Acta Obstetricia et Gynecologica.

2009; 88: 1180–1189

ACTA REVIEW

Systematic review of progesterone for the prevention of preterm birth

in singleton pregnancies

LINE RODE1, JENS LANGHOFF-ROOS5, CHARLOTTE ANDERSSON2, JAKOB DINESEN3,

Acta Obstet Gynecol Scand Downloaded from informahealthcare.com by Brown University Library on 05/17/12

METTE SCHOU HAMMERUM4, HANNE MOHAPELOA6 & ANN TABOR1,7

1
Department of Fetal Medicine and Ultrasound, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark,
2
Department of Obstetrics and Gynecology, Aalborg Hospital, Aalborg, Denmark, 3Department of Obstetrics and
Gynecology, Herning Hospital, Herning, Denmark, 4Department of Obstetrics and Gynecology, Hilleroed Hospital,
Hilleroed, Denmark, 5Department of Obstetrics and Gynecology, Rigshospitalet, Copenhagen University Hospital,
Copenhagen, Denmark, 6Department of Obstetrics and Gynecology, Vendsyssel Hospital, Hjørring, Denmark, and
7
Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark

Abstract
For personal use only.

Background. A Cochrane review in 2006 concluded that further knowledge is required before recommendation can be made
with regard to progesterone in the prevention of preterm birth. Objective. To provide an update on the preventive effect of
progesterone on preterm birth in singleton pregnancies. Search strategy. A search in the PubMed, Embase, and Cochrane
database was performed using the keywords: pregnancy, progesterone, preterm birth/preterm delivery, preterm labor,
controlled trial, and randomized controlled trial. Selection criteria. Studies on singleton pregnancies. Data collection and
analysis. A meta-analysis was performed on randomized trials including singleton pregnancies with previous preterm birth.
Main results. Two new randomized controlled trials of women with previous preterm birth were added to the four analyzed in
the Cochrane review, and the meta-analysis of all six studies now showed that progesterone supplementation was associated
with a significant reduction of delivery before 32 weeks and of perinatal mortality. Furthermore, a third trial showed a positive
effect on women with a short cervix at 23 weeks, and a fourth study showed that progesterone reduces the risk of preterm
delivery in women with preterm labor. Conclusions. In women with a singleton pregnancy and previous preterm delivery,
progesterone reduces the rates of preterm delivery before 32 weeks, perinatal death, as well as respiratory distress syndrome
and necrotizing enterocolitis in the newborn. Women with a short cervix or preterm labor may also benefit from progesterone,
but further evidence is needed to support such a recommendation. Follow-up studies should focus on possible metabolic
complications in the mother or the offspring.

Key words: Progesterone, preterm birth, singletons, high-risk pregnancies

Introduction of prematurity, intraventricular hemorrhage, necro-

Despite improvements in standard of living and
progress in medical science, preterm birth still repre-
sents an obstetrical challenge worldwide. Neonatal
survival as well as both short-term and longer-term
morbidity is directly related to gestational age at
birth. The most severe sequelae are related to very
preterm delivery before 32 weeks of gestation. In the
neonatal period, these sequelae include retinopathy
tizing enterocolitis, bronchopulmonary dysplasia,
sepsis, and cerebral palsy (1,2). In later life, abnor-
malities of neuromotor function and mental devel-
opment are more frequent in preterm than in term
children, and preterm children have a greater risk of
underachieving educationally (3,4).
The incidence of preterm birth has been rising
during the last decades in most countries (5). In
Denmark, the incidence of delivery of singleton

Correspondence: Line Rode, Department of Fetal Medicine and Ultrasound 4002, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK-2100
Copenhagen, Denmark. E-mail: linoodo@dadlnot.dk

(Received 05 June 2009; accepted 07 August 2009)

ISSN 0001-6349 print/ISSN 1600-0412 online
2009 Informa UK Ltd. (Informa Healthcare, Taylor & Francis AS)
DOI: 10.3109/00016340903280982

infants before 32 weeks of gestation has risen from
0.73% in 1997 to 1.00% in 2007 (an increase of 37%)
(Danish National Board of Health). Approximately
one-third of preterm births are indicated and
associated with pregnancy complications such as
intrauterine growth retardation, preeclampsia, and
placental abruption. The remaining two-thirds are
spontaneous. Spontaneous preterm birth may be
caused by maternal or fetal stress, inflammation,
decidual hemorrhage, or excessive distension of the
uterus (e.g. polyhydramnios, multiple gestation), and
cervical shortening precedes many cases. The two
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major risk factors for preterm birth are previous pre-
term birth and cervical shortening in the second
trimester (6,7).
Since 1989, several meta-analyses on prevention of
preterm birth through progesterone therapy have
been published (8–14), including a review from
the Cochrane Collaboration published in 2006. The
Cochrane review (14) included six trials with varying
gestational age and with participation of a total of
988 women. The study populations were character-
ized by pregnant women believed to be at increased
risk of preterm birth, which in four studies was
For personal use only.
defined as one or more previous preterm deliveries.
A reduction in the risk of preterm birth <37 weeks
was reported (relative risk (RR) = 0.65, 95% CI
(confidence interval): 0.54–0.79) and also preterm
birth <34 weeks (RR = 0.15, 95% CI: 0.04–0.64).
Furthermore, children born by mothers treated with
progesterone were less likely to have birth weight
<2,500 g (RR = 0.63, 95% CI: 0.49–0.81) and
intraventricular hemorrhage (RR = 0.25, 95% CI:
0.08–0.82). Reported outcomes in the six included
studies varied, and the clinically important outcomes
in the Cochrane review were based mainly on two
newer studies from 2003, by Meis et al. (15) and
da Fonseca et al. (16), The first included 463 women
randomized to either weekly injections of intramus-
cular 17-a-hydroxyprogesterone or placebo, while
the latter included 157 women randomized to daily
application of either a vaginal pessary of proges-
terone or placebo. Only Meis et al. reported on neo-
natal outcomes. As these results were based on a
limited number of studies, no reduction in infant
mortality was found and there was little information
about the safety of progesterone use during preg-
nancy. This led the authors to conclude, ‘further
knowledge is required before recommendations can
be made with regard to progesterone in the prevention
of preterm birth’.
Cervical ripening and increased myometrial
responsiveness to stimuli precede the onset of labor.
The mechanisms that initiate labor are still not fully
elucidated, but it is widely accepted that the hormone
Prevention of preterm birth by progesterone 1181
progesterone plays an essential role in both fertili-
zation, maintenance of pregnancy, and onset of
parturition (17–20).
In humans, progesterone is initially produced by
the corpus luteum and from 7–8 weeks of gestation,
increasingly by the placenta (21,22). At term, the
placenta produces approximately 250–300 mg pro-
gesterone per day in a singleton pregnancy (18). In
1970, Papiernik-Berkhauer was the first to describe
the use of progesterone for prevention of preterm
birth in humans (23).
Progesterone seems to have three different modes
of action:
(1) Earlier studies have shown that inhibition of
the production/effect of progesterone will induce
parturition in mammals, including humans.
Progesterone withdrawal precedes parturition
in mammals, except old-world monkeys and
humans. A functional progesterone withdrawal
has been suggested to be essential in humans,
i.e. on the receptor level as an increase in the
ratio between the progesterone receptor A and
progesterone receptor B and a changed metab-
olism of progesterone (17,19,20).
(2) Maternal levels of placental corticotrophin-
releasing hormone (CRH) increase with gesta-
tional age and peak at delivery. The rise in
placental CRH levels is more rapid in women
who deliver preterm compared to women who
deliver at term. Progesterone has an inhibi-
tory effect on placental CRH production (19).
Hence, progesterone treatment may prevent pre-
term birth by resulting in a lower placental CRH
production (7).
(3) Labor is preceded by maturation of the cervix
through up-regulation of interleukins and
increased prostaglandin synthesis. A study
showed that progesterone attenuated these
effects, indicating an anti-inflammatory effect.
This observation has been documented in pre-
labor cells only – not in post labor cells in the
cervix – probably as a result of downregulation of
the progesterone receptors during labor (24).
A recent in vitro study on human myometrium
obtained at prelabor cesarean section showed that
progesterone – but not 17-a-hydroxyprogesterone –
inhibited spontaneous myometrial activity by
non-genomic mechanisms (25). The fact that 17-a-
hydroxyprogesterone in this study failed to inhibit
myometrial activity does not necessarily mean that
it is not effective during labor or as an inhibitor of
cervical ripening.
No studies have shown teratogenic effects of
treatment with progesterone (26–29). In one paper,
 1182 L. Rode et al.
the safety of 17-a-hydroxyprogesterone caproate was
questioned, mainly based on literature from animal
studies (26). The general side effects from progester-
one treatment are headache, nausea, coughing, local
irritation, and breast tension.
Progesterone may be administered orally, intra-
muscularly, or vaginally. Vaginal progesterone of pes-
saries or gel is administered once daily. This may be
associated with increased vaginal flux, but systemic
side effects are rare. Intramuscular injection has been
given daily, three times/week, and weekly, and is
associated with local pain from the injection site as
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the main side effect. Oral doses are given daily, often
in large amounts because of the first-pass metabolism,
poor absorption, and short biologic half-life. Oral
administration may increase the risk of intrahepatic
cholestasis (29–32).
The aim of this systematic review is to update
evidence-based knowledge on the effect of progester-
one for the prevention of preterm delivery or treat-
ment of preterm labor in singleton pregnancies.
Material and methods
For personal use only.
We performed a systematic search in the PubMed,
Embase, and Cochrane database to identify all
publications from randomized controlled trials on
the effect of progesterone for prevention of preterm
birth in non-symptomatic women as well as women
with preterm labor. The search was performed
24 July 2009, and we used the following key words:
progesterone, pregnancy, preterm birth, preterm
delivery, preterm labor, controlled trial, and ran-
domized controlled trial, and did not apply any lan-
guage restriction in the searches. We included studies
using intramuscular, vaginal, or oral progesterone
starting treatment during the second trimester of
pregnancy in singleton pregnancies. We performed
a manual search of the reference lists of all papers
found in the PubMed, Embase, and Cochrane data-
base and also searched www.clinicaltrials.gov and
www.controlled-trials.com in order to identify ongoing
trials. Table I shows the main characteristics of four
new studies published in 2007 and 2008 and, hence,
not included in the most recent Cochrane review.
Statistical methods
We used the computer program Review Manager
(Version 4.2 for Windows. Copenhagen: Nordic
Cochrane Centre, Cochrane Collaboration, 2003) to
perform meta-analyses on all trials comparing pro-
gesterone with placebo treatment in women with
singleton pregnancies and previous preterm birth.
Results are reported as RRs with the corresponding
95% CIs using the fixed effect model. Risk differences
are reported as the risk in the placebo groups minus
the risk in the progesterone groups.
Results
Previous preterm birth
In 2007, a large multicenter trial by O’Brien et al. (33)
was published. A total of 659 pregnant women with a
history of preterm birth were randomized to either
daily treatment with progesterone vaginal gel or
placebo. Both maternal and neonatal outcomes
were reported (Table I). In this study, there were
no differences between groups as regards gestational
age at delivery and, not surprisingly, no differences in
neonatal outcomes. In contrast to the previous stud-
ies, women in this study had a transvaginal scan to
determine cervical length before inclusion. Women
who were selected for cervical cerclage by their obste-
trician were excluded. This may explain why the
number of women with cervical length less than
25 mm in this study population was lower (4%)
than expected (10% in a low risk population (34)).
The exclusion of a group of women at especially high
risk from the study population may also partly explain
why the results of this study differed from other large
trials. A separate study of the subgroup of women with
a short cervix has been published (35).
In the newest study from 2008 (36), 150 women
with a history of a singleton delivery between 20 and
36 weeks + 6 days were randomized to oral micron-
ized progesterone (100 mg) or placebo, beginning
treatment from 18 to 24 weeks of gestation. The study
showed a positive effect of progesterone on the risk of
birth before 37 weeks (39% in the progesterone group
vs. 59% in the placebo group). The main effect was
found before 32 weeks as 2/74 women (2.7%) deliv-
ered before 32 weeks in the progesterone group com-
pared to 18/74 (24.3%) in the placebo group. It was
not possible to show a statistically significant reduc-
tion in neonatal mortality.
Table II shows the outcomes from all trials to date
comparing progesterone with placebo treatment in
women with singleton pregnancies and previous pre-
term birth. The meta-analysis shows that treatment
with progesterone reduces the risk of preterm birth
before 37, 35, and 32 weeks of gestation, and reduces
the rate of children with birth weight < 2,500g. Neo-
natal mortality was reduced with a RR of 0.54 (95%
CI 0.31–0.93). Furthermore, a risk reduction of nec-
rotizing enterocolitis and respiratory distress syn-
drome was found.
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Table I. Main characteristics of the four new randomized trials published in 2007 and 2008.
Population
O’Brien et al. (33) Women with a history of
prior spontaneous singleton
preterm birth at between
20 + 0 and 35 + 0 weeks
Rai et al. (36) Women with at least one
previous spontaneous
singleton delivery between
20 and 36 weeks plus 6 days
Fonseca et al. (34) Women with a cervical
length of <16 mm at 20–25
weeks’ gestation
Facchinetti et al. (38) Women admitted for
threatened preterm labor
between 25 and 33 + 6 days
of gestation
For personal use only.
No of participants
Progesterone Placebo Progesterone treatment
332 327 Vaginal gel (micronized
progesterone), 90 mg per day
From 16 + 0 to 22 + 6 weeks’
gestation until 37 + 0 weeks’
gestation
75 75 Oral capsules (micronized
progesterone), 100 mg per day
From 18 to 24 weeks’ gestation
until 36 weeks’ gestation
125 125 Vaginal pessaries (micronized
progesterone), 200 mg per day
From 24 weeks’ gestation until
33 + 6 weeks’ gestation
30 30 Intramuscular injections
(17-a-hydroxyprogesterone
caproate), 341 mg every 4 days
Primary outcome
Delivery before 32 completed
weeks
Mean prolongation of
pregnancy in weeks and days
of gestation and the risk of
delivery <28, 28–31, 32–33,
34–36 and ‡37 weeks
Spontaneous delivery before
34 completed weeks
Change in cervical length
Secondary outcomes
Neonatal morbidity during
initial hospitalization
Preterm birth at £28, £35 and
£37 weeks
Hospital admission for
preterm labor
Neonatal hospital days
Interval to delivery from
tocolysis
Change in cervical length
Neonatal outcome
Response to tocolytics
Inhibition of preterm labor
Adverse effects
Drug toxicity
Birth weight
Fetal/neonatal death
Major adverse outcomes
before discharge from
hospital
Need for neonatal special care
Gestational age at parturition
Birth weight
Prevention of preterm birth by progesterone
1183
 1184 L. Rode et al.

Table II. Meta-analysis of the outcomes from trials comparing progesterone with placebo treatment in women with singleton pregnancies and
previous preterm birth.

Outcome References No. of Relative risk Risk difference: Numbers needed

participants (95% CI) placebo–progesterone to treat
(95% CI) (95% CI)

Birth < 37 weeks’ gestation (15,16,23,33,37) 1,354 0.77 (0.67–0.87) 0.10 (0.06–0.15) 10 (6–16)
Birth < 35 weeks’ gestation (15,33) 1,070 0.77 (0.63–0.96) 0.06 (0.01–0.12) 17 (9–100)
Birth < 32 weeks’ gestation (15,33,36) 1,218 0.61 (0.45–0.82) 0.06 (0.02–0.10) 16 (10–50)
Admission for preterm labor (15,16,33) 1,211 0.99 (0.79–1.23) 0.00 (–0.04 to 0.05) Not estimable
Antenatal corticosteroid therapy (15,33) 1,055 0.93 (0.74–1.18) 0.01 (–0.04 to 0.07) Not estimable
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Tocolytic therapy (15,33,36,37) 1,260 1.02 (0.78–1.35) 0.00 (–0.04 to 0.04) Not estimable
Perinatal/neonatal death (15,23,33,36,37) 1,358 0.54 (0.31–0.93) 0.02 (0.00–0.05) Not estimable*
Birth weight < 2,500 g (15,23,37) 595 0.62 (0.48–0.80) 0.14 (0.07–0.22) 7 (5–13)
Respiratory distress syndrome (15,33) 1,068 0.75 (0.57–0.99) 0.05 (0.00–0.09) Not estimable*
Intraventricular hemorrhage (15,33) 1,069 0.55 (0.25–1.19) 0.01 (–0.01 to 0.03) Not estimable
Necrotizing enterocolitis (15,33) 1,068 0.30 (0.10–0.93) 0.01 (0.00–0.03) Not estimable*
Spontaneous abortion or (15,33,37) 1,114 0.85 (0.35–2.03) 0.00 (–0.01 to 0.02) Not estimable
intrauterine fetal death

*Not possible to estimate numbers needed to treat due to a lower limit of the 95% CI for the risk difference of 0%.
Note: CI, confidence interval.
For personal use only.

The risk differences (which equals the absolute risk
reduction) for preterm delivery between the placebo
and progesterone groups with the corresponding
95% CIs, as well as the estimated numbers needed
to treat (NNT) in order to prevent one event, are also
shown in Table II. The risk difference for delivery
before 32 weeks is 6%, which corresponds to an
NNT of 16 (95% CI 10–50) singleton pregnancies
with previous preterm birth in order to prevent one
delivery < 32 weeks. Calculations based on the five
studies on women with previous preterm birth that
have reported results on neonatal/perinatal mortality
show that the risk difference is 2% (95% CI 0–5%)
(15,23,33,37). It was not possible to calculate NNT
as the lower limit of the 95% CI was 0%. The meta-
analysis showed a risk difference for respiratory dis-
tress syndrome of 5% and for necrotizing enterocolitis
of 1%. It was also not possible to calculate NNT, as
the lower limits of the 95% CI for the risk differences
were 0%. O’Brien et al. reported the mean number
of days in the neonatal intensive care unit (NICU)
per admittance in the two groups. They found that
infants from the progesterone group were admitted
for 14.2 days (standard deviation (SD) 16.6) com-
pared to 20.5 days (SD 30.7) in the placebo group.
This corresponded to a mean difference of –6.2 days
(–15.2 to 2.8). A total of 17.5% of the infants in the
progesterone group were admitted to NICU com-
pared to 21.5% in the placebo group (RR 0.75,
95% CI 0.51–1.11). Unfortunately, data on NICU
admittance are not available from the other trials.
Short cervix
In 2007, Fonseca et al. (34) reported the results of
a multicenter randomized controlled trial of vaginal
progesterone (200 mg/day) from 24 to 34 weeks of
gestation. The primary outcome was spontaneous
delivery before 34 weeks. A total of 29,918 women
with singleton or twin pregnancies who underwent
routine ultrasonography at 20–25 weeks for exami-
nation of fetal anatomy and growth were offered a
transvaginal ultrasonographic measurement of cer-
vical length as a predictor of spontaneous preterm
delivery. Women with a cervical length of 15 mm or
less were invited to take part. A total of 250 women
with a cervical length of 15 mm or less (226 singleton
and 24 pairs of twins) agreed to participate and were
randomized. Spontaneous birth before 34 weeks of
gestation occurred in 19.2% of the participants in the
progesterone group and 34.4% in the placebo group
(RR = 0.56, 95% CI 0.36–0.86). Among women
without a short cervix and a previous preterm delivery
before 34 weeks, the incidence of spontaneous pre-
term birth was significantly higher in the placebo than
in the progesterone group (34 of 109 (31.2%) vs. 20
of 112 (17.9%); RR = 0.57, 95% CI 0.35–0.93;
p = 0.03). Among women with singleton pregnancies,
the incidence of spontaneous preterm birth was
significantly higher in the placebo than in the pro-
gesterone group (36 of 112 (32.1%) vs. 20 of 114
(17.5%); RR = 0.54, 95% CI 0.34–0.88; p = 0.02).
Progesterone was associated with a non-significant

reduction in combined neonatal morbidity (8.1 vs.
13.8%; RR = 0.59, 95% CI 0.26–1.25; p = 0.17).
Fonseca et al. concluded that in women with a
short cervix, the daily vaginal administration of
200 mg of progesterone from 24 to 34 weeks of ges-
tation significantly reduced the rate of spontaneous
preterm delivery. This conclusion was supported by
DeFranco et al. (35) in the previously mentioned sub-
study of the O’Brien trial (33) on 46 women with
a cervical length < 28 mm (19 women in the study
group and 27 in the control group). The rate of
preterm birth at or before 32 weeks was significantly
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lower in the study group compared to the control
group (0 vs. 29.6%, p = 0.014). Fewer infants were
admitted to the NICU in the progesterone group
(15.8 vs. 51.9%, p = 0.016). The study was weakened
by the small number of participants, especially in the
progesterone group and by the fact that the cut-off
of cervical length < 28 mm was chosen because it
was not possible to reach significance by the pre-set
cut-off of 25 mm cervical length.
For personal use only.
Preterm labor
The effect of progesterone in preventing preterm
delivery in women, who are hospitalized for preterm
labor, has been evaluated in very few studies, mostly
using progesterone as a part of acute tocolysis. In
a randomized study published in 2007, Facchinetti
et al. (38) introduced progesterone in women with
preterm labor, not as a part of tocolysis, but after
start of tocolysis. Tocolysis (atosiban) was given for
48 hours. The study included 60 singleton pregnant
women with preterm labor and intact membranes,
between 25 and 33 weeks + 6 days of gestation. The
women were allocated to either observation or intra-
muscular administration of 341 mg of 17-a-hydro-
xyprogesterone caproate twice a week until 36 weeks
of gestation or delivery. Cervical length was measured
by transvaginal ultrasound scanning at discharge from
hospital as well as 7 and 21 days after discharge.
In the total material, women who remained unde-
livered after an episode of preterm labor had progres-
sive cervical ripening during the observation period of
three weeks. Treatment with progesterone was asso-
ciated with a reduction in the risk of cervical short-
ening as well as a reduced risk of preterm delivery.
There was a highly significant reduction in preterm
deliveries before 37 weeks and a non-significant
reduction in deliveries before 35 weeks.
The effect of progesterone in preterm labor is a sub-
ject of two ongoing studies, one in Switzerland, includ-
ing 626 women, the other at Yale University, with
375 women enrolled. Both are randomized, placebo
Prevention of preterm birth by progesterone 1185
controlled trials with delivery before 37 weeks as a
primary outcome measure and delivery before 32 and
34 weeks as secondary outcome measures. Whether
progesterone treatment reduces recurrent episodes
of preterm labor and reduces infant mortality and
morbidity will be evaluated in these studies as well.
Discussion
Based on previously published meta-analyses of data
on women with a singleton pregnancy and a history
of preterm birth, progesterone seems to have a ben-
eficial effect on pregnancy length and some sec-
ondary neonatal outcomes. Inclusion of the most
recent studies in a meta-analysis even shows that
infant survival is significantly increased in the pro-
gesterone group compared to the placebo group. The
strengthening of evidence should be considered in
obstetric practice.
The conclusions from the new meta-analysis in
Table II are concordant with the recently pub-
lished recommendations from the American College
of Obstetricians and Gynecologists (ACOG) com-
mittee opinion (39), which states that progesterone
treatment should be offered to women with singleton
pregnancies and previous spontaneous preterm birth.
ACOG also concluded that progesterone treatment
might be considered for asymptomatic women with
an incidentally identified short cervix, but they do
not recommend that cervical length is screened for
routinely in asymptomatic singleton pregnancies.
We found that NNT in order to prevent one deliv-
ery before 32 weeks was 16. The corresponding num-
ber was 17 and 10, respectively, for delivery before 35
and 37 weeks. With the inclusion of the latest trial on
women with previous preterm delivery in the meta-
analysis, the RR for perinatal mortality was signifi-
cantly decreased in the progesterone group. It was
not possible to estimate NNT in the meta-analyses
due to a lower risk reduction limit of 0%. The obser-
vations in the Fonseca trial on short cervix indicate an
absolute risk reduction for neonatal death of 3.6%
(95% CI –0.7% to 7.8%), It is important to notice that
these results include data from twin gestations.
Estimating NNT is important when evaluating a
treatment that may have side effects for either mother
or infant(s). Progesterone is known to have diabeto-
genic effects, and a recent study by Rebarber et al.
(40) examined the incidence of gestational diabetes
mellitus (GDM) in women who had received weekly
17-a-hydroxyprogesterone caproate injections for
the prevention of recurrent preterm birth. In this
study, an incidence of GDM of 12.9% was found in
the women treated with progesterone compared to
 1186 L. Rode et al.
4.9% in the controls. This corresponds to an absolute
risk increase of 8.0% (95% CI 5.0–11.0%). The
number needed to harm could therefore be as high
as 13 (95% CI 9–20), which means that for each
13 women treated with intramuscular progesterone,
one woman could develop GDM as a result of the
treatment. These results are, however, not based on
a randomized population, as the study population
was identified retrospectively from women receiving
outpatient perinatal services for pregnancy-related
conditions. The diabetogenic effect of progesterone
may have contributed to the increased birth weight
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found in progesterone groups compared to placebo
groups in some studies. The association between
progesterone treatment and GDM should be inves-
tigated further.
It is important to note that the effect of proges-
terone treatment may rely on gestational age at pre-
vious preterm delivery. Spong et al. (41) investigated
this association in a subgroup analysis of the Meis
study from 2003 (15) and found the greatest effect of
progesterone treatment in women with a previous
preterm delivery before 34 weeks’ gestation. In addi-
tion, some of the previously mentioned meta-analyses
For personal use only.
have shown that while progesterone treatment signif-
icantly reduces the risk of preterm delivery, the inci-
dence of spontaneous preterm labor is not affected
(42). Hence, progesterone treatment may predomi-
nantly add an effect to tocolytics by sensitizing the
uterus to tocolytic drugs.
When introducing a new treatment in pregnancy,
it is crucial not only to focus on short-term outcome
but also investigate longer-term outcome for the
infants. At present, progesterone treatment during
pregnancy seems to be safe for both mothers and
infants (42–45). From the late 1960s till the early
1980s, the effects of prenatal hormone exposure on
human behavior were investigated in several studies.
A meta-analysis from 1991 summarizes this knowl-
edge (46). It is important to discriminate between
synthetic progestational substances, often derived
from androgenic or estrogenic steroids, and natural
progesterone. Whereas synthetic progestogens have
been shown to have either a virilizing or feminizing
effect on children and youngsters exposed in utero,
few adverse effects of natural progesterone have been
reported. The suggested adverse effects of natural
progesterone in male subjects mainly constitute an
increased interest in sports and aggressive activities in
childhood and a slightly delayed sexual maturation.
Female subjects also seem to be feminized with regard
to behavior. Some studies found enhanced teacher
ratings of academic performance in male and female
subjects exposed to natural progesterone in-utero. It
is noteworthy; however, that the daily mean dosage of
progesterone exposure in most of the studies of this
meta-analysis is much higher than 90 mg per day
(range 50–9,400 mg). Recently, Northen et al. (44)
evaluated a total of 278 (80%) out of 348 surviving
children of women who participated in the Meis study
using the Ages and Stages Questionnaire at the age
of 48 months (194 in the 17-a-hydroxyprogesterone
caproate group and 84 in the placebo group). The
group did not find any significant differences in
health status or physical examination, including gen-
ital anomalies, between the 17-a-hydroxyprogesterone
caproate and placebo groups, and scores for gender-
specific roles were similar between the two groups.
This latter finding is in accordance with the conclu-
sions from two large reviews assessing the effect of
progesterone on mother and infant (43,45).
Cerclage may have a beneficial effect in women
with a short cervix and especially in those with a prior
preterm birth (47). Since progesterone also seems
to have an effect on a short cervix, it is a reasonable
hypothesis that a combination of cerclage and pro-
phylactic progesterone with different targets would
have an even better effect. However, there is no
documentation for an effect of such a combination
since women with a cerclage suture were excluded in
the randomized studies on progesterone and a short
cervix. Also, there is no information on the combined
effect of other measures that are usually applied in
clinical practice to address the heterogeneous etiol-
ogy and pathogenesis of preterm delivery. Bed rest
and cerclage are offered for mechanical reasons and
to improve the immunological effect of the cervical
plug, while progesterone is given to improve hor-
monal status, tocolytics to reduce contractions and
antibiotics to address subclinical genital infection.
Even though none of these measures individually
have been shown to improve fetal outcome, some of
them have been recommended in national guidelines
for several years. Therefore, it would be impossible to
set up a successful randomized clinical trial to study
the effect of a combination of all of these measures
compared to placebo. A randomized clinical trial com-
paring a combination of cerclage and progesterone
with cerclage alone, however, would be a feasible and
highly relevant study to perform.
A change of practice was noticed in USA already
in 2005 where 67% of obstetricians used progester-
one compared to 38% in 2003. In many European
centers and in Australia and New Zealand, however,
progesterone treatment is not used routinely for the
prevention of preterm delivery (42), although cost-
effectiveness analyses have shown (48,49) that pro-
gesterone treatment for pregnant women with a
previous spontaneous preterm delivery may substan-
tially reduce medical costs due to hospitalization and
 Acta Obstet Gynecol Scand Downloaded from informahealthcare.com by Brown University Library on 05/17/12
For personal use only.

Table III. Currently registered placebo-controlled randomized clinical trials on progesterone for the prevention of preterm birth in singleton pregnancies.

Title Treatment Study population Anticipated study Sample size Primary outcome NCT/ISRCTN
period number

Previous preterm birth

Vaginal progesterone to reduce Progesterone as vaginal gel Singleton pregnancies with April 2004 to 636 Delivery £ 32 weeks NCT00086177
the risk of another preterm birth versus placebo previous preterm birth January 2009
Australasian collaborative trial Progesterone pessaries Women with prior spontaneous October 2005 to 984 Neonatal lung ISRCTN-20269066
of vaginal progesterone therapy versus placebo preterm birth January 2009 disease
Comparing IM vs. vaginal Intramuscular progesterone Singleton pregnancies with October 2006 to 264 Maternal, fetal, and NCT00579553
progesterone for pre-term birth versus vaginal progesterone previous preterm birth August 2013 neonatal outcomes
Short cervix
RCT of progesterone to Intramuscular progesterone Nulliparous women with April 2007 to June 1,000 Delivery £ 37 weeks NCT00439374
prevent preterm birth in versus placebo singleton gestation and cervical 2010
nulliparous women with a short length < 30 mm
cervix
PREGNANT Short Cervix Progesterone as vaginal gel Singleton pregnancies with March 2008 to 300 Delivery £ 32 weeks NCT00615550
Trial versus placebo cervical length of 10–20 mm March 2009
Preterm labor
Vaginal progesterone to prevent Vaginal progesterone versus Singleton pregnancies with July 2006 to July 626 Delivery £ 37 weeks NCT00536003
preterm delivery in women with placebo preterm labor 2008
preterm labor
Investigation into the Progesterone pessaries Women who became pregnant July 2008 to 302 Delivery £ 37 weeks ISRCTN-06959967
effectiveness of progesterone versus standard care, i.e. no after IVF/ICSI December 2009
prevention of preterm labor in placebo group
women who became pregnant
by IVF/ICSI
Vaginal progesterone as Progesterone pessaries Singleton pregnancies with June 2008 to 2011 350 Delivery £ 34 weeks NCT00646802
maintenance treatment after an versus placebo active preterm labor who have
episode of preterm labor been successfully treated with
(PROMISE study) tocolytics and have a cervical
length < 25 mm
Previous preterm birth and/or short cervix and positive for fibronectin
Does progesterone prophylaxis Progesterone pessaries Women with previous preterm Early 2009 to 2014 750 Delivery £ 34 weeks, ISRCTN-14568373
to prevent preterm labour versus placebo birth/PPROM, late abortion, or neonatal outcome,
improve outcome? a cervical length <25 mm and a childhood cognitive
(OPPTIMUM study) positive fFN at 22 weeks development,
economic evaluation
Prevention of preterm birth by progesterone

Sources: www.clinicaltrials.gov and www.controlled-trials.com.

Note: IVF, in vitro fertilization; ICSI, intracytoplasmic sperm injection; PPROM, preterm premature rupture of membranes; fFN, fetal fibronectin.
1187
 1188 L. Rode et al.
treatment of infants with low birth weight and com-
plications of preterm birth.
Clinical guidelines usually rely on updated meta-
analyses. Since implementations of changes in
guidelines are laborious – the introduction of new
interventions and not least removal of learnt prac-
tices – it is important to know which studies are
currently in the pipeline. Table III gives an overview
of the clinical trials on progesterone for the preven-
tion of preterm birth in singleton pregnancies that
are currently registered at www.clinicaltrials.gov and
www.controlled-trials.com. Results from these eight
Acta Obstet Gynecol Scand Downloaded from informahealthcare.com by Brown University Library on 05/17/12
placebo-controlled trials, three on women with pre-
vious preterm deliveries, two on women with a short
cervix, and three on women in preterm labor are
expected to be available within the next 5–10 years.
Conclusion
In women with a singleton pregnancy and previous
preterm delivery, progesterone reduces the rates of
preterm delivery before 32 weeks with an NNT of 16.
In addition, progesterone treatment significantly
For personal use only.
reduces the relative risk of low birth weight, perinatal
death, fetal respiratory distress syndrome, and nec-
rotizing enterocolitis. The risk of admission for
preterm labor, antenatal corticosteroid therapy, and
tocolytic therapy is not decreased in women who are
treated prophylactically with progesterone. Women
with a short cervix or preterm labor may also bene-
fit from progesterone treatment, but further evi-
dence is needed to support such a recommendation.
Follow-up studies should focus on possible metabolic
complications in the mother or the offspring as an
observational study has shown that there is an asso-
ciation between progesterone treatment and the risk
of developing gestational diabetes.
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