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Further studies on the oxytocin-oxytocinase system
CURRENT INVESTIGATION
Further studies on the oxytocin-oxytocinase system RUDOLF
KLIMEK,
KRZYSZTOF
DREWNIAK,
ANDRZEJ Cracow,
M.D.
BIENIASZ,
M.D M.D.
Poland
The dynamic oxytocin test and the chemical assay of serum oxytocinase were carried out in 426 pregnant women with the aim of predicting the date of labor. In cases in which the oxytocin dynamic test showed decreasing values or rising levels of oxytocinase, conservative procedure was followed. In the remaining cases labor was induced by means of Syntocinon. In the prenatal period oxytocinase levels show steady increase in 79.9 per cent of cases, while the values of the oxytocin test decrease in 87.2 per cent. Both situations were observed simultaneously in 76.6 per cent of cases. Prediction of the date of labor by this biochemical method is 9 times as accurate as the prediction based upon Naegele’s rule.
Material
I N A P R E V I 0 u s communication, it was shown that serum’oxytocinase levels are related to endogenous oxytocin production and, moreover, undergo characteristic changes under the influence of exogenous oxytocin.3-7 On the basis of this observation a technique depending upon the simultaneous performance of the oxytocin intravenous test and the determination of the level of oxytocinase for the purpose of predicting the date of labor and studying the course of pregnancy was devised.l-lo This paper presents supplementary data and summarizes the findings to date.
and
procedures
The study was carried out on 426 pregnant women admitted to the Department of Pregnancy Observation. The “dynamic oxytocin test” was performed by injecting 10 mu. synthetic oxytocin (Syntocinon) in 5 per cent glucose solution intravenously at 1 minute intervals until the appearance of the first uterine contraction, as registered by a Lorand tocograph. A total dose of 70 mu. was, however, not exceeded. Each IO mU. of required oxytocin was interpreted as indicating one remaining day before onset of labor. If labor failed to begin on the predicted date, the oxytocin test was repeated on this day. If the result of this second test was lower than the earlier one by 10 or more milliunits, the dynamic oxy-
From the Central Endocrinological Laboratory and the First Obstetrical and Gynecological Clinic, Medical Academy, Cracow.
427
428
Klimek,
Drewniak,
and
October 1, 1969 Am. J. Obst. & Gynec.
Bieniasz
NUUI HuLf
-----
PAtiS 1 PARAS
0 lllllllrll~
-6
days
111”““” -4
after
-2 labor
2
0
4
&or
Fig. 1. Relative accordance biochemical method taking
days
between real day into account values
of labor and of first test.
6 before probable
date
a
12
IO
I4
labor of labor
predicted
by
cased
i\ I: A I\ A
P7/
\\ \\ A
I/’ /I\
NULLIPARAS MULTI PARAS
--es-
I
-6 days
-4
after
-2
labor
Fig. 2. Relative accordance biochemical method taking
0
2
labor between real day into account values
4
days
6
0
I
1
12
labor
before
of labor and probable of second test.
1
IO
date
of labor
predicted
by
1
I
I4
Volume Number
105 3
Oxytocin-oxytocinase
tocin test was considered to be decreasing. If the value obtained was greater than in the first test by 10 mu. or more, then the dynamic oxytocin test was regarded as increasing. Differences of less than 10 mu. between the tests classify the condition as steady. Serum levels of oxytocinase were assayed simultaneously with chemical methods described previously.3l 6ps Differences of 0.1 mu. per liter per minute were considered significant to classify the changes in enzyme concentration as decreasing or increasing. The: results of these tests, combined with obstetric considerations, are the basis for the decision to induce labor. In cases where the test showed decreasing values of oxytocin required or rising levels of oxytocinase, a conservative course was followed. In the remaining cases, labor was induced with Syntocino:n. Decisions were not based on Naegele’s rule, since statistical data show that in 95 per cent of women labor begins during a wide interval, 281 f 22 days counting from the date of the first day of the last menstruation.4> 5
system
429
Results
Among the 426 patients in this series, the oxytocin test was performed in 51 per cent only once (nulliparas, 50.5 per cent; multiparas, 51.3 per cent) ; in 28.8 per cent twice (nulliparas, 29.2 per cent; multiparas, 28.6 per cent), and in the remainder (20.0 per cent) three times or more. These results showed there was no difference between the nulliparas and multiparas in this regard or with respect to efficiency of the test in predicting the probable date of labor. Figs. 1 and 2 show the accordance between the actual date of labor and predicted date of labor based on the first and second tests. From the above data it appears that in using this method it is not necessary to divide the patients by parity, a point made in the former papers. The mean values with standard errors of the first and last oxytocin tests are listed in Table I. This table shows the number of days between the test day and the onset of labor. It indicates the mean difference between predicted onset of labor derived from
Table I Differences
-
(probable Test
A day
(days)
day
of
examination
and
B of
Mean
First Last
between
labor)
(real
rt S.E.
3.1 2.1
day
of
Mean
0.15 0.19
5.4 2.7
2 S.E.
Difference between A and B (days)
0.80 0.24
2.2 0.6
Labor)
Table II Onytocin Serum
oxytocinase
I Decreasing
zz Steady
III Rising
327 76.7%
B [steady)
19 44%
21 49%
21 7%
42 10.0%
C (decreasing)
26 61%
2;%
a 18%
43 10.9%
37 8.7%
17 3.9%
426 100.0%
372 87.3%
7 1.6%
Total
A (rising)
Total
7 1.6%
test
341 79.9%
430
Klimek,
Drewniak,
and
Bieniasz
the first test and the actual time of onset is 2.2 days, while depending on the last test it is 0.6 day. Taking into account both differences, the mean error between the day indicated by the tests and the actual onset of labor is 1.4 days. The mean error between the day of onset of labor as predicted according to Naegele’s rule was 13.4 days per case. One may conclude, therefore, the prediction of the day of labor by the biochemical method is 9.4 times as accurate as prediction by Naegele’s rule. The mode of eventual obstetric intervention as indicated by the tests is shown in Table II. Here the values of the oxytocin test and the serum oxytocinase level are classified in three groups. Decreasing values of the oxytocin test are designated, I ; steady values, II; and rising values, III. The oxytocinase levels are similarly designated as rising levels, A; steady levels, B; and decreasing levels, C. On the basis of simultaneous evaluation of the oxytocin test and the oxytocinase level, the term of labor was predicted and compared with Naegele’s rule. Only in Groups IIB, IIC, IIIB, and IIIC was labor induced. Of the total of 426 deliveries, including 4 twin deliveries, 329 (77.3 per cent) were spontaneous. The remaining 97 cases included 41 cesarean sections, 13 with forceps deliveries, 16 with speculum, and 27 deliveries with manual assistance. The number of live-born neonates was 423, of which 2 died in the perinatal period (1 forceps delivery, 1 with eclampsia) , constituting
REFERENCES
1.
Bieniasz, A., Drewniak,
K., and Klimek,
AM.
98:
J. OBST.
& GYNEC.
535,
R.:
1967.
2. Drewniak, K.: Kliniczna ocena biochemicznej metody oznaczania terminu porodu, Doctor’s Thesis, Krakow, 1964. 3. 4. 5.
Klimek, Klimek, 1967. Klimek, Foetus, Foundation,
R.: Ginek. Polska R.: Gynaecologia R.: In Intra-Uterine Amsterdam, 1967, p. 504.
34: 289, (Basle)
473; 1963. 163: 48,
Dangers Excerpta
to the Medica
0.46 per ctnt mortality. Eleven stillborn fetuses were delivered of patients who were admitted to the clinic with already dead fetuses. The condition of the mothers and the other neonates was satisfactory. The results presented above pertain to pregnant patients admitted to the Department of Pregnancy Observation for various reasons. This explains the high percentage of operative deliveries, which in this series is twice as high as the over-all clinical avcrage. On the other hand, the perinatal mortality of the neonates was similar to the over-all average in this Clinic. Comment Serum oxytocinase levels reach a peak in the perinatal period. The findings in this study show that the enzyme levels continue to rise up to labor in 79.9 per cent of cases (Table II, Column A). In 10 per cent levels remain steady, and in the remaining cases a drop occurs. The accuracy and reproducibility of the results allow their practical application in obstetrics. Many authors, however, hold different opinions regarding the oxytocin test. In our data on enzyme levels, the test showed decreasing values up to the onset of labor in 87.2 per cent of cases (Table II, Column I). According to our previous studies, the uterine contractions elicited in the test are the result of supplementation of the endogenous oxytocin level.3-” The mean error between the day indicated by biochemical method and real day of labor is 1.4 days.
6. 7. 8. 9. 10.
Klimek, R.: Ginek. Polska 39: 253, 1968. Klimek, R.: Clin. Chim. Acta 20: 233, 1968. Klimek, R., and Bieniasz, A.: AM. J. OBST. & GYNEC. In press. Klimek, R., and Pietrzycka, M.: Clin. Chim. Acta 6: 326, 1961. Klimek, R., and Turzafrska, T.: Bull. Polish M. SC. & Hist. 10: 125, 1967. ul. Kopernika 2.7 Cracow, Poland
Further studies on the oxytocin-oxytocinase system RUDOLF
KLIMEK,
KRZYSZTOF
DREWNIAK,
ANDRZEJ Cracow,
M.D.
BIENIASZ,
M.D M.D.
Poland
The dynamic oxytocin test and the chemical assay of serum oxytocinase were carried out in 426 pregnant women with the aim of predicting the date of labor. In cases in which the oxytocin dynamic test showed decreasing values or rising levels of oxytocinase, conservative procedure was followed. In the remaining cases labor was induced by means of Syntocinon. In the prenatal period oxytocinase levels show steady increase in 79.9 per cent of cases, while the values of the oxytocin test decrease in 87.2 per cent. Both situations were observed simultaneously in 76.6 per cent of cases. Prediction of the date of labor by this biochemical method is 9 times as accurate as the prediction based upon Naegele’s rule.
Material
I N A P R E V I 0 u s communication, it was shown that serum’oxytocinase levels are related to endogenous oxytocin production and, moreover, undergo characteristic changes under the influence of exogenous oxytocin.3-7 On the basis of this observation a technique depending upon the simultaneous performance of the oxytocin intravenous test and the determination of the level of oxytocinase for the purpose of predicting the date of labor and studying the course of pregnancy was devised.l-lo This paper presents supplementary data and summarizes the findings to date.
and
procedures
The study was carried out on 426 pregnant women admitted to the Department of Pregnancy Observation. The “dynamic oxytocin test” was performed by injecting 10 mu. synthetic oxytocin (Syntocinon) in 5 per cent glucose solution intravenously at 1 minute intervals until the appearance of the first uterine contraction, as registered by a Lorand tocograph. A total dose of 70 mu. was, however, not exceeded. Each IO mU. of required oxytocin was interpreted as indicating one remaining day before onset of labor. If labor failed to begin on the predicted date, the oxytocin test was repeated on this day. If the result of this second test was lower than the earlier one by 10 or more milliunits, the dynamic oxy-
From the Central Endocrinological Laboratory and the First Obstetrical and Gynecological Clinic, Medical Academy, Cracow.
427
428
Klimek,
Drewniak,
and
October 1, 1969 Am. J. Obst. & Gynec.
Bieniasz
NUUI HuLf
-----
PAtiS 1 PARAS
0 lllllllrll~
-6
days
111”““” -4
after
-2 labor
2
0
4
&or
Fig. 1. Relative accordance biochemical method taking
days
between real day into account values
of labor and of first test.
6 before probable
date
a
12
IO
I4
labor of labor
predicted
by
cased
i\ I: A I\ A
P7/
\\ \\ A
I/’ /I\
NULLIPARAS MULTI PARAS
--es-
I
-6 days
-4
after
-2
labor
Fig. 2. Relative accordance biochemical method taking
0
2
labor between real day into account values
4
days
6
0
I
1
12
labor
before
of labor and probable of second test.
1
IO
date
of labor
predicted
by
1
I
I4
Volume Number
105 3
Oxytocin-oxytocinase
tocin test was considered to be decreasing. If the value obtained was greater than in the first test by 10 mu. or more, then the dynamic oxytocin test was regarded as increasing. Differences of less than 10 mu. between the tests classify the condition as steady. Serum levels of oxytocinase were assayed simultaneously with chemical methods described previously.3l 6ps Differences of 0.1 mu. per liter per minute were considered significant to classify the changes in enzyme concentration as decreasing or increasing. The: results of these tests, combined with obstetric considerations, are the basis for the decision to induce labor. In cases where the test showed decreasing values of oxytocin required or rising levels of oxytocinase, a conservative course was followed. In the remaining cases, labor was induced with Syntocino:n. Decisions were not based on Naegele’s rule, since statistical data show that in 95 per cent of women labor begins during a wide interval, 281 f 22 days counting from the date of the first day of the last menstruation.4> 5
system
429
Results
Among the 426 patients in this series, the oxytocin test was performed in 51 per cent only once (nulliparas, 50.5 per cent; multiparas, 51.3 per cent) ; in 28.8 per cent twice (nulliparas, 29.2 per cent; multiparas, 28.6 per cent), and in the remainder (20.0 per cent) three times or more. These results showed there was no difference between the nulliparas and multiparas in this regard or with respect to efficiency of the test in predicting the probable date of labor. Figs. 1 and 2 show the accordance between the actual date of labor and predicted date of labor based on the first and second tests. From the above data it appears that in using this method it is not necessary to divide the patients by parity, a point made in the former papers. The mean values with standard errors of the first and last oxytocin tests are listed in Table I. This table shows the number of days between the test day and the onset of labor. It indicates the mean difference between predicted onset of labor derived from
Table I Differences
-
(probable Test
A day
(days)
day
of
examination
and
B of
Mean
First Last
between
labor)
(real
rt S.E.
3.1 2.1
day
of
Mean
0.15 0.19
5.4 2.7
2 S.E.
Difference between A and B (days)
0.80 0.24
2.2 0.6
Labor)
Table II Onytocin Serum
oxytocinase
I Decreasing
zz Steady
III Rising
327 76.7%
B [steady)
19 44%
21 49%
21 7%
42 10.0%
C (decreasing)
26 61%
2;%
a 18%
43 10.9%
37 8.7%
17 3.9%
426 100.0%
372 87.3%
7 1.6%
Total
A (rising)
Total
7 1.6%
test
341 79.9%
430
Klimek,
Drewniak,
and
Bieniasz
the first test and the actual time of onset is 2.2 days, while depending on the last test it is 0.6 day. Taking into account both differences, the mean error between the day indicated by the tests and the actual onset of labor is 1.4 days. The mean error between the day of onset of labor as predicted according to Naegele’s rule was 13.4 days per case. One may conclude, therefore, the prediction of the day of labor by the biochemical method is 9.4 times as accurate as prediction by Naegele’s rule. The mode of eventual obstetric intervention as indicated by the tests is shown in Table II. Here the values of the oxytocin test and the serum oxytocinase level are classified in three groups. Decreasing values of the oxytocin test are designated, I ; steady values, II; and rising values, III. The oxytocinase levels are similarly designated as rising levels, A; steady levels, B; and decreasing levels, C. On the basis of simultaneous evaluation of the oxytocin test and the oxytocinase level, the term of labor was predicted and compared with Naegele’s rule. Only in Groups IIB, IIC, IIIB, and IIIC was labor induced. Of the total of 426 deliveries, including 4 twin deliveries, 329 (77.3 per cent) were spontaneous. The remaining 97 cases included 41 cesarean sections, 13 with forceps deliveries, 16 with speculum, and 27 deliveries with manual assistance. The number of live-born neonates was 423, of which 2 died in the perinatal period (1 forceps delivery, 1 with eclampsia) , constituting
REFERENCES
1.
Bieniasz, A., Drewniak,
K., and Klimek,
AM.
98:
J. OBST.
& GYNEC.
535,
R.:
1967.
2. Drewniak, K.: Kliniczna ocena biochemicznej metody oznaczania terminu porodu, Doctor’s Thesis, Krakow, 1964. 3. 4. 5.
Klimek, Klimek, 1967. Klimek, Foetus, Foundation,
R.: Ginek. Polska R.: Gynaecologia R.: In Intra-Uterine Amsterdam, 1967, p. 504.
34: 289, (Basle)
473; 1963. 163: 48,
Dangers Excerpta
to the Medica
0.46 per ctnt mortality. Eleven stillborn fetuses were delivered of patients who were admitted to the clinic with already dead fetuses. The condition of the mothers and the other neonates was satisfactory. The results presented above pertain to pregnant patients admitted to the Department of Pregnancy Observation for various reasons. This explains the high percentage of operative deliveries, which in this series is twice as high as the over-all clinical avcrage. On the other hand, the perinatal mortality of the neonates was similar to the over-all average in this Clinic. Comment Serum oxytocinase levels reach a peak in the perinatal period. The findings in this study show that the enzyme levels continue to rise up to labor in 79.9 per cent of cases (Table II, Column A). In 10 per cent levels remain steady, and in the remaining cases a drop occurs. The accuracy and reproducibility of the results allow their practical application in obstetrics. Many authors, however, hold different opinions regarding the oxytocin test. In our data on enzyme levels, the test showed decreasing values up to the onset of labor in 87.2 per cent of cases (Table II, Column I). According to our previous studies, the uterine contractions elicited in the test are the result of supplementation of the endogenous oxytocin level.3-” The mean error between the day indicated by biochemical method and real day of labor is 1.4 days.
6. 7. 8. 9. 10.
Klimek, R.: Ginek. Polska 39: 253, 1968. Klimek, R.: Clin. Chim. Acta 20: 233, 1968. Klimek, R., and Bieniasz, A.: AM. J. OBST. & GYNEC. In press. Klimek, R., and Pietrzycka, M.: Clin. Chim. Acta 6: 326, 1961. Klimek, R., and Turzafrska, T.: Bull. Polish M. SC. & Hist. 10: 125, 1967. ul. Kopernika 2.7 Cracow, Poland