Premature labor and indomethacin

PREMATURE N. WiqvistX,

LABOR AND INDOMETHACIN V. Lundstr6m

and K. Green

Department of Obstetrics and Gynecology, Karolinska Hospital, Stockholm, Sweden

ABSTRACT Women in the 29th - 32nd week of gestation were admitted to hospital following the onset of premature labor contractions. After treatment with bed rest and 8-stimulating drugs, those patients with persistent uterine contractions were treated with oral indomethacin (25 mg every 6 hours for 5 days). The effect of indomethacin therapy was monitored by serial external tocometry recordings. This treatment schedule with indomethacin was repeated on several occasions at intervals of 5 to 10 days. Using a standardized technique, uterine contractility was monitored every second or third day throughout the entire treatment period. In this way, the frequency of contractions was evain the presence or absence of indomethacin therapy. luated Following indomethacin treatment, there was a significant decrease in the frequency of contractions in all cases and a complete arrest of contractions occurred in some women. An increased frequency of contractions was observed during those times that the patient did not receive indomethacin. The plasma concentration of 15-keto-13, 14-dihydrowas determined PGF the major serum metabolite of PGF by $& gas chromatography - mass spectra I%&ry method before and after indomethacin in a limited number of cases. At the doses given for the duration of therapy used, no untoward effects could be detected in either the mother or the infant. These results indicate that indomethacin is a potent and useful drug in the treatment of premature labor.

ACKNOWLEDGEMENTS This study was supported in part by research grants from the Swedish Medical Research Council (grants 2019 and 2028) and the WHO Prostaglandin Task Force. The authors also wish to express their gratitude to the Clinical Research Unit nursing staff and to Mrs Ebba Bennet for her assistance in the typing of the manuscript. X

Present address - Department of Obstetrics and Gynecology, University of Gothenburg, Sahlgrenska Hospital, S - 413 45 Gothenburg, Sweden

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INTRODUCTION A variety of different mechanisms may be involved in the etiology and pathogenesis of premature labor. These mechanisms can be related to the condition of the fetus or the mother but can be correlated also to local alterations in the uterus such as a necrotic myoma or a hemorrhage between the uterine wall and membranes. There are many reasons to believe that prostaglandins are involved in the process of initiation of normal labor at term and it seems probable also that these compounds play a role in the pathogenesis of premature labor. Evidence supporting this view is derived from the increasing concentrations of primary prostaglandins in amniotic fluid or of their metabolites in blood plasma and maternal urine during activation of the uterus (1 - 6). Indirect evidence is available also from experiments in which the administration of prostaglandin synthetase inhibitors prevents the onset of labor in the rhesus monkey (7), delays the abortion process in saline-induced abortions (8) or prolongs labor in the human female (9). A report on the use of indomethacin for the treatment of premature labor has been published recently and the results indicate that uterine contractions decreased within a few hours following rectal administration of 100 mg of the drug and that, in the majority of cases, delivery could be postponed until greater fetal maturity could be achieved (10). The present study was undertaken as an attempt to lend additional support to the value of indomethacin as a part of the therapeutic armamentarium for the management of premature labor. The study was based on a limited number of cases of premature labor in the 28th - 32nd week of gestation. The cases were followed by serial external tocometry recordings over a period of 1 - 3 months. The level of uterine contractility was evaluated in the presence and absence of indomethacin treatment, i.e. the patients served as their own controls. In addition, blood samples were collected for analysis of the 15-keto-13, ll-dihydro-PGF concentration in plasma as indicators for endogenous progpaglandin formation.

MATERIAL

AND METHODS

The case material consisted of 9 women admitted to the hospital in early premature labor between the 28th - 32nd week of gestation. The etiology of premature labor was unknown in most cases, while in two cases the premature contractions probably were due to fetal malformation and necrotic myoma. The initial treatment included conventional therapeutic measures - bedrest and isoxsuprine, a B-stimulating drug. In cases where slight or moderate premature contractions SEPTEMBER

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continued in spite of this treatment, those patients were also given oral indomethacin at a dose of 25 mg 4 times per day. Indomethacin was administered for a period of 5 days after which the treatment was continued with B-stimulating drugs only. After an interval of 5 - 10 days, another indomethacin course was given. A series of treatment periods with indomethacin in addition to isoxsuprine could then be compared with periods when the former drug had been temporarily discontinued. Uterine contractility was recorded in 8 women by a standardized external tocometry technique by midwives who were not informed about what drugs were used. A recording of at least one hour was performed every 2nd - 4th day. The amplitude of the contractions as measured by external tocometry could not be evaluated accurately from a quantitative point of view. However, the method allows identification of significant contraction waves which permits a determination of contraction frequency for comparison of various recording days. To measure endogenous prostaglandin levels a volume of 40 ml blood was drawn from 5 patients before and during treatment with indomethacin. All samples were immediately centrifuged a& 4000 x g and the plasma was isolated and stored at -20 until analyzed. The concentration of the major plasma metabolite of PGF 15-keto-13, 14-dihydro, was analyzed by gas cfi &matography-mass spectrometry Yae cordance with methods described earlier (11). RESULTS Our findings are illustrated graphically in figures 1 6. Each individual contraction was identified visually on the tracings and plotted in relation to time, irrespective of relative amplitude. The first case (fig. 1) shows a schematic representation with the frequency of contractions recorded on 13 different occasions. The original tracings that correspond to the latter half of the first recording on October 29th and that of October 31st are shown in fig. 2. Intravenous isoxsuprine infusion had little if any effect in reducing contractility as illustrated by the second tracing made on October 29th. Indomethacin suppressed the frequency of uterine contractions significantly and an increase in contractility appeared after discontinuation of the drug. A similar reduction of uterine contractility by indomethatin was observed in the remaining five patients although the response was doubtful in case I.S. (fig. 6). This patient had slight vaginal bleeding. The graph illustrating case A.H. (fig. 7) shows an excellent response to indomethacin and frequent contractions as soon as the therapy was discontinued. This patient was admitted in the 30th week of gestation with signs of marked uterine hypertonicity. True labor could be postponed until the 38th week when she gave SEPTEMBER

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Oct. 29

A A A

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Figure

1.

28 years. Admitted in the 31st week of pregnancy (Oct. 14) in premature labor. Cervix 75 % effaced. Treated with i.v. B-stimulating drugs without arrest of the contractions.

M.J.,

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Figure

518

2.

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Original external tocometry tracings illustrating the last 30 min. period of recording on October 29th (upper curve) and October 31st in case M.J. fig. 1.

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April 1)

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Figure

3.

The effect of oral indomethacin treatment on premature uterine contractions in the 31st week of pregnancy (33 year old primipara with necrobiotic fibromyoma). Schematic illustration of external tocograms. 1974 Sept.26 Oct.

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I.B., 25 years. (1973 spontaneous abortion 6th month). Cerclage 14th week. Admitted in the 29th week in premature labor. Oral isoxsuprine over the entire treatment period.

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Dec.

18

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5.

B-S. 29 years. Para 1, 3 spontaneous abortions. Admitted in the 28th week with premature contractions.

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6.

Previously delivered from a I.S. 27 years. stillborn fetus. Admitted in the 28th week with slight vaginal bleeding and premature contractions. SEPTEMBER

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Nbv.21

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Admitted in the 30th week of A.H. 27 years. pregnancy. Signs of placental abruption with marked uterine hypertonus. Cervix 75 % effaced.

birth to a chondrodystrophic fetus with palatoschisis. Table I summarizes the total material of uterine contractility recordings expressed in terms of mean _ _ number of contractions per hour. It is evident that the frequency was considerably lower when the patients were under indomethacin treatment. Table 1. Mean number of premature labor contractions per hour without and after 1 - 2 days of indomethacin treatment Patient

Without indomethacin 6.0

M.R. I.B. M.J. I.S. A.H. C.B.S. L.J.

3.6 7.2 5.2 13.2 11.1 13.0 9.0

K.M.

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With indomethacin 1.6 0.3 1.6 3.5 2.5 2.8 2.0 3.0

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Table II. Plasma concentration of 15-keto-13, 14-dihydroPGF during premature labor in the 28th - 32nd week of ges 8 %tion without and with indomethacin treatment Patient

Delivery postponed

Delivery progressed

Without indomethacin

L.J.

36 pgx)

K.M.

31 "

A.H.

48 "

M.R.

24 "

L.P.

447 #I

With indomethacin

Comment


Necrobiotic fibromyoma

890 V

xl pg = picogram/ml

Table II shows the plasma concentration of 15-keto-13, ll-dihydro-PGF in a limited number of subjects. The level of the metabol ? &e varied between 25 and 50 pg/ml before initiating indomethacin treatment. Under the influence of indomethacin two of the three successfully treated cases had undetectable amounts of the metabolite whereas the patient (M.R.) with a necrobiotic fibromyoma had a concentration of 65 pg/ml. The patient whose labor progressed (L.P.) showed a very high concentration of the metabolite on admission and the level was even higher following one day of indomethacin treatment (three hours prior to delivery).

DISCUSSION External tocometry as a method of evaluating uterine contractility has obvious limitations. The amplitude and appearance of the contractions may vary as a function of the tightness of the girdle around the abdomen and the position of the patient. However, the recordings were managed routinely by midwives who were unaware of the actual treatment of the patient and no effort was made to try to quantitate or compare the amplitude of contractions when evaluating the recordings. It is difficult also to assess whether the patients were in true or false premature labor. In view of the fact that the cervix was partially effaced in 4 of the 8 recorded cases it seems reasonable to assume that effective contractions were present in at least 4 of these cases. It has been shown that the amplitude of the labor contractions at term must exceed 30 mm Hg before any influence upon the

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cervix can be observed (12). However, irrespective of the problem of whether the patients were in false or true labor the study shows that oral treatment with indomethacin can reduce the frequency of uterine contractions. It has been shown that the endogenous levels of 15-keto13, 14-dihydro-PGF2u range between 20 - 60 pg/ml during the last 4 weeks of normal pregnancy. The levels increase during active labor at term, reaching values between 300 1000 pg/ml (2). The corresponding normal plasma levels in the 28th - 32nd week of gestation have never been determined using the gas chromatography mass spectrometry method. However, estimation of the daily excretion of the major urinary metabolite (5 -, 7 -dihydroxy-ll-keto-tetranorprostane-1, 16-dioic %cid)cof PGF shows up to a 5-fold increase of the values as term pr@nancy approaches. The data presented in this investigation indicate that the levels in connection with early premature labor are of the same order of magnitude as those found in normal pregnancy shortly before term when prelabor contractions are normally present. The only case in the present study where significantly higher prostaglandin concentrations were found was the patient in advanced premature labor. Indomethacin, at the doses applied, did not reduce the concentration of 15-keto-13, 14-dihydro-PGF in this case nor in the patient with a necrobiotic f 1gromyoma. In two other women the concentration of the metabolite was very low, i.e. less than 10 pg/ml. It has been demonstrated that two to three days of treatment with indomethacin at a dose of 50 mg x 4 daily effects a reduction of the endogenous production of prostaglandin F to very small amounts (13). It is possible that the do& used in the case with advanced premature labor was too small and given too late to have a significant effect on the outcome. Manipulation of tissues or cell damage (such as burns) are known to cause increase of the biosynthesis of prostaglandins. It is therefore possible that prostaglandins were synthesized in and released from the necrotic myoma leading to increased plasma levels of 15-keto-13, 14-dihydro-PGF2u and, perhaps, to increased uterine contractions. The comparatively high plasma concentration of the metabolite found in this case could indicate that the indomethacin dose was too low or that the drug did not penetrate efficiently enough into the necrotic area. It can be concluded that indomethacin can effect a significant reduction of uterine contractility in cases of premature labor provided that the process has not progressed too far. These results are in agreement with those of Zuckerman et al. (10) and support the view that prostaglandin synthetase inhibitors are of at least the same significance as B-stimulating drugs in the treatment of this condition. Based upon theoretical and clinical evidence, the two pharmacological actions should complement each other.

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Animal experiments indicate that prostaglandins play a siqnificant role in maintaining an open ductus arteriosus and it has been shown that ductal contraction occurs in utero in fetuses of rats and rabbits given indomethacin shortly before term (14). Also there has been at least one documented case of in utero ductal closure in man associated with salicylate exposure at 35 weeks of pregnancy (15). These findings raise doubts as to the safety of using indomethatin in the treatment of premature labor. However, it has also been shown that ductal closure in rodents can only be induced during the last few days of pregnancy. A large dose of indomethacin administered in rats effected closure of the ductus on day 20 and 22 of pregnancy but not on day 18 (14). Moreover, in Zuckermans et al. series of 50 women having a cervical dilatation ranging between 1 and 5 cm there was a salvage of 45 infants. These babies were examined by the pediatrician and no ill effects related to the treatment were observed. The remaining 5 infants were born within the 27th - 32nd week of pregnancy with birth weights ranging between 730 - 1450 g and did not survive. The present series is small. One infant, the condrodystrophic fetus, did not survive. However, the reamining babies were all in normal condition during the post natal period and careful pediatric examination did not reveal any circulatory disturbances or other abnormalities. Before the use of prostaglandin synthetase inhibitors can be recommended in the routine it should be emphasized that additional evidence as to the safety of these drugs is needed. For the time being it seems that carefully controlled trials should be limited to the period around the 30th week of gestation when ductal patency should be less dependent on prostaglandins as judged from animal experimental data. In this early stage of gestation there is also little to lose since the alternative is a fetus with little or no chance at all to survive.

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REFERENCES 1.

Karim, S.M.M. and Devlin, J. Prostaglandin content of amniotic fluid during pregnancy and labour. J. Obstet. Gynaec. Brit. Cwlth. 74:230, 1967.

2.

Green, K., Bygdeman, M., Toppozada, M. and Wiqvist, N. The role of prostaglandin F2 in human parturition. Endogenous plasma levels 8f 15-keto-13, 14dihydro-PGF during labor. Am. J. Obstet. Gynec. 120:25, 197%:

3.

Hamberg, M. Quantitative studies on prostaglandin synthesis in man. III. Excretion of the major urinary metabolite of prostaglandin Flcland Fza during pregnancy. Life Sci. 14:247, 1974.

4.

Salmon, J.A. and Amy, J.J. Levels of prostaglandin in amniotic fluid during pregnancy and labour. F2 Pr8staglandins 4:523, 1973.

5.

Keirse, M.J.N., Flint, A.P.F. and Turubull, A.C. F prostaglandins in amniotic fluid during pregnancy and labour. J. Obstet. Gynaec. Brit. Cwlth. 81:131, 1974.

6.

Wiqvist, N. Endogenous prostaglandins in normal pregnancy and labor. In: International Encyclopedia of Pharmacology and Therapeutics (Specialist Subject. Ed. K.H. Mosler). Pergamon Press, Oxford, vol. 1. In press.

7.

Novy, M.J., Cook, M.J. and Manaugh, L. Indomethacin block of normal onset of parturition in primates. Am. J. Obstet. Gynec. 118:412, 1974.

8.

Waltman, R., Tricomi, V. and Palav, A. Aspirin and indomethacin: Effect on instillation/abortion time of mid-trimester hypertonic saline induced abortion. Prostaglandins 3:47, 1973.

9.

Lewis, R.B. and Schulman, J.D. Aspirin and labour. Lancet ii, 1159, 1973.

10.

Zuckerman, H., Reiss, U. and Rubinstein, I. Inhibition of human premature labor by indomethacin. Obstet. and Gynec. 44:787, 1974.

11.

GrGen, K., Granstriim,E., Samuelsson, B. and Axen, U. Methods for quantitative analysis of PGF PGE 11 -dihydroxy-15-keto-prost-5-enoic acid'%nd 9': Yn;, 15%rihydroxy-prost-5-enoic acid from body flufds using deuterated carriers and gas chromatography mass spectrometry. Anal. Biochem. 54~434, 1973.

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12.

Lindgren, L. and Fagerlund, N. Uterine motility and resistance of the lower parts of the uterus at the onset of labor. Acta Obst. et Gynec. Stand. 44:265, 1965.

13.

Hamberg, M. Inhibition of prostaglandin synthesis in man. Biochem. Biophys. Res. Commun. 49:720, 1972.

14.

Sharpe, G.L., Larsson, K.S. and Thalme, B. Studies on closure of the ductus arteriosus. XII. In utero effect of indomethacin and sodium salicylate in rats and rabbits. Prostaglandins. In press.

15.

Arcilla, R.A., Thilenius, O.G. and Ranniger, K. Congestive heart failure from suspected ductal closure in utero. J. of Pediat. 75:74, 1960.

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