.34 ± 0.27 seconds, and the mean standard deviation was 0.756 ± 0.12 seconds. Hyperoxia did not produce any significant changes in the variability of breathing rates. There was also no significant alteration in variability of breath-to-breath intervals over the time of observation (r = 0.3283, p> 0.05, df = 16). During the 272 observed 5-minute epochs, there
This study has shown that the induction of maternal hyperoxia in normal term pregnancies does not result in significant alterations in fetal breathing activity, breathing rates, breath interval variability, or incidence of body movements. The overall incidence of fetal breathing movements corresponded closely to that reported by Patrick and associates1o in the second and third postprandial hours, and by Natale and associates9 105 minutes after the giving of a 50 gm bolus of glucose to normal mothers. Although blood glucose values were not determined during this study, the observation periods were initiated during a time when maximal breathing activity, associated with peak maternal levels of glucose, would be expected. Previous efforts to demonstrate the relationship between fetal breathing activity and maternal levels of oxygen were largely based on animal studies. Boddy and associates l demonstrated that maternal hyperoxia had little or no effect on normally oxygenated lamb fetuses. In chronically hypoxemic fetal lambs, fetal breathing movements may continue, although often at a reduced leveJ,2· 3 but when acidosis is present or the hypoxic insult is acute, fetal breathing movements may be totally abolished and may respond to maternal hyperoxia only after a considerable delay.3 Even normal chronic lamb preparations may exhibit apnea with P0 2 fluctuations in the hypoxic range « 16 mm Hg) unless PC02 is elevated. 11 In humans, efforts to study the effects of acute induced maternal hypoxia on fetal vital functions have produced fetal compromise5 and thus been discontinued. A case report by Manning and Platt,6 in which fetal breathing movements were abolished during acute hypoxemia and restored with hyperoxia in a patient with sickle cell crisis, suggests that human fetal breathing activity can be affected by changes in maternal P0 2 levels. The effects of induced hyperoxia on fetal heart rate patterns have been studied extensively; however, there is little direct evidence to suggest how quickly fetal P0 2 may be altered by maternal hyperoxia. Khazin and associates,12 using sampling of fetal capillary blood, demonstrated that maternal hyperoxia (Pao, > 300 mm Hg) produces small increments in fetal Po 2, on the order of 3.0 to 5.0 mm Hg. These alterations in fetal P0 2 tended to parallel maternal levels and fell rapidly after discontinuation of the enriched oxygen mixture.
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Table I. Mean breath-to-breath intervals and coefficients of variation
Time (min)
0-5 6-10 11-15 16-20 21-25 26-30 31-35 36-40 41-45 46-50 51-55 56-60 61-65 66-70 71-75 76-80 81-85 86-90
Mean breath interoal ( ± SD) (sec)
1.651 1.419 1.354 1.380 1.4 77 1.467 1.524 1.363 1.407 1.343 1.319 1.378 1.316 1.418 1.368 1.319 1.500 1.688
± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±
0.722 0,388 0,234 0.310 0.543 0.483 0,558 0.576 0,380 0,341 0,342 0,374 0.252 0.339 0,287 0.463 0,344 0.654
Marsal and colleagues13 investigated hyperoxia in nine normal third-trimester pregnant women. When transcutaneous P0 2 was raised to 70% to 100% above control levels, capillary pH and Pco2 remained constant. Fetal breathing movements decreased significantly in the first 5 minutes but subsequently returned to control levels. Ritchie and Lakhani7 reported that maternal hyperoxia, induced by 50% oxygen in 32 women with normal third-trimester pregnancies, resulted in slightly but not significantly increased incidences of fetal breathing movements. Conversely, in 16 pregnancies complicated by severe preeclampsia or intrauterine growth retardation, fetal breathing movements increased significantly, rising to normal levels during hyperoxia. Arterial P0 2 was measured intermittently in only two patients and rose by nearly 100%. Neither study controlled for maternal variables, such as time of day, meals, and gestational age. Marsal and colleagues used gated A-mode transducers, thereby introducing potential observation artifacts, whereas Ritchie and Lakhani used very short, i.e., 35-minute, observation periods. The present study differs from these earlier two studies in several major respects. The conditions under which women were studied were uniform for all subjects. Maternal hyperoxia was achieved at higher levels than in either of the other studies and was measured on a minute-to-minute basis, thus demonstrating where fetal effects should be observed. All women were in the last month of gestation, thus eliminating possible confounding effects due to gestational age. Finally, the study period was clearly long enough to complete at least one cycle of breathing activity, as evidenced by the symmetrical rise and fall of fetal breathing movements
Mean standard deviation ( ± SD) (sec)
0,817 0.791 0,678 0.728 0.706 0.654 0.686 0,585 0.773 0.683 0.637 0,691 0,718 0,749 0.737 0,801 0,809 0,829
± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±
0,343 0,247 0,190 0.357 0,283 0.300 0.238 0,255 0.230 0,236 0.159 0.233 0.212 0,333 0.251 0,186 0,228 0,328
Coefficient of variation
0.498 0,557 0.501 0.528 0.478 0.486 0.450 0.429 0.549 0.509 0.483 0.502 0.546 0.528 0.539 0.607 0.539 0.491
incidence, corresponding to the beginning and end of observations. We conclude that normal fetuses supported by adequate placentas should respond predictably to a standard carbohydrate load, as previously demonstrated by Patrick and associates. 10 Furthermore, in the absence of hypoxia or acidosis, fetal breathing activity should not be altered by the slight increase in fetal P0 2 expected with maternal hyperoxia. The cyclical nature of fetal breathing activity in normal pregnancy is unaffected by maternal hyperoxia. Therefore, the observation of fetal breathing movements in the presence of transient maternal hyperoxia may provide a means of evaluating pregnancies in which placental function is compromised, intrauterine growth retardation is suspected, or other parameters suggest that intrauterine hypoxia may exist. We wish to thank Drs. Paul Harding, Graham Chance, and Fraser Fellows for their interest in our work, and Ms. T. Clarke and Ms. V. Clemons for their excellent technical assistance.
REFERENCES 1. Boddy, K., Dawes, G. S., Fisher, R., et al.: Fetal respira-
tory movements. Electrocortical and cardiovascular responses to hypoxemia and hypercapnea in sheep, J. Physiol. (Lond.) 234:599, 1974. 2. Dawes, G. S.: Breathing and rapid-eye-movements before birth, in Comline, R, S., Gross, D, W., Dawes, G. S., and Nathanielsz, P. S., editors: Foetal and Noenatal Physiology, Cambridge, 1973, Cambridge University Press, p. 360.
3. Dalton, K. S., Dawes, G. S., and Patrick, J. E,: Diurnal, respiratory and other rhythms of fetal heart rate in lambs, AM. J. OBSTET. GYNECOL. 127:414, 1976. 4. Martin, C. B., Murata, y, U., Ikenoue, T., et al.: Effects of
Devoe et al.
5. 6. 7. 8. 9.
10.
alterations of P02 and Pco2 on fetal breathing movements in rhesus monkeys. Gynecol. Obstet. Invest. 6:74, 1975. Wood, C., Hammond, j., Lumley, j., et al.: Effect of maternal inhalation of 10% oxygen upon the human fetus, Aust. N. Z. j. Obstet. Gynecol. 11:85, 1971. Manning, F. A., and Platt, L. D.: Maternal hypoxemia and fetal breathing movements, Obstet. Gynecol. 53:758, 1979. Ritchie, j. W. K., and Lakhani, K.: Fetal breathing movements and maternal hyperoxia, Br. j. Obstet. Gynaecol. 87:1084, 1980. Bailey, N. T. j.: Statistical Methods in Biology, London, 1973, English Universities Press, p. 50. Natale, R., Patrick, j., and Richardson, B.: Effects of human maternal venous plasma glucose concentrations on fetal breathing movements. AM. j. OBSTET. GYNECOL. 132:36, 1978. Patrick, j., Campbell, K., Carmichael, L., et al.: Patterns
March 15, 1984 Am. J. Obstet. Gynecol.
II.
12. 13. 14.
of human fetal breathing in the last 10 weeks of pregnancy, Obstet. Gynecol. 56:24, 1980. Bissonnette, j. M., Hohimer, A. R., Cronan, j. Z., et al.: Effect of oxygen and of carbon dioxide tension on the incidence of apnea in fetal lambs, AM. j. OBSTET. GYNECOL. 137:575, 1980. Khazin, A. F., Hon, E. H., and Hehre, F. W.: Effects of maternal hyperoxia on the fetus. I. Oxygen tension, AM. j. OBSTET. GYNECOL. 109:628, 1971. Marsal, K., Gennser, G., and Lofgren, 0.: Effects on fetal breathing movements of maternal challenges, Acta Obstet. Gynecol. Scand. 58:335, 1979. Patrick, j., Campbell, K., Carmichael, L., Natale, R., and Richardson, B.: A definition of human fetal apnea and the distribution of fetal apneic intervals during the last 10 weeks of pregnancy, AM. j. OBSTET. GYNECOL. 136:471, 1980.
Acute effects of cigarette smoking on pregnant women and nonpregnant control subjects David E. Stetson, M.A., and Frank Andrasik, Ph.D. Albany, New York The effect of cigarette smoking on the pulse rate and carboxyhemoglobin concentration of the pregnant smoker was studied. The aim of this investigation was threefold: (1) to standardize cigarette consumption for studying short-term smoking effects in pregnant smokers, (2) to test for these effects by use of two noninvasive measures (concentration of carboxyhemoglobin in expired air and digital pulse rate), and (3) to compare the acute effects evidenced by pregnant smokers to those of a carefully matched group of nonpregnant control subjects. Increases in pulse rate and concentration of carboxyhemoglobin were found to be positively correlated with the level of intake of nicotine and concentration of inhaled mainstream smoke, respectively. The results, however, showed no evidence of significant differences between the pregnant and nonpregnant groups on either of the smoking measures. The methodologic implications of these findings are discussed. (AM. J. OBSTET. GYNECOL. 148:794, 1984.)
Increased concern about the health hazards of smoking during pregnancy has spawned several lines of investigative research. One such line of research concerns acute effects on the developing fetus,1-4 whereas another concerns acute effects on the pregnant smoker herself.5 The latter line of investigation seeks to assess whether the acute effects of smoking on a woman are compounded by the increased physiologic stress of pregnancy itself. From the State University of New York at Albany. Supported in part by funds provided by the State University of New York at Albany Benevolent Association. Receivedfor publication July 27,1982. Revised August 22,1983. Accepted October 20, 1983. Reprint requests: Frank Andrasik, Ph.D., Department of Psychology, State University of New York at Albany, 1400 Washington Ave., Albany, New York 12222.
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When one conducts investigations of acute effects of smoking, it is exceedingly important to exercise precise control over the independent variable (e.g., consumption of nicotine) and, in regards to the second area of research, to include appropriate nonpregnant control subjects. The main measure of smoking behavior used by investigators in the past was invasive and involved the collection and analysis of blood. Methodologic advances in the manipulation of the delivery of tobacco nicotine6 and the availability of an economical noninvasive method 1 , 8 of analysis of carbon monoxide afford the researcher the opportunity to observe acute physiologic changes consistent with those observed with venipuncture techniques. 6 - lo The present investigation was designed to address several of the preceding concerns and had three specific aims. The first of these was to test the adequacy of