Obstetrics and Gynecology

The Rebirth of Progesterone in the Prevention of Preterm

Labor
Vanessa M Schmouder, Gina M Prescott, Albert Franco, Patty Fan-Havard

reterm birth, defined as childbirth

occurring at <37 weeks gestational
OBJECTIVE: To evaluate data since 2003 on the efficacy and safety of progesterone
age, is the chief cause of neonatal morsupplementation in the prevention of preterm labor.
bidity and mortality in the US.1 The rate
DATA SOURCES: A MEDLINE and Ovid database search (January 2003of preterm delivery has increased by apSeptember 2012) was performed using the search terms preterm, progesterone,
and 17-hydroxyprogesterone caproate. All relevant abstracts were reviewed.
proximately 20% since 1997, representing
1
STUDY SELECTION: For efficacy and safety data, the search was limited to
12.8% of all live births in the US in 2007.
randomized, double-blind, placebo-controlled trials with the primary outcome of
In 2005, preterm birth was associated with
preterm delivery, fetal loss, or neonatal morbidity or mortality. Quality of the
a cost of approximately $26.2 billion.2 Alstudies was assessed using the CONSORT (Consolidated Standards of
though medical interventions have been
Reporting Trials) guidelines for reporting parallel-group randomized trials. Eleven
successful at improving neonatal outarticles were selected for review.
comes in premature infants, strategies to
DATA SYNTHESIS: Preterm birth, prior to 37 weeks gestation, remains the leading
prevent preterm birth, by preventing or
cause of neonatal morbidity and mortality in the US due to lack of treatment
options. Recently, the use of progesterone to prevent preterm labor, deemed
halting preterm labor, have been largely
decades ago to be ineffective, has been reexamined. Progesterone formulations
unsuccessful.3 Additionally, risk factors
and dosage regimens varied greatly between studies. In patients with prior preterm
for recurrent preterm birth, including pribirth or shortened cervix shown on transvaginal ultrasound, progesterone appears
or preterm birth, gestational age at prior
efficacious in reducing the rate of preterm birth. However, this benefit was not
preterm birth, African American race,
demonstrated in multiple-gestation pregnancies. Overall, progesterone was well
and short cervical length (<25 mm)
tolerated and appeared safe for mother and fetus. More studies are needed to
confirm the dosage regimen and population that will benefit most from progesterone.
shown on transvaginal ultrasound, are
CONCLUSIONS
: Progesterone appears to be safe and efficacious in reducing the
useful in identifying women at increased
risk
of
preterm
birth in a select group of high-risk women with prior spontaneous
risk, but are not useful for determining
preterm births and those with an ultrasound-confirmed short cervix. Women with
4,5
cause. These infants are at increased
multiple gestations do not benefit from progesterone supplementation.
risk for respiratory distress syndrome
Ann Pharmacother 2013;47:527-36.
(RDS), necrotizing enterocolitis, and
Published Online, 27 Mar 2013, theannals.com, doi: 10.1345/aph.1R281
retinopathy, and many have long-term
complications such as learning disabilities and cerebral palsy.3
taneous, which results in preterm labor or preterm rupture
Premature birth is classified as medically indicated, reof the membranes. Spontaneous preterm labor is attributed
sulting from a complication in the mother or fetus, or sponto pathologic changes in the normal parturition process.
This process includes cervical ripening, membrane rupAuthor information provided at end of text.
ture, and coordination of myometrial contractions, and is
primarily modulated through maturation of the fetal hy 1967-2013 Harvey Whitney Books Co. All rights reserved. No part
of this document may be reproduced or transmitted in any form or
pothalamus-pituitary axis.6 As pregnancy advances, rising
by any means without prior written permission of Harvey Whitney
levels of corticotrophin-releasing hormone stimulate inBooks Co. For reprints of any article appearing in The Annals,
creased fetal production of cortisol and dehydroepiandrosplease contact 415sales@hwbooks.com

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VM Schmouder et al.

terone.7 Cortisol stimulates the release of several contractionassociated proteins, including surfactant proteins, prostaglandins, and inflammatory cytokines.8 These mediators release
extracellular matrix-degrading proteases that weaken fetal
membranes and soften the cervix.9 Estrogen is formed
from dehydroepiandrosterone, where it also stimulates the
release of contraction-associated proteins and promotes
oxytocin receptor development and gap junction formation. Through increasing myocyte contractility and connectivity, these changes allow for coordinated uterine contraction.10,11
Any conditions that mimic or accelerate the typical parturition process can lead to preterm labor. Maternal stress
can increase cortisol levels, which inappropriately activates
the maternal-fetal hypothalamus-pituitary axis.6 Both infection and decidual hemorrhage can lead to increased production of inflammatory mediators, resulting in membrane
rupture and cervical degradation. Any condition that greatly stretches the uterus, including multifetal pregnancies,
can lead to increased myocyte contractility through gap
junction formation and prostaglandin synthesis.11
Given that the preparation for parturition begins weeks
before the onset of contractions, it is not surprising that
therapeutic strategies aimed at altering contraction frequency are ineffective. For example, tocolytic therapy (magnesium sulfate, nifedipine, and indomethacin), commonly
used for women in preterm labor, only slightly increases
the time to delivery and does not improve neonatal outcomes. Therefore, the need for a primary prevention strategy for women at increased risk of preterm labor is obvious.
Progesterone supplementation is the only therapy that has
shown promising results.
Progesterone is vital to the development and maintenance of pregnancy by antagonizing many of estrogens
proexcitatory actions. Progesterone prevents the production of many inflammatory mediators, thus inhibiting contraction-associated proteinmediated myometrial contraction and extracellular matrix-degrading protease-mediated
degradation of the cervix.6 Several decades ago, this knowledge provided the basis for numerous studies that tested
the hypothesis that progesterone supplementation would
prevent preterm birth in human pregnancy. Unfortunately,
not only were study results conflicting, but varied progesterone formulations, unclear study protocols, and lack of
safety data resulted in differing conclusions on progesterones effectiveness.12 Furthermore, progesterones
mechanism of action in human parturition was unclear.
The sharp decline in progesterone level that facilitates the
onset of parturition in other mammalian species could not
be demonstrated in humans. Additionally, serum progesterone concentration was not different between women
who delivered term versus preterm infants. Consequently,
progesterone was dismissed as an ineffective treatment for
many years.
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The Annals of Pharmacotherapy

Recently, the use of progesterone was reconsidered after

new insights offered potential explanations for these discrepancies. A theory known as functional progesterone
withdrawal attempted to explain how human pregnancy
may mimic progesterone withdrawal without producing
detectable differences in concentration. Changes in the
concentration, distribution, and isoform of nuclear progesterone receptors, alteration of progesterone receptor function by inflammatory mediators, and decrease in co-activators necessary for progesterone receptor function have all
been observed.13-15 Nongenomic actions of progesterone,
through membrane receptors, may also be possible.16,17 In
2003, the results of a multicenter randomized controlled
trial indicated that 17-hydroxyprogesterone caproate
(17P), a synthetic progesterone derivative of 17-hydroxyprogesterone, significantly increased gestational age and
decreased neonatal morbidity in women with a prior spontaneous preterm birth.18 This prompted the American
Board of Obstetrics and Gynecology to release a statement
recommending the use of 17P in women with singleton
pregnancies and a prior spontaneous preterm birth.19 These
findings set into motion several other randomized controlled trials, with hopes of pinpointing the population and
progesterone regimen best suitable for prophylaxis. On
February 6, 2011, hydroxyprogesterone caproate (Makena)
became the first Food and Drug Administration (FDA)-approved medication labeled to prevent preterm birth, which
caused controversy in the health care community. The cost
of $1500 per injection was significantly grater than the
$200-300 cost of hydroxyprogesterone caproate supplied
by compounding pharmacies.20 This controversy called
into question the economic utility of progesterone prophylaxis, the roles of pharmacists to prepare and administer
this medication, and how FDA approval may change prescribing practices and patient opinions.
This review assesses recent literature on the safety and
efficacy of progesterone supplementation in preventing
preterm labor and identifies what this means for management of preterm labor from a pharmacists perspective.
Study Selection

A MEDLINE and Ovid database search (January 2003September 2012) was performed using the key terms
preterm, progesterone, and 17-hydroxyprogesterone
caproate. All relevant abstracts were reviewed. For efficacy and safety data, the search was limited to randomized,
double-blind, placebo-controlled trials with the primary
outcome measures of preterm delivery, fetal loss, or neonatal morbidity or mortality. Our determination of the quality
of the studies was based on the CONSORT (Consolidated
Standards of Reporting Trials) guidelines for reporting parallel-group randomized trials.21,22 Citations were reviewed
for other pertinent trials. Thirteen articles were select-

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The Rebirth of Progesterone in the Prevention of Preterm Labor

ed.18,23-34 One trial was excluded because methods of blinding and randomization were not adequate31 and another because progesterone was being used for treatment, not prophylaxis.30 Eleven articles were included for analysis.

thetic progesterone.38,39 Although oral administration is associated with extensive first-pass metabolism, the micronized formulation improves absorption and bioavailability
that is similar to that of synthetic progestins.40,41 Vaginal administration provides greater endometrial concentrations of
progesterone than intramuscular administration, possibly because of direct transport of progesterone from the vagina to
the uterus.38 Of the studies using vaginal delivery, 3 used 90mg gel,26,33,34 1 used a 100-mg suppository,35 and 3 used capsules at a dose of 200 mg/day.29,32,33 Vaginal discomfort and
discharge were the most frequently occurring symptoms and
appeared at similar rates between the placebo and control
groups. Mean adherence rates ranged from 55% to 94% and
were also similar between the placebo and control groups.
The single study using oral micronized progesterone 100 mg
reported minimal adverse effects, including acne, esophageal
reflux, and somnolence.25 All adverse effects were similar between the placebo and control groups.

Progesterone Dosing Regimens

Progesterone is available in both natural and synthetic formulations and in various dosage forms. The specific formulation, dose, route, frequency, and duration of use used are
summarized in Table 1. Six studies used vaginal application
of natural progesterone,26,29,32-35 4 used 17P,18,24,27,28 and 1 used
oral micronized progesterone.25
Hydroxyprogesterone caproate is administered as an injection. When given intramuscularly, 17P can provide sustained systemic concentrations with an elimination half-life
of approximately 1 week,36,37 and thus provides the convenience of once-weekly dosing; however, it is associated with
mild injection site reactions and, rarely, anaphylaxis. In all
studies using 17P, it was consistently given at a dose of 250
mg intramuscularly at weekly intervals, and injections were
supplied by compounding pharmacies. Adverse reactions
were reported in 3 studies.18,27,28 The frequency of adverse reactions was high (50-69% for both the progesterone and
placebo groups in all studies), but consisted primarily of minor injection site reactions, including soreness, swelling,
bruising, and itching. Two trials reported significant adverse
events leading to discontinuation, including intense injection
site reactions in 4 women receiving 17P and 1 receiving
placebo.27,28 Adherence ranged from 91.5% to 98.5% and
was similar between the placebo and treatment groups.
Natural progesterone, available in both oral and vaginal
formulations, is identical to progesterone produced by the
body and is typically associated with fewer sedative and
hypnotic effects, presumably due to the metabolites of syn-

Reference

Progesterone

Delivery
Vehicle

17P

Castor oil

Combs (2010)24

17P

Castor oil

Caritis (2009)27

OBrien (2007)34

17P

Castor oil

17P

Rates of prematurity are summarized in Table 2. Discussion of premature delivery is divided by risk factor: prior
spontaneous preterm birth, multiple gestation, and short
cervix.
SINGLETON PREGNANCY WITH PRIOR SPONTANEOUS
PRETERM BIRTH

Four trials specifically addressed the efficacy of progesterone in women with a current singleton pregnancy and prior spontaneous preterm birth18,23,34,35; 2 of these trials indicated significant reductions in the rate of preterm birth.18,35
A large randomized, placebo-controlled, multicenter
study of 17P to determine rates of preterm delivery before

Table 1. Characteristics of Progesterone Agents

Meis (2003)18

Rouse (2007)28

Premature Delivery

Castor oil

Natural progesterone Gel

Dose
(mg)

Route

Frequency

Intramuscular Weekly

Prepared by pharmacy

Study site

250

Intramuscular Weekly

Prepared by pharmacy

At study site or by
partner at home

250
250
90

Intramuscular Weekly
Intramuscular Weekly
Vaginal

Twice daily

Rode (2011)32

Natural progesterone Gel

90

Natural progesterone Capsule

Natural progesterone Capsule

17P = 17-hydroxyprogesterone caproate.

theannals.com

90

100
200

Vaginal
Vaginal

Vaginal

Study site

Manufacturer (Crinone 8%) Self

Oral

Hassan (2011)33

Natural progesterone Gel

Vaginal

Study site

Daily

Rai (2009)25

200

Prepared by pharmacy

Manufacturer (Crinone 8%) Self

Nightly

Natural progesterone Capsule

Prepared by pharmacy

Daily

Vaginal

Norman (2009)26

Administration
Site

250

da Fonseca (2003)35 Natural progesterone Suppository 100

Fonseca (2007)29

Supplier

Daily

Manufacturer (Utrogestan)

Self

Self

Self

Every morning Manufacturer (Crinone 8%) Self

Daily

Manufacturer (Utrogestan)

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Vaginal progesterone
200-mg capsule

20-23 6/7

Triplet pregnancy

Triplet pregnancy

Twin pregnancy

Prior SPTB, singleton

pregnancy

Population

33 6/7, PROM, or
delivery

36 or delivery

36 6/7 WGA, rupture

of membranes, or
delivery

Delivery (10 weeks)

33 6/7

34

Twin pregnancy

Prior SPTB, singleton

pregnancy

Delivery <34 WGA

Mean prolongation of pregnancy

in weeks and days of gestation
(15.57 [7.38] vs 11.10 [7.01];
p < 0.001) risk of delivery at
various gestational ages

Short cervix, singleton Delivery < 33 WGA

pregnancy

Twin pregnancy

Delivery or fetal death <34 WGA

Delivery at <37 WGA

Delivery at 32 WGA

Delivery or
fetal death
<35

Delivery or
fetal death
<35

<37
<35
<32

<34

<28
28 to <32
32 to <34
34 to <37
Total

<33

Delivery or
fetal death
<34

<34

<37
<34

<37
<35
<32
<28

Intervention

Placebo

n = 334
51 (15.3)

n = 74
0
2 (2.7)
20 (27.0)
7 (9.5)
29 (39.2)

n = 235
21 (8.9)

n = 247
61 (24.7)

n = 125
24 (19.2)

n = 72
10 (13.8)
2 (2.8)

n = 309
129 (41.7)
70 (22.7)
31 (10)
10 (3.2)

n = 56
43 (76)
19 (34)
9 (16)

n = 71
59 (83)

n = 325
135 (41.5)

n = 310
111 (36.3)
63 (20.6)
35 (11.4)

n = 341
63 (18.5)

n = 74
3 (4)
15 (20.3)
19 (25.7)
7 (9.5)
44 (59.5)

n = 223
36 (16.1)

n = 247
48 (19.4)

n = 125
43 (34.4)

n = 70
20 (28.5)
13 (18.6)

n = 302
123 (40.7)
80 (26.5)
34 (11.3)
9 (3.0)

n = 25
13 (84)
13 (52)
2 (8)

n = 63
53 (84)

OR 0.8 (0.5-1.2)

RR 0.20 (0.05-0.73)
RR 0.86 (0.60-1.22)
RR 0.83 (0.48-1.45)

RR 0.55 (0.33-0.92)

OR 1.36 (0.89-2.09)

RR 0.56 (0.36-0.86)

OR 1.08 (0.76-1.52)
OR 0.9 (0.61-1.34)
OR 0.9 (0.52-1.56)
OR 1.07 (0.38-2.96)

RR 2.0 (0.5-8.6)
RR 0.7 (0.4-1.1)
RR 0.9 (0.7-1.1)

RR 1.0 (0.9-1.1)

RR 0.66 (0.54-0.81)
RR 0.67 (0.48-0.93)
RR 0.58 (0.37-0.91)

RR/OR
(95% CI)

n = 330
RR 1.1 (0.9-1.3)
123 (37.3)

n = 153
84 (54.9)
47 (30.7)
30 (19.6)

Preterm Deliveries, n (%)

WGA

Composite neonatal morbidity

(63/168 [38%] vs 31/75 [41%];
<35
OR 0.9 [95% CI 0.4-2.0]; p = 0.71) <32
<28

Delivery or fetal loss <35 WGA

Delivery or fetal death <35 WGA

Preterm delivery <37 WGA

Primary
Outcome

Short cervix, singleton Spontaneous delivery at <34 WGA

or twin pregnancy

High-risk for preterm

birth, singleton
pregnancy

37, PROM, or delivery Prior SPTB, singleton

pregnancy

34 or delivery

35 or delivery

35 or delivery

36 or delivery

Cessation
(WGA)

17P = 17-hydroxyprogesterone caproate; PROM = premature rupture of the membranes; SPTB = spontaneous preterm birth; WGA = weeks gestational age.

Rode
(2011)32

Rai (2009)25 Micronized proges18-24

terone capsule 100 mg
orally twice daily

20-23 6/7

24

Vaginal progesterone
gel 90 mg/day in
morning

Vaginal progesterone
gel 90 mg daily

Hassan
(2011)33

Norman
(2009)26

Vaginal micronized
24
progesterone capsule
200 mg daily

24

18-22 6/7

16-23 6/7

16-20 6/7

16-20 3/7

16-20 6/7

Initiation
(WGA)

Fonseca
(2007)29

da Fonseca Vaginal progesterone

(2003)35
suppository 100 mg
nightly

OBrien
(2007)34

Vaginal progesterone
gel 90 mg daily

17P 250 mg intramuscularly weekly

17P 250 mg intramuscularly weekly

Combs
(2010)24

Caritis
(2009)27

17P 250 mg intramuscularly weekly

17P 250 mg intramuscularly weekly

Progesterone

Rouse
(2007)28

Meis
(2003)18

Reference

Table 2. Characteristics and Outcomes of Selected Progesterone Trials

0.49
0.15
0.56

NA

<0.001
0.02
0.02

p Value

VM Schmouder et al.

theannals.com

37 weeks was conducted by the National Institute of Child

Health and Human Development Maternal-Fetal Medicine
Units Network.18 Women with a history of spontaneous
preterm delivery and current singleton pregnancy were eligible and were enrolled between 16 and 20 weeks gestational age. Women received intramuscular 17P 250 mg
weekly (n = 310) or placebo (n = 153) until 36 weeks gestational age. The primary outcome, delivery at <37 weeks,
was reduced from 54.9% in the placebo group to 36.3% in
the treatment group (RR 0.66; 95% CI 0.54-0.81). This reduction remained significant when data were analyzed at
gestational age of <35 and <32 weeks. Secondary safety
outcomes were also analyzed, and significant reductions in
neonatal morbidity, including necrotizing enterocolitis (RR
not reported), intraventricular hemorrhage (RR 0.25; 95%
CI 0.8-0.82), and need for supplemental oxygen (RR 0.62;
95% CI 0.42-0.92), were seen in the progesterone group.
Other neonatal outcomes, including mortality, trended toward improvement with 17P; however, the trial was not
adequately powered to detect such differences.
The sole study using oral micronized progesterone also
showed efficacy in this population.25 Women with a history
of at least 1 spontaneous preterm delivery and current singleton pregnancy were randomized to receive oral micronized progesterone 100-mg capsules twice daily (n =
75) or identical placebo (n = 75) from time of recruitment
(18-24 weeks gestational age) until delivery or 36 weeks
gestational age. The primary outcomes were mean prolongation of pregnancy and risk of delivery at various gestational ages. Overall, women in the treatment group experienced significantly lower rates of preterm delivery than
compared with women in the placebo group (29/74 vs
44/74, respectively; p = 0.002), corresponding to a mean
pregnancy prolongation [SD] of 15.57 [7.38] weeks in the
treatment group versus 11.10 [7.01] weeks in the control
group (p < 0.001). When broken down by delivery at gestational age, only births from 28 to 31 6/7 weeks gestational age remained significant (2/74 vs 17/74; p = 0.001). No
difference was seen from 32 to 33 6/7 or 34 to 36 6/7 weeks.
This may suggest efficacy of oral micronized progesterone
in preventing only very early preterm births or may be attributable to lack of power given the small sample size.
Secondary infant safety outcomes, including mean birth
weight, time in the neonatal intensive care unit (NICU),
and APGAR scores at 1 and 10 minutes, were significantly
improved in babies of women treated with progesterone (p
< 0.001 in all cases). This study argues for the ability of
oral micronized progesterone to prevent recurrent preterm
birth in singleton pregnancies, but small sample size, lack
of significant efficacy over 32 weeks gestational age, and
restriction to 1 hospital are noteworthy limitations.
In contrast to the efficacy seen with 17P and oral micronized progesterone, the largest trial using vaginal delivtheannals.com

The Rebirth of Progesterone in the Prevention of Preterm Labor

ery of progesterone found no significant difference in outcomes between treatment groups.34 Women with singleton
gestations and a history of spontaneous preterm birth were
enrolled between 18 and 22 6/7 weeks gestational age, randomized to receive progesterone vaginal gel 90 mg daily
(n = 309) or placebo (n = 302) until 37 weeks gestational
age, premature rupture of membranes, or delivery, whichever came first. The primary outcome of the study was delivery at 32 weeks gestational age or younger; no significant difference was found. Further analysis also revealed
no significant difference in delivery at gestational ages of
37, 35, and 28 weeks. Additionally, no significant differences in neonatal morbidity or mortality outcomes, including birth weight, RDS, necrotizing enterocolitis, or neonatal death, was observed between treatment groups.
Although lack of efficacy of vaginal administration of
progesterone is a potential reason for the efficacy discrepancies found between the aforementioned studies, other
studies using vaginal progesterone in different formulations have shown efficacy in other pregnancies at high risk
for preterm birth. One such study recruited women at increased risk for preterm delivery with singleton pregnancies, with the primary outcome of delivery at <37 weeks
gestational age.35 In this study, increased risk was defined
as prior spontaneous preterm birth, prophylactic cervical
cerclage, and uterine malformation. Women were randomized to receive a vaginal progesterone 100-mg suppository
(n = 72) inserted nightly or placebo (n = 70), from 24 to 34
weeks gestational age. Overall, incidence of preterm delivery was significantly lower in the progesterone group at
37 weeks (10/72 vs 20/70, p = 0.03).
The total weekly dose may also be of concern with the
largest vaginal progesterone study34; however, a previous
study using nearly the same dose has shown efficacy in
prevention of preterm labor, which may make this concern
less likely.35
Furthermore, in the study of vaginal progesterone that
lacked efficacy,34 women were excluded from randomization if they showed early-onset cervical shortening (cervical length 25 mm), a risk factor for preterm birth.23 Cervical shortening was not an exclusion criterion in the other
studies, and therefore may have been a possible reason for
the difference seen in effect. Overall, these results suggest
that the lack of progesterones efficacy may rely more on
risk factors for preterm birth than on progesterone formulation.
MULTIPLE GESTATIONS

Several multicenter trials have consistently shown that

progesterone has no efficacy in reducing the recurrence of
preterm birth in women with multiple gestations.24,26-28,32
Three large studies, 1 using 17P, 1 using progesterone gel,
and 1 using progesterone capsules, evaluated the use of

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progesterone in twin pregnancies. In a 14-center study

conducted by Rouse et al.,28 women with a twin pregnancy
between the gestational ages of 16 and 20 3/7 weeks were eligible for randomization. Six hundred sixty-one women were
randomized to receive intramuscular 17P 250 mg weekly (n
= 325) or placebo (n = 330) from randomization through
week 35 of gestation, delivery, or fetal death, whichever
came first. The primary study outcome, rate of fetal death or
delivery before 35 weeks gestational age, showed no significant difference between groups (17P 41.5% vs placebo
37.3%; RR 1.1; 95% CI 0.9-1.3). Additionally, rates of fetal
or neonatal death and other composite adverse neonatal outcomes were not significantly different between the groups
(17P 20.2% vs placebo 18%; RR 1.1; 95% CI 0.9-1.5). Although no benefit was seen, approximately 45% of the women were nulliparous, and less than 10% of women in the trial
had a history of spontaneous preterm birth, so it is uncertain
whether using 17P in these populations of women with current twin gestations would be beneficial.
In the STOPPIT trial (Study of Progesterone for the Prevention of Preterm Birth in Twins), women with a current
uncomplicated twin pregnancy were randomized to receive
progesterone gel 90 mg daily (n = 250) or placebo (n = 250)
at 24 weeks gestational age through delivery.26 The primary
outcome, delivery or fetal death before 34 weeks, was not
significantly different between groups (progesterone 61/247
vs placebo 48/247; OR 1.36, 95% CI 0.89-2.09; p = 0.16).
Although prevalence of cesarean section or operative vaginal delivery was lower in the progesterone group, no significant differences were observed in secondary maternal outcomes including gestational age at delivery, duration of labor, and safety outcomes. Secondary neonatal outcomes,
including neonatal unit admission and duration of neonatal
care, were also similar between groups.
The PREDICT (Prevention of preterm delivery in twin
gestations) trial also found no significant differences between progesterone and placebo.32 In this trial, women
with twin gestations were randomized to receive vaginal
progesterone 200-mg capsules (n = 334) or placebo (n =
343) daily between 20 and 23 6/7 until 33 6/7 weeks gestational age, premature rupture of membranes, or delivery.
The primary outcome was incidence of delivery at <34
weeks gestational age, and was not significantly different
between treatment groups (progesterone 51/334 vs placebo
63/341; OR 0.8, 95% CI 0.5-1.2). Additional outcomes, including mean birth weight, days of maternal hospitalization, and fetal or infant death, were also similar.
The 2 multicenter studies in triplet pregnancies, both using 17P, came to similar conclusions.24,27 Both trials recruited women with healthy triplet pregnancies confirmed by
ultrasound. Women were randomly assigned to receive intramuscular 17P 250 mg (n = 56,24 n = 7127) or placebo (n
= 25,24 n = 6327) between the gestational ages of 16 and 23
6 24
/7 and 16 and 20 6/7 weeks.24,27 17P supplementation was
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The Annals of Pharmacotherapy

given through 34 or 35 weeks gestation or delivery,

whichever came first. In both cases, gestational age at delivery was similar between treatment and placebo groups.
Interestingly, fetal loss was significantly higher (13/168 vs
0/75 fetuses; p < 0.05) for women receiving 17P in 1 trial,24 while a lower rate of fetal loss (1/71 vs 3/63 mothers),
although statistically insignificant, was observed in the other.27 Adverse neonatal outcomes, including neonatal death,
were not significantly different between treatment groups.
Given the small sample sizes used in these studies, adequate power to detect differences in neonatal outcomes
was likely not reached.
Although the reason for the lack of efficacy of progesterone in multiple gestations is unclear, 2 possible mechanisms have been proposed. One is that the dose of progesterone given in singleton pregnancies is insufficient in multiple gestations. In all cases of 17P, the 250-mg dose was
chosen based on its efficacy in singleton gestations. The
study using vaginal progesterone administered a 90-mg dose,
the low end of proven effective doses in singleton pregnancies. Women with twin or triplet pregnancies may have larger
volumes of distribution and, therefore, a higher dose of progesterone may be needed for effect. However, the only published study analyzing the pharmacokinetics of 17P in pregnancy found no association between 17P concentrations, fetal
number, and parity.36 Additionally, it is possible that a different mechanism of preterm labor prevails in multiple gestations versus singleton pregnancies. While a proposed mechanism of action of progesterone is suppression of the inflammatory mediators that signal myometrial contraction,42,43
another mechanism of myometrial contraction, myometrial
stretch, may be more likely to prevail in multiple gestations.44
If myometrial stretch is the factor most likely to induce labor
in women with multiple gestations, it is not surprising that
progesterone would be ineffective.
SHORT CERVIX

In addition to prior spontaneous preterm delivery and

multiple gestations, another established risk factor for
spontaneous preterm delivery is a shortened cervix as confirmed by transvaginal ultrasound.45,46
The efficacy of vaginal progesterone in this population
was evaluated in 2 large multicenter trials.29,33 In one study,
women with singleton or twin gestations with a cervical
length of 15 mm or less confirmed by ultrasonography between 20 and 25 weeks gestational age were eligible for
enrollment.29 Two hundred fifty women (226 singleton, 24
twin pregnancies) were randomized at 24 weeks gestational age to receive micronized progesterone 200-mg capsules (n = 125) or placebo (n = 125), and instructed to insert 1 capsule vaginally nightly until 34 weeks or delivery.
The primary study outcome, spontaneous birth before 34
weeks gestation, was 19.2% in the progesterone group

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versus 34.4% in the placebo group (24/125 vs 43/125; RR

0.56, 95% CI 0.36-0.86; p = 0.02). Interestingly, this difference remained significant for women without a history
of spontaneous preterm birth (p = 0.03). When results were
restricted to women with twin gestations, there was a nonsignificant reduction in preterm delivery, which corroborates other studies in multiple gestations. Secondary outcomes, including fetal and neonatal death, birth weight,
and composite adverse outcomes, were similar between
placebo and treatment groups.
These results are further substantiated by another multicenter trial of vaginal progesterone.33 Women with a current singleton pregnancy and short cervix (10-20 mm) at
19-23 6/7 weeks gestational age were eligible for enrollment, and received either micronized vaginal progesterone
gel 90 mg (n = 235) or placebo (n = 223) every morning
from 20 to 23 6/7 weeks gestational age until 37 weeks.
The primary outcome, preterm birth before 33 weeks ges-

Reference

Outcome

2/153 (1.3)

10/325 (3.1)

Caritis (2009)27

Neonatal mortality

5/212 (2)

Combs (2010)24

Neonatal mortality

OBrien (2007)34

Neonatal mortality

Fonseca (2007)29
Norman (2009)26
Hassan (2011)33

Rai (2009)25
Rode (2011)32
Not reported.

theannals.com

Perinatal mortality

Congenital malformationsa

Perinatal mortality

Congenital malformationsa

Perinatal mortality

Congenital malformations

Neonatal mortality

Table 3 summarizes the perinatal and neonatal mortality

and congenital malformation outcomes associated with
progesterone therapy. In one trial,18 a nonsignificant increase in fetal deaths observed (RR 1.5; 95% CI 0.31-7.34)

6/306 (2.0)

Neonatal mortality

Congenital malformations

INCREASED RISK OF PERINATAL/NEONATAL DEATH

Placebo, n (%)

Rouse (2007)28

Perinatal mortality

Safety

Treatment, n (%)

Neonatal mortality

Congenital malformations

tation, was 8.9% in the treatment group versus 16.1% in

the placebo group (21/235 vs 36/223; RR 0.55, 95% CI
0.33-0.92; p = 0.02) and remained significant when adjusted for covariates. The rate of preterm birth before 35 and
28 weeks was also significantly lower among women
treated with progesterone. Additionally, neonates of mothers treated with progesterone had significantly lower incidences of RDS (3% vs 7.6%; p = 0.04), any neonatal morbidity or mortality event (7.7% vs 13.5%; p = 0.04), and
birth weight <1500 g (6.4% vs 13.6%; p = 0.01).

Table 3. Select Safety Outcomes

Meis (2003)18

Perinatal mortality

The Rebirth of Progesterone in the Prevention of Preterm Labor

8/306 (2.6)

6/306 (2.0)

9/153 (5.9)

1/71 (1.4)

3/63 (4.8)

4/648 (0.6)

RR 2.2 (0.4-12.4)

6/155 (4)

2/75 (3)

OR 1.5 (0.3-8.1)

6/309 (1.9)

7/309 (2.3)

OR 0.87 (0.29-2.60)

7/125 (5.1)

RR 0.29 (0.06-1.42)

5/309 (1.6)

2/309 (0.6)

2/125 (1.5)

2/75 (3)

Fetal mortality

6/247 (2.4)

4/247 (1.6)

Congenital malformations
Neonatal death

Perinatal death

Fetal death

Congenital malformations
Neonatal mortality

Perinatal mortality

Congenital malformationsa
Neonatal mortality

Fetal mortality

Congenital malformations

3/235 (1.3)

6/247 (2.4)
5/223 (2.2)

11/223 (4.9)

3/74 (4.1)

7/74 (9.5)

5/235 (2.1)

9/664 (1.4)

2/334 (0.6)

25/663 (3.8)

RR 0.57 (0.14-2.35)

RR 0.69 (0.28-1.68)

6/223 (2.7)

RR 0.79 (0.25-2.57)

3/223 (1.3)

RR 0.32 (0.03-3.02)

8/678 (1.2)

0.05

0.13

0.98

0.52

0.431

0.413

0.700

0.29

0.190

OR 1.2 (0.3-4.0)

2/341 (0.6)

OR 1.0 (0.1-7.3)

27/677 (4.0)

The Annals of Pharmacotherapy

0.66

0.59

8/235 (3.4)

1/235 (0.43)

OR 1.22 (0.33-4.61)

2/302 (0.6)

1/125 (0.7)

8/247 (3.2)

OR 4.7 (1.0-22.0)

4/302 (1.3)

1/125 (0.7)

Neonatal mortality

RR 0.5 (0.1-2.4)

2/183 (1)

19/168 (11)

p Value

RR 1.50 (0.31-7.34)

8/330 (2.4)

10/330 (3.0)

Fetal mortality

Congenital malformationsa

RR 0.44 (0.17-1.13)

3/153 (2.0)

16/632 (2.5)

3/632 (0.5)

RR/OR (95% CI)

OR 1.0 (0.5-1.7)

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VM Schmouder et al.

led the FDA to raise concern about the potential of increased

fetal mortality with the use of 17P19; the package insert for
Makena mentions the increased miscarriage and stillbirth associated with the clinical trial.37 Fetal and neonatal mortality
data for analyzed studies are listed in Table 3, and results are
inconclusive. Overall, only 1 study had a significantly higher
incidence in mortality with progesterone versus placebo
(perinatal mortality 11% with progesterone vs 3% with placebo; OR 4.7 [95% CI 1.0-22.0]; p = 0.05).24 Although this
raises potential concern, this study involved triplet pregnancies, which, as mentioned previously, do not seem to benefit
from progesterone therapy. Furthermore, overall pregnancy
loss (9% with 17P vs 0% with placebo) is close to that expected in triplet pregnancies.
A recent meta-analysis with data pooled from 16 randomized controlled trials studied adverse outcomes in patients administered progesterone.47 The primary outcome of
this study was the rate of neonatal mortality, with secondary
outcomes including perinatal complications (RDS, grade 3-4
intraventricular hemorrhage, sepsis, necrotizing enterocolitis,
and retinopathy). Progesterone administration was associated
with a significant decrease in the composite adverse outcome
(RR 0.576 [95% CI 0.373-0.891]), neonatal death (RR 0.487
[95% CI 0.290-0.818]), RDS (RR 0.677 [95% CI 0.4900.935]), and NICU admission (RR 0.410 [95% CI 0.2040.823]) in at-risk singleton pregnancies (n = 7). No significant differences were found with the other outcomes. However, in the twin pregnancies (n = 7), a significant increase in
the rate of the composite adverse outcome (RR 1.211 [95%
CI 1.029-1.425]), perinatal death (RR 1.551 [95% CI 1.0142.372]), and RDS (RR 1.218 [95% CI 1.038-1.428]) was
found. The triplet pregnancies (n = 2) did not show any significant differences.
With the conflicting data thus far, it is likely that if an
association exists between progesterone supplementation
and increased fetal/neonatal mortality, it is minimal. However, the possibility illustrates the importance of identifying the patient population in which the risks of treatment
outweigh the benefits.
CONGENITAL DEFECTS

In addition to mortality, concerns with congenital defects have been a historical fear with the use of synthetic
progestational agents. Six of the studies analyzed congenital defects (Table 3).
Earlier studies, some of which used high doses during the
first trimester, implicated that progesterone supplementation
during pregnancy may cause masculinization of female genitalia48-50; however, this association has since been discredited.51-53 Of the trials that mention congenital malformations,
no significant difference between occurrences was noted in
treatment and placebo groups. Additionally, in a long-term
follow up to the initial NICHD (National Institute of Child
534

The Annals of Pharmacotherapy

Health and Human Development) trial, 278 (194 in the 17P

group and 84 in the placebo group) of the original 429 discharged infants were located and enrolled between the ages
of 30 and 64 months. No significant differences were reported in health or physical examination status, gender-specific
roles, or incidence of congenital or genital malformations.54

Summary

Given the wide variety of treatment regimens found in

the current literature, the importance of the route of administration, dose, and duration of progesterone therapy on
safety and efficacy has not been fully delineated. Specifically, important questions include the proper selection of
candidates and the appropriate timeframe to begin progesterone supplementation. Progesterone seems to reduce the
risk of preterm birth in a select group of high-risk women;
in particular, those with prior spontaneous preterm birth
and those with an ultrasound-confirmed short cervix. For
women with a prior spontaneous preterm birth, intramuscular 17P 250 mg weekly is safe and efficacious in women
with a current singleton pregnancy when initiated between
16 and 20 6/7 weeks and continued until 36 weeks or delivery. At this time, data on the use of vaginal progesterone
are conflicting23 and not supported by the largest clinical
trial in this population.34 Only one small trial is available to
support the use of oral micronized progesterone.25 In women with an ultrasound-confirmed short cervix with or without a prior spontaneous preterm delivery, micronized progesterone 200-mg capsules inserted vaginally daily, from
24 weeks until 34 weeks or delivery, appears to be safe and
efficacious.29 At this time, the use of progesterone in multiple gestations is not supported by clinical evidence.24,28,36,40
More clinical trials are needed to identify the best progesterone regimen, women who will benefit most from prophylactic progesterone administration, and the impact of progesterone on improving neonatal morbidity and mortality.
Vanessa M Schmouder, PharmD Student, School of Pharmacy
and Pharmaceutical Sciences, University at Buffalo, Amherst, NY

Gina M Prescott PharmD, Clinical Assistant Professor, Depart-

ment of Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo
Albert Franco MD, Associate Professor, Department of Obstetrics
and Gynecology, Division of Maternal-Fetal Medicine, Carolinas
Healthcare System, Charlotte, NC; Assistant Clinical Professor,
School of Medicine, University of North Carolina, Chapel Hill
Patty Fan-Havard PharmD, Interim Associate Dean, Associate
Professor, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo; Associate Professor, Department of Obstetrics
and Gynecology, Division of Maternal-Fetal Medicine, College of
Medicine, The Ohio State University, Columbus
Correspondence: Dr. Fan-Havard, pfhavard@buffalo.edu
Reprints/Online Access: www.theannals.com/cgi/reprint/aph.1R281

Conflict of interest: Authors reported none

1967-2013 Harvey Whitney Books Co. All rights reserved. No part

of this document may be reproduced or transmitted in any form or
by any means without prior written permission of Harvey Whitney

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reduce neonatal morbidity or prolong triplet pregnancy: a double-blind, randomized clinical trial. Am J Obstet Gynecol 2010;203:248.e1-9.
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the rate of preterm birth in women with a sonographic short cervix: a
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34. OBrien JM, Adair CD, Lewis DF, et al. Progesterone vaginal gel for the
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35. da Fonseca EB, Bitter RE, Carvalho MH, et al. Prophylactic administration
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42. Facchinetti F, Dante G, Venturini P, et al. 17alpha-hydroxy-progesterone
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EXTRACTO

El Resurgimiento de Progesterona en la Prevencin del Parto

Prematuro
VM Schmouder, GM Prescott, A Franco, P Fan-Havard
Ann Pharmacother 2013;47:527-36.

El objetivo de este repaso es evaluar los datos desde 2003 en

la eficacia y seguridad de la suplementacin de progesterona en la
prevencin de parto prematuro.
FUENTES DE DATOS: Una bsqueda en las fuentes de datos MEDLINE y
Ovid fue llevada a cabo para las fechas de enero de 2003 hasta
septiembre de 2012, usando los trminos prematuro, progesterona, y
caproato de 17-hidroxiprogesterona. Todos los extractos fueron
revisados.
SELECCIN DE ESTUDIOS: Para datos de eficacia y seguridad, la bsqueda
fue limitada a ensayos aleatorios, doble ciegos, controlados por placebo
con el resultado primario de parto prematuro, prdida fetal o morbilidad
o mortalidad neonatal. La calidad de los estudios fue avaluada usando
las guas CONSORT para reportar ensayos aleatorios en grupos
paralelos. Once artculos fueron seleccionados para este repaso.
OBJETIVO:

536

The Annals of Pharmacotherapy

Nacimiento prematuro, antes de las 37 semanas de

gestacin, es la causa principal de morbilidad y mortalidad neonatal en
los Estados Unidos por la falta de opciones de tratamiento. Recientemente,
el uso de progesterona para prevenir parto prematuro, considerado
inefectivo hace dcadas, ha vuelto a resurgir. Las formulaciones de
progesterona y los regmenes de dosificacin varan grandemente entre
estudios. En pacientes con partos prematuros anteriores o con crvix
acortada confirmada en ultrasonido tras-vaginal, la progesterona
aparenta ser efectiva en reducir la tasa de nacimiento prematuro. Sin
embargo, este beneficio no ha sido demostrado en embarazos mltiples.
En general, progesterona, fue bien tolerada y parece ser segura para
ambos, la madre y el feto. Ms estudios son necesarios para confirmar el
rgimen de dosificacin especfico y la poblacin de pacientes que se
beneficiar ms con la progesterona.
CONCLUSIONES: Progesterona aparenta ser segura y eficaz en reducir el
riesgo de nacimiento prematuro en un grupo selecto de mujeres con
riesgo alto con nacimientos prematuros espontneos anteriores y
aquellas con crvix acortada confirmada por ultrasonido. Las mujeres
con embarazos mltiples no se benefician de suplementacin con
progesterona.
SNTESIS DE DATOS:

RSUM

Traducido por Sonia I Lugo

La Progestrone pour Prvenir le Travail Prmatur

VM Schmouder, GM Prescott, A Franco, P Fan-Havard

Ann Pharmacother 2013;47:527-36.

valuer la documentation scientifique quant lefficacit et

linnocuit de progestrone pour la prvention du travail prmatur.
SOURCES DINFORMATION: Une recherche de littrature a t effectue
dans les banques de donnes MEDLINE et Ovid jusquau mois de
septiembre 2012 en utilisant les mots-cls suivants: prmatur,
progestrone, caproate de 17-alpha-hydroxyprogestrone. Tous les
abrgs scientifiques pertinents ont t inclus pour une valuation.
SELECTION DE LINFORMATION ET EXTRACTION DES DONNES: Linclusion
des articles pour cette revue sest limite aux essais cliniques mens en
double-aveugle, avec une rpartition alatoire et un contrle avec un
groupe placebo et ayant valu, comme paramtre principal defficacit,
le taux daccouchement avant terme, davortement spontan, de
morbidit et de mortalit nonatale. La qualit des tudes a t value
selon les lignes tablies par CONSORT. Onze tudes ont t values
pour cette revue.
RESULTATS: La prmaturit (tel que dfinie par une naissance avant la
37ime semaine de gestation) demeure la cause la plus frquente de
morbidit et de mortalit nonatale aux Etats-Unis, tant donn le
nombre limit doptions thrapeutiques. Le rle de la progestrone pour
retarder laccouchement avant terme a rcemment t revu aprs avoir
t juge dune faible efficacit durant des dcennies. Chez les patientes
ayant une histoire de travail prmatur ou un col raccourci confirm par
une chographie transutrine, la progestrone semble efficace rduire
le taux de prmaturit. Cependant, ce bnfice na pas t dmontr chez
les femmes ayant eu des grossesses multiples. De faon gnrale, la
progestrone semble bien tolre et scuritaire pour la mre ainsi que le
nouveau-n. Des tudes additionnelles sont requises afin de confirmer
les rgimes posologiques optimaux et les populations de patientes
pouvant bnficier le plus de la progestrone.
CONCLUSIONS: La progestrone semble tre efficace et scuritaire pour
retarder laccouchement chez des patientes prsentant un haut risque de
travail prmatur. Les femmes ayant eu des grossesses multiples ne
semblent toutefois pas bnficier dun apport additionnel de
progestrone.
OBJECTIF:

2013 April, Volume 47

Downloaded from aop.sagepub.com at UNIV OF MISSISSIPPI MEDICAL CENTER on November 11, 2016

Traduit par Sylvie Robert

theannals.com