General obstetrics

DOI: 10.1111/1471-0528.13061
www.bjog.org

Prevention of preterm delivery with vaginal

progesterone in women with preterm labour
(4P): randomised double-blind placebo-controlled
trial
B Martinez de Tejada,a A Karolinski,b MC Ocampo,b C Laterra,c I Hosli,d D Fernandez,e D Surbek,f
M Huespe,g G Drack,h A Bunader,i S Rouillier,j G Lopez de Degani,k E Seidenstein,l E Prentl,m
J Anton,n F Krahenmann,o D Nowacki,p M Poncelas,q JC Nassif,r R Papera,s C Tuma,t R Espoile,u
O Tiberio,v G Breccia,w A Messina,x B Peker,y E Schinner,z BW Mol,aa L Kanterewicz,b V Wainer,b
M Boulvain,a V Othenin-Girard,a MV Bertolino,b O Irion,a for the 4P trial group*
a

Department of Obstetrics and Gynaecology, Faculty of Medicine, Geneva University Hospitals and University of Geneva, Geneva, Switzerland
Centro de Investigacion en Salud Poblacional -CISAP- (Population Health Research Centre), Hospital GA Carlos G Durand, Buenos Aires,
Argentina c Department of Obstetrics and Gynaecology, Hospital Materno Infantil Ramon Sarda, Buenos Aires, Argentina d Department of
Obstetrics and Gynaecology, University Hospital, University Basel, Basel, Switzerland e Department of Obstetrics and Gynaecology, Hospital
Materno Infantil de San Isidro, San Isidro, Provincia de Buenos Aires, Argentina f Department of Obstetrics and Gynaecology, Faculty of
Medicine, University Hospital and University of Bern, Bern, Switzerland g Department of Obstetrics and Gynaecology, Hospital Donacion
Francisco Santojanni, Buenos Aires, Argentina h Department of Obstetrics and Gynaecology, Frauenklinik, Kantonspital, St Gall, Switzerland
i
Department of Obstetrics and Gynaecology, Hospital Maternidad Nuestra Senora De Las Mercedes, San Miguel de Tucuman, Argentina
j
Department of Obstetrics and Gynaecology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland k Department of Obstetrics and
Gynaecology, Hospital Materno Infantil San Roque, Entre Ros, Argentina l Department of Obstetrics and Gynaecology, Hospital Bernardino
Rivadavia, Buenos Aires, Argentina m Department of Obstetrics and Gynaecology, Frauenklinik, Kantonspital, Winterthur, Switzerland
n
Department of Obstetrics and Gynaecology, Hospital Heroes de Malvinas, Merlo, Provincia de Buenos Aires, Argentina o Department of
Obstetrics and Gynaecology, University Hospital Zurich, Zurich, Switzerland p Department of Obstetrics and Gynaecology, Hospital
Magdalena V. de Martnez, General Pacheco, Provincia de Buenos Aires, Argentina q Department of Obstetrics and Gynaecology, Hospital Dr.
Cosme Argerich, Buenos Aires, Argentina r Department of Obstetrics and Gynaecology, Hospital Carlos G Durand, Buenos Aires, Argentina
s
Department of Obstetrics and Gynaecology, Hospital Villa Dolores, Cordoba, Argentina t Hospital Virgen del Carmen, Zarate, Provincia de
Buenos Aires, Argentina u Department of Obstetrics and Gynaecology, Hospital Municipal Ostaciana B de Lavignolle, Moron, Provincia de
Buenos Aires, Argentina v Department of Obstetrics and Gynaecology, Hospital Comunal de Tigre, Tigre, Provincia de Buenos Aires,
Argentina w Department of Obstetrics and Gynaecology, Hospital J. M. Penna, Buenos Aires, Argentina x Department of Obstetrics and
Gynaecology, Hospital Dr. T. Alvarez, Buenos Aires, Argentina y Department of Obstetrics and Gynaecology, Hospital Interzonal Alberto
Antranik Eurnekian, Ezeiza, Provincia de Buenos Aires, Argentina z Department of Obstetrics and Gynaecology, Hospital J. B. Iturraspe, Santa
Fe, Argentina aa Department of Obstetrics and Gynaecology, Academic Medical Centre, Amsterdam, the Netherlands
Correspondence: B Martinez de Tejada, Department of Obstetrics and Gynaecology, Faculty of Medicine, Geneva University Hospitals, 30
Boulevard de la Cluse, 1211 Geneva 14, Switzerland. Email begona.martinezdetejada@hcuge.ch
b

Accepted 17 July 2014. Published Online 11 September 2014.

Objective To evaluate the effectiveness of 200 mg of daily vaginal

Methods Participants were randomly allocated to either 200 mg

natural progesterone to prevent preterm birth in women with

preterm labour.

daily of self-administered vaginal progesterone or placebo within

48 hours of starting acute tocolysis.

Design Multicentre, randomised, double-blind, placebo-controlled

Main outcome measures Primary outcome was delivery before

trial.

37 weeks of gestation. Secondary outcomes were delivery before 32

and 34 weeks, adverse effects, duration of tocolysis, re-admissions
for preterm labour, length of hospital stay, and neonatal morbidity
and mortality. The study was ended prematurely based on results of
the intermediate analysis.

Setting Twenty-nine centres in Switzerland and Argentina.

0/7

Population A total of 385 women with preterm labour (24

336/7 weeks of gestation) treated with acute tocolysis.

Trial registration number: NCT00536003.

*4P Trial group members are in Appendix 1.

80

to

Results Preterm birth occurred in 42.5% of women in the

progesterone group versus 35.5% in the placebo group (relative
risk [RR] 1.2; 95% confidence interval [95% CI] 0.931.5).

2014 Royal College of Obstetricians and Gynaecologists

Vaginal progesterone in women with preterm labour

Delivery at <32 and <34 weeks did not differ between the two
groups (12.9 versus 9.7%; [RR 1.3; 95% CI 0.72.5] and 19.7
versus 12.9% [RR 1.5; 95% CI 0.92.4], respectively). The
duration of tocolysis, hospitalisation, and recurrence of preterm
labour were comparable between groups. Neonatal morbidity
occurred in 44 (22.8%) cases on progesterone versus 35 (18.8%)
cases on placebo (RR: 1.2; 95% CI 0.821.8), whereas there were
4 (2%) neonatal deaths in each study group.
Conclusion There is no evidence that the daily administration of

Keywords Maternal tolerance, neonatal morbidity, neonatal

mortality, neonatology, obstetrics, preterm delivery, preterm
labour, vaginal progesterone.
Linked article This article is commented on by ER Norwitz, p.
92 in this issue. To view this mini commentary visit http://
dx.doi.org/10.1111/1471-0528.13108.
The article has journal club discussion points, p. 93 in this issue.
To view these online visit http://dx.doi.org/10.1111/1471-0528.
13196.

200 mg vaginal progesterone decreases preterm birth or improves

neonatal outcome in women with preterm labour.
Please cite this paper as: Martinez de Tejada B, Karolinski A, Ocampo MC, Laterra C, Hosli I, Fernandez D, Surbek D, Huespe M, Drack G, Bunader A,
Rouillier S, Lopez de Degani G, Seidenstein E, Prentl E, Anton J, Krahenmann F, Nowacki D, Poncelas M, Nassif JC, Papera R, Tuma C, Espoile R, Tiberio
O, Breccia G, Messina A, Peker B, Schinner E, Mol BW, Kanterewicz L, Wainer V, Boulvain M, Othenin-Girard V, Bertolino MV, Irion O, for the 4P trial
group. Prevention of preterm delivery with vaginal progesterone in women with preterm labour (4P): randomised double-blind placebo-controlled trial.
BJOG 2015;.122:8093.

Introduction
Preterm birth (PTB) (<37 weeks of gestation) is the leading
cause of neonatal morbidity and mortality. In developed
countries, the incidence of preterm delivery varies between
7 and 12%.1,2 This rate is higher in developing countries
where there is limited availability of neonatal care and
there are poorer clinical outcomes.3,4 Infants born preterm
account for 75% of perinatal deaths and half of all childhood neurodevelopmental disabilities.5,6 Consequently, PTB
contributes to a large burden of disease, including high
immediate and long-term medical care costs, the need for
special education services and institutionalised care for
physically and mentally disabled infants.7,8
In many cases, PTB occurs after spontaneous preterm
labour (PTL) (preterm uterine contractions with cervical
effacement and/or dilatation) and intact membranes.9,10
Despite the identification of various risk factors, no intervention has been found to be effective for the reduction of
PTB in women with symptoms of PTL.11,12 Acute tocolysis
is effective in delaying the delivery of the fetus for 27 days
in the short term but it has not been shown to reduce long-term complications from preterm birth.1318 In addition,
studies have failed to show a beneficial effect of maintenance
tocolysis on pregnancy and perinatal outcomes.1922
In recent years, progesterone was found to be effective
for the prevention of PTB in women with a previous history of PTB and in those with a mid-trimester short cervix.2330 However, its effectiveness in women with PTL has
been less well evaluated with conflicting results reported.
Several small and unblinded clinical studies have reported a
beneficial effect of natural progesterone or 17-hydroxyprogesterone caproate (17P) in reducing the duration of tocolysis treatment and preventing PTB.3134 Nevertheless, the
largest study published to date found no efficacy for the
prevention of PTB with the use of 17P.35 In an attempt to

2014 Royal College of Obstetricians and Gynaecologists

bridge this knowledge gap, we conducted a multicentre,

placebo-controlled trial to determine whether the administration of natural progesterone vaginally was effective in
decreasing the risk of preterm delivery in women with
PTL, who were also treated with tocolysis.

Methods
The Prevention of Preterm Delivery with Vaginal Progesterone in Women with Preterm Labour (4P) study was an
international, multicentre, randomised, prospective, double-blind, placebo-controlled trial comparing vaginal natural progesterone versus placebo in women with PTL.

Setting and participants

We carried out the trial in nine hospitals in Switzerland
(from July 2006 to February 2011) and 20 hospitals in Argentina (from September 2008 to September 2012). Study coordination was carried out at the research unit of Geneva
University Hospitals (HUG) (Geneva, Switzerland) and the
Centro de Investigacion en Salud Poblacional (Population
Health Research Centre [CISAP]) (Buenos Aires, Argentina).
Pregnant women with threatened PTB between 24 and
<34 weeks of gestation (based on ultrasound scan before
22 weeks of gestation) and treated with acute tocolysis
(b-mimetics, oxytocin receptor antagonist, or calcium-channel blockers, depending on local protocols) and
corticosteroids for fetal lung maturation were eligible for
inclusion in the study. Threatened PTB was defined as regular phasic uterine contractions with a minimum of two
painful contractions in 10 minutes averaged over 30 minutes on cardiotocogram, together with at least one of the
following criteria: shortened cervix detected by vaginal
ultrasound scanning (cervical length 30 mm until
31 weeks of gestation or 25 mm from 32 weeks of gestation onwards);3638 short and dilated cervix detected

81

Martinez de Tejada et al.

clinically (cervical length 10 mm or Bishop score 6);39

progressive cervical shortening detected by serial clinical or
ultrasound examinations (5 mm difference between two
examinations); or a positive qualitative fetal fibronectin test
(if available in the centre; QuikcheckfFN or TCM Hologic).4042
Exclusion criteria were: maternal age <18 years, multiple
pregnancy, cervical cerclage in situ, polyhydramnios
(defined as an amniotic fluid index >95th centile for gestational age or a greatest amniotic pocket >8 cm), premature
rupture of membranes, suspected clinical chorioamnionitis
(defined as elevated white blood cell count, elevated
C-reactive protein, maternal and/or fetal tachycardia, uterine tenderness and/or foul smelling amniotic fluid), cervical
dilatation >3 cm, placenta praevia or suspected placental
abruption, intrauterine growth restriction, non-reassuring
fetal wellbeing, pre-eclampsia, severe hypertension, any
other maternal or fetal pathology that required medically
indicated preterm delivery and anticipated difficulty with
follow up. Eligible women were informed about the study
by the local investigator and provided written consent
before recruitment.

the provision of unnecessary capsules and allowed the stratification of the recruited women in the two study groups
by gestational age at inclusion. Each centre was provided
initially with five boxes of each set and regularly supplied
with additional boxes as necessary.

Practical issues
Study participants were monitored using the following clinical and laboratory examinations, depending on local practices: temperature; heart rate and blood pressure
measurement; fetal heart rate monitoring; cervical examination; white blood cell count and C-reactive protein measurement; and urinary, genital and recto-vaginal
microbiological cultures. Women with positive culture
results were treated with specific antibiotics following the
local guidelines at each centre. For each PTL episode resulting in a new hospitalisation, the standard local protocol
was repeated and clinical data were collected. Regarding
Group B Streptococcus (GBS) prophylaxis, women were
screened for GBS colonisation at admission and received
intrapartum GBS antibiotic prophylaxis if colonised or if
unknown status and delivering preterm.

Randomisation and intervention

Usual care

After obtaining informed consent and within 48 hours after

initiating tocolysis, the local investigator randomly allocated participants to either vaginal capsules of 200 mg of
natural progesterone or placebo. The woman was asked to
self-administer the treatment once a day until 36 weeks
and 6 days of gestation or until preterm delivery, whichever
occurred first. Medication was stopped after preterm rupture of the membranes before term. Randomisation was
performed in a 1:1 ratio using a list created with an independent, centralised, computer-generated randomisation
sequence (PASW STATISTICS, version 18; IBM Corp.,
Armonk, NY, USA) stratified by centre and by gestational
age group at inclusion (group 1: <28 weeks; group 2: 28 to
<32 weeks; group 3: 32 weeks). The randomisation codes
were kept at the pharmacy departments of HUG and
CISAP.
Placebo capsules had the same appearance, feel and
odour as the active medication. Both the active drug and
placebo were stored in boxes with the same appearance
and weight (i.e. the local investigator, the clinical team and
the women were not aware of the type of medication
administered). Three different sets of boxes containing progesterone or placebo to be administered either from 24 to
37 weeks (91 days), 28 to 37 weeks (63 days), or 32 to
37 weeks (35 days) of gestation were centrally prepared at
the HUG pharmacy for the Swiss centres and at the CISAP
pharmacy for the Argentinean centres. Boxes were clearly
labelled with the corresponding study number, gestational
age group and number of capsules. This strategy minimised

Women were managed by their obstetrician from the time

of inclusion until delivery. Antenatal care decisions were
left to the attending clinicians at each institution. Members
of the research team were available to respond to any queries regarding the study protocol.

82

Outcomes
The primary outcome was preterm delivery before 37 weeks
of gestation. Prespecified secondary outcomes were as follows.
Obstetrical outcomes: preterm delivery before 34 weeks
and before 32 weeks of gestation; duration of tocolysis; length of hospital stay for the initial episode; and
the overall number of re-admissions for PTL.
Neonatal outcomes: newborn birth weight; hospitalisation at the neonatal intensive care unit; a composite
estimate of neonatal morbidity including the following
variables: transient tachypnoea; respiratory distress syndrome; bronchopulmonary dysplasia; ventilatory support (continuous positive airway pressure, intubation),
necrotising enterocolitis; intraventricular haemorrhage;
periventricular leucomalacia; retinopathy; sepsis and
patent ductus arteriosus; and neonatal death.
Drug tolerance: local reactions (soreness, itching, bruising, and vaginal discharge) and systemic reactions (any
documented unusual sign or symptom possibly related
to drug administration).
Definitions of obstetrical and neonatal complications
were standardised across centres according to the World

2014 Royal College of Obstetricians and Gynaecologists

Vaginal progesterone in women with preterm labour

Health Organization standards. Charts were locally

reviewed by an obstetrician and a neonatologist unaware of
the allocation to the study group to determine the clinical
outcomes (assessor blinding).

Data collection and management

After informed consent, we collected baseline characteristics
including a socio-economic score (range 212) that took
into account the womans educational level and partners
professional status. A score >10 indicated having achieved
tertiary education/high socio-economic status.43 Pregnancy
outcomes and medication side effects were prospectively
collected using a case report form designed specifically for
the trial. Every 2 weeks, participants were asked to provide
the number of vaginal suppositories that they had used.
They were asked also whether they had consulted a physician for PTL symptoms, had experienced adverse events,
had undergone any medical procedures, or had been given
any other medication since their last visit. After delivery, the
study personnel reviewed all prenatal, delivery, postpartum
and newborn records and documented the date of delivery,
newborn birthweight and other neonatal outcomes.
Severe maternal or neonatal complications were immediately reported to the coordinating centres, which notified
the Swiss regulatory agency for the authorisation and
supervision of therapeutic products (Swissmedic) or its
Argentinean counterpart (ANMAT: Administracion Nacional de Medicamentos, Alimentos y Tecnologa Medica).
We assessed compliance by counting the number of
unused capsules returned to the coordinating centres. We
defined noncompliance as being when the woman has
administered <80% of the capsules prescribed.
After completion, case report forms were sent to the
research coordinating centre to ensure quality and completion of data, and for entry into a dedicated database. Clinical audits were regularly carried out to evaluate the quality
of data collection by each hospital.

percentage of the total allocation arm and compared using

Fishers exact test. Continuous measures were presented as
means with standard deviations and compared using
Students t-test, or as medians and ranges and compared
using nonparametric statistics if not normally distributed. A
P-value < 0.05 (two-tailed) was considered to indicate statistical significance. The incidence of the primary outcome
(delivery before 37 weeks) and of most secondary outcomes
was calculated among all women with the relevant data at
delivery. The incidence of preterm delivery before 32 weeks
of gestation was computed with women included into the
study before 32 weeks of gestation as the denominator.
The effect of the intervention was expressed as relative
risk (RR) and 95% confidence intervals (CI) around these
estimates. We performed a secondary analysis (per protocol
analyses) excluding women who were wrongly included in
the study (violation of inclusion and/or exclusion criteria)
or who discontinued treatment, either by themselves or by
their physicians. A time-to-event analysis was performed to
compare the probability of remaining undelivered after 36
completed weeks between the two groups. KaplanMeier
curves were compared using the log-rank test. The analysis
was conducted without any knowledge of group allocation.
A planned interim analysis (after collection of delivery
data on 300 recruited women) on the effectiveness and
safety was performed by a panel of independent experts
(data safety monitoring board and two independent statisticians) not involved in the trial or its design. The criteria
to stop the study were described in the protocol and followed the OBrien and Fleming rule, i.e. P < 0.015 for the
primary outcome.45 At the interim analysis, conducted
when outcome data were available for 302 women (48% of
the planned sample), a conditional power analysis revealed
that even if recruitment continued to the final sample size
of 626 women, the probability of showing a benefit of progesterone for the primary outcome was 0%. Based on the
result of this analysis, study enrolment was stopped in June
2012. At that time, 385 women had been randomised.

Sample size
We calculated our sample size based on differences between
the two study groups in the likelihood of preterm delivery
before 37 weeks of gestation. Preterm delivery among
women with PTL receiving routine care was postulated to
occur in 3040% of cases.44 A sample of 626 women was
sufficient to detect a risk reduction from 30 to 20% in preterm delivery before 37 weeks with 80% power and a two
-sided type I error of 5%.

Statistical methods
The main statistical analyses were performed on an intention-to-treat basis using IBM SPSS (version 19; SPSS Inc., Chicago, IL, USA) and OPEN EPI softwares. Frequencies in
categorical variables were expressed as a number with the

2014 Royal College of Obstetricians and Gynaecologists

Results
Of 1466 women hospitalised for PTL during the study period, 576 were eligible for inclusion into the study, of whom
191 declined to participate in the trial. In total, 385 women
were included and randomly allocated to progesterone
(n = 197) or placebo (n = 188). Six women (four in the
progesterone group and two in the placebo group) were
lost to follow up (no data on delivery and newborn). Data
from 379 women were included in the analysis, of which
193 were randomised to receive progesterone and 186 to
placebo (Figure 1).
For the per protocol analysis, 19 women (eight in the placebo group and 11 in the progesterone group) were excluded

83

Martinez de Tejada et al.

Enrolment

Assessed for eligibility (n = 1467)

Excluded (n = 1082)
Not meeting inclusion criteria (n = 890)
Declined to participate (n = 192)
Other reasons (n = 0)

Randomised (n = 385)

Allocation
Allocated to PROGESTERONE (n = 197)
Received allocated intervention (n = 197)

Allocated to PLACEBO (n = 188)

Received allocated intervention (n = 188)

Follow up
Lost to follow up (No data from delivery because
delivered in other hospital) (n = 3)

Lost to follow up (No data from delivery because

delivered in other hospital (n = 2)

Discontinued intervention (withdrew consent) (n = 1)

Discontinued intervention (n = 0)

Analysis
Analysed (intention-to-treat) (n = 193)
Excluded from analysis per protocol (n = 11)
Randomised without meeting inclusion criteria (n = 6)
Stopped treatment (n = 5)

Analysed (intention-to-treat) (n = 186)

Excluded from analysis per protocol (n = 8)
Randomised without meeting inclusion criteria (n = 4)
Stopped treatment (n = 4)

Figure 1. Randomisation, treatment and follow up of participants.

because of protocol violations (n = 10) or treatment interruption (n = 9; four cases of voluntary withdrawal by
women and five cases due to the decision made by the
attending physicians) leading to 360 women (Figure 1).
Baseline characteristics of the women included in the
two groups were comparable (Table 1). Included women
had a mean age of 27.6 years (SD 6.2), and a mean gestational age at study entry of 29.5 weeks (SD 2.7). There
were 136 (35.9%) nulliparous women and 91 (24.0%) had
a history of previous preterm delivery or late miscarriage.
Data on cervical length were available only for patients
from Swiss centres; data on fetal fibronectin were available
in 61 women from Switzerland.
The overall number of women with preterm delivery was
148 (39%) <37 weeks, 62 (16.4%) <34 weeks, and 36 out
of 317 women (11%) <32 weeks. There were 44 (11.6%)
cases of premature rupture of the membranes before term
(22 in each group) and 26 cases of delivery induced before
term (8/193 [4.1%] in the progesterone group and 18/186
[9.7%] in the placebo group; P = 0.05).

84

Two hundred and seventy-three (72%) women

returned their unused medication and empty blisters to
the coordinating centres: 142 women (52%) in the progesterone group and 131 women (48%) in the placebo
group. Among those, compliance was good in 83 (58%)
women in the progesterone group and in 76 (58%) in
the placebo group. Information for not complying with
the study medication in the remaining women was not
recorded.

Primary outcome and preterm delivery

Preterm birth <37 weeks occurred in 42.5% of women in the
progesterone group versus 35.5% of women in the placebo
group (P = 0.20). Delivery before 34 weeks and delivery
before 32 weeks were also similar between groups (Table 2).
After excluding women with an indication for elective
preterm delivery, there were 74/185 (40.0%) spontaneous
preterm deliveries among the progesterone group and 48/
168 (28.6%) in the placebo group (RR 1.4; 95% CI 1.04
1.88; P = 0.03).

2014 Royal College of Obstetricians and Gynaecologists

Vaginal progesterone in women with preterm labour

Table 1. Baseline characteristics of participants at study entry

Characteristics
Ethnic origin, n/total (%)
Caucasian
Hispanic
Other
Maternal age, n/total (%)
Maternal age in years,
mean (SD) and range
Maternal weight, n/total (%)
Maternal weight in kg
(mean  SD) and range
Family situation
Couple
Single with no partner
Professional situation
Working (employed or independent)
Other
SEE score
10
>10
Gynaecological surgery/malformation (yes)
Nulliparity (yes)
One or more late abortion (yes)
One or more preterm birth (yes)
Smoking during pregnancy (yes)
Haemorrage during pregnancy (yes)
Gestational age at entry, n/total (%)
Gestational age at entry, weeks
(mean  SD) and range
CL measurement at entry (yes)
CL at entry, mm (mean  SD)
fFN at entry, n/total (%)
Positive fFN at entry, n/total (%)
Tocolyses given at randomisation
Indomethacin
b-mimetic
Oxytocin receptor antagonist
Calcium inhibitors

Progesterone (n = 193)

98/192
79/192
15/192
193/193
27.92

(51.0)
(41.1)
(7.8)
(100)
(6.47) [1842]

Placebo (n = 186)

92/184
85/184
7/184
186/186
27.34

(50.0)
(46.2)
(3.8)
(100)
(5.79) [1843]

187/193 (96.9)
58.98 (11.51) [40109]

183/186 (98.4)
58.42 (9.77) [3695]

183/193 (94.8)
10/193 (5.2)

174/183 (95.1)
9/183 (4.9)

82/190 (43.2)
108/190 (56.8)

86/184 (46.7)
98/184 (53.3)

170/193
23/193
19/193
63/193
2/193
46/193
37/193
19/192
193/193
29.50

(88.1)
(11.9)
(9.8)
(32.6)
(1.0)
(23.8)
(19.2)
(9.9)
(100)
(2.74) [2434]

162/186
24/186
23/186
73/186
1/186
39/186
37/186
19/186
186/186
29.51

(87.1)
(12.9)
(12.4)
(39.2)
(0.5)
(21.0)
(19.9)
(10.2)
(100)
(2.72) [2433]

124/193
19.35
27/191
12/26
193/193
3/193
158/193
15/193
22/193

(64.2)
(8.36) [445]
(14.1)
(46.2)
(100)
(1.5)
(81.0)
(7.6)
(11.1)

124/186
19.56
34/183
14/33
186/186
4/186
143/186
20/186
26/186

(66.7)
(8.15) [046]
(18.6)
(42.4)
(100)
(2.1)
(74.1)
(10.4)
(13.7)

CL, cervical length; fFN, fibronectin; SD, standard deviation; SEE score, socio-economic score.

The time-to-event (preterm delivery) analysis with

censoring at 37 weeks when delivering at term showed a
hazard ratio of 1.3 (95% CI 0.91.8; log-rank MantelCox:
0.11; Figure 2). Duration of tocolysis, hospitalisation, and
frequency of a new episode of PTL were comparable
between the study groups, as were the number of women
receiving corticosteroids for fetal lung maturation and
undergoing caesarean delivery (Table 2).
After exclusion of cases of protocol violation and discontinuation of medication, the per protocol analysis showed
similar rates of preterm delivery before 37 and <32 weeks
of gestation between the two groups. In this analysis, there
were more women delivering before 34 weeks of gestation

2014 Royal College of Obstetricians and Gynaecologists

in the progesterone group compared with the placebo

group (RR 1.7; 95% CI 1.012.67; Table 2).

Neonatal outcomes
Neonatal weight at birth, Apgar score at 5 min <7, neonatal intensive care unit hospitalisation, neonatal mortality
and the composite outcome of morbidity were also comparable between the two groups (Table 3).

Side effects/adverse events

The incidence of side effects (mainly vaginal pruritus,
burning, or increased secretions) was comparable between
the two groups: 11 (5.7%) in the progesterone group and

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Martinez de Tejada et al.

Table 2. Obstetrical endpoints

Variable

Progesterone (n = 193)

Gestational age at delivery (weeks) (mean  SD) and range

Delivery <37 weeks, n/total n (%)
Delivery <34 weeks, n/total n (%)
Delivery <32 weeks, n/total n (%)
Tocolysis duration (hours), median (range)
Readmissions for preterm labour (yes)
Duration of hospitalisation (days), median (range)
Time to delivery (days), median (range)
Caesarean section, n/total n (%)
Corticosteroids for lung maturation, n/total (%)
Analysis per protocol*
Delivery <37 weeks, n/total n (%)
Delivery <34 weeks, n/total n (%)
Delivery <32 weeks, n/total n (%)

36.05
82/193
38/193
21/163
48.00
13/193
6.00
45.00
41/193
191/193

(3.54) [2441]
(42.5)
(19.7)
(12.9)
(01740)
(6.7)
(097)
(0114)
(21.2)
(99.0)

77/182 (55.0)
37/182 (20.3)
20/154 (13.0)

Placebo (n = 186)
36.63
66/186
24/186
15/154
48.00
19/184
7.00
52.00
37/186
185/186

(3.11) [2541]
(35.5)
(12.9)
(9.7)
(01672)
(10.3)
(168)
(2112)
(19.9)
(99.5)

63/178 (35.4)
22/178 (12.4)
15/148(10.1)

P
0.09
0.20
0.10
0.48
0.84
0.29
0.09
0.13
0.84
>0.99
0.22
0.06
0.55

RR

95% CI

1.2
1.5
1.32

0.931.5
0.952.4
0.712.5

0.65

0.331.28

1.07
0.99

0.721.59
0.971.01

1.20
1.65
1.28

0.921.55
1.012.67
0.682.41

*Analysis after exclusion of protocol violations and medication discontinuations.

In the placebo group, there were two neonatal deaths (at

24 and 28 weeks), one intrauterine death at 35 weeks, one
fetus with hydrocephalus diagnosed at 24 weeks of gestation, one case of polyhydramnios at term with a neonatal
diagnosis of genital malformation and hypotonus, and
one women was hospitalised at 31 weeks due to a car
accident.

Discussion
Main findings
In women with PTL treated with acute tocolysis, treatment
with 200 mg of vaginal natural progesterone daily did not
reduce preterm delivery or improve perinatal outcomes.
Progesterone treatment had no effect on the duration of
tocolysis, the duration of the first or any subsequent hospital stays, or the rate of recurrence of PTL.

Strengths and limitations

Figure 2. Distribution of time to delivery (in days) in the progesterone
and placebo groups.

12 (6.5%) in the placebo group (RR 0.9; 95% CI 0.40

1.96).
There were ten serious adverse events (four in the progesterone group and six in the placebo group). In the
progesterone arm, there were three neonatal deaths from
complications due to extreme prematurity (two at
24 weeks and one at 28 weeks) and one pregnant woman
with liver cholestasis who had labour induced at 37 weeks.

86

Our study is the largest randomised trial evaluating the

effectiveness of progesterone to prevent PTB in women
with singleton pregnancies and PTL. The inclusion criteria
were strict and corresponded to those most frequently used
in clinical practice. The trial was conducted in different
hospitals over two countries (Switzerland and Argentina)
with different health systems and among women of different socio-economic levels. This increased the generalisability of our results to other settings. The fact that the
tocolytic treatments employed in the study are those that
are currently used by most clinicians leads also to an
increased ability for generalisation of our results. We chose
vaginal progesterone suppositories because most previous

2014 Royal College of Obstetricians and Gynaecologists

Vaginal progesterone in women with preterm labour

Table 3. Neonatal outcome

Progesterone (n = 193)
Birthweight (g), median (range)
Apgar <7 at 5 minutes, n/total (%)
Neonatal mortality, n/total (%)
NICU hospitalisation, n/total (%)
Morbidity, n/total (%)*

2880.00
7/193
4/193
57/191
44/193

(5004685)
(3.6)
(2.1)
(29.8)
(22.8)

Placebo (n = 186)
2955.00
5/186
4/186
47/185
35/186

(8204900)
(2.7)
(2.2)
(25.4)
(18.8)

RR

95% CI

0.5
0.82
>0.99
0.42
0.41

1.35
0.96
1.17
1.21

0.434.18
0.243.80
0.841.63
0.821.80

NICU, neonatal intensive care unit.

*Composite outcome including any of the following: transient tachypnoea, respiratory distress syndrome, bronchopulmonary dysplasia, ventilatory
support (CPAP, intubation), necrotising enterocolitis; intraventricular haemorrhage, periventricular leucomalacia, retinopathy, sepsis, and patent
ductus arteriosus.

studies had shown a beneficial effect of this treatment

among asymptomatic women with a short cervix.46 Moreover, vaginal progesterone is better tolerated and more
easily administered than intramuscular 17P.
A weakness of our study is the method used to assess
compliance to drug treatment. Over 25% of participating
women did not return the unused medication, and among
those who did, we cannot be certain that they really
administered it. The number of women returning medication and demonstrating adequate medication compliance
was similar between the two groups.

Interpretation
We included women with a short cervix as measured by
vaginal ultrasound (<10th centile for the gestational age at
inclusion),47 as well as women with marked clinical
changes of the cervix.4850 We included also women with
contractions and positive fibronectin test results, which is
another group at high risk for preterm delivery.26,41 Nevertheless, fibronectin was investigated in only 16% of the
women. Although our inclusion criteria were heterogeneous
due to the multiple centres participating in the study, the
high preterm delivery rate (39%) implies that the population was indeed at high risk for preterm delivery to assess
the effectiveness of progesterone in the prevention of this
outcome.
We investigated the effect of progesterone in women
in conjunction with acute tocolysis as previous studies
showed that the combination of progesterone with nifedipine
or b-mimetics had synergistic effects and the total dosage of
tocolytic medications could be reduced.5153 However, we
found neither a difference in the duration of tocolytic
treatment between the progesterone and the placebo group
nor an interaction between progesterone and the various
tocolytics.
Several randomised controlled studies have assessed the
effectiveness of progesterone on prolongation of pregnancy
or reduction of prematurity in women with PTL. Some
have used intramuscular 17P as maintenance tocolysis: Fac-

2014 Royal College of Obstetricians and Gynaecologists

chinetti et al.33,34 found that 17P was associated with both

a reduction in the risk of cervical shortening and preterm
delivery. By contrast, Rozenberg et al. (the largest trial so
far) and Tan et al. found no difference in median time to
delivery, rates of preterm delivery before 37, 34 or 32 weeks
of gestation, or adverse perinatal outcomes, with Rozenberg
et al. specifically reporting a potential worsening of the
outcome after the use of 17P. Of note, none of these studies was placebo controlled.35,54 Regarding natural progesterone, two studies have used oral progesterone and observed
some positive effects.53,55 Noblot et al.55 performed a double-blind trial of 44 women randomised during an episode
of preterm labour and treated with intravenous b-agonists.
Although they showed no significant difference in the prolongation of pregnancy, the mean quantity of b-agonists
administered and associated costs were significantly lower
in the progesterone group.55 In the study by Erny et al.,53
high doses of progesterone were used as acute tocolysis and
compared with placebo. Both studies recruited very few
women (that of Noblot et al. only included 44 of the 60
cases required) and were of low quality. In relation to the
use of vaginal natural progesterone, Borna and Sahabi (70
women) and Arikan et al. (83 women) showed that, in
women with PTL, vaginal progesterone (400 and 200 mg
daily, respectively) was effective in prolonging the mean
gestational age at the time of delivery or in postponing the
delivery.31,56 In addition, progesterone was effective in
increasing neonatal weight and in reducing the incidence of
low birthweight and admission to the neonatal intensive
care unit. These studies were small, not placebo-controlled
and restricted to a single centre. Our study is larger than
previous trials and placebo-controlled. In addition, PTL
was defined either with objective criteria (sonographic
short cervix or positive fibronectin test) or with specific
and strict clinical criteria. Borna and Sahabi, and Arikan
et al. included women with contractions and a clinical
modified cervix (defined as shortening and dilatation), but
with no additional specifications.31,56 Hence, the included
women could represent a lower risk population (PTB rate

87

Martinez de Tejada et al.

is not given in Bornas study) for PTB compared with our

study. Compared with Arikan et al., our study included
women with a lower mean gestational age and a shorter
cervical length at admission.
Recently, in a nonrandomised, retrospective study, Bomba-Opon et al.32 reported a strong effect of vaginal progesterone in women with PTL. The study was small (190
women) and women were included if hospitalised for PTL
diagnosed as the presence of contractions and tocolysis.
Although the gestational age at delivery was similar between
groups, the authors stated that there were fewer PTB before
34 weeks of gestation in the progesterone group (22 versus
16 women). We did not observe any benefit for the prevention of PTB at earlier gestational ages (i.e. <34 or <32 weeks
of gestation) and in the per protocol analysis, we found a
trend towards a higher rate of PTB <34 weeks of gestation
in the group of women on progesterone. We found also a
significantly higher rate of spontaneous preterm delivery in
the group treated with progesterone. Progesterone is known
to have an immune-modulator effect, which might enhance
the inflammatory cascade already initiated during PTL.57
Caution should be exercised regarding this finding as spontaneous preterm delivery was not a prespecified outcome
and numbers were small.
It can be argued that we did not use progesterone as
maintenance tocolysis because some of the women delivered within the first 48 hours and were not stabilised
with acute tocolysis. Nevertheless, only nine women
delivered within the first 48 hours. To investigate this
potential bias, we performed a secondary analysis including only women stabilised for at least 48 hours and
obtained the same result, i.e. progesterone did not
decrease the risk of PTB.
Meta-analyses have confirmed the efficacy of various
progesterone treatments in the reduction of PTB in women
with a previous PTB.30,5861 Based on this, the American
College of Obstetricians and Gynecologists recommend
administering prophylactic progesterone treatment to this
high-risk group of women and strongly encourages further
randomised trials in other high-risk populations such as
women with PTL.28 However, the two largest studies performed until now (Rozenberg et al. with 17P and our trial
with vaginal natural progesterone) have shown no benefit
with progesterone treatment in the prevention of PTB in
women with PTL.

Conclusion
There is no evidence that the further administration of
200 mg daily of vaginal progesterone decreases PTB or
improves neonatal outcome in women with PTL following
tocolytic therapy.

88

Disclosure of interests
All authors have completed the ICMJE uniform disclosure
form at www.icmje.org/coi_disclosure.pdf (available on
request from the corresponding author). BMT has received
a travel grant from Besins Laboratory. All other authors
declare no other relationships or activities with companies
that might have an interest in the submitted work.

Contribution to authorship
BMT, MB and OI contributed to the design of the trial.
BMT, MB and OI wrote the grant application. BMT and
AK obtained funding for the study. All authors except
BWM participated in recruitment of participants and data
collection. BMT, VOG, MB, MCO, LK, VW, MVB and AK
analysed and interpreted the data. BMT, AK and BWM
drafted the manuscript. All authors critically reviewed the
manuscript. All authors (BMT, AK, MCO, CL, IH, DF, DS,
MH, GD, AB, SR, GLD, ES, EP, JA, FK, DN, MP, JCN, RP,
CT, RE, QT, GB, AM, BP, BWM, LK, VW, MB, VOG,
MVB, OI) except FS (who recently died) read and
approved the final manuscript before submission. BMT
accepts full responsibility for this work and acts as guarantor for the study.

Details of ethics approval

In Switzerland, ethical approval for the study was given by
the independent ethics committees of the Swiss centres
with central approval in Geneva (CER:04-196 in Geneva).
In Argentina, ethical approval was obtained from a central
independent committee of ethics in clinical research (CEMIC), from the institutional review board of the coordinating centre CISAP/Hospital Durand (authorisation no.
0537), and from each institutional review board of the
Argentinean hospitals participating in the trial. The study
was notified to the national drug regulatory agencies
(Swissmedic and ANMAT) and conducted in accordance
with Good Practice in Clinical Trials (GPCT) guidelines.
Registration at www.clinical-trials.gov was ensured with
identification number NCT00536003. All participants gave
written informed consent before taking part in the study.

Funding
The project was supported by grants from the University
Hospitals of Geneva (PRD-05103), the HUG Clinical
Research Center of the Swiss National Foundation (main
sponsor), Department of Reproductive Health and
Research, World Health Organization, Ministry of Health
of Ciudad Autonoma de Buenos Aires (grant for A Karolinski, resolution no. 2124/2011- Investigators career) and
a personal scholarship for Mrs MC Ocampo (degree no.
685/10). Besins Laboratory produced and supplied the
study drugs (utrogestan and placebo) free of charge. The

2014 Royal College of Obstetricians and Gynaecologists

Vaginal progesterone in women with preterm labour

funding sources did not participate in the study design,

data analysis, data interpretation, or writing of the report.

Acknowledgements
We thank the research nurses, research midwives and secretaries of our study consortium, including the residents,
nurses, midwives and gynaecologists of the participating
centres, for their help with participant recruitment and data
collection. We thank also B. Cerrutti, A. Gayet-Ageron, and
T Perneger for their help in data analysis and interpretation.
Special thanks to the members of the data safety monitoring
committee (J. Demoles, JJ Pasquier and F Goffinet) for
monitoring the trial and performing the interim analysis.
We thank Besins International, France, for the production
of study medication. We thank M. Merialdi, Department of
Reproductive Health and Research, World Health Organization, for partial support of the implementation of the 4P
Trial in Argentina. We thank R Sudan for her editing work
of the final version of the paper.

Transparency statement
The manuscript is an honest, accurate, and transparent
account of the study being reported. We confirm that no
important aspects of the study have been omitted.

Data sharing
Patient-level data are available from the corresponding
author.

Appendix 1
List of participating departments and
collaborators
In Switzerland, the 4P group comprises:
1 Geneva University Hospitals and University of Geneva Faculty of Medicine, Geneva (global and Swiss coordinating centre): B Martinez de Tejada, O Irion, M Boulvain, M Tellenbach, V Othenin-Girard, E Vogele, R
Azbar.
2 University Hospital, University Basel, Basel: I Hosli, A Raggi, A Birkenmaier, S Kann.
3 University Hospital and University of Bern, Bern: D Surbek, K Scheibner, M Huguelet, E Amann, M Baumann, E Jakob.
4 Kantonales Frauenspital Chur, Chur: K Biedermann.
5 Frauenklinik Kantonspital Luzern, Lucerne: M Hodel.
6 Frauenklinik Kantonspital St Gall, St Gall: G Drack, T Fischer, K Pfau,
K Estermann.
7 Centre Hospitalier Universitaire Vaudois, Lausanne: P Hohlfeld, S Gerber, S Rouiller-Cornu, R Capoccia Brugger, A Nessi, C Rodriguez-Maillot, PA Pradervand, P Bodenmann, S Fornage.
8 Frauenklinik Kantonspital Winterthur, Winterthur: E Prentl, E Amann.
9 University Hospital Zurich, Zurich: F Krahenmann, R Zimmermann.

In Argentina:
1 Centro de Investigacion en Salud Poblacional Population Health
Research Centre)/Hospital Durand, Ciudad Autonoma de Buenos
Aires (CABA) (Argentinean coordinating centre): A Karolinski, MV

2014 Royal College of Obstetricians and Gynaecologists

Bertolino, MC Ocampo, V Wainer, L Kanterewicz, C Rodriguez, L

Colazo.
2 Hospital Materno Infantil Ramon Sarda, CABA: C Laterra, S Ramirez Almanza, E Swistak, Y Gonzalez.
3 Hospital Materno Infantil de San Isidro, San Isidro, Provincia de
Buenos Aires: D Fernandez, G Zalazar, M Rubino, B Sanchez, A
Rivara, C Mercado, S Sagarna.
4 Hospital Donacion Francisco Santojanni, CABA: M Huespe, R
Luca, L Claus, V Castellano, L Domingo, C Castro, D Gil, ME
Rodriguez.
5 Hospital Maternidad Nuestra Senora De Las Mercedes, Tucuman: A
Bunader, NE Capua, M Romano, ME Longo, E Balbo, S Martnez
Lozano, C Petros.
6 Hospital Materno Infantil San Roque, Entre Ros: G Lopez de Degani, M Coniglio, R Harris, M Leanga, R Martnez, F Felici, M de
Bueno, F Reffino, J Castagnola, P Brarda, ME Parra, R Montenegro,
G Fernandez, G Schmadke.
7 Hospital Bernardino Rivadavia, CABA: E Seidenstein, R Pontoriero,
C Gonzalez, J Alduncin.
8 Hospital Heroes de Malvinas, Provincia de Buenos Aires: J Anton,
M Damiano, G Sanchez, M Rebottaro, L Altamira, V Garbarino, C
Rebottaro.
9 Hospital Magdalena V. de Martnez, Provincia de Buenos Aires: D
Nowacki, M Ferrary, C Buttner, P Gonzalez, Y Godoy.
10 Hospital Dr. Cosme Argerich, CABA: M Poncelas, E Bertola, L
Langdon, O Jimenez, L Mezzabota.
11 Hospital Carlos G. Durand, CABA: JC Nassif, CA Becker, JM Baier,
M Grichener, P Trotti.
12 Hospital Regional Villa Dolores, Cordoba: R Papera, M Chaloupka,
M Zarate, L Bogino, E Bertone, F Olmedo, M Barrionuevo, N Mariojouls.
13 Hospital Virgen del Carmen, Provincia de Buenos Aires: C Tuma, C
Gregoris.
14 Hospital Municipal Ostaciana B. de Lavignolle, Provincia de Buenos
Aires: R Espoile, C Muzio, C Nocetto, D Carozzi, V Pelaez, C De
Moura.
15 Hospital Comunal de Tigre, Provincia de Buenos Aires: O Tiberio, M
Sagastume, L Martnez, D Morales.
16 Hospital J. M. Penna, CABA: G Breccia, E Aguilera, E Werbicki, S
Bover.
17 Hospital Dr. T. Alvarez, CABA: A Messina, MF Stillo, M Joao, D
Crema, L Wiliams, C Espada, V Gomariz, ME Calo.
18 Hospital Interzonal Alberto Antranik Eurnekian, Provincia de Buenos
Aires: B Peker, D Longhi, ML Pisanelli, L Giglio, J Rodrguez, R Perez
Petruzzelli, I Gores.
19 Hospital J. B. Iturraspe, Santa Fe: E Schinner, MV Morcillo, F
Terenzani.
20 Hospital Italiano de Buenos Aires, CABA: G Izbizky, ML Gimenez,
C Meller, M Grasso, M Martinotti.
21 Hospital Municipal Materno Infantil Comodoro Meisner, Provincia
de Buenos Aires; I Scheller, J Marinelli, L Carrizo, S Baro, N Marasco.

Supporting Information
Additional Supporting Information may be found in the
online version of this article:
Data S1. Powerpoint slides summarising the study. n

89

Martinez de Tejada et al.

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