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The use of large doses of progesterone in delaying the onset of labor after premature spontaneous rupture of the membranes
THE USE OF LARGE DOSES OF PROGESTERONE IN DELAYING ONSET OF LABOR AFTER PREMATURE SPONTANEOUS RUPTURE OF THE MEMBRANES ~EDUARD EICHNER, (From
the Division
M.D., E’.A.C.S., AI\‘D KALMAN CLEVELAND, OHIO of
Obstetrics
rind
Gplecolog,y,
Xt.
KUNIN, Sinai
THE
M.D.,
IIospitnl)
T HAS been noted frequently of late that future improvements in fetal salvage will depend not on improved medical or nursing care, and not on better obstetric or nursery facilities, but probably most of all on the prevention of premature births. Intracranial hemorrhage and pulmonary atelectasis, the two most common factors in fetal death, have an increased incidence in premature babies.
I
For almost two hundred years medical authorities have known of the relationship between labor and rupture of the membranes. Recent authors in general agree that about 60 per cent of patients with ruptured membranes are in labor within an hour, and 90 per cent within twenty-four hours. There is no fully acceptable explanation for a longer latent period. Almost all recent reports have limited their figures and discussions to pregnancies of thirty-six. weeks or more. However, Ballard’ reports 425 cases with 12 mothers delivered prematurely of 13 infants, all of whom were born alive and died in the neonatal period, one of cerebral hemorrhage and 12 of prematurity. She reports a delay of over twenty-four hours in 10.1 per cent of her total cases, the longest delay being 336 hours in a mature fetus. She states that there is no relationship between the babies’ weights and the latent period. Plass and Seibert7 report their longest delay as 88 hours, whereas Mason,G King,5 and Greig2 register latent periods of 120 hours. From these and other reports it is evident that prolonged delay in the onset of labor a.fter premature rupture of the ,membranes is infrequent, and that apparently prematurity per se does not influence this latent period. Hain Snyder,g and Heckel and Allen,” as well as others, have demonstrated in the rat and rabbit that progesterone will prolong pregnancy and delay the onset of labor. This is done by permitting the uterus to accommodate itself to the growing fetus. Reynolds’ summarizes this work, “. . . and therefore progesterone must be withdrawn before parturition mechanisms can become effective.” A little later he says: “When labor occurs, however, progesterone is not present in physiologically effective amounts; of this there is no question. ” Results in human beings have been equivocal because of the variability and great inadequacy of the average dose which may be as low as 0.1 mg. weekly. Some recent reports have given 100 mg. daily. The critical period in fetal development lies between the twenty-fourth and thirtieth weeks of gestation. It is at this time that a delay of a week 01 more in the onset of labor may spell the difference between a child capable of independent extrauterine existence, and one incapable. We have attempted to delay the onset of labor and to abort early active labor in 14 consecutive 633
-was furnished by Schering Corporation *Proluton, 50 to 200 mg. per cubic cenrirneter, the kind ausoices of Dr. Norman Heminwav. Associate Director of Research. ?In some cases only one daily injection was givkn. In others, the actual amounts recefved by the patient were unknown as progesterone crystalhzed out of solution on cold days. ~ResoluThe tise of a wet syringe ocoasionallv aroduced L)PCtion occurred with warming of the vial: In sever81 cases progesterone and penicflltn Were cipttation of progesterone inside the vml. These errors occurred in the early days of given in the same site through the same needle, the series. throueh
Volume 6 I Number 3
LARGE
DOSES
OF
PROGESTERONE
TO
DELAY
LABOR
655
regularly c,ontinued at 50 mg. per injection through the thirtieth week of gestation, when it was discontinued. Spontaneous labor began in the forty-second week of gestation on Nov. 27, 1949. She was admitted to the hospital (AC 11287) where ,she delivered a 3,000 gram infant from right occipitoposterior position without difficulty. Recovery was satisfactory, and mother and baby left the hospital together on the fifth day. Of the remaining five patients, pregnancy was extended from two to ten weeks after the rupture of the membranes. Two liveborn infants expired of immaturity, and two were stillborn. Death was caused by prolspsed cord in one case and by intrauterine asphyxia secondary to premature separation of the placenta in the other. The fifth patient delivered a premature child who lived. This is CaSE 4: D. K., aged 31 years, para o, gravida ii, was put to bed at home one hour after the spontaneous rupture of membranes on July 14, 1950. Last menstrual period had begun on Nov. 27, 1949, and though this was the thirty-third week of gestation, the uterus did not appear over the size compatible with a six lunar months’ gestation. Routine was established at home. Proge’sterone was administered 100 mg. twice a day, and continued for ten days. The patient was permitted out of bed on the eighth day. Progesterone was continued 100 mg. twice weekly for the next four weeks. Seepage continued through pregnancy which ended with spontaneous tempestuous labor on Sept. 2.5, 1950 (B 46334) in the forty-fourth week of amenorrhea. Premature separation of the placenta occurred at the end of the first stage with active hemorrhage and loss of fetal heart tones. Rapid delivery was done, and the infant (1,830 grams) was resuscitated with difficulty. Convalescence after this was normal for mother and infant, and the latter left the hospital one month later weighing 5v2 pounds. In view of the uterine size at rupture of the membranes, and the weight of the baby at “term,” we believe that the rupture ocourred not later than the twenty-fifth week, and possibly sooner.
No patient in this small series developed sepsis or unusual morbidity, though foul lochia was present in four. There were no recognizable fetal abnormal.ities. Intrapartum bleedin, v occurred five times, and was severe in one patient. Prolapsed cord was present once, and was a cause of fetal death. The prolapse occurred during labor. This study is now being continued with an “alternating case” control, and hormone studies are being done on the patients in the continuing series. Summary This is a report on the use of high dosage of progesterone on fourteen consecutive patients with ruptured membranes at 18 to 32 weeks’ gestation. Four women delivered during the first hospital day. Progesterone did not stop the labor or interfere with the convalescence. None of these infants lived. In the others labor was delayed from over five days to term. Two were delivered at term with living babies. Three were delivered on the sixth hospital day, and none of these infants lived beyond the seventh day. One other premature infant was delivered in the forty-fourt,h week of amenorrhea with a birth weight of 1,830 grams. He survived. The fetal salvage uncorrected was thus 21.4 per cent. Intrapartum bleeding occurred five times. Four patients had foul lochia, but morbidity was not serious. Delay in the onset of labor was greater than that statistically predicted.
Conclusion The results reported here warrant further study on the apparently use of high doses of progesterone in the prevention of premature labor.
safe
Ballard, Margaret B.: A&f. J. OBBT. & GYXEO. 32: 443, 1936. Greig, D. S.: J. Obst. $ Gynaec. Brit. Etnp. 50: 337, 1943. Hain, A. M.: Quart. J. Exper. Physiol. 22: 249, 19X?. Heckel, G. P., and Allen, W. M.: AN. J. Ossr. C GYNE~. 35: 131, 1938. King, A. G.: J. A. hf. ,4. 114: 238, 1940. Mason, L. W.: A.w. J. OBST. & GYNEC. 26: 393, 1933. Plass, E. D., and Siebert, C. W.: AM. J. OBST. Ps GYNEC. 32: 783, 1936. Reynolds, S. H. &I.: Physiology of the tTtrtus, ed. 2, P\Tew York; 1950, Paul B. Hoeher, p, 5.33. !I. Snyder, F. F.: Bull. Johns Hopkins Hosp. 54: 1. 193-I.
1. 2. 3. 4. 5. 6. 7. 8.
10465 CARNEGIE AVENUE 1800 EAST 105~11 STREET
the Division
M.D., E’.A.C.S., AI\‘D KALMAN CLEVELAND, OHIO of
Obstetrics
rind
Gplecolog,y,
Xt.
KUNIN, Sinai
THE
M.D.,
IIospitnl)
T HAS been noted frequently of late that future improvements in fetal salvage will depend not on improved medical or nursing care, and not on better obstetric or nursery facilities, but probably most of all on the prevention of premature births. Intracranial hemorrhage and pulmonary atelectasis, the two most common factors in fetal death, have an increased incidence in premature babies.
I
For almost two hundred years medical authorities have known of the relationship between labor and rupture of the membranes. Recent authors in general agree that about 60 per cent of patients with ruptured membranes are in labor within an hour, and 90 per cent within twenty-four hours. There is no fully acceptable explanation for a longer latent period. Almost all recent reports have limited their figures and discussions to pregnancies of thirty-six. weeks or more. However, Ballard’ reports 425 cases with 12 mothers delivered prematurely of 13 infants, all of whom were born alive and died in the neonatal period, one of cerebral hemorrhage and 12 of prematurity. She reports a delay of over twenty-four hours in 10.1 per cent of her total cases, the longest delay being 336 hours in a mature fetus. She states that there is no relationship between the babies’ weights and the latent period. Plass and Seibert7 report their longest delay as 88 hours, whereas Mason,G King,5 and Greig2 register latent periods of 120 hours. From these and other reports it is evident that prolonged delay in the onset of labor a.fter premature rupture of the ,membranes is infrequent, and that apparently prematurity per se does not influence this latent period. Hain Snyder,g and Heckel and Allen,” as well as others, have demonstrated in the rat and rabbit that progesterone will prolong pregnancy and delay the onset of labor. This is done by permitting the uterus to accommodate itself to the growing fetus. Reynolds’ summarizes this work, “. . . and therefore progesterone must be withdrawn before parturition mechanisms can become effective.” A little later he says: “When labor occurs, however, progesterone is not present in physiologically effective amounts; of this there is no question. ” Results in human beings have been equivocal because of the variability and great inadequacy of the average dose which may be as low as 0.1 mg. weekly. Some recent reports have given 100 mg. daily. The critical period in fetal development lies between the twenty-fourth and thirtieth weeks of gestation. It is at this time that a delay of a week 01 more in the onset of labor may spell the difference between a child capable of independent extrauterine existence, and one incapable. We have attempted to delay the onset of labor and to abort early active labor in 14 consecutive 633
-was furnished by Schering Corporation *Proluton, 50 to 200 mg. per cubic cenrirneter, the kind ausoices of Dr. Norman Heminwav. Associate Director of Research. ?In some cases only one daily injection was givkn. In others, the actual amounts recefved by the patient were unknown as progesterone crystalhzed out of solution on cold days. ~ResoluThe tise of a wet syringe ocoasionallv aroduced L)PCtion occurred with warming of the vial: In sever81 cases progesterone and penicflltn Were cipttation of progesterone inside the vml. These errors occurred in the early days of given in the same site through the same needle, the series. throueh
Volume 6 I Number 3
LARGE
DOSES
OF
PROGESTERONE
TO
DELAY
LABOR
655
regularly c,ontinued at 50 mg. per injection through the thirtieth week of gestation, when it was discontinued. Spontaneous labor began in the forty-second week of gestation on Nov. 27, 1949. She was admitted to the hospital (AC 11287) where ,she delivered a 3,000 gram infant from right occipitoposterior position without difficulty. Recovery was satisfactory, and mother and baby left the hospital together on the fifth day. Of the remaining five patients, pregnancy was extended from two to ten weeks after the rupture of the membranes. Two liveborn infants expired of immaturity, and two were stillborn. Death was caused by prolspsed cord in one case and by intrauterine asphyxia secondary to premature separation of the placenta in the other. The fifth patient delivered a premature child who lived. This is CaSE 4: D. K., aged 31 years, para o, gravida ii, was put to bed at home one hour after the spontaneous rupture of membranes on July 14, 1950. Last menstrual period had begun on Nov. 27, 1949, and though this was the thirty-third week of gestation, the uterus did not appear over the size compatible with a six lunar months’ gestation. Routine was established at home. Proge’sterone was administered 100 mg. twice a day, and continued for ten days. The patient was permitted out of bed on the eighth day. Progesterone was continued 100 mg. twice weekly for the next four weeks. Seepage continued through pregnancy which ended with spontaneous tempestuous labor on Sept. 2.5, 1950 (B 46334) in the forty-fourth week of amenorrhea. Premature separation of the placenta occurred at the end of the first stage with active hemorrhage and loss of fetal heart tones. Rapid delivery was done, and the infant (1,830 grams) was resuscitated with difficulty. Convalescence after this was normal for mother and infant, and the latter left the hospital one month later weighing 5v2 pounds. In view of the uterine size at rupture of the membranes, and the weight of the baby at “term,” we believe that the rupture ocourred not later than the twenty-fifth week, and possibly sooner.
No patient in this small series developed sepsis or unusual morbidity, though foul lochia was present in four. There were no recognizable fetal abnormal.ities. Intrapartum bleedin, v occurred five times, and was severe in one patient. Prolapsed cord was present once, and was a cause of fetal death. The prolapse occurred during labor. This study is now being continued with an “alternating case” control, and hormone studies are being done on the patients in the continuing series. Summary This is a report on the use of high dosage of progesterone on fourteen consecutive patients with ruptured membranes at 18 to 32 weeks’ gestation. Four women delivered during the first hospital day. Progesterone did not stop the labor or interfere with the convalescence. None of these infants lived. In the others labor was delayed from over five days to term. Two were delivered at term with living babies. Three were delivered on the sixth hospital day, and none of these infants lived beyond the seventh day. One other premature infant was delivered in the forty-fourt,h week of amenorrhea with a birth weight of 1,830 grams. He survived. The fetal salvage uncorrected was thus 21.4 per cent. Intrapartum bleeding occurred five times. Four patients had foul lochia, but morbidity was not serious. Delay in the onset of labor was greater than that statistically predicted.
Conclusion The results reported here warrant further study on the apparently use of high doses of progesterone in the prevention of premature labor.
safe
Ballard, Margaret B.: A&f. J. OBBT. & GYXEO. 32: 443, 1936. Greig, D. S.: J. Obst. $ Gynaec. Brit. Etnp. 50: 337, 1943. Hain, A. M.: Quart. J. Exper. Physiol. 22: 249, 19X?. Heckel, G. P., and Allen, W. M.: AN. J. Ossr. C GYNE~. 35: 131, 1938. King, A. G.: J. A. hf. ,4. 114: 238, 1940. Mason, L. W.: A.w. J. OBST. & GYNEC. 26: 393, 1933. Plass, E. D., and Siebert, C. W.: AM. J. OBST. Ps GYNEC. 32: 783, 1936. Reynolds, S. H. &I.: Physiology of the tTtrtus, ed. 2, P\Tew York; 1950, Paul B. Hoeher, p, 5.33. !I. Snyder, F. F.: Bull. Johns Hopkins Hosp. 54: 1. 193-I.
1. 2. 3. 4. 5. 6. 7. 8.
10465 CARNEGIE AVENUE 1800 EAST 105~11 STREET