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Treatment of threatened premature labor with large doses of progesterone
Treatment
of threatened
premature
labor
with large doses of progesterone
S I N c E the dominant cause of death in the neonatal period is prematurity, attempts to r-educe infant mortality must he directed above all toward a reduction of the frequcncy of premature delivery. A number of social, nutritional, and medical factors that contribute to prrma turc deliveries ar(* kown.” and avcrything must he done, of thrsr factors. Unforroursc’, to climinatc t Imatcly. thoqh they may well be analyzd statistically, it is difficult to predict their inIluc~ncr~ upon the individual case. In clinical obstetrics. therefore. a substance capable 01 inhihitirq \rtr.rint‘ contractions is badl\~ ncfdcd. Encouraged by thy work of Csapo”. ’ who has carried out a long sr-rics of studies of the rabbit uterus from the molecular level to the uterus in sitIt, making it possible to formulate ;I theory on the hormonal control 01 myomctrial function. wt‘ dccidcd to carr) out a clinical trial of progesterone in tlireatt~~l premature labor-. 11 s?emf.d possihlr that onv of the rt’aqons for pI’e\;ious failures could hc- thta IISV of too small doses, since* ir
From Obstetrical Department Rigshospitalet, llniversity CopenhagelL.
of
has hecn realized only in the last few years that the turnov<>r of progesterone is as high 11s 200 to 303 mg. or more per day at the end of pregnancy in the human. It was decided, therefore. to conduct a double-blind controlled study with fairly large doses of progesterone, gi\,cn pa.rcmterally. Material
methods
Approsimatt~ly 150 patients with symptoms of thrc>atencd premature labor wcrr treat4 during the. 2 year period 1956-1957. IT the symptoms subsided during treatment ~-he patknts wcrc discharged from the hospital aftf,r. varying periods of time. Some were deli\~r~r~cl c:lsc\\-here and some were still undelivered 31 the: time of this analvsis. Thcsts cases have been excluded, leaving ‘1% cases for the present rev&. ‘I‘hc treatrnc~nt with progesterone was started after a period of observation varying from one or 2 hours to 2-4 hours or more. Thosc~ patit’nts in whom I)artllrition seemed imminent were not treated. Patients Ikit uric\ w admission numbers \Ct!r(’ rrc*ntcd wit11 ;I preparation label~tl Progcs[crone A\ arid thc)sc with even numbers rcc&cd f’rogc~stcrone K. One preparation contain& crystalline progcstercme dissolved in vegetable oil with a concentration of 25 trig. 1”’ milliliter. and the: other preparation was the: sitnlr oil without progesterone. Not until tbc: completion of tht* present analysis t\‘as the identity of thra preparationx disclosed to th staff. including the autlL0l.h.
A,
Read in abbreuinted form at the Second World Congress of the International Federation of Gymecology and Obstetrics, Montreal, Canada. June 22-28. 1958 “Present addresr: Department Gynecology, Kommunehospitalet, Copu,lhngen, Denmark.
and
o/
172
Progesterone
Progesterone A contained inactive oil, while Progesterone B contained the active substance. ‘The dosage was 200 mg. daily for 3 days, 159 mg. for 2 days, and then 100 mg. per day. If the symptoms subsided, treatment was discontinued a week after their disappe.arance. Only 50 mg. was given on the last day. The treatment caused no reactions that required its discontinuation. Some patients had tender infiltrations on the injection sites, and one patient in Group A and 2 in Group B did not want to continue for this or other reasons. It has been maintained that treatment with progesterone during pregnancy can cause virilization of female fetuses.?. ” In our study, virilization of neithrr infants nor mothers was observed. The age distribution of the patients is shown in Table I and the obstetrical history in Table II. It is seen that 39 of the
I. Age distribution
Table Age
(years)
Under 20-29 30-39 ---___ Over ---~ Total
Table II.
20
40
Series A
Series B
14 36 12 1
5 43 14 1
63
63
of previous
Outcome
A
Series
I’reuious deliveries None One premature One premature one term One premature two term Two premature Two premature one term Three or more One term Two term Three or more
Labor
173
patients had had one or more previous abortions, and 19 had had one or more premature deliveries.
Table. III Symptoms
causing
Symptom Hemorrhage from the vagina Rupture of the membranes Rhythmic or constant pains or backache
admission Series A
Series B
28 19
23 21
16
19 _
_.---
The number of patients having had episodes of bleeding and pains rarlier in the present pregnancy was 10 in Group A and 23 in Group B. One patient in Group A and 4 in Group B had been treated with progesterone for such episodes. The symptoms causing admission to the hospital for threatened premature labor are shown in Table III. The stage of pregnancy at the time of admission is shown in Table III, and the symptoms found on admission, in Table V. The interval between the onset of symptoms and the first injection of progesterone is seen in Table VI.
Stage
{month)
Fifth and Seventh Eighth Ninth
on admission _-.Series A
sixth
7 27 25 4
--
Series B 11 22 28 2 ~-~ -_
B
abortions
or more
Premature
Table IV. Stage of pregnancy
pregnancies
Series Previous No One Two Three
in Threatened
45 16 1 1
42 16 3 2
29 7
19 2
3
0
Table
V. Symptoms
found
Symptoms Hemorrhage from the vagina Passage of amniotic fluid Uterine contractions No objective symptoms
on admission Series A
Series B
23 18 27 4
15 23 24 11
and and 3 1 and premature
term
15 5 3
1 1 23 7 6
Table VI. Interval
between onset of symptoms and first injection of progesterone Interval Less than 12 hours 12-24 hours 24-48 hours 2-4 days More than 4 days
Series A
Series B
10 15 11 10 17
II ‘) ‘I ;:i 7 10
174
Fuchs
and
Stakemann
If treatment was not interrupted by drlivery it was continued for varying periods of time, depcndin ,g on how long the symptoms were present. Table VII indicates the length of treatment in SIIC~ cases, while thtx cases in which delivery- took place during treatment arc shown in the first half of Table VIII.
Table VII. interrupted
Duration of treatment by delivery
Duration
Series A
when
not
Series R
Less than one week 8-14 days 15-21 days 22-28 days More than -1 weeks
initial
Time symptoms
Results Table VII1 shows that there are no differences between the two groups with regard to results: the number of patients in whom delivery was successfully postponed was equal in both groups. A breakdown of the figures to show the relation to the initial symptom---hemorrhage, rupture of the membranesF and pains--~-does not change the wsults.
As seen frorn the tables, the two groups are in good agreement with regard to age distribution, obstetrical history, and symptoms. A statistical analysis with the use of the X”-test; confirms that. any difference between Group A and Group R is dur to chance. The values of X’ are below the 5 per cent significance limit in all cases escrpt in Table I and the second half of Table II. where the values fall between the 5 and 10 per cent limits. Group A comprises mart patients under 20 years of age and more patients without previous deliveries than
Table VIII.
Group H. btlt in most casts these patients are identical. It can therefore be concluded that the figures in l‘ablcs I-VII do not disagree \vith the assumption that the differcnces between the two groups arc due to ctrancc.
of d e 1’ivery in relation
‘To ascertain that the dominance of paricnts without previous deliveries in Group A does not invalidate this conclusion WC have arranged the material in the following groups: (I? patients with no previous de! 2 ‘1 patients with 0nIy normal liveries: delivrries previously; (3‘1 patients with prcmature deliveries previously. An evaluation of the results in these three groups in the same \vay as in Table VIII does not revaal any difference between Group A and Group 1% Placenta prr\ia. was found to be the caus< of the symptoms of threatened premature labor in 5 patients in Group A and in 6 pa-
to treatment>
Deliuery during treatment First or second day Third-seventh day Eighth-fourteenth da! Fifteenth-twenty-eighth da) After twenty-eighth day Total Delicesy after trecitntezit During first week During second week Third or fourth week After fourth week Total
/ Series B
after
l’asraqc nmniot;c
Hrrnorrhuqc ~ Series A
divided
i
Series A
i
the dominant
oj flz;ul Series B
Rhythmic or (onitant paim ; Series A
/ Series R
Volume Number
79 1
Progesterone
tients in Group B. Abruptio placentae occurred in 6 and 3 cases, respectively. In these cases the necessary obstetrical intervention, of course, determined the time of delivery. The close agreement between the two groups is further illustrated by Table IX, which shows the birth weight of the infants.
Table IX. Weight Weinht
distribution
(warns)
Series A
Less than 1,000 1,000-1,450 i,500-1,950 2,000-2,450 2,500-2,950 More than 3.000 *Includes
one
of infants
stillborn
0 12* 10 13” 15 13
Series B
2 7 11 15 9 19
infant.
Comment
Haskins* found a decrease in the placental content of progesterone after the onset of labor, and Hoffmann and Uhdel” found a reduction of the progesterone concentration in the blood of pregnant patients before and during labor. It has not yet been demonstrated, however, that a reduction of circulating progesterone occurs before the onset of premature labor. Eichner and co-workers** 5 have had good results with large doses of progesterone in delaying the onset of labor after premature rupture of the membranes, but control material is lacking. Smith and SmithI I4 claim a general reduction of pregnancy complications with the prophylactic use of stilbestrol and progesterone. The fetal loss from prematurity was reduced, but the incidence of premature deliveries was not significantly lowered. ‘The present series is not large in view of the many factors that may cause premature delivery. Perhaps it should be further reduced by those cases in which delivery occurred during the first 48 hours after the beginning of treatment (13 cases in each group). It has been shown by Csapo,3 in rabbits, that the effect of progesterone upon
in Threatened
Premature
Labor
175
the pregnant uterus has a latent period of 12 to 24 hours, and it is possible that the latent period is even longer in the human. Even after omission of these cases, however, the material is large enough
Summary
and
conclusions
A double-blind controlled study of ‘treatment of threatened premature labor with large doses of progesterone given intramuscularly has been presented. Sixty-three patients were treated with progesterone in oil in doses of 200 mg. daily initially, decreasing to 100 mg. daily as a maintenance dose. A similar number of patients were given inactive oil in the same quantities. The two groups were in good agreement with regard to age distribution, previous obstetrical history, and symptoms. The number of patients in whom delivery was successfully postponed was equal in the two groups.
176
-1. i. 6.
Fuchs
and
Stakemann
REFERENCES
i.
Csapo. A. I.: Proc. Internat. Gong. Gyncsc,. & Oh.. Geneva. 1954. p. 693. Csapo. ‘4. I.: In Bowes. K.. editor: Modern Trends in Obstetrics and Gynarcology (Setond Series). I.ondon. 19.55, Rutterworth & Co.. Ltd.> p. ‘0. Eichncr, E.. and Kunin. K.: Ast. J. 013s~ Ei GYSEC. 61: 653. 1951. Eichner, E.. Kunin, K.. I,inden, M., Goldberg. I.. Salingu, L., and Prller, Z.: AM. J. &ST. B GYNEC. 67: 939, 195-k. Fuchs. F.. and Fuchs. A.-R.: .4cta endocrinol. 29: 615. 1958.
9. I (I. Il. I ‘.
13. 11.
Hald. .\.: Statistitxl Methods, NIV l.ol-k, 1952: .John Wiley & Sons, 1n1,. IIaskins. A. I,.: AYV. .I. 013s~. & C;\N~:(:. 67: 330. 1954. Haylcs. A. 1%. and Nob, R. I%.: Proc. Staff Mwt. Mayo Cllin. 33: 200. 19S8. Hoffmann. F., and Uhdc. G.: Zc~ntralhl. Gynak. 77: 1909, 1958. Jones, H. W.: Ohst. Pr Gynvc.. Stir\, 12: ?l.i, 19.55. Xorrqaard. S.: Aarsagerne til for tidlig fodscl (Thesis). Coprnhagen. 1953, .4rnc Frost-Hansrn, Publisher. Smith, 0. W., and Smith. C;. V. S.: A.nr. .I. ChST. B (;YNEC. 58: 994, 1949. Smith. C. V. S., and Smith. 0. W.: Ohst. & (;yncc. 1: 1’9. 1954
of threatened
premature
labor
with large doses of progesterone
S I N c E the dominant cause of death in the neonatal period is prematurity, attempts to r-educe infant mortality must he directed above all toward a reduction of the frequcncy of premature delivery. A number of social, nutritional, and medical factors that contribute to prrma turc deliveries ar(* kown.” and avcrything must he done, of thrsr factors. Unforroursc’, to climinatc t Imatcly. thoqh they may well be analyzd statistically, it is difficult to predict their inIluc~ncr~ upon the individual case. In clinical obstetrics. therefore. a substance capable 01 inhihitirq \rtr.rint‘ contractions is badl\~ ncfdcd. Encouraged by thy work of Csapo”. ’ who has carried out a long sr-rics of studies of the rabbit uterus from the molecular level to the uterus in sitIt, making it possible to formulate ;I theory on the hormonal control 01 myomctrial function. wt‘ dccidcd to carr) out a clinical trial of progesterone in tlireatt~~l premature labor-. 11 s?emf.d possihlr that onv of the rt’aqons for pI’e\;ious failures could hc- thta IISV of too small doses, since* ir
From Obstetrical Department Rigshospitalet, llniversity CopenhagelL.
of
has hecn realized only in the last few years that the turnov<>r of progesterone is as high 11s 200 to 303 mg. or more per day at the end of pregnancy in the human. It was decided, therefore. to conduct a double-blind controlled study with fairly large doses of progesterone, gi\,cn pa.rcmterally. Material
methods
Approsimatt~ly 150 patients with symptoms of thrc>atencd premature labor wcrr treat4 during the. 2 year period 1956-1957. IT the symptoms subsided during treatment ~-he patknts wcrc discharged from the hospital aftf,r. varying periods of time. Some were deli\~r~r~cl c:lsc\\-here and some were still undelivered 31 the: time of this analvsis. Thcsts cases have been excluded, leaving ‘1% cases for the present rev&. ‘I‘hc treatrnc~nt with progesterone was started after a period of observation varying from one or 2 hours to 2-4 hours or more. Thosc~ patit’nts in whom I)artllrition seemed imminent were not treated. Patients Ikit uric\ w admission numbers \Ct!r(’ rrc*ntcd wit11 ;I preparation label~tl Progcs[crone A\ arid thc)sc with even numbers rcc&cd f’rogc~stcrone K. One preparation contain& crystalline progcstercme dissolved in vegetable oil with a concentration of 25 trig. 1”’ milliliter. and the: other preparation was the: sitnlr oil without progesterone. Not until tbc: completion of tht* present analysis t\‘as the identity of thra preparationx disclosed to th staff. including the autlL0l.h.
A,
Read in abbreuinted form at the Second World Congress of the International Federation of Gymecology and Obstetrics, Montreal, Canada. June 22-28. 1958 “Present addresr: Department Gynecology, Kommunehospitalet, Copu,lhngen, Denmark.
and
o/
172
Progesterone
Progesterone A contained inactive oil, while Progesterone B contained the active substance. ‘The dosage was 200 mg. daily for 3 days, 159 mg. for 2 days, and then 100 mg. per day. If the symptoms subsided, treatment was discontinued a week after their disappe.arance. Only 50 mg. was given on the last day. The treatment caused no reactions that required its discontinuation. Some patients had tender infiltrations on the injection sites, and one patient in Group A and 2 in Group B did not want to continue for this or other reasons. It has been maintained that treatment with progesterone during pregnancy can cause virilization of female fetuses.?. ” In our study, virilization of neithrr infants nor mothers was observed. The age distribution of the patients is shown in Table I and the obstetrical history in Table II. It is seen that 39 of the
I. Age distribution
Table Age
(years)
Under 20-29 30-39 ---___ Over ---~ Total
Table II.
20
40
Series A
Series B
14 36 12 1
5 43 14 1
63
63
of previous
Outcome
A
Series
I’reuious deliveries None One premature One premature one term One premature two term Two premature Two premature one term Three or more One term Two term Three or more
Labor
173
patients had had one or more previous abortions, and 19 had had one or more premature deliveries.
Table. III Symptoms
causing
Symptom Hemorrhage from the vagina Rupture of the membranes Rhythmic or constant pains or backache
admission Series A
Series B
28 19
23 21
16
19 _
_.---
The number of patients having had episodes of bleeding and pains rarlier in the present pregnancy was 10 in Group A and 23 in Group B. One patient in Group A and 4 in Group B had been treated with progesterone for such episodes. The symptoms causing admission to the hospital for threatened premature labor are shown in Table III. The stage of pregnancy at the time of admission is shown in Table III, and the symptoms found on admission, in Table V. The interval between the onset of symptoms and the first injection of progesterone is seen in Table VI.
Stage
{month)
Fifth and Seventh Eighth Ninth
on admission _-.Series A
sixth
7 27 25 4
--
Series B 11 22 28 2 ~-~ -_
B
abortions
or more
Premature
Table IV. Stage of pregnancy
pregnancies
Series Previous No One Two Three
in Threatened
45 16 1 1
42 16 3 2
29 7
19 2
3
0
Table
V. Symptoms
found
Symptoms Hemorrhage from the vagina Passage of amniotic fluid Uterine contractions No objective symptoms
on admission Series A
Series B
23 18 27 4
15 23 24 11
and and 3 1 and premature
term
15 5 3
1 1 23 7 6
Table VI. Interval
between onset of symptoms and first injection of progesterone Interval Less than 12 hours 12-24 hours 24-48 hours 2-4 days More than 4 days
Series A
Series B
10 15 11 10 17
II ‘) ‘I ;:i 7 10
174
Fuchs
and
Stakemann
If treatment was not interrupted by drlivery it was continued for varying periods of time, depcndin ,g on how long the symptoms were present. Table VII indicates the length of treatment in SIIC~ cases, while thtx cases in which delivery- took place during treatment arc shown in the first half of Table VIII.
Table VII. interrupted
Duration of treatment by delivery
Duration
Series A
when
not
Series R
Less than one week 8-14 days 15-21 days 22-28 days More than -1 weeks
initial
Time symptoms
Results Table VII1 shows that there are no differences between the two groups with regard to results: the number of patients in whom delivery was successfully postponed was equal in both groups. A breakdown of the figures to show the relation to the initial symptom---hemorrhage, rupture of the membranesF and pains--~-does not change the wsults.
As seen frorn the tables, the two groups are in good agreement with regard to age distribution, obstetrical history, and symptoms. A statistical analysis with the use of the X”-test; confirms that. any difference between Group A and Group R is dur to chance. The values of X’ are below the 5 per cent significance limit in all cases escrpt in Table I and the second half of Table II. where the values fall between the 5 and 10 per cent limits. Group A comprises mart patients under 20 years of age and more patients without previous deliveries than
Table VIII.
Group H. btlt in most casts these patients are identical. It can therefore be concluded that the figures in l‘ablcs I-VII do not disagree \vith the assumption that the differcnces between the two groups arc due to ctrancc.
of d e 1’ivery in relation
‘To ascertain that the dominance of paricnts without previous deliveries in Group A does not invalidate this conclusion WC have arranged the material in the following groups: (I? patients with no previous de! 2 ‘1 patients with 0nIy normal liveries: delivrries previously; (3‘1 patients with prcmature deliveries previously. An evaluation of the results in these three groups in the same \vay as in Table VIII does not revaal any difference between Group A and Group 1% Placenta prr\ia. was found to be the caus< of the symptoms of threatened premature labor in 5 patients in Group A and in 6 pa-
to treatment>
Deliuery during treatment First or second day Third-seventh day Eighth-fourteenth da! Fifteenth-twenty-eighth da) After twenty-eighth day Total Delicesy after trecitntezit During first week During second week Third or fourth week After fourth week Total
/ Series B
after
l’asraqc nmniot;c
Hrrnorrhuqc ~ Series A
divided
i
Series A
i
the dominant
oj flz;ul Series B
Rhythmic or (onitant paim ; Series A
/ Series R
Volume Number
79 1
Progesterone
tients in Group B. Abruptio placentae occurred in 6 and 3 cases, respectively. In these cases the necessary obstetrical intervention, of course, determined the time of delivery. The close agreement between the two groups is further illustrated by Table IX, which shows the birth weight of the infants.
Table IX. Weight Weinht
distribution
(warns)
Series A
Less than 1,000 1,000-1,450 i,500-1,950 2,000-2,450 2,500-2,950 More than 3.000 *Includes
one
of infants
stillborn
0 12* 10 13” 15 13
Series B
2 7 11 15 9 19
infant.
Comment
Haskins* found a decrease in the placental content of progesterone after the onset of labor, and Hoffmann and Uhdel” found a reduction of the progesterone concentration in the blood of pregnant patients before and during labor. It has not yet been demonstrated, however, that a reduction of circulating progesterone occurs before the onset of premature labor. Eichner and co-workers** 5 have had good results with large doses of progesterone in delaying the onset of labor after premature rupture of the membranes, but control material is lacking. Smith and SmithI I4 claim a general reduction of pregnancy complications with the prophylactic use of stilbestrol and progesterone. The fetal loss from prematurity was reduced, but the incidence of premature deliveries was not significantly lowered. ‘The present series is not large in view of the many factors that may cause premature delivery. Perhaps it should be further reduced by those cases in which delivery occurred during the first 48 hours after the beginning of treatment (13 cases in each group). It has been shown by Csapo,3 in rabbits, that the effect of progesterone upon
in Threatened
Premature
Labor
175
the pregnant uterus has a latent period of 12 to 24 hours, and it is possible that the latent period is even longer in the human. Even after omission of these cases, however, the material is large enough
Summary
and
conclusions
A double-blind controlled study of ‘treatment of threatened premature labor with large doses of progesterone given intramuscularly has been presented. Sixty-three patients were treated with progesterone in oil in doses of 200 mg. daily initially, decreasing to 100 mg. daily as a maintenance dose. A similar number of patients were given inactive oil in the same quantities. The two groups were in good agreement with regard to age distribution, previous obstetrical history, and symptoms. The number of patients in whom delivery was successfully postponed was equal in the two groups.
176
-1. i. 6.
Fuchs
and
Stakemann
REFERENCES
i.
Csapo. A. I.: Proc. Internat. Gong. Gyncsc,. & Oh.. Geneva. 1954. p. 693. Csapo. ‘4. I.: In Bowes. K.. editor: Modern Trends in Obstetrics and Gynarcology (Setond Series). I.ondon. 19.55, Rutterworth & Co.. Ltd.> p. ‘0. Eichncr, E.. and Kunin. K.: Ast. J. 013s~ Ei GYSEC. 61: 653. 1951. Eichner, E.. Kunin, K.. I,inden, M., Goldberg. I.. Salingu, L., and Prller, Z.: AM. J. &ST. B GYNEC. 67: 939, 195-k. Fuchs. F.. and Fuchs. A.-R.: .4cta endocrinol. 29: 615. 1958.
9. I (I. Il. I ‘.
13. 11.
Hald. .\.: Statistitxl Methods, NIV l.ol-k, 1952: .John Wiley & Sons, 1n1,. IIaskins. A. I,.: AYV. .I. 013s~. & C;\N~:(:. 67: 330. 1954. Haylcs. A. 1%. and Nob, R. I%.: Proc. Staff Mwt. Mayo Cllin. 33: 200. 19S8. Hoffmann. F., and Uhdc. G.: Zc~ntralhl. Gynak. 77: 1909, 1958. Jones, H. W.: Ohst. Pr Gynvc.. Stir\, 12: ?l.i, 19.55. Xorrqaard. S.: Aarsagerne til for tidlig fodscl (Thesis). Coprnhagen. 1953, .4rnc Frost-Hansrn, Publisher. Smith, 0. W., and Smith. C;. V. S.: A.nr. .I. ChST. B (;YNEC. 58: 994, 1949. Smith. C. V. S., and Smith. 0. W.: Ohst. & (;yncc. 1: 1’9. 1954