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A computer analysis of the atropine test for placental function
A computer analysis of the atropine test for placental function L. M. HELLMAN, M.D. G. W. MORTON, M.E.E. W. E. TOLLES, M.S. L. P. FILLISTI
Brookl}•n, New York
travenous administration of atropine to mothers with pregnancies complicated by toxaemia, Rhesus immunization and prolongation leads to an increase in the fetal heart rate less frequently than during normal pregnancy." Although their experiments, as well as ours, were very few in number, we both concluded that the time delay of the atropine effect represented, in a large measure, its placental transfer time. If this conclusion is correct, and there is no reason seriously to doubt it, and if an end point for the time delay could be defined, we would have a simple, safe test for placental function in the intact woman. The value of such a test is self-evident. Not only could it aid in indicating the optimum time for delivery in the face of serious maternal disease, but, if the findings of Fairweather 2 are correct that mental retardation occurs more frequently in poorly growing infants--such a test could aid in the reduction of this type of damage. The definition of the end point of the atropine time delay is the crux of the matter and constitutes the subject of this study.
ABouT 4 years ago, Hon 7 called our attention to the fact that the rate of the fetal heart could be accelerated by the intravenous administration of atropine to the mother. His primary interest in the production of fetal vagal blockade was the possibility that it might help to differentiate various types of fetal bradycardia and arrhythmias.5• 6 Knowledge about the effect of atropine on the fetal heart rate came to us most opportunely, for we had been searching for stimuli which could alter the rate in one manner in well babies and in a different manner in those not so welL Preliminary experiments with atropine showed a rather long time delay from the onset of the injection of the drug until the production of vagal blockade in the fetus. 4 Furthermore, in some severely pre-eclamptic mothers no fetal atropine effect could be observed. At about the same time, Soiva and Salmi11 made identical observations as follows, "InFrom the Department of Obstetrics and Gynecology, State University of New York Downstate Medical Center and the Kings County Hospital, Brooklyn, and Airborne Instruments Laboratory, Inc., Deer Park, Long Island, New York. Supported by United States Public Health Service Grant H3678. Presented at the Seventy-third Annual Meeting of the American Association of Obstetricians and Gynecologists, Hot Springs, Virginia, Sept. 6-8, 1962.
Materials and methods Instantaneous fetal and maternal heart rates* were recorded simultaneously by *The rates are not quite instantaneousl being an average of about 2 beats rather than a beat-to-beat rate.
610
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means of the phonocardiograph (fetal) and electrocardiograph (maternal) as previously described. 4 The analog data thus obtained were displayed by a graphic recorder for visual analysis and on magnetic tape for computer studies. The analog data on the magnetic tape were converted to digital data by means of an analog to digital converter. 8 Here both fetal and maternal data were sampled once every % second and recorded on punched paper tape. The data on the paper tape were transferred to punched cards and were fed into an IBM 7090 for computer analysis. Plots of the computer processed data were constructed automatically by a standard graphic recorder. Thirty normal gravidas in the last half of pregnancy constitute the experimental subjects for this study. Most experiments were done in the morning, the patient having had her usual breakfast. She was placed in a semisupine position and allowed to rest one half hour. The fetal heart rate was then recorded over a 20 minute control period followed by the administration of atropine. During the entire experiment, the patient received a slow intravenous infusion of 5 per cent dextrose in water. One milligram of atropine sulfate ( 2.5 mi.) diluted to 5 mi. with 5 per cent dextrose vyas given into the infusion tubing, close to the needle, over a 2 minute period. The onset of the atropine injection was recorded as zero time, the recording continuing for 45 minutes to one hour after this. Although all 30 records were studied visually and analyzed on the computer, only a selected few are cited in this paper. Statement of the problem
Soiva11 defined the fetal atropine effect as a pronounced change in rate, but he admitted that this was not very precise. If the fetal rate change were as dramatic as the maternal (Fig. 1), perhaps an end point could be defined on the basis of the visual change of rate alone. While the fetus does occasionally show a sudden and discernible rate change comparable to the adult, this does not occur with sufficient frequency to
Atropine test for placental function
611
satisfy the requirements of a placental function test. There is another and much more constant change brought about by vagal blockade, namely a diminution in both the short- and long-term variation in rate. Such reduction is represented by a flattening of the tracing and is clearly seen in both the adult record in Fig. 1 and the fetal record in Fig. 2. As a matter of fact, the change is so clear and so abrupt in Fig. 2 that the end point can be recognized by eye with an error of less than a minute. Were this always the case, visual measurement would suffice. Unhappily, such a record is rare, and the more common varieties are shown in Figs. 3 and 4. In the former, blockade could be said to have taken place in at least two separated points while in the latter the atropine delay time, if present at all, cannot be discovered visually. If this test is to be useful, some better method of looking at and analyzing these long records must be developed. Computer analysis
The digital computer is ideally suited for the analysis of just such long and indigestible records. The instrument performs a series of mathematical analyses, prints them out, and records them graphically for redisplay with incredible speed (about 2 minutes of computer time to one of our records), but, contrary to some opinion, computers do not think and thus must be asked thoughtful and precise questions, and, more important, the right questions, or meaningful results will not be obtained. For experienced personnel, programming and the working of the machinery is a relatively simple process. Even the formulation of the questions is not too difficult, but the selection of the right questions is time-consuming and takes great thought and familiarity with the data. In reality, the computer shows nothing that is not present on the graphic record but, by compressing the record and redisplaying it in a different fashion, it elucidates events which are not readily distinguishable. We knew from visual evidence that atropine produced a change in rate and varia-
612
Hellman et al.
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1. Effect of atropine on normal adult heart. Starting a little more than one minute after the onset of the injection of atropine, there is a rapid increase in rate and a flattening of both short- and long-term variability. Time to blockade in this patient would be about 1.5 minutes.
ATROPINE
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10
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12
13
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5
14
15
6
16
7
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Fig. 2. Effect of maternally injected atropine on fetal heart. The changes, namely increase in rate and decrease in variability, were the same as in Fig. 1 but less marked. This is almost an ideal tracing with the time to fetal blockade being somewhere between 11 and 12 minutes.
bility of the fetal heart. These changes were not always obvious and did not always occur abruptly, and therefore some arbitrary mathematical end point was going to have to be selected, as shown in Fig. 5. This is a schematic diagram of imaginary analog data showing typical variability around a mean. In this plot when a stimulus is administered to a subject, the data change with time. There is a change in the mean and in the variability around the mean. One could say
that the end point in time occurred when the mean changed two standard deviations or when the variability around the mean was halved or when some combination of both of these changes occurred. This illustration exactly forms the questions to be asked in our atropine experiments. Rate change is easily and well displayed by use of a running mean. We have done this by deriving a 5 minute mean and shifting 1 minute for each subsequent calculation.
Atropine test for placental function
Volume 85 Number 5
The problem of flattening or decrease in the variability of the instantaneous rate is more difficult. Our first attempt was to derive the correlation functions. These are
4
613
the cross and auto correlations. The former defines the relationship between two events, as for example a change in rate of the fetal heart occurring at a specific time after a
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Fig. 3. Effect of maternally injected a.tropine on fetal heart. This is the more common type of response. The same changes but their time of onset could have been anywhere between 11 and 15 minutes.
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Fig. 4. Effect of maternally injected atropine on fetal heart. There has been a visible change in the characteristics of the fetal heart in this record, but the time of their onset is not visually definable.
614
Hellman et al.
Fig. 5. Schematic diagram showing change in mean fetal hea rt rate and variability around the mean after a given stimulus.
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( T) of 3 seconds. Inasmuch as correlation functions define a relationship between two events, if this were 1 to 1 or perfect, the correlation function would be said to be 1. A graphic representation of the correlation functions shows a high correlation a t any elapsed time where the area under the curve is large and the peak approaches 1. A straight line would have an auto corrdation function of 1 for all elapsed times and similarly would have a maximum value under its curve. Inasmuch as the fla ttening of the heart rate tracings after atropine represents an approach to a straight line, one might expect an abrupt change in the auto correlation function at the time of vagal blockade. To test this, two plots of a typical atropine experiment are shown in Fig. 6. The first represents the control period, and the second 30 minutes post atropine. There is no evidence of any significant degree of cross correlation between fetal and maternal heart rates for values of up to 90 seconds. Both the maternal and fetal auto correlation functions showed the expected increase in the short-term coherence after atropine. as evidenced by an increase in the areas under th e curves of the auto correlation functions. Even with a high-speed computer, this calculation is rather a cumbersome way of
0 -0.2 16 MINUTES PRE-ATROPINE
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Fig. 6. The correlation functions of the fetal heart rate prior to and 30 minutes after atropine. The increase in area under the fetal curve is quite marked for small values of r.
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change in rate of the mother's heart. The auto correlation measures the similarity of events occurring in the same individual at specific time intervals T. An example of this could be found in a patient breathing at 20 times a minute who displayed a respiratory arrhythmia. The auto correlation of the cardiac rate would be high for a time
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Fig. 7. Raw data plot and least squares fit of th e fetal heart rate before and after vagal blockade. The residue is the standard deviation of the difference between the two.
handling the data and the change shown is neither abrupt enough nor striking enough to give us our desired end point. Our next attempted analysis concerned the best fit of the rate data by the method of least squares with a calculation of the residual or standard deviation. A decrease in the variability of the instantaneous rate should bring about a corresponding diminution in this residual. To test this, a sample analysis was made of a typical atropine experiment before and 22 minutes after the administration of the drug. The least squares fit and the raw data plots are shown in Fig. 7. The residue is the standard deviation of the difference between the two and decreases from a value of 15.6 before atropine to 1.06 after atropine, i.e., the variability decreased markedly after the drug was given. A similar computer analysis of the three experiments previously shown in Figs. 2, 3, and 4 was carried out on the fetal records and the plots of the computer processed data are shown in Figs. 8, 9, and 10, which are in the same respective order as the former figures. The upper curve represents a plot of the running mean, derived as previously described. The lower curve represents the running mean of the residue calculated from the best fit curve described above. To obtain these curves, the computer analyzes 15 seconds of record obtaining the best fit curve from the 21 data points and then shifting % of a second (one data point) and repeating the process. The residue is approximately the standard deviation of the variation of the rate around the mean value of the best fit curve in each 15 second period. The running mean of the rate gives a fairly good end point for the first two tests but fails to do so in the third. On the other hand, if the fall of the running mean of the residue to unity is taken as the end point, it forms a clear-cut point in all three records. Comment
There have been several attempts to measure placental function. The measurements
615
Atropine test for placental function
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Fig. 9. Curves of the running means and residual of the fetal heart rate showing the entire experiment depicted in Fig. 3 as having a questionable end point.
Hellman et al.
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of pregnanediol excretion and blood progesterone levels at repeated intervals in pregnancy9 • 10 furnishes a promising lead. The measure of transfer of labeled substances in the acute experiments of Flexner·3 was a similar attempt, albeit impractical from a clinical standpoint. Similarly, an impractical but workable test can be derived from our unpublished data on the differen-
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tial disappearance rates of two diss1milar isotopes from the intervillous space.' 'Ve now seem to han· a safer and mon: practical test for placental fttnction in the delay time of atropine transfer acros~ the placenta. From our work to date, we believe, at least tcntati\·ely. that the end pr>int of this delay can be defined mathematically. Many mort" records will ha\·e to rw examined before this can be stated conclusively. A great many patients whose placentas are believed to be malfunctioning will have to be studied and differences found before the test can be accepted as a Yalid one. And finally, blood atropine levels in both mother and fetus may have to be studied in order to discover why delay in transfer inhibits the atropine effect in the fetus. In othtT words, what has been presented above represents a promising lead toward a placental function test, but is in no way tht> finished product. Conclusions
1. Intravenously administered atropine to the mother produces a change in the performance of the fetal heart that can be mathematically defined. 2. The time delay from the injection of atropine to the onset of the change represents the atropine transfer time. 3. The atropine transfer time may furnish a simple and practical test for placental function.
" REFERENCES
1. Chesley, L. C., and Hellman, L. M.: (To be published.) 2. Fairweather, D. V. I., and Illsley, R.: Brit. J. Prev. & Soc. Med. 14: 149, 1960. 3. Flexner, L. B., Cowie, D. B., Hellman, L. M., Wilde, W. S., and Vosburgh, G. J.: AM. J. 0BST. & GYNEC. 55: 469, 1948. 4. Hellman, L. M., Johnson, H. L., Tolles, W., and Jones, E. H.: AM. J. 0BST. & GYNEC. 82{ 1055, 1961. 5. Hon, E. H.: AM. J. 0BST. & GYNEC. 83: 333, 1962. 6. Hon, E. H.: Fetal bradycardia, read before
7. 8. 9. 10. 11.
the Society for Gynecologic Investigation, 1962. (Unpublished.) Hon, E. H.: Personal communication. Morton, G. W., Tolles, W. E., and Hellman, L. M.: (To be published.) Russell, C. S., Paine, C. G., Coyle, M. G., and Dewhurst, C. J.: J. Obst. & Gynaec. Brit. Emp. 64: 649, 1957. Russell, C. S., Dewhurst, C. J., and Blakey, D. H.: J. Obst. & Gynaec. Brit. Emp. 67: 1_, 1960. Soiva, K., and Salmi, H.: Ann. chir. et gynaec. Finneae 48: 287, 1959.
Brookl}•n, New York
travenous administration of atropine to mothers with pregnancies complicated by toxaemia, Rhesus immunization and prolongation leads to an increase in the fetal heart rate less frequently than during normal pregnancy." Although their experiments, as well as ours, were very few in number, we both concluded that the time delay of the atropine effect represented, in a large measure, its placental transfer time. If this conclusion is correct, and there is no reason seriously to doubt it, and if an end point for the time delay could be defined, we would have a simple, safe test for placental function in the intact woman. The value of such a test is self-evident. Not only could it aid in indicating the optimum time for delivery in the face of serious maternal disease, but, if the findings of Fairweather 2 are correct that mental retardation occurs more frequently in poorly growing infants--such a test could aid in the reduction of this type of damage. The definition of the end point of the atropine time delay is the crux of the matter and constitutes the subject of this study.
ABouT 4 years ago, Hon 7 called our attention to the fact that the rate of the fetal heart could be accelerated by the intravenous administration of atropine to the mother. His primary interest in the production of fetal vagal blockade was the possibility that it might help to differentiate various types of fetal bradycardia and arrhythmias.5• 6 Knowledge about the effect of atropine on the fetal heart rate came to us most opportunely, for we had been searching for stimuli which could alter the rate in one manner in well babies and in a different manner in those not so welL Preliminary experiments with atropine showed a rather long time delay from the onset of the injection of the drug until the production of vagal blockade in the fetus. 4 Furthermore, in some severely pre-eclamptic mothers no fetal atropine effect could be observed. At about the same time, Soiva and Salmi11 made identical observations as follows, "InFrom the Department of Obstetrics and Gynecology, State University of New York Downstate Medical Center and the Kings County Hospital, Brooklyn, and Airborne Instruments Laboratory, Inc., Deer Park, Long Island, New York. Supported by United States Public Health Service Grant H3678. Presented at the Seventy-third Annual Meeting of the American Association of Obstetricians and Gynecologists, Hot Springs, Virginia, Sept. 6-8, 1962.
Materials and methods Instantaneous fetal and maternal heart rates* were recorded simultaneously by *The rates are not quite instantaneousl being an average of about 2 beats rather than a beat-to-beat rate.
610
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Number 5
means of the phonocardiograph (fetal) and electrocardiograph (maternal) as previously described. 4 The analog data thus obtained were displayed by a graphic recorder for visual analysis and on magnetic tape for computer studies. The analog data on the magnetic tape were converted to digital data by means of an analog to digital converter. 8 Here both fetal and maternal data were sampled once every % second and recorded on punched paper tape. The data on the paper tape were transferred to punched cards and were fed into an IBM 7090 for computer analysis. Plots of the computer processed data were constructed automatically by a standard graphic recorder. Thirty normal gravidas in the last half of pregnancy constitute the experimental subjects for this study. Most experiments were done in the morning, the patient having had her usual breakfast. She was placed in a semisupine position and allowed to rest one half hour. The fetal heart rate was then recorded over a 20 minute control period followed by the administration of atropine. During the entire experiment, the patient received a slow intravenous infusion of 5 per cent dextrose in water. One milligram of atropine sulfate ( 2.5 mi.) diluted to 5 mi. with 5 per cent dextrose vyas given into the infusion tubing, close to the needle, over a 2 minute period. The onset of the atropine injection was recorded as zero time, the recording continuing for 45 minutes to one hour after this. Although all 30 records were studied visually and analyzed on the computer, only a selected few are cited in this paper. Statement of the problem
Soiva11 defined the fetal atropine effect as a pronounced change in rate, but he admitted that this was not very precise. If the fetal rate change were as dramatic as the maternal (Fig. 1), perhaps an end point could be defined on the basis of the visual change of rate alone. While the fetus does occasionally show a sudden and discernible rate change comparable to the adult, this does not occur with sufficient frequency to
Atropine test for placental function
611
satisfy the requirements of a placental function test. There is another and much more constant change brought about by vagal blockade, namely a diminution in both the short- and long-term variation in rate. Such reduction is represented by a flattening of the tracing and is clearly seen in both the adult record in Fig. 1 and the fetal record in Fig. 2. As a matter of fact, the change is so clear and so abrupt in Fig. 2 that the end point can be recognized by eye with an error of less than a minute. Were this always the case, visual measurement would suffice. Unhappily, such a record is rare, and the more common varieties are shown in Figs. 3 and 4. In the former, blockade could be said to have taken place in at least two separated points while in the latter the atropine delay time, if present at all, cannot be discovered visually. If this test is to be useful, some better method of looking at and analyzing these long records must be developed. Computer analysis
The digital computer is ideally suited for the analysis of just such long and indigestible records. The instrument performs a series of mathematical analyses, prints them out, and records them graphically for redisplay with incredible speed (about 2 minutes of computer time to one of our records), but, contrary to some opinion, computers do not think and thus must be asked thoughtful and precise questions, and, more important, the right questions, or meaningful results will not be obtained. For experienced personnel, programming and the working of the machinery is a relatively simple process. Even the formulation of the questions is not too difficult, but the selection of the right questions is time-consuming and takes great thought and familiarity with the data. In reality, the computer shows nothing that is not present on the graphic record but, by compressing the record and redisplaying it in a different fashion, it elucidates events which are not readily distinguishable. We knew from visual evidence that atropine produced a change in rate and varia-
612
Hellman et al.
5
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7
6
9
8
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10
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12
14
13
Fi~.
1. Effect of atropine on normal adult heart. Starting a little more than one minute after the onset of the injection of atropine, there is a rapid increase in rate and a flattening of both short- and long-term variability. Time to blockade in this patient would be about 1.5 minutes.
ATROPINE
0
2
e
9
10
2
MINUTES
II
12
13
4
5
14
15
6
16
7
17
MINUTES
Fig. 2. Effect of maternally injected atropine on fetal heart. The changes, namely increase in rate and decrease in variability, were the same as in Fig. 1 but less marked. This is almost an ideal tracing with the time to fetal blockade being somewhere between 11 and 12 minutes.
bility of the fetal heart. These changes were not always obvious and did not always occur abruptly, and therefore some arbitrary mathematical end point was going to have to be selected, as shown in Fig. 5. This is a schematic diagram of imaginary analog data showing typical variability around a mean. In this plot when a stimulus is administered to a subject, the data change with time. There is a change in the mean and in the variability around the mean. One could say
that the end point in time occurred when the mean changed two standard deviations or when the variability around the mean was halved or when some combination of both of these changes occurred. This illustration exactly forms the questions to be asked in our atropine experiments. Rate change is easily and well displayed by use of a running mean. We have done this by deriving a 5 minute mean and shifting 1 minute for each subsequent calculation.
Atropine test for placental function
Volume 85 Number 5
The problem of flattening or decrease in the variability of the instantaneous rate is more difficult. Our first attempt was to derive the correlation functions. These are
4
613
the cross and auto correlations. The former defines the relationship between two events, as for example a change in rate of the fetal heart occurring at a specific time after a
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1
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Fig. 3. Effect of maternally injected a.tropine on fetal heart. This is the more common type of response. The same changes but their time of onset could have been anywhere between 11 and 15 minutes.
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Fig. 4. Effect of maternally injected atropine on fetal heart. There has been a visible change in the characteristics of the fetal heart in this record, but the time of their onset is not visually definable.
614
Hellman et al.
Fig. 5. Schematic diagram showing change in mean fetal hea rt rate and variability around the mean after a given stimulus.
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( T) of 3 seconds. Inasmuch as correlation functions define a relationship between two events, if this were 1 to 1 or perfect, the correlation function would be said to be 1. A graphic representation of the correlation functions shows a high correlation a t any elapsed time where the area under the curve is large and the peak approaches 1. A straight line would have an auto corrdation function of 1 for all elapsed times and similarly would have a maximum value under its curve. Inasmuch as the fla ttening of the heart rate tracings after atropine represents an approach to a straight line, one might expect an abrupt change in the auto correlation function at the time of vagal blockade. To test this, two plots of a typical atropine experiment are shown in Fig. 6. The first represents the control period, and the second 30 minutes post atropine. There is no evidence of any significant degree of cross correlation between fetal and maternal heart rates for values of up to 90 seconds. Both the maternal and fetal auto correlation functions showed the expected increase in the short-term coherence after atropine. as evidenced by an increase in the areas under th e curves of the auto correlation functions. Even with a high-speed computer, this calculation is rather a cumbersome way of
0 -0.2 16 MINUTES PRE-ATROPINE
-0.4
RESIDUE • 15.6
-0.6 0
Fig. 6. The correlation functions of the fetal heart rate prior to and 30 minutes after atropine. The increase in area under the fetal curve is quite marked for small values of r.
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change in rate of the mother's heart. The auto correlation measures the similarity of events occurring in the same individual at specific time intervals T. An example of this could be found in a patient breathing at 20 times a minute who displayed a respiratory arrhythmia. The auto correlation of the cardiac rate would be high for a time
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70
Fig. 7. Raw data plot and least squares fit of th e fetal heart rate before and after vagal blockade. The residue is the standard deviation of the difference between the two.
handling the data and the change shown is neither abrupt enough nor striking enough to give us our desired end point. Our next attempted analysis concerned the best fit of the rate data by the method of least squares with a calculation of the residual or standard deviation. A decrease in the variability of the instantaneous rate should bring about a corresponding diminution in this residual. To test this, a sample analysis was made of a typical atropine experiment before and 22 minutes after the administration of the drug. The least squares fit and the raw data plots are shown in Fig. 7. The residue is the standard deviation of the difference between the two and decreases from a value of 15.6 before atropine to 1.06 after atropine, i.e., the variability decreased markedly after the drug was given. A similar computer analysis of the three experiments previously shown in Figs. 2, 3, and 4 was carried out on the fetal records and the plots of the computer processed data are shown in Figs. 8, 9, and 10, which are in the same respective order as the former figures. The upper curve represents a plot of the running mean, derived as previously described. The lower curve represents the running mean of the residue calculated from the best fit curve described above. To obtain these curves, the computer analyzes 15 seconds of record obtaining the best fit curve from the 21 data points and then shifting % of a second (one data point) and repeating the process. The residue is approximately the standard deviation of the variation of the rate around the mean value of the best fit curve in each 15 second period. The running mean of the rate gives a fairly good end point for the first two tests but fails to do so in the third. On the other hand, if the fall of the running mean of the residue to unity is taken as the end point, it forms a clear-cut point in all three records. Comment
There have been several attempts to measure placental function. The measurements
615
Atropine test for placental function
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Hellman et al.
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of pregnanediol excretion and blood progesterone levels at repeated intervals in pregnancy9 • 10 furnishes a promising lead. The measure of transfer of labeled substances in the acute experiments of Flexner·3 was a similar attempt, albeit impractical from a clinical standpoint. Similarly, an impractical but workable test can be derived from our unpublished data on the differen-
Oh~t. & (;ynt~c.
tial disappearance rates of two diss1milar isotopes from the intervillous space.' 'Ve now seem to han· a safer and mon: practical test for placental fttnction in the delay time of atropine transfer acros~ the placenta. From our work to date, we believe, at least tcntati\·ely. that the end pr>int of this delay can be defined mathematically. Many mort" records will ha\·e to rw examined before this can be stated conclusively. A great many patients whose placentas are believed to be malfunctioning will have to be studied and differences found before the test can be accepted as a Yalid one. And finally, blood atropine levels in both mother and fetus may have to be studied in order to discover why delay in transfer inhibits the atropine effect in the fetus. In othtT words, what has been presented above represents a promising lead toward a placental function test, but is in no way tht> finished product. Conclusions
1. Intravenously administered atropine to the mother produces a change in the performance of the fetal heart that can be mathematically defined. 2. The time delay from the injection of atropine to the onset of the change represents the atropine transfer time. 3. The atropine transfer time may furnish a simple and practical test for placental function.
" REFERENCES
1. Chesley, L. C., and Hellman, L. M.: (To be published.) 2. Fairweather, D. V. I., and Illsley, R.: Brit. J. Prev. & Soc. Med. 14: 149, 1960. 3. Flexner, L. B., Cowie, D. B., Hellman, L. M., Wilde, W. S., and Vosburgh, G. J.: AM. J. 0BST. & GYNEC. 55: 469, 1948. 4. Hellman, L. M., Johnson, H. L., Tolles, W., and Jones, E. H.: AM. J. 0BST. & GYNEC. 82{ 1055, 1961. 5. Hon, E. H.: AM. J. 0BST. & GYNEC. 83: 333, 1962. 6. Hon, E. H.: Fetal bradycardia, read before
7. 8. 9. 10. 11.
the Society for Gynecologic Investigation, 1962. (Unpublished.) Hon, E. H.: Personal communication. Morton, G. W., Tolles, W. E., and Hellman, L. M.: (To be published.) Russell, C. S., Paine, C. G., Coyle, M. G., and Dewhurst, C. J.: J. Obst. & Gynaec. Brit. Emp. 64: 649, 1957. Russell, C. S., Dewhurst, C. J., and Blakey, D. H.: J. Obst. & Gynaec. Brit. Emp. 67: 1_, 1960. Soiva, K., and Salmi, H.: Ann. chir. et gynaec. Finneae 48: 287, 1959.