Download 17 Hydroxyprogesterone for the Prevention of Preterm Delivery

CLINICAL EXPERT SERIES
We have invited select authorities to present background information on challenging clinical problems and
practical information on diagnosis and treatment for use by practitioners.
17 Hydroxyprogesterone for the Prevention of Preterm
Delivery
Paul J. Meis, MD, for the Society for Maternal–Fetal Medicine
The recent publication of 2 large randomized trials of 17
alpha hydroxyprogesterone caproate (17P) and progesterone suppositories, respectively, for the prevention of premature labor have renewed interest in the use of progesterone to prevent preterm birth. The results of these trials
have reinforced the positive results of earlier smaller trials
of 17P to prevent preterm delivery. A large body of evidence attests to the lack of teratogenic effects of 17P in
pregnancy. Although progesterone is known to have many
actions beneficial to the maintenance of pregnancy, the
exact mode of action of 17P therapy in preventing preterm
labor and delivery is not known. Current evidence supports the use of 17P treatment, begun early in the second
trimester of gestation and continued weekly until 36 weeks,
for women with a history of a previous spontaneous preterm delivery. At present no evidence exists for the use of
17P to prevent preterm delivery in women with multiple
gestation, a short uterine cervix, or other high-risk conditions. The use of 17P or other progestins should not be
encouraged for these indications outside of randomized
trials. At present no evidence exists for the efficacy of any oral
progesterone compound in preventing preterm labor. Four
trials reporting the use of a progestational drug in patients
with symptoms of preterm labor found no efficacy in prolonging pregnancy, and the use of 17P or other progestational
drugs as tocolytic therapy should not be encouraged.
(Obstet Gynecol 2005;105:1128 –35. © 2005 by The
American College of Obstetricians and Gynecologists.)
The concept that progesterone therapy may improve
pregnancy outcome has been under consideration for
over 50 years. Early studies of this therapy examined the
use of progesterone in women with threatened abortion
or as a treatment for women with a history of repeated
From the Department of Obstetrics and Gynecology, Maternal–Fetal Medicine,
Winston-Salem, North Carolina.
The editor’s thank the following individuals who, in addition to members of our
Editorial Board, will serve as referees for this series: Dwight P. Cruikshank, MD,
Ronald S. Gibbs, MD, Gary D.V. Hankins, MD, Philip B. Mead, MD, Kenneth L.
Noller, MD, Catherine Y. Spong, MD, and Edward E. Wallach, MD.
1128
VOL. 105, NO. 5, PART 1, MAY 2005
© 2005 by The American College of Obstetricians and Gynecologists.
Published by Lippincott Williams & Wilkins.
early pregnancy loss. The results of randomized controlled trials of progesterone for these indications have
failed to show efficacy, and progesterone treatment is not
currently recommended for the treatment of threatened
abortion. However, other studies of progesterone examined whether this treatment might be effective in preventing preterm birth; the first of these was by Papiernik
in 1970.1 Since that time, a number of trials of progesterone for prevention of preterm delivery have been reported. In this review, we will discuss historically important trials of progesterone for the prevention of preterm
delivery, including 2 meta-analyses and more recent
trials of progesterone, 17 alpha hydroxyprogesterone
caproate (17P), and medroxyprogesterone. In preparation for this review, we performed a search of all literature in English from 1966 to February 2005 in MEDLINE for the terms “progesterone” and “preterm birth,”
which yielded 150 citations.
The most successful of these early trials employed
17P. Although most of these trials reported efficacy for
progesterone therapy in reducing the rate of preterm
delivery, the trials had relatively small numbers of subjects, and the treatment never achieved wide acceptance.
Recently, the publication of 2 large randomized trials, one
of 17P2 and the other of progesterone vaginal suppositories,3 have stimulated renewed interest in the use of this
treatment modality and have also stimulated basic research about the mechanisms of progesterone function.
Preterm birth, that is, delivery before 37 completed
weeks of gestation, is the major determinant of infant
mortality in developed countries.4 The rate of preterm
birth is greater in the United States than in most developed countries and is the factor most responsible for the
relatively high rate of infant mortality in the United
States.4 In addition, the rate of preterm birth in the
United States has increased progressively over the past 2
decades, from 9% to 12% of all births (Fig. 1).5 The rate
of preterm delivery is particularly high for African-
0029-7844/05/$30.00
doi:10.1097/01.AOG.0000160432.95395.8f
ACTIONS OF PROGESTERONE
Fig. 1. Rates of preterm birth in the United States.
(National Center for Health Statistics. Final natality data.
Available at: www.marchofdimes.com/peristats. Retrieved
February 10, 2005.)
Meis. 17 Hydroxy Progesterone. Obstet Gynecol 2005.
American women, who experience rates of low birth
weight and preterm delivery twice as high as those for
white women in the United States.4 Preterm birth is
hazardous to the surviving children. Preterm birth increases the risk for developmental problems, and preterm birth is the largest single cause of cerebral palsy.4 In
addition, the financial costs of preterm birth are high. In
2001, the total national bill for premature babies was estimated at $13.6 billion.6 For these reasons, preterm birth is a
very significant public health problem for the United States.
Many attempts have been made to find ways to reduce
the incidence of preterm birth. Beginning in the 1970s,
drug therapy for the prevention of preterm delivery
became widely used and focused mainly on the use of
tocolytic drugs to halt preterm labor after it had begun.
Although trials of various tocolytic drugs have shown
effectiveness in halting labor for up to several days, the
use of these drugs has not reduced the incidence of
preterm delivery and has not resulted in any improvement in perinatal outcome.7 Cervical cerclage has long
been employed for women thought to have a weakness
of cervical integrity, but randomized trials of cervical
cerclage have generally not shown effectiveness.8 Although vaginal infections are known to be associated
with an increased risk of preterm delivery, the largest
and best controlled trials in low-risk women have found
no improvement in rates of preterm birth as a result of
screening for and treating vaginal infections.9,10 Despite
many trials of reduced physical activity, the use of tocolytic drugs to halt labor, antibiotic therapy, and other
strategies for prevention, no effective and reproducible
method of preventing preterm birth has been discovered.11 Thus, the enigma of preterm birth is widely
considered to be the greatest problem in obstetrics in the
developed world.
VOL. 105, NO. 5, PART 1, MAY 2005
Progesterone, produced by secretion from the corpus
luteum and the placenta, is known to be essential for the
maintenance of pregnancy early in gestation.12,13 In addition, progesterone is known to have actions that maintain pregnancy later in gestation. Progesterone acts to
relax smooth muscle in many organs, including the
pregnant uterus. Progesterone has immunosuppressive
activity against the activation of T lymphocytes and
blocks effects of oxytocin on myometrium.13,14 Perhaps
most importantly, progesterone is a potent inhibitor of
the formation of gap junctions between myometrial
cells.15 These intercellular communications are essential
for the propagation of coordinated uterine muscle activity leading to labor.
In addition to actions of progesterone for general
maintenance of pregnancy, evidence exists from data
obtained from both animals and humans, that changes in
local or systemic concentrations of progesterone may
play a role in the initiation of labor. The importance of
progesterone in regulating the onset of labor is supported
by the observation that, in sheep, goats, and many other
mammalian species, a decrease in plasma progesterone
and an increase in estrogen precedes the onset of labor.16
These findings of changes in the progesterone/estrogen
ratio are consistent with the concept of “progesterone
block,” which was advanced and championed by
Csapo17 in the 1950s, based on his extensive and pioneering experiments in pregnant rabbits.
The role of progesterone or of changes in the progesterone/estrogen ratio in human beings and other primates is less well known. Although investigators have
described low progesterone concentrations or low progesterone/estrogen ratios in the plasma of women destined to deliver prematurely,18,19 no consistent evidence
exists of changes in plasma progesterone or the progesterone/estrogen ratio before the onset of labor at term or
before term. Nonetheless, some evidence exists that local
changes in progesterone or the progesterone/estrogen
ratio in the placenta, decidua, or fetal membranes may be
important in the initiation of labor in human beings.20,21
Several investigators have reported the effects of administering progesterone antagonists to women at term. The
results were an increased rate of spontaneous onset of
labor and, in the women whose labor was induced with
oxytocin, an increased sensitivity to oxytocin compared
with placebo-treated controls.22–24 Although these data
support the concept that progesterone plays a role in
maintaining gestation in human beings, the actual mechanisms by which progesterone therapy may avert preterm labor and delivery are not known.
Meis
17 Hydroxyprogesterone
1129
EARLY TRIALS OF 17 ALPHA HYDROXYPROGESTERONE
TO PREVENT PRETERM DELIVERY
Among the earliest prophylactic trials of 17P for the
prevention of preterm delivery was the study of Papiernik in 1970.1 This trial enrolled women identified as
being at risk of preterm delivery by using a risk-scoring
system. Ninety-nine women were randomly assigned to
receive 17P or placebo injections. Preterm delivery occurred less frequently in the treated group (4%) than in
the placebo group (18%). In 1975, Johnson reported the
results of a trial of 17P for women who had a history of
2 spontaneous abortions, 2 preterm deliveries, or a combination of these outcomes in the pregnancies immediately preceding the index pregnancy.25 Of the 43 women
in the trial, 18 were randomized to weekly injections of
250 mg 17P, and 22 were randomized to placebo injections. The treatment was started as soon as the patients
registered for care and were continued to 37 weeks of
gestation. Three patients in the placebo group and 4
patients in the treatment group also received a cervical
cerclage. The primary outcome was delivery at less than
36 weeks of gestation. The rate of preterm delivery in the
placebo group was 41% (9 women), whereas none of the
treatment group delivered before 36 weeks. The treatment group showed significant differences from the control group in mean duration of pregnancy, mean birth
weight, and perinatal mortality rate. The publication of
this trial in a major medical journal stimulated considerable interest in the use of this drug to prevent preterm
birth. Johnson concluded that large-scale trials were
needed to demonstrate the efficacy of this treatment.
Johnson wished to pursue a larger, more definitive trial,
but no support for a larger trial was available, and the
funding agency for this trial indicated that, in view of the
positive results of the trial, a further placebo-controlled
trial could not be supported ethically.19
The results of these early reported trials of progesterone for prevention of preterm labor and delivery were
evaluated by 2 different meta-analyses. Goldstein et al26
in 1989 published the results of a meta-analysis of randomized controlled trials involving the use of progesterone or other progestational agents for the maintenance of
pregnancy. Fifteen trials of variously defined high-risk
subjects were felt to be suitable for analysis. The trials
employed 6 different progestational drugs. The pooled
odds ratios for these trials showed no statistically significant effect on rates of miscarriage, stillbirth, neonatal
death, or preterm birth. The authors concluded that
“progestogens should not be used outside of randomized
trials at present.”26
In response to this publication, Keirse27 in 1990 presented the results of an analysis of a more focused
1130
Meis
17 Hydroxyprogesterone
selection of trials. This meta-analysis was restricted to
trials that employed 17P, the most fully studied progestational agent, and included all placebo-controlled trials
that used this drug. Pooled odds ratios found no significant effect on rates of miscarriage, perinatal death, or
neonatal complications. However, in contrast to Goldstein’s review, the odds ratio for reduction of preterm
birth was significant, 0.5 (95% confidence interval 关CI兴
0.30 – 0.85), as was the odds ratio for birth weight ⬍
2,500 g, 0.46 (95% CI 0.27– 0.80). Keirse commented
that the results demonstrated by these trials contrast
markedly with the poor effectiveness of other efforts to
reduce the occurrence of preterm birth, but that since no
effect was demonstrated to result in lower perinatal
mortality or morbidity, “further well-controlled research
would be necessary before it is recommended for clinical
practice.”27
Although most of these trials employing 17P showed
positive results for the prevention of preterm birth, 2
trials did not show efficacy. Hartikainen-Sorri et al28 in
1980 reported the results of a trial in twin pregnancies.
Seventy-seven women were identified as having twin
gestations at 28 –33 weeks of gestation and were then
randomly assigned to receive weekly injections of either
250 mg 17P or a placebo injection until 37 weeks of
gestation. No significant differences were seen for rates
of preterm delivery (30.8% in the treatment group versus
23.7% in the placebo group), mean duration of pregnancy, mean birth weight, or rates of perinatal mortality.
To date, this remains the only reported trial of 17P or
other progestogen in multiple gestation. Hauth et al29 in
1983 reported the results of a trial of 17P in a relatively
low-risk group of pregnant women. The selection of
subjects for this trial was of women on active duty in the
military. The women were randomly assigned at 16 –20
weeks of gestation to receive weekly injections of 1,000
mg 17P (80 subjects) or a placebo injection (88 subjects),
continuing until 36 weeks of gestation. No difference was
seen for any pregnancy outcome studied. The rate of low
birth weight birth for the treatment group was 7.5%,
compared with 9% for the placebo infants. The results of
this trial are notable for the low rate of preterm and low
birth weight delivery in the population studied. Because
of the low prevalence of the outcome studied in this
population, the trial did not have sufficient power to
detect a difference in rates of low birth weight birth. To
show a 40% reduction in the treatment group compared
with placebo in the rate of the outcome measured, ie, low
birth weight, would have required a total sample of 1,540
subjects. The results of this trial suggest that progesterone therapy is not useful in women at low risk for
preterm delivery.
OBSTETRICS & GYNECOLOGY
RECENT TRIALS
da Fonseca et al3 reported the results of a randomized,
placebo-controlled trial of progesterone vaginal suppositories in 142 women. The subjects were selected as
being at high risk for preterm birth. The risk factor in
over 90% of the subjects was that of a previous preterm
delivery. The patients were randomly assigned to daily
insertion of either a 100-mg progesterone suppository or
a placebo suppository. The treatment period was 24 –34
weeks of gestation. All patients were monitored for uterine contractions once weekly for 1 hour with an external
tocodynamometer. Although 81 progesterone and 76
placebo patients were entered into the study, several
patients were excluded from analysis because of premature
rupture of the fetal membranes or were lost to follow-up,
leaving 72 progesterone and 70 placebo subjects. The rate
of preterm delivery at less than 37 weeks of gestation in the
progesterone patients was 13.8%, significantly less than the
rate in the placebo patients of 28.5%. The rate of preterm
delivery at less than 34 weeks in the treatment group was
2.8%, compared with 18.6% in the placebo group. These
differences were statistically significant. The rate of uterine
contractions measured by the weekly hour-long recording
was significantly less between 28 and 34 weeks in the
progesterone patients compared with the placebo patients.
Analysis of the results by intent to treat showed smaller
differences between the groups, but these differences remained statistically significant.
Meis et al2 reported the results of a large multicenter
trial of 17P conducted by the Maternal–Fetal Medicine
Units Network of the National Institute of Child Health
and Human Development. The study enrolled women
with a documented history of a previous spontaneous
preterm delivery, which occurred as a consequence of
either spontaneous preterm labor or preterm premature
rupture of the fetal membranes. After receiving an ultrasound examination to rule out major fetal anomalies and
to determine gestational age, the subjects were offered
the study and given a test dose of the placebo injection to
assess compliance. If they chose to continue, they were
randomly assigned, using a 2:1 ratio, to weekly injections
of 250 mg 17P or a placebo injection. Treatment was
begun between 16 and 20 weeks of gestation and was
continued until delivery, or 37 weeks of gestation, whichever came first. The study planned to enroll 500 subjects,
a sample size estimated to be sufficient to detect a 37%
reduction in the rate of preterm birth. However, enrollment was halted at 463 subjects, 310 in the treatment
group and 153 in the placebo group, following a scheduled evaluation by the Data Safety and Monitoring
Committee, which found that the evidence of efficacy for
the primary outcome was such that further entry of patients
VOL. 105, NO. 5, PART 1, MAY 2005
Fig. 2. Percentages of births at less than 32 weeks of
gestation in the treatment (17P) and placebo groups.
Meis. 17 Hydroxy Progesterone. Obstet Gynecol 2005.
would not be ethical. In this study, delivery at less than 37
weeks was reduced from 54.9% in the placebo group to
36.3% in the treatment group. Similar reductions were seen
in delivery at less than 35 weeks, from 30.7% to 20.6%, and
delivery at less than 32 weeks, from 19.6% to 11.4% (Fig. 2).
Rates of birth weight less than 2,500 g were reduced. All of
these differences were statistically significant. Although the
sample size of the study was not powered to examine effects
on neonatal morbidity and mortality, a strong trend was
found for reduction in rates of neonatal death, transient
tachypnea, respiratory distress syndrome, bronchopulmonary dysplasia, need for ventilatory support, supplementary oxygen, intraventricular hemorrhage, necrotizing enterocolitis, patent ductus arteriosis, and retinopathy. These
differences were statistically significant for rates of intraventricular hemorrhage (but not for grades III–IV), necrotizing
enterocolitis, and need for supplemental oxygen and ventilatory support (Fig. 3).
Fig. 3. Rates of respiratory distress syndrome (RDS),
bronchopulmonary dysplasia (BPD), retinopathy of prematurity (ROP), intraventricular hemorrhage (IVH), and necrotizing enterocolitis (NEC) in the treatment (17P) and
placebo groups. * P ⬍ .05.
Meis. 17 Hydroxy Progesterone. Obstet Gynecol 2005.
Meis
17 Hydroxyprogesterone
1131
The women enrolled in this study had unusually high
rates of preterm birth. This could be explained in part by
the fact that the mean gestational age of their previous
preterm delivery was quite early, at 31 weeks. In addition, one third of the women had had more than one
previous spontaneous preterm delivery. Despite random
allocation, more women in the placebo group had had
more than one preterm delivery. Adjustment of the
analysis controlling for the imbalance found that the
treatment effect remained significantly different from
that of the placebo. A majority of the women were of
African-American ethnicity, and the treatment with 17P
showed equal efficacy in the African-American women
and the non–African-American subjects.
SAFETY OF 17 ALPHA HYDROXYPROGESTERONE
CAPROATE
The evidence for the safety of the use of 17P in pregnancy consists of theoretical considerations, animal studies, and clinical studies. 17 Hydroxyprogesterone is a
naturally occurring metabolite of progesterone. Progesterone and 17 hydroxyprogesterone are produced in
large amounts in human pregnancy.30 The quantities
produced in pregnancy, mainly by the placenta, exceed
pharmacologic doses employed in clinical use. 17 Hydroxyprogesterone has no androgenic activity.31 Logically, it is not reasonable to expect ill effects of a nonandrogenic progestin, naturally found in large quantities,
upon human gestation.
The effects of 17P upon pregnancy in experimental
animals has been studied in rats, rabbits, mice, and
monkeys (Macaca mulatta).32–35 These studies found no
evidence of androgenic or glucocorticoid activity, no
virilizing effects upon female fetuses, and no teratogenic
effects.
A number of authors have reported the results of
well-controlled clinical studies that examine the safety of
17P in human pregnancy. Varma and Morsman36 examined the outcome of 150 pregnancies treated with hydroxyprogesterone because of threatened abortion and
compared them with 150 patients who experienced early
pregnancy bleeding but were not treated with the drug.
No evidence was found that the drug had any adverse
effect on the fetus or the outcome of the pregnancy.
Michaelis et al,37 in a cohort study of 13,643 pregnancies
in West Germany, found no increase in malformations
in infants exposed in utero to 17P, compared with controls. Resseguie et al38 examined a cohort of 24,000
pregnancies delivered in Olmstead County, Minnesota,
1936 –1974, and found that the 649 offspring exposed to
17P showed no increase in congenital anomalies or other
ill effects compared with controls. Check et al39 per-
1132
Meis
17 Hydroxyprogesterone
formed a follow-up study by questionnaire of 382
women treated with progestins during pregnancy and
found no increase in anomalies compared with control
offspring. Katz et al40 studied 1,608 infants exposed to
progestins in utero and compared them with 1,146 control infants. No difference was found in rates of all
malformations (120/1,000 and 123.9/1,000, respectively)
or in rates of major malformations (63.4/1,000 and 71.5/
1,000, respectively). Kester41 examined a group of adolescent males who were exposed in utero to 17P and
performed a battery of psychological tests on the subjects
and on matched control subjects. They found no significant differences between the groups in psychological
testing. Longer-term evaluations of any possible effects
of in utero exposure to 17P are important and are
currently in progress.
Several extensive reviews of the literature have been
published regarding the safety of the use of progestins in
pregnancy. Schardein,42 in an extensive review, found
“no justification (exists) for undue concern over the
induction of nongenital malformations through hormone use in pregnancy.” This review found that, although some androgenic compounds have the potential
for masculinization of the female fetus, progesterone and
17P have no such potential. Raman-Wilms et al43 performed a meta-analysis of the literature after review of
186 published articles. The meta-analysis showed no
association between first-trimester exposure to sex hormones and external genital malformations. In the current REPROTOX17 computer database, supported by
Micomedex, the review of hydroxyprogesterone concludes that “There is no available evidence that the
administration of this agent (17P) during pregnancy is
harmful.”44 In summary, the safety of 17P administration in pregnancy is well documented by animal and
clinical studies. Reviews of this topic by knowledgeable
authors have uniformly concluded that no evidence
exists that administration of 17P in pregnancy represents
a significant risk to mother, fetus, or newborn.
CHOICE OF DRUG
At present, the greatest body of evidence for efficacy in
preventing preterm delivery in women at high risk exists
for 17P, with 5 reported successful trials of this compound.1,2,25,45,46 One trial of progesterone suppositories
has found efficacy for this preparation.3 No other progestational drugs have been shown to have efficacy in
randomized trials, but insufficient data are available for
these other compounds. The dose of 17P used in most of
the reported trials has been 250 mg/wk. Little data exist
from pharmacokinetic or pharmacotherapeutic studies
to argue for or against this dose. The rate of adverse
OBSTETRICS & GYNECOLOGY
effects from this drug or from the inert oil vehicle (castor
oil) appears to be small, even with higher doses. Hauth et
al29 used 1,000 mg/wk of the drug and comparable
volumes of the placebo oil, and Sherman47 used up to
2,000 mg of 17P with no reported maternal or fetal
adverse effects. Without doubt, new studies of the pharmacokinetic and pharmacotherapeutic characteristics of
17P would be of significant value. At the time of this
writing, 17P is available in the United States only from
compounding pharmacies. We anticipate and hope that
the U.S. Food and Drug Administration will approve its
manufacture by pharmaceutical companies for the indication of preventing recurrent preterm birth.
Little information exists for the potential efficacy of
oral progestational agents. The only drug submitted to a
large prophylactic trial to prevent preterm delivery is
medroxyprogesterone. This drug has been shown to
have effective anti-inflammatory and pregnancy-preserving properties in a rat model of uterine infection in
pregnancy.48 However, in the clinical trial of Hobel et
al,49 no evidence of efficacy was seen by intent-to-treat
analysis. The possible reasons for the failure of prevention of preterm delivery in this trial include the fact that
the subjects were at fairly low risk for preterm delivery,
and the rate of compliance was very low.
INDICATIONS FOR TREATMENT
Currently, the group of patients who have been found to
benefit from prophylactic treatment with progesterone to
prevent preterm delivery are women at high risk for
preterm delivery because of a history of a prior spontaneous preterm delivery caused by spontaneous preterm
labor or preterm premature rupture of the fetal membranes. Treatment with progesterone for other high-risk
conditions, such as multiple gestation or short uterine
cervix, should not be encouraged outside of randomized
trials. Several such trials are in progress or in development at the time of this writing. The only published trial
of progesterone therapy for twin pregnancy failed to
show efficacy, although this failure may have been related to the fact that therapy was begun at 29 weeks of
gestation or later.28
Although 17P treatment is effective in preventing recurrent preterm delivery in women at risk, this treatment
can have only a modest impact on the rate of preterm
birth in the general population.50 More trials are urgently needed to determine whether 17P treatment is
effective for women with other high-risk pregnancy conditions. In addition, improved methods of screening for
risk and subsequent prophylactic treatment are needed
for women in their first pregnancy.
VOL. 105, NO. 5, PART 1, MAY 2005
The timing of initiation of progesterone therapy is
likely to be important for its effectiveness. Successful
trials have started treatment at no later than 24 weeks of
gestation. It is reasonable to wait until 16 weeks of
gestation to start treatment, and we recommend beginning as soon after this time as possible.
Four published trials have used a progestational drug
for patients in preterm labor, and one trial, in an attempt
to prolong pregnancy in patients close to term, used a
progestational drug.51–55 Although the design of these
trials and the drugs they used varied, none of these
studies have demonstrated any efficacy in prolonging
pregnancy. Thus, the use of progesterone as a tocolytic
drug, or as an adjunct to tocolytic agents for patients in
preterm labor, is to be discouraged outside of randomized trials. It is likely that, once the physiologic or pathologic processes that precede labor (such as the formation
of gap junctions or activation of the inflammatory cascade) have occurred, treatment with progesterone is not
effective in halting this process.
In summary, evidence is sufficient for clinicians to
choose to use progesterone therapy to prevent recurrent
preterm delivery in women at risk. The greater body of
evidence of efficacy at this time is for treatment of 17P at
250 mg/wk beginning as soon as possible after 16 weeks
of gestation and continuing to 36 weeks. The safety of
the use of this drug has been clearly documented. Some
evidence exists to support the use of daily progesterone
suppositories. Further research will be necessary to support the use of progesterone for other high-risk conditions. In addition, further research is needed to elucidate
the mechanism of action of 17P and progesterone in
preventing preterm labor and delivery.
REFERENCES
1. Papiernik E. Double blind study of an agent to prevent
pre-term delivery among women at increased risk. In:
Edition Schering, Serie IV, fiche 3. 1970;65– 8.
2. Meis PJ, Klebanoff M, Thom E, Dombrowski MP, Sibai B,
Moawad AH, et al. Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate 关published
erratum appears in N Engl J Med. 2003;349:1299兴. N Engl
J Med 2003;348:2379 – 85.
3. da Fonseca EB, Bittar RE, Carvalho MHB, Zugaib M.
Prophylactic administration of progesterone by vaginal
suppository to reduce the incidence of spontaneous preterm birth in women at increased risk: a randomized
placebo-controlled double-blind study. Am J Obstet
Gynecol 2003;188:419 –24.
4. Paneth NS. The Problem of Low Birth Weight. Future
Child 1995;5:19 –34
Meis
17 Hydroxyprogesterone
1133
5. Mattison DR, Damus K, Fiore E, Petrini J, Alter C. Preterm delivery: a public health perspective. Paediatr Perinat
Epidemiol 2001;15(suppl 2):7–16.
6. Agency of Heathcare Research and Quality. Overview of the
HCUP Nationwide Inpatient Sample 2001. Available at:
http://www.hcup-us.ahrq.gov/nisoverview.jsp. Retrieved
March 2, 2005.
7. Gyetvai D, Hannah ME, Hodnett ED, Ohlsson A. Tocolytics for preterm labor: a systematic review. Obstet
Gynecol 1999;94:869 –77.
8. Harger JH. Cerclage and cervical insufficiency: an evidence-based analysis. Obstet Gynecol 2002;100:1313–27.
9. Carey JC, Klebanoff MA, Hauth JC, Hillier SL, Thom EA,
Ernest JM, et al. Metronidazole to prevent preterm delivery in pregnant women with asymptomatic bacterial vaginosis. N Engl J Med 2000;342:534 – 40.
10. Klebanoff MA, Carey JC, Hauth JC, Hillier SL, Nugent
RP, Thom EA, et al. Failure of metronidazole to prevent
preterm delivery among pregnant women with asymptomatic Trichomonas vaginalis infection. N Engl J Med 2001;345:
487–93.
11. Creasy RK. Preterm birth prevention: where are we? Am J
Obstet Gynecol 1993;168:1223–30.
12. Rebar RW, Cedars MI. Hypergonadotropic forms of
amenorrhea in young women. Endocrinol Metab Clin
North Am 1992;21:173–91.
13. Stites DP, Siiteri PK. Steroids as immunosuppressants in
pregnancy. Immunol Rev 1983;75:117–38.
14. Siiteri PK, Seron-Ferre M. Some new thoughts on the
feto-placental unit and parturition in primates. In: Novy
MJ, Reskko JA, editors. Fetal endocrinology. New York
(NY): Academic Press; 1981. p. 1-34.
15. Garfield RE, Dannan MS, Daniel EE. Gap junction formation in myometrium: control by estrogens, progesterone,
and prostaglandins. Am J Physiol 1980;238:C81–9.
16. Challis JRG. Sharp increase in free circulating oestrogens
immediately before parturition in sheep. Nature 1971;229:
208.
17. Csapo AI. Progesterone block. Am J Anat 1956;98:
273–91.
18. Cousins LM, Hobel CJ, Chang RJ, Okada DM, Marshall
JR. Serum progesterone and estradiol-17b levels in premature and term labor. Am J Obstet Gynecol 1977;127:
612–5.
19. Johnson JWC, Lee PA, Zachary AS, Calhoun S, Migeon
CJ. High-risk prematurity–progestin treatment and steroid
studies. Obstet Gynecol 1979;54:412– 8.
20. Mitchell B , Cruickshank B , McLain, Challis J. Local
modulation of progesterone production in human fetal
membranes. J Clin Endocrinol Metab 1982;55:1237-9.
21. Romero R, Scoccia B, Mazor M, Wu YK, Benveniste R.
Evidence for a local change in the progesterone/estrogen
ratio in human parturition at term. Am J Obstet Gynecol
1988;159:657– 60.
1134
Meis
17 Hydroxyprogesterone
22. Frydman R, LeLaidier C, Baton-Saint-Mleux C, Fernandez H, Vial M, Bourget P. Labor induction in women at
term with mifepristone (RU 486): a double-blind, randomized, placebo-controlled study. Obstet Gynecol 1992;80:
972–5.
23. LeLaidier C, Baton C, Benifla JL, Fernandez H, Bourget P,
Frydman R. Mifepristone for labour induction after previous caesarean section. Br J Obstet Gynaecol 1994;101:
501–3.
24. Chwalisz K, Fahrenholz F, Hackenbery M, Hackenberg
M, Garfield R, Elger W. The progesterone antagonist
onapristone increases the effectiveness of oxytocin to produce delivery without changing the myometrial oxytocin
receptor concentrations. Am J Obstet Gynecol 1991;165:
1760 –70.
25. Johnson JWC, Austin KL, Jones GS, Davis GH, King TM.
Efficacy of 17alpha-hydroxyprogesterone caproate in the
prevention of premature labor. N Engl J Med 1975;293:
675– 80.
26. Goldstein P, Berrier J, Rosen S, Sacks HS, Chalmers TC.
A meta-analysis of randomized control trials of progestational agents in pregnancy. Br J Obstet Gynaecol 1989;96:
265–74.
27. Keirse MJNC. Progesterone administration in pregnancy
may prevent preterm delivery. Br J Obstet Gynaecol 1990;
97:149 –54.
28. Hartikainen-Sorri AL, Kauppila A, Tuimala R. Inefficacy
of 17 alpha hydroxyprogesterone caproate in the prevention of prematurity in twin pregnancy. Obstet Gynecol
1980;56:692–5.
29. Hauth JC, Gilstrap LC 3rd, Brekken AL, Hauth JM. The
effect of 17 alpha-hydroxyprogesterone caproate on pregnancy outcome in an active-duty military population. Am J
Obstet Gynecol 1983;146:187–90.
30. Tulchinsky D, Simmer H. Sources of plasma 17alphahydroxyprogesterone in human pregnancy. J Clin Endocrinol Metab 1972;35:799 – 808.
31. Kessler W, Borman A. Some biological activities of certain
progestogens.I. 17 alpha-hydroxyprogesterone 17-n-caproate.Ann N Y Acad Sci 1958;71:486 –93.
32. Johnstone EE, Franklin RR. Assay of progestins for fetal
virilizing properties using the mouse. Obstet Gynecol
1964;23:359 – 62.
33. Courtney KD, Valerio DA. Teratology in the Macaca
mulatta. Teratology 1968;1:163–72.
34. Carbone JP, Brent RL. Genital and nongenital teratogenesis of prenatal progesterone therapy: the effects of
17alpha-hydroxyprogesterone caproate on embryonic and
fetal development and endochondral ossification in the
C57B1/6L mouse. Am J Obstet Gynecol 1993;169:
1292– 8.
35. See miller RE, Nelson GW, Johnson CK. Evaluation of
teratogenic potential of Delalutin, (17 alpha-hydroxyprogesterone caproate) in mice. Teratology 1983;28:201– 8.
OBSTETRICS & GYNECOLOGY
36. Varma T, Morsman J. Evaluation of the use of ProlutonDepot (hydroxyprogesterone hexonate) in early pregnancy. Int J Gnyaecol Obstet 1982;20:13–7.
37. Michaelis J, Michaelis H, Gluck E, Keller S. Prospective
studies of suspected association between certain drugs
administered in early pregnancy and congenital malformations. Teratology 1983;27:57– 64.
38. Resseguie LJ, Hick JF, Bruen JA, Noller KL, O’Fallon
WM, Kurland LT. Congenital malformations among offspring exposed in utero to progestins, Olmstead County,
Minnesota 1936-1974. Fertil Steril 1985;43:514 –9.
39. Check JH, Rankin A, Teichman M. The risk of fetal
anomalies as a result of progesterone therapy during pregnancy. Fertil Steril 1986;45:575–7.
40. Katz Z, Lancet M, Skornik J, Chemke J, Mogilner BM,
Klinberg M. Teratogenicity of progestogens given during
the first trimester of pregnancy. Obstet Gynecol 1985;65:
775– 80.
41. Kester PA. Effects of prenatally administered 17 alphahydroxyprogesterone caproate in adolescent males. Arch
Sex Behav 1984;13:441–55.
42. Schardein JL. Congenital abnormalities and hormones
during pregnancy: a clinical review. Teratology 1980;22:
251–70.
43. Raman-Wilms L, Tseng AL, Wighardt S, Einarson TR,
Koren G. Fetal genital effects of first-trimester sex hormone exposure: a meta-analysis. Obstet Gynecol 1995;85:
141–9.
44. REPROTOX 1997 Healthcare Series. Vol 92. Greenwood Village (CO): Micromedex Inc; 1997.
45. LeVine L. Habitual abortion: a controlled clinical study of
pregestational therapy. West J Surg Obstet Gynecol 1964;
72:30 – 6.
46. Yemini M, Borenstein R, Dreazen E, Apelman Z, Mogilner BM, Kessler I, et al. Prevention of premature labor by
17 alpha-hydroxyprogesterone caproate. Am J Obstet
Gynecol 1985;151:574 –7.
47. Sherman AI. Hormonal therapy for control of the incompetent os of pregnancy. Obstet Gynecol 1966;28:198 –205.
VOL. 105, NO. 5, PART 1, MAY 2005
48. Elovitz M, Wang Z. Medroxyprogesterone acetate, but
not progesterone, protects against inflammation-induced
parturition and intrauterine fetal demise. Am J Obstet
Gynecol 2004;190:693–701.
49. Hobel CJ, Ross MG, Bemis RL, Bragonier JR, Nessim S,
Sandhu M, et al. The West Los Angeles Preterm Birth
Prevention Project. I. Program impact on high-risk
women. Am J Obstet Gynecol 1994;170:54 – 62.
50. Petrini JR, Callaghan WM, Klebanoff M, Green NS, Lackritz EM, Howse JL, et al. Estimated effect of 17 alphahydroxyprogesterone caproate on preterm birth in the
United States. Obstet Gynecol 2005;105:267–72.
51. Fuchs F, Stakemann G. Treatment of threatened premature labor with large doses of progesterone. Am J Obstet
Gynecol 1960;79:172– 6.
52. Kauppila A, Hartikainen-Sorri AL, Janne O, Tuimala R,
Jarvinen PA. Suppression of threatened premature labor
by administration of cortisol and 17 alpha-hydroxyprogesterone caproate: a comparison with ritodrine. Am J Obstet
Gynecol 1980;138:404 – 8.
53. Erny R, Pigne A, Prouvost C, Gamerre M, Malet C,
Serment H, et al. The effects of oral administration of
progesterone for premature labor. Am J Obstet Gynecol
1986;154:525–9.
54. Noblot G, Audra P, Dargent D, Faguer B, Mellier G, et al.
The use of micronized progesterone in the treatment of
menace of preterm delivery. Eur J Obstet Gynecol Reprod
Biol 1991;40:203–9.
55. Brenner WE, Hendricks CH. Effect of medroxyprogesterone acetate upon the duration and characteristics of
human gestation and labor. Am J Obstet Gynecol 1962;83:
1094 – 8.
Address reprint requests to: Paul J. Meis, MD , Department of
Obstetrics and Gynecology, Maternal–Fetal Medicine, Medical Center Boulevard, Winston-Salem, NC 27157; e-mail:
[email protected].
Received January 13, 2005. Received in revised form February 2, 2005.
Accepted February 10, 2005.
Meis
17 Hydroxyprogesterone
1135