Sie sind auf Seite 1von 12

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 Hösli,d D Fernández,e D Surbek,f
M Huespe,g G Drack,h A Bunader,i S Rouillier,j G López de Degani,k E Seidenstein,l E Prentl,m
J Antón,n F Krähenmann,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
b
Centro de Investigación 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 Ramón Sardá, 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 Donación
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 Señora De Las Mercedes, San Miguel de Tucumán, 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 Rı́os, 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 Zürich, Zurich, Switzerland p Department of Obstetrics and Gynaecology, Hospital
Magdalena V. de Martı́nez, 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, Córdoba, Argentina t Hospital Virgen del Carmen, Zárate, Provincia de
Buenos Aires, Argentina u Department of Obstetrics and Gynaecology, Hospital Municipal Ostaciana B de Lavignolle, Morón, 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

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 daily of self-administered vaginal progesterone or placebo within
preterm labour. 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,
Setting Twenty-nine centres in Switzerland and Argentina.
re-admissions for preterm labour, length of hospital stay,
0/7
Population A total of 385 women with preterm labour (24 to and neonatal morbidity and mortality. The study was
336/7 weeks of gestation) treated with acute tocolysis. ended prematurely based on results of the intermediate
analysis.

Trial registration number: NCT00536003. Results Preterm birth occurred in 42.5% of women in the
*4P Trial group members are in Appendix 1.
progesterone group versus 35.5% in the placebo group (relative

ª 2014 Royal College of Obstetricians and Gynaecologists 1


Martinez de Tejada et al.

risk [RR] 1.2; 95% confidence interval [95% CI] 0.93–1.5). Conclusion There is no evidence that the daily administration of
Delivery at <32 and <34 weeks did not differ between the two 200 mg vaginal progesterone decreases preterm birth or improves
groups (12.9 versus 9.7%; [RR 1.3; 95% CI 0.7–2.5] and 19.7 neonatal outcome in women with preterm labour.
versus 12.9% [RR 1.5; 95% CI 0.9–2.4], respectively). The
Keywords Maternal tolerance, neonatal morbidity, neonatal
duration of tocolysis, hospitalisation, and recurrence of preterm
mortality, neonatology, obstetrics, preterm delivery, preterm
labour were comparable between groups. Neonatal morbidity
labour, vaginal progesterone.
occurred in 44 (22.8%) cases on progesterone versus 35 (18.8%)
cases on placebo (RR: 1.2; 95% CI 0.82–1.8), whereas there were Linked article This article is commented on by NorwitzThom
4 (2%) neonatal deaths in each study group. ER. To view this mini commentary visit http://dx.doi.org/10.1111/
1471-0528.13108.

Please cite this paper as: Martinez de Tejada B, Karolinski A, Ocampo MC, Laterra C, Hösli I, Fernández D, Surbek D, Huespe M, Drack G, Bunader A,
Rouillier S, López de Degani G, Seidenstein E, Prentl E, Antón J, Krähenmann 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 2014; DOI: 10.1111/1471-0528.13061.

bridge this knowledge gap, we conducted a multicentre,


Introduction
placebo-controlled trial to determine whether the adminis-
Preterm birth (PTB) (<37 weeks of gestation) is the leading tration of natural progesterone vaginally was effective in
cause of neonatal morbidity and mortality. In developed decreasing the risk of preterm delivery in women with
countries, the incidence of preterm delivery varies between PTL, who were also treated with tocolysis.
7 and 12%.1,2 This rate is higher in developing countries
where there is limited availability of neonatal care and
Methods
there are poorer clinical outcomes.3,4 Infants born preterm
account for 75% of perinatal deaths and half of all child- The Prevention of Preterm Delivery with Vaginal Progester-
hood neurodevelopmental disabilities.5,6 Consequently, PTB one in Women with Preterm Labour (4P) study was an
contributes to a large burden of disease, including high international, multicentre, randomised, prospective, dou-
immediate and long-term medical care costs, the need for ble-blind, placebo-controlled trial comparing vaginal natu-
special education services and institutionalised care for ral progesterone versus placebo in women with PTL.
physically and mentally disabled infants.7,8
In many cases, PTB occurs after spontaneous preterm Setting and participants
labour (PTL) (preterm uterine contractions with cervical We carried out the trial in nine hospitals in Switzerland
effacement and/or dilatation) and intact membranes.9,10 (from July 2006 to February 2011) and 20 hospitals in Argen-
Despite the identification of various risk factors, no inter- tina (from September 2008 to September 2012). Study coor-
vention has been found to be effective for the reduction of dination was carried out at the research unit of Geneva
PTB in women with symptoms of PTL.11,12 Acute tocolysis University Hospitals (HUG) (Geneva, Switzerland) and the
is effective in delaying the delivery of the fetus for 2–7 days Centro de Investigación en Salud Poblacional (Population
in the short term but it has not been shown to reduce long-- Health Research Centre [CISAP]) (Buenos Aires, Argentina).
term complications from preterm birth.13–18 In addition, Pregnant women with threatened PTB between 24 and
studies have failed to show a beneficial effect of maintenance <34 weeks of gestation (based on ultrasound scan before
tocolysis on pregnancy and perinatal outcomes.19–22 22 weeks of gestation) and treated with acute tocolysis
In recent years, progesterone was found to be effective (b-mimetics, oxytocin receptor antagonist, or cal-
for the prevention of PTB in women with a previous his- cium-channel blockers, depending on local protocols) and
tory of PTB and in those with a mid-trimester short cer- corticosteroids for fetal lung maturation were eligible for
vix.23–30 However, its effectiveness in women with PTL has inclusion in the study. Threatened PTB was defined as reg-
been less well evaluated with conflicting results reported. ular phasic uterine contractions with a minimum of two
Several small and unblinded clinical studies have reported a painful contractions in 10 minutes averaged over 30 min-
beneficial effect of natural progesterone or 17-hydroxypro- utes on cardiotocogram, together with at least one of the
gesterone caproate (17P) in reducing the duration of tocol- following criteria: shortened cervix detected by vaginal
ysis treatment and preventing PTB.31–34 Nevertheless, the ultrasound scanning (cervical length ≤30 mm until
largest study published to date found no efficacy for the 31 weeks of gestation or ≤25 mm from 32 weeks of gesta-
prevention of PTB with the use of 17P.35 In an attempt to tion onwards);36–38 short and dilated cervix detected

2 ª 2014 Royal College of Obstetricians and Gynaecologists


Vaginal progesterone in women with preterm labour

clinically (cervical length ≤10 mm or Bishop score ≥ 6);39 the provision of unnecessary capsules and allowed the strat-
progressive cervical shortening detected by serial clinical or ification of the recruited women in the two study groups
ultrasound examinations (≥5 mm difference between two by gestational age at inclusion. Each centre was provided
examinations); or a positive qualitative fetal fibronectin test initially with five boxes of each set and regularly supplied
(if available in the centre; QuikcheckfFN or TCM Holog- with additional boxes as necessary.
ic).40–42
Exclusion criteria were: maternal age <18 years, multiple Practical issues
pregnancy, cervical cerclage in situ, polyhydramnios Study participants were monitored using the following clin-
(defined as an amniotic fluid index >95th centile for gesta- ical and laboratory examinations, depending on local prac-
tional age or a greatest amniotic pocket >8 cm), premature tices: temperature; heart rate and blood pressure
rupture of membranes, suspected clinical chorioamnionitis measurement; fetal heart rate monitoring; cervical examina-
(defined as elevated white blood cell count, elevated tion; white blood cell count and C-reactive protein mea-
C-reactive protein, maternal and/or fetal tachycardia, uter- surement; and urinary, genital and recto-vaginal
ine tenderness and/or foul smelling amniotic fluid), cervical microbiological cultures. Women with positive culture
dilatation >3 cm, placenta praevia or suspected placental results were treated with specific antibiotics following the
abruption, intrauterine growth restriction, non-reassuring local guidelines at each centre. For each PTL episode result-
fetal wellbeing, pre-eclampsia, severe hypertension, any ing in a new hospitalisation, the standard local protocol
other maternal or fetal pathology that required medically was repeated and clinical data were collected. Regarding
indicated preterm delivery and anticipated difficulty with Group B Streptococcus (GBS) prophylaxis, women were
follow up. Eligible women were informed about the study screened for GBS colonisation at admission and received
by the local investigator and provided written consent intrapartum GBS antibiotic prophylaxis if colonised or if
before recruitment. unknown status and delivering preterm.

Randomisation and intervention Usual care


After obtaining informed consent and within 48 hours after Women were managed by their obstetrician from the time
initiating tocolysis, the local investigator randomly allo- of inclusion until delivery. Antenatal care decisions were
cated participants to either vaginal capsules of 200 mg of left to the attending clinicians at each institution. Members
natural progesterone or placebo. The woman was asked to of the research team were available to respond to any que-
self-administer the treatment once a day until 36 weeks ries regarding the study protocol.
and 6 days of gestation or until preterm delivery, which-
ever occurred first. Medication was stopped after preterm Outcomes
rupture of the membranes before term. Randomisation was The primary outcome was preterm delivery before
performed in a 1:1 ratio using a list created with an inde- 37 weeks of gestation. Prespecified secondary outcomes
pendent, centralised, computer-generated randomisation were as follows.
sequence (PASW STATISTICS, version 18; IBM Corp., Obstetrical outcomes: preterm delivery before 34 weeks and before
Armonk, NY, USA) stratified by centre and by gestational 32 weeks of gestation; duration of tocolysis; length of hospital stay
for the initial episode; and the overall number of re-admissions for
age group at inclusion (group 1: <28 weeks; group 2: 28 to
PTL.
<32 weeks; group 3: ≥32 weeks). The randomisation codes
Neonatal outcomes:newborn birth weight; hospitalisation at the neonatal
were kept at the pharmacy departments of HUG and intensive care unit; a composite estimate of neonatal morbidity includ-
CISAP. ing the following variables: transient tachypnoea; respiratory distress
Placebo capsules had the same appearance, feel and syndrome; bronchopulmonary dysplasia; ventilatory support (continu-
odour as the active medication. Both the active drug and ous positive airway pressure, intubation), necrotising enterocolitis;
placebo were stored in boxes with the same appearance intraventricular haemorrhage; periventricular leucomalacia; retinopathy;
sepsis and patent ductus arteriosus; and neonatal death.
and weight (i.e. the local investigator, the clinical team and
Drug tolerance: local reactions (soreness, itching, bruising, and vaginal
the women were not aware of the type of medication
discharge) and systemic reactions (any documented unusual sign or
administered). Three different sets of boxes containing pro- symptom possibly related to drug administration).
gesterone or placebo to be administered either from 24 to Definitions of obstetrical and neonatal complications
37 weeks (91 days), 28 to 37 weeks (63 days), or 32 to were standardised across centres according to the World
37 weeks (35 days) of gestation were centrally prepared at Health Organization standards. Charts were locally
the HUG pharmacy for the Swiss centres and at the CISAP reviewed by an obstetrician and a neonatologist unaware of
pharmacy for the Argentinean centres. Boxes were clearly the allocation to the study group to determine the clinical
labelled with the corresponding study number, gestational outcomes (assessor blinding).
age group and number of capsules. This strategy minimised

ª 2014 Royal College of Obstetricians and Gynaecologists 3


Martinez de Tejada et al.

Data collection and management using nonparametric statistics if not normally distributed.
After informed consent, we collected baseline characteristics A P-value < 0.05 (two-tailed) was considered to indicate
including a socio-economic score (range 2–12) that took statistical significance. The incidence of the primary out-
into account the woman’s educational level and partner’s come (delivery before 37 weeks) and of most secondary
professional status. A score >10 indicated having achieved outcomes was calculated among all women with the rele-
tertiary education/high socio-economic status.43 Pregnancy vant data at delivery. The incidence of preterm delivery
outcomes and medication side effects were prospectively before 32 weeks of gestation was computed with women
collected using a case report form designed specifically for included into the study before 32 weeks of gestation as the
the trial. Every 2 weeks, participants were asked to provide denominator.
the number of vaginal suppositories that they had used. The effect of the intervention was expressed as relative
They were asked also whether they had consulted a physi- risk (RR) and 95% confidence intervals (CI) around these
cian for PTL symptoms, had experienced adverse events, estimates. We performed a secondary analysis (per proto-
had undergone any medical procedures, or had been given col analyses) excluding women who were wrongly included
any other medication since their last visit. After delivery, in the study (violation of inclusion and/or exclusion crite-
the study personnel reviewed all prenatal, delivery, postpar- ria) or who discontinued treatment, either by themselves
tum and newborn records and documented the date of or by their physicians. A time-to-event analysis was per-
delivery, newborn birthweight and other neonatal out- formed to compare the probability of remaining undeliv-
comes. ered after 36 completed weeks between the two groups.
Severe maternal or neonatal complications were immedi- Kaplan–Meier curves were compared using the log-rank
ately reported to the coordinating centres, which notified test. The analysis was conducted without any knowledge of
the Swiss regulatory agency for the authorisation and group allocation.
supervision of therapeutic products (Swissmedic) or its A planned interim analysis (after collection of delivery
Argentinean counterpart (ANMAT: Administración Nac- data on 300 recruited women) on the effectiveness and
ional de Medicamentos, Alimentos y Tecnologı́a Medica). safety was performed by a panel of independent experts
We assessed compliance by counting the number of (data safety monitoring board and two independent statis-
unused capsules returned to the coordinating centres. We ticians) not involved in the trial or its design. The criteria
defined noncompliance as being when the woman has to stop the study were described in the protocol and fol-
administered <80% of the capsules prescribed. lowed the O’Brien and Fleming rule, i.e. P < 0.015 for the
After completion, case report forms were sent to the primary outcome.45 At the interim analysis, conducted
research coordinating centre to ensure quality and comple- when outcome data were available for 302 women (48% of
tion of data, and for entry into a dedicated database. Clini- the planned sample), a conditional power analysis revealed
cal audits were regularly carried out to evaluate the quality that even if recruitment continued to the final sample size
of data collection by each hospital. of 626 women, the probability of showing a benefit of pro-
gesterone for the primary outcome was 0%. Based on the
Sample size result of this analysis, study enrolment was stopped in June
We calculated our sample size based on differences between 2012. At that time, 385 women had been randomised.
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
Results
occur in 30–40% of cases.44 A sample of 626 women was Of 1466 women hospitalised for PTL during the study per-
sufficient to detect a risk reduction from 30 to 20% in pre- iod, 576 were eligible for inclusion into the study, of whom
term delivery before 37 weeks with 80% power and a two 191 declined to participate in the trial. In total, 385 women
-sided type I error of 5%. were included and randomly allocated to progesterone
(n = 197) or placebo (n = 188). Six women (four in the
Statistical methods progesterone group and two in the placebo group) were
The main statistical analyses were performed on an inten- lost to follow up (no data on delivery and newborn). Data
tion-to-treat basis using IBM SPSS (version 19; SPSS Inc., from 379 women were included in the analysis, of which
Chicago, IL, USA) and OPEN EPI softwares. Frequencies in 193 were randomised to receive progesterone and 186 to
categorical variables were expressed as a number with the placebo (Figure 1).
percentage of the total allocation arm and compared using For the per protocol analysis, 19 women (eight in the
Fisher’s exact test. Continuous measures were presented as placebo group and 11 in the progesterone group) were
means with standard deviations and compared using excluded because of protocol violations (n = 10) or treat-
Student’s t-test, or as medians and ranges and compared ment interruption (n = 9; four cases of voluntary with-

4 ª 2014 Royal College of Obstetricians and Gynaecologists


Vaginal progesterone in women with preterm labour

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) Allocated to PLACEBO (n = 188)


Received allocated intervention (n = 197) Received allocated intervention (n = 188)

Follow up
Lost to follow up (No data from delivery because Lost to follow up (No data from delivery because
delivered in other hospital) (n = 3) delivered in other hospital (n = 2)

Discontinued intervention (withdrew consent) (n = 1) Discontinued intervention (n = 0)

Analysis

Analysed (intention-to-treat) (n = 193) Analysed (intention-to-treat) (n = 186)

Excluded from analysis per protocol (n = 11) Excluded from analysis per protocol (n = 8)
Randomised without meeting inclusion criteria (n = 6) Randomised without meeting inclusion criteria (n = 4)
Stopped treatment (n = 5) Stopped treatment (n = 4)

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

drawal by women and five cases due to the decision made Two hundred and seventy-three (72%) women returned
by the attending physicians) leading to 360 women (Fig- their unused medication and empty blisters to the coordi-
ure 1). nating centres: 142 women (52%) in the progesterone
Baseline characteristics of the women included in the group and 131 women (48%) in the placebo group. Among
two groups were comparable (Table 1). Included women those, compliance was good in 83 (58%) women in the
had a mean age of 27.6 years (SD 6.2), and a mean gesta- progesterone group and in 76 (58%) in the placebo group.
tional age at study entry of 29.5 weeks (SD 2.7). There Information for not complying with the study medication
were 136 (35.9%) nulliparous women and 91 (24.0%) had in the remaining women was not recorded.
a history of previous preterm delivery or late miscarriage.
Data on cervical length were available only for patients Primary outcome and preterm delivery
from Swiss centres; data on fetal fibronectin were available Preterm birth <37 weeks occurred in 42.5% of women in the
in 61 women from Switzerland. progesterone group versus 35.5% of women in the placebo
The overall number of women with preterm delivery was group (P = 0.20). Delivery before 34 weeks and delivery
148 (39%) <37 weeks, 62 (16.4%) <34 weeks, and 36 out before 32 weeks were also similar between groups (Table 2).
of 317 women (11%) <32 weeks. There were 44 (11.6%) After excluding women with an indication for elective
cases of premature rupture of the membranes before term preterm delivery, there were 74/185 (40.0%) spontaneous
(22 in each group) and 26 cases of delivery induced before preterm deliveries among the progesterone group and 48/
term (8/193 [4.1%] in the progesterone group and 18/186 168 (28.6%) in the placebo group (RR 1.4; 95% CI 1.04–
[9.7%] in the placebo group; P = 0.05). 1.88; P = 0.03).

ª 2014 Royal College of Obstetricians and Gynaecologists 5


Martinez de Tejada et al.

Table 1. Baseline characteristics of participants at study entry

Characteristics Progesterone (n = 193) Placebo (n = 186)

Ethnic origin, n/total (%)


Caucasian 98/192 (51.0) 92/184 (50.0)
Hispanic 79/192 (41.1) 85/184 (46.2)
Other 15/192 (7.8) 7/184 (3.8)
Maternal age, n/total (%) 193/193 (100) 186/186 (100)
Maternal age in years, 27.92 (6.47) [18–42] 27.34 (5.79) [18–43]
mean (SD) and range
Maternal weight, n/total (%) 187/193 (96.9) 183/186 (98.4)
Maternal weight in kg 58.98 (11.51) [40–109] 58.42 (9.77) [36–95]
(mean  SD) and range
Family situation
Couple 183/193 (94.8) 174/183 (95.1)
Single with no partner 10/193 (5.2) 9/183 (4.9)
Professional situation
Working (employed or independent) 82/190 (43.2) 86/184 (46.7)
Other 108/190 (56.8) 98/184 (53.3)
SEE score
≤10 170/193 (88.1) 162/186 (87.1)
>10 23/193 (11.9) 24/186 (12.9)
Gynaecological surgery/malformation (yes) 19/193 (9.8) 23/186 (12.4)
Nulliparity (yes) 63/193 (32.6) 73/186 (39.2)
One or more late abortion (yes) 2/193 (1.0) 1/186 (0.5)
One or more preterm birth (yes) 46/193 (23.8) 39/186 (21.0)
Smoking during pregnancy (yes) 37/193 (19.2) 37/186 (19.9)
Haemorrage during pregnancy (yes) 19/192 (9.9) 19/186 (10.2)
Gestational age at entry, n/total (%) 193/193 (100) 186/186 (100)
Gestational age at entry, weeks 29.50 (2.74) [24–34] 29.51 (2.72) [24–33]
(mean  SD) and range
CL measurement at entry (yes) 124/193 (64.2) 124/186 (66.7)
CL at entry, mm (mean  SD) 19.35 (8.36) [4–45] 19.56 (8.15) [0–46]
fFN at entry, n/total (%) 27/191 (14.1) 34/183 (18.6)
Positive fFN at entry, n/total (%) 12/26 (46.2) 14/33 (42.4)
Tocolyses given at randomisation 193/193 (100) 186/186 (100)
Indomethacin 3/193 (1.5) 4/186 (2.1)
b-mimetic 158/193 (81.0) 143/186 (74.1)
Oxytocin receptor antagonist 15/193 (7.6) 20/186 (10.4)
Calcium inhibitors 22/193 (11.1) 26/186 (13.7)

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

The time-to-event (preterm delivery) analysis with in the progesterone group compared with the placebo
censoring at 37 weeks when delivering at term showed a group (RR 1.7; 95% CI 1.01–2.67; Table 2).
hazard ratio of 1.3 (95% CI 0.9–1.8; log-rank Mantel–Cox:
0.11; Figure 2). Duration of tocolysis, hospitalisation, and Neonatal outcomes
frequency of a new episode of PTL were comparable Neonatal weight at birth, Apgar score at 5 min <7, neona-
between the study groups, as were the number of women tal intensive care unit hospitalisation, neonatal mortality
receiving corticosteroids for fetal lung maturation and and the composite outcome of morbidity were also compa-
undergoing caesarean delivery (Table 2). rable between the two groups (Table 3).
After exclusion of cases of protocol violation and discon-
tinuation of medication, the per protocol analysis showed Side effects/adverse events
similar rates of preterm delivery before 37 and <32 weeks The incidence of side effects (mainly vaginal pruritus,
of gestation between the two groups. In this analysis, there burning, or increased secretions) was comparable between
were more women delivering before 34 weeks of gestation the two groups: 11 (5.7%) in the progesterone group and

6 ª 2014 Royal College of Obstetricians and Gynaecologists


Vaginal progesterone in women with preterm labour

Table 2. Obstetrical endpoints

Variable Progesterone (n = 193) Placebo (n = 186) P RR 95% CI

Gestational age at delivery (weeks) (mean  SD) and range 36.05 (3.54) [24–41] 36.63 (3.11) [25–41] 0.09
Delivery <37 weeks, n/total n (%) 82/193 (42.5) 66/186 (35.5) 0.20 1.2 0.93–1.5
Delivery <34 weeks, n/total n (%) 38/193 (19.7) 24/186 (12.9) 0.10 1.5 0.95–2.4
Delivery <32 weeks, n/total n (%) 21/163 (12.9) 15/154 (9.7) 0.48 1.32 0.71–2.5
Tocolysis duration (hours), median (range) 48.00 (0–1740) 48.00 (0–1672) 0.84
Readmissions for preterm labour (yes) 13/193 (6.7) 19/184 (10.3) 0.29 0.65 0.33–1.28
Duration of hospitalisation (days), median (range) 6.00 (0–97) 7.00 (1–68) 0.09
Time to delivery (days), median (range) 45.00 (0–114) 52.00 (2–112) 0.13
Caesarean section, n/total n (%) 41/193 (21.2) 37/186 (19.9) 0.84 1.07 0.72–1.59
Corticosteroids for lung maturation, n/total (%) 191/193 (99.0) 185/186 (99.5) >0.99 0.99 0.97–1.01
Analysis ‘per protocol’*
Delivery <37 weeks, n/total n (%) 77/182 (55.0) 63/178 (35.4) 0.22 1.20 0.92–1.55
Delivery <34 weeks, n/total n (%) 37/182 (20.3) 22/178 (12.4) 0.06 1.65 1.01–2.67
Delivery <32 weeks, n/total n (%) 20/154 (13.0) 15/148(10.1) 0.55 1.28 0.68–2.41

*Analysis after exclusion of protocol violations and medication discontinuations.

37 weeks. 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 hospi-
tal stays, or the rate of recurrence of PTL.

Strengths and limitations


Our study is the largest randomised trial evaluating the
Figure 2. Distribution of time to delivery (in days) in the progesterone
effectiveness of progesterone to prevent PTB in women
and placebo groups. 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
12 (6.5%) in the placebo group (RR 0.9; 95% CI 0.40– hospitals over two countries (Switzerland and Argentina)
1.96). with different health systems and among women of differ-
There were ten serious adverse events (four in the pro- ent socio-economic levels. This increased the generalisabili-
gesterone group and six in the placebo group). In the ty of our results to other settings. The fact that the
progesterone arm, there were three neonatal deaths from tocolytic treatments employed in the study are those that
complications due to extreme prematurity (two at are currently used by most clinicians leads also to an
24 weeks and one at 28 weeks) and one pregnant woman increased ability for generalisation of our results. We chose
with liver cholestasis who had labour induced at vaginal progesterone suppositories because most previous

ª 2014 Royal College of Obstetricians and Gynaecologists 7


Martinez de Tejada et al.

Table 3. Neonatal outcome

Progesterone (n = 193) Placebo (n = 186) P RR 95% CI

Birthweight (g), median (range) 2880.00 (500–4685) 2955.00 (820–4900) 0.5


Apgar <7 at 5 minutes, n/total (%) 7/193 (3.6) 5/186 (2.7) 0.82 1.35 0.43–4.18
Neonatal mortality, n/total (%) 4/193 (2.1) 4/186 (2.2) >0.99 0.96 0.24–3.80
NICU hospitalisation, n/total (%) 57/191 (29.8) 47/185 (25.4) 0.42 1.17 0.84–1.63
Morbidity, n/total (%)* 44/193 (22.8) 35/186 (18.8) 0.41 1.21 0.82–1.80

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 chinetti et al.33,34 found that 17P was associated with both
among asymptomatic women with a short cervix.46 More- a reduction in the risk of cervical shortening and preterm
over, vaginal progesterone is better tolerated and more delivery. By contrast, Rozenberg et al. (the largest trial so
easily administered than intramuscular 17P. far) and Tan et al. found no difference in median time to
A weakness of our study is the method used to assess delivery, rates of preterm delivery before 37, 34 or 32 weeks
compliance to drug treatment. Over 25% of participating of gestation, or adverse perinatal outcomes, with Rozenberg
women did not return the unused medication, and among et al. specifically reporting a potential worsening of the
those who did, we cannot be certain that they really outcome after the use of 17P. Of note, none of these stud-
administered it. The number of women returning medica- ies was placebo controlled.35,54 Regarding natural progester-
tion and demonstrating adequate medication compliance one, two studies have used oral progesterone and observed
was similar between the two groups. some positive effects.53,55 Noblot et al.55 performed a dou-
ble-blind trial of 44 women randomised during an episode
Interpretation of preterm labour and treated with intravenous b-agonists.
We included women with a short cervix as measured by Although they showed no significant difference in the pro-
vaginal ultrasound (<10th centile for the gestational age at longation of pregnancy, the mean quantity of b-agonists
inclusion),47 as well as women with marked clinical administered and associated costs were significantly lower
changes of the cervix.48–50 We included also women with in the progesterone group.55 In the study by Erny et al.,53
contractions and positive fibronectin test results, which is high doses of progesterone were used as acute tocolysis and
another group at high risk for preterm delivery.26,41 Never- compared with placebo. Both studies recruited very few
theless, fibronectin was investigated in only 16% of the women (that of Noblot et al. only included 44 of the 60
women. Although our inclusion criteria were heterogeneous cases required) and were of low quality. In relation to the
due to the multiple centres participating in the study, the use of vaginal natural progesterone, Borna and Sahabi (70
high preterm delivery rate (39%) implies that the popula- women) and Arikan et al. (83 women) showed that, in
tion was indeed at high risk for preterm delivery to assess women with PTL, vaginal progesterone (400 and 200 mg
the effectiveness of progesterone in the prevention of this daily, respectively) was effective in prolonging the mean
outcome. gestational age at the time of delivery or in postponing the
We investigated the effect of progesterone in women in delivery.31,56 In addition, progesterone was effective in
conjunction with acute tocolysis as previous studies showed increasing neonatal weight and in reducing the incidence of
that the combination of progesterone with nifedipine or low birthweight and admission to the neonatal intensive
b-mimetics had synergistic effects and the total dosage of care unit. These studies were small, not placebo-controlled
tocolytic medications could be reduced.51–53 However, we and restricted to a single centre. Our study is larger than
found neither a difference in the duration of tocolytic previous trials and placebo-controlled. In addition, PTL
treatment between the progesterone and the placebo group was defined either with objective criteria (sonographic
nor an interaction between progesterone and the various short cervix or positive fibronectin test) or with specific
tocolytics. and strict clinical criteria. Borna and Sahabi, and Arikan
Several randomised controlled studies have assessed the et al. included women with contractions and a clinical
effectiveness of progesterone on prolongation of pregnancy modified cervix (defined as shortening and dilatation), but
or reduction of prematurity in women with PTL. Some with no additional specifications.31,56 Hence, the included
have used intramuscular 17P as maintenance tocolysis: Fac- women could represent a lower risk population (PTB rate

8 ª 2014 Royal College of Obstetricians and Gynaecologists


Vaginal progesterone in women with preterm labour

is not given in Borna’s study) for PTB compared with our Disclosure of interests
study. Compared with Arikan et al., our study included All authors have completed the ICMJE uniform disclosure
women with a lower mean gestational age and a shorter form at www.icmje.org/coi_disclosure.pdf (available on
cervical length at admission. request from the corresponding author). BMT has received
Recently, in a nonrandomised, retrospective study, Bom- a travel grant from Besins Laboratory. All other authors
ba-Opon et al.32 reported a strong effect of vaginal proges- declare no other relationships or activities with companies
terone in women with PTL. The study was small (190 that might have an interest in the submitted work.
women) and women were included if hospitalised for PTL
diagnosed as the presence of contractions and tocolysis. Contribution to authorship
Although the gestational age at delivery was similar between BMT, MB and OI contributed to the design of the trial.
groups, the authors stated that there were fewer PTB before BMT, MB and OI wrote the grant application. BMT and
34 weeks of gestation in the progesterone group (22 versus AK obtained funding for the study. All authors except
16 women). We did not observe any benefit for the preven- BWM participated in recruitment of participants and data
tion of PTB at earlier gestational ages (i.e. <34 or <32 weeks collection. BMT, VOG, MB, MCO, LK, VW, MVB and AK
of gestation) and in the per protocol analysis, we found a analysed and interpreted the data. BMT, AK and BWM
trend towards a higher rate of PTB <34 weeks of gestation drafted the manuscript. All authors critically reviewed the
in the group of women on progesterone. We found also a manuscript. All authors (BMT, AK, MCO, CL, IH, DF, DS,
significantly higher rate of spontaneous preterm delivery in MH, GD, AB, SR, GLD, ES, EP, JA, FK, DN, MP, JCN, RP,
the group treated with progesterone. Progesterone is known CT, RE, QT, GB, AM, BP, BWM, LK, VW, MB, VOG,
to have an immune-modulator effect, which might enhance MVB, OI) except FS (who recently died) read and
the inflammatory cascade already initiated during PTL.57 approved the final manuscript before submission. BMT
Caution should be exercised regarding this finding as spon- accepts full responsibility for this work and acts as guaran-
taneous preterm delivery was not a prespecified outcome tor for the study.
and numbers were small.
It can be argued that we did not use progesterone as Details of ethics approval
maintenance tocolysis because some of the women deli- In Switzerland, ethical approval for the study was given by
vered within the first 48 hours and were not stabilised the independent ethics committees of the Swiss centres
with acute tocolysis. Nevertheless, only nine women with central approval in Geneva (CER:04-196 in Geneva).
delivered within the first 48 hours. To investigate this In Argentina, ethical approval was obtained from a central
potential bias, we performed a secondary analysis inclu- independent committee of ethics in clinical research (CE-
ding only women stabilised for at least 48 hours and MIC), from the institutional review board of the coordinat-
obtained the same result, i.e. progesterone did not ing centre CISAP/Hospital Durand (authorisation no.
decrease the risk of PTB. 0537), and from each institutional review board of the
Meta-analyses have confirmed the efficacy of various Argentinean hospitals participating in the trial. The study
progesterone treatments in the reduction of PTB in women was notified to the national drug regulatory agencies
with a previous PTB.30,58–61 Based on this, the American (Swissmedic and ANMAT) and conducted in accordance
College of Obstetricians and Gynecologists recommend with ‘Good Practice in Clinical Trials’ (GPCT) guidelines.
administering prophylactic progesterone treatment to this Registration at www.clinical-trials.gov was ensured with
high-risk group of women and strongly encourages further identification number NCT00536003. All participants gave
randomised trials in other high-risk populations such as written informed consent before taking part in the study.
women with PTL.28 However, the two largest studies per-
formed until now (Rozenberg et al. with 17P and our trial Funding
with vaginal natural progesterone) have shown no benefit The project was supported by grants from the University
with progesterone treatment in the prevention of PTB in Hospitals of Geneva (PRD-05103), the HUG Clinical
women with PTL. Research Center of the Swiss National Foundation (main
sponsor), Department of Reproductive Health and
Research, World Health Organization, Ministry of Health
Conclusion
of Ciudad Autónoma de Buenos Aires (grant for A Karo-
There is no evidence that the further administration of linski, resolution no. 2124/2011- Investigator’s career) and
200 mg daily of vaginal progesterone decreases PTB or a personal scholarship for Mrs MC Ocampo (degree no.
improves neonatal outcome in women with PTL following 685/10). Besins Laboratory produced and supplied the
tocolytic therapy. study drugs (utrogestan and placebo) free of charge. The

ª 2014 Royal College of Obstetricians and Gynaecologists 9


Martinez de Tejada et al.

funding sources did not participate in the study design, Bertolino, MC Ocampo, V Wainer, L Kanterewicz, C Rodriguez, L
data analysis, data interpretation, or writing of the report. Colazo.
2 Hospital Materno Infantil Ramón Sardá, CABA: C Laterra, S Ra-
mirez Almanza, E Swistak, Y González.
Acknowledgements 3 Hospital Materno Infantil de San Isidro, San Isidro, Provincia de
We thank the research nurses, research midwives and secre- Buenos Aires: D Fernández, G Zalazar, M Rubino, B Sánchez, A
taries of our study consortium, including the residents, Rivara, C Mercado, S Sagarna.
nurses, midwives and gynaecologists of the participating 4 Hospital Donación Francisco Santojanni, CABA: M Huespe, R
centres, for their help with participant recruitment and data Luca, L Claus, V Castellano, L Domingo, C Castro, D Gil, ME
collection. We thank also B. Cerrutti, A. Gayet-Ageron, and Rodriguez.
5 Hospital Maternidad Nuestra Señora De Las Mercedes, Tucumán: A
T Perneger for their help in data analysis and interpretation.
Bunader, NE Capua, M Romano, ME Longo, E Balbo, S Martı́nez
Special thanks to the members of the data safety monitoring Lozano, C Petros.
committee (J. Demoles, JJ Pasquier and F Goffinet) for 6 Hospital Materno Infantil San Roque, Entre Rı́os: G López de De-
monitoring the trial and performing the interim analysis. gani, M Coniglio, R Harris, M Leanga, R Martı́nez, F Felici, M de
We thank Besins International, France, for the production Bueno, F Reffino, J Castagnola, P Brarda, ME Parra, R Montenegro,
of study medication. We thank M. Merialdi, Department of G Fernández, G Schmadke.
Reproductive Health and Research, World Health Organiza- 7 Hospital Bernardino Rivadavia, CABA: E Seidenstein, R Pontoriero,
C González, J Alduncin.
tion, for partial support of the implementation of the 4P
8 Hospital Heroes de Malvinas, Provincia de Buenos Aires: J Antón,
Trial in Argentina. We thank R Sudan for her editing work M Damiano, G Sánchez, M Rebottaro, L Altamira, V Garbarino, C
of the final version of the paper. Rebottaro.
9 Hospital Magdalena V. de Martı́nez, Provincia de Buenos Aires: D
Transparency statement Nowacki, M Ferrary, C Buttner, P González, Y Godoy.
The manuscript is an honest, accurate, and transparent 10 Hospital Dr. Cosme Argerich, CABA: M Poncelas, E Bertola, L
account of the study being reported. We confirm that no Langdon, O Jimenez, L Mezzabota.
11 Hospital Carlos G. Durand, CABA: JC Nassif, CA Becker, JM Baier,
important aspects of the study have been omitted.
M Grichener, P Trotti.
12 Hospital Regional Villa Dolores, Córdoba: R Papera, M Chaloupka,
Data sharing M Zárate, L Bogino, E Bertone, F Olmedo, M Barrionuevo, N Mari-
Patient-level data are available from the corresponding ojouls.
author. 13 Hospital Virgen del Carmen, Provincia de Buenos Aires: C Tuma, C
Gregoris.
Appendix 1 14 Hospital Municipal Ostaciana B. de Lavignolle, Provincia de Buenos
Aires: R Espoile, C Muzio, C Nocetto, D Carozzi, V Pelaez, C De
Moura.
List of participating departments and 15 Hospital Comunal de Tigre, Provincia de Buenos Aires: O Tiberio, M
collaborators Sagastume, L Martı́nez, D Morales.
In Switzerland, the 4P group comprises: 16 Hospital J. M. Penna, CABA: G Breccia, E Aguilera, E Werbicki, S
1 Geneva University Hospitals and University of Geneva Faculty of Medi- Bover.
cine, Geneva (global and Swiss coordinating centre): B Martinez de Tej- 17 Hospital Dr. T. Alvarez, CABA: A Messina, MF Stillo, M Joao, D
ada, O Irion, M Boulvain, M Tellenbach, V Othenin-Girard, E Vögele, R Crema, L Wiliams, C Espada, V Gomariz, ME Calo.
Azbar. 18 Hospital Interzonal Alberto Antranik Eurnekian, Provincia de Buenos
2 University Hospital, University Basel, Basel: I Hösli, A Raggi, A Bir- Aires: B Peker, D Longhi, ML Pisanelli, L Giglio, J Rodrı́guez, R Perez
kenmaier, S Kann. Petruzzelli, I Gores.
3 University Hospital and University of Bern, Bern: D Surbek, K Scheib- 19 Hospital J. B. Iturraspe, Santa Fe: E Schinner, MV Morcillo, F
ner, M Huguelet, E Amann, M Baumann, E Jakob. Terenzani.
4 Kantonales Frauenspital Chur, Chur: K Biedermann. 20 Hospital Italiano de Buenos Aires, CABA: G Izbizky, ML Gimenez,
5 Frauenklinik Kantonspital Luzern, Lucerne: M Hodel. C Meller, M Grasso, M Martinotti.
6 Frauenklinik Kantonspital St Gall, St Gall: G Drack, T Fischer, K Pfau, 21 Hospital Municipal Materno Infantil Comodoro Meisner, Provincia
K Estermann. de Buenos Aires; I Scheller, J Marinelli, L Carrizo, S Baro, N Marasco.
7 Centre Hospitalier Universitaire Vaudois, Lausanne: P Hohlfeld, S Ger-
ber, S Rouiller-Cornu, R Capoccia Brugger, A Nessi, C Rodriguez-Mail-
lot, PA Pradervand, P Bodenmann, S Fornage. References
8 Frauenklinik Kantonspital Winterthur, Winterthur: E Prentl, E Amann.
1 Chang HH, Larson J, Blencowe H, Spong CY, Simpson JL, Lawn JE.
9 University Hospital Zurich, Zurich: F Krähenmann, R Zimmermann.
Preterm births in countries with a very high human development
In Argentina: index—authors’ reply. Lancet 2013;381:1356–7.
1 Centro de Investigación en Salud Poblacional –Population Health 2 Hamilton BE, Martin JA, Ventura SJ. Births: preliminary data for
Research Centre)/Hospital Durand, Ciudad Autónoma de Buenos 2005. Natl Vital Stat Rep 2006;55:1–18.
Aires (CABA) (Argentinean coordinating centre): A Karolinski, MV

10 ª 2014 Royal College of Obstetricians and Gynaecologists


Vaginal progesterone in women with preterm labour

3 Ngoc NT, Merialdi M, Abdel-Aleem H, Carroli G, Purwar M, Zavaleta 22 Papatsonis D, Flenady V, Liley H. Maintenance therapy with oxytocin
N, et al. Causes of stillbirths and early neonatal deaths: data from antagonists for inhibiting preterm birth after threatened preterm
7993 pregnancies in six developing countries. Bull World Health labour. Cochrane Database Syst Rev 2009:CD005938.
Organ 2006;84:699–705. 23 Meis PJ, Klebanoff M, Thom E, Dombrowski MP, Sibai B,
4 Feresu SA, Harlow SD, Welch K, Gillespie BW. Incidence of and Moawad AH, et al. Prevention of recurrent preterm delivery by 17
socio-demographic risk factors for stillbirth, preterm birth and low a-hydroxyprogesterone caproate. N Engl J Med 2003;348:2379–
birthweight among Zimbabwean women. Paediatr Perinat Epidemiol 85.
2004;18:154–63. 24 da Fonseca EB, Bittar RE, Carvalho MH, Zugaib M. Prophylactic
5 Mercer B. Preterm premature rupture of the membranes. Obstet administration of progesterone by vaginal suppository to reduce the
Gynecol 2003;101:178–93. incidence of spontaneous preterm birth in women at increased risk:
6 Hack M, Taylor HG, Klein N, Eiben R, Schatschneider C, a randomized placebo-controlled double-blind study. Am J Obstet
Mercuri-Minich N. School-age outcomes in children with birth Gynecol 2003;188:419–24.
weights under 750 g. N Engl J Med 1994;331:753–9. 25 Preterm birth: what can be done? Lancet 2008;371:2.
7 Martin JA, Hamilton BE, Ventura SJ, Osterman MJ, Kirmeyer S, 26 Chandiramani M, Di Renzo GC, Gottschalk E, Helmer H, Henrich W,
Mathews TJ, et al. Births: final data for 2009. Natl Vital Stat Rep Hoesli I, et al. Fetal fibronectin as a predictor of spontaneous
2011;60:1–70. preterm birth: a European perspective. J Matern Fetal Neonatal Med
8 Murray CJ, Vos T, Lozano R, Naghavi M, Flaxman AD, Michaud 2011;24:330–6.
C, et al. Disability-adjusted life years (DALYs) for 291 diseases and 27 Society for Maternal-Fetal Medicine Publications Committee, with
injuries in 21 regions, 1990–2010: a systematic analysis for the assistance of Vincenzo Berghella. Progesterone and preterm birth
Global Burden of Disease Study 2010. Lancet 2012;380:2197– prevention: translating clinical trials data into clinical practice. Am J
223. Obstet Gynecol 2012;206:376–86.
9 Lockwood CJ, Kuczynski E. Risk stratification and pathological 28 Committee on Practice Bulletins—Obstetrics, The American College
mechanisms in preterm delivery. Paediatr Perinat Epidemiol 2001;15 of Obstetricians and Gynecologists. Practice bulletin no. 130:
(Suppl 2):78–89. prediction and prevention of preterm birth. Obstet Gynecol
10 Romero R, Gomez R, Chaiworapongsa T, Conoscenti G, Kim JC, 2012;120:954–73.
Kim YM. The role of infection in preterm labour and delivery. 29 Su LL, Samuel M, Chong YS. Progestational agents for treating
Paediatr Perinat Epidemiol 2001;15(Suppl 2):41–56. threatened or established preterm labour. Cochrane Database Syst
11 Lockwood CJ, Dudenhausen JW. New approaches to the prediction Rev 2010:CD006770.
of preterm delivery. J Perinat Med 1993;21:441–52. 30 Dodd JM, Jones L, Flenady V, Cincotta R, Crowther CA. Prenatal
12 Copper RL, Goldenberg RL, Davis RO, Cutter GR, DuBard MB, administration of progesterone for preventing preterm birth in
Corliss DK, et al. Warning symptoms, uterine contractions, and women considered to be at risk of preterm birth. Cochrane
cervical examination findings in women at risk of preterm delivery. Database Syst Rev 2013;7:CD004947.
Am J Obstet Gynecol 1990;162:748–54. 31 Borna S, Sahabi N. Progesterone for maintenance tocolytic therapy
13 Treatment of preterm labor with the b-adrenergic agonist ritodrine. after threatened preterm labour: a randomised controlled trial. Aust
The Canadian Preterm Labor Investigators Group. N Engl J Med N Z J Obstet Gynaecol 2008;48:58–63.
1992;327:308–12. 32 Bomba-Opon DA, Kosinska-Kaczynska K, Kosinski P, Wegrzyn P,
14 King JF, Grant A, Keirse MJ, Chalmers I. Beta-mimetics in preterm Kaczynski B, Wielgos M. Vaginal progesterone after tocolytic
labour: an overview of the randomized controlled trials. BJOG therapy in threatened preterm labor. J Matern Fetal Neonatal Med
1988;95:211–22. 2012;25:1156–9.
15 Romero R, Sibai BM, Sanchez-Ramos L, Valenzuela GJ, Veille JC, 33 Facchinetti F, Dante G, Venturini P, Paganelli S, Volpe A.
Tabor B, et al. An oxytocin receptor antagonist (atosiban) in the 17a-hydroxy-progesterone effects on cervical proinflammatory
treatment of preterm labor: a randomized, double-blind, agents in women at risk for preterm delivery. Am J Perinatol
placebo-controlled trial with tocolytic rescue. Am J Obstet Gynecol 2008;25:503–6.
2000;182:1173–83. 34 Facchinetti F, Paganelli S, Comitini G, Dante G, Volpe A. Cervical
16 Niebyl JR, Blake DA, White RD, Kumor KM, Dubin NH, Robinson JC, length changes during preterm cervical ripening: effects of
et al. The inhibition of premature labor with indomethacin. Am J 17-a-hydroxyprogesterone caproate. Am J Obstet Gynecol
Obstet Gynecol 1980;136:1014–19. 2007;196:453.e451–4; discussion 421.
17 Ferguson JE II, Dyson DC, Schutz T, Stevenson DK. A comparison of 35 Rozenberg P, Chauveaud A, Deruelle P, Capelle M, Winer N,
tocolysis with nifedipine or ritodrine: analysis of efficacy and Desbriere R, et al. Prevention of preterm delivery after successful
maternal, fetal, and neonatal outcome. Am J Obstet Gynecol tocolysis in preterm labor by 17 a-hydroxyprogesterone caproate: a
1990;163:105–11. randomized controlled trial. Am J Obstet Gynecol
18 Keirse MJ. The history of tocolysis. BJOG 2003;110(Suppl 20): 2012;206:206.e201–9.
94–7. 36 Leitich H, Brunbauer M, Kaider A, Egarter C, Husslein P. Cervical
19 Roos C, Spaanderman ME, Schuit E, Bloemenkamp KW, Bolte AC, length and dilatation of the internal cervical os detected by vaginal
Cornette J, et al. Effect of maintenance tocolysis with nifedipine in ultrasonography as markers for preterm delivery: a systematic
threatened preterm labor on perinatal outcomes: a randomized review. Am J Obstet Gynecol 1999;181:1465–72.
controlled trial. JAMA 2013;309:41–7. 37 Hoesli I, Tercanli S, Holzgreve W. Cervical length assessment by
20 Dodd JM, Crowther CA, Dare MR, Middleton P. Oral b-mimetics for ultrasound as a predictor of preterm labour—is there a role for
maintenance therapy after threatened preterm labour. Cochrane routine screening? BJOG 2003;110(Suppl 20):61–5.
Database Syst Rev 2006:CD003927. 38 Hoesli IM, Strutas D, Tercanli S, Holzgreve W. Charts for cervical
21 Han S, Crowther CA, Moore V. Magnesium maintenance therapy length in singleton pregnancy. Int J Gynaecol Obstet 2003;82:161–5.
for preventing preterm birth after threatened preterm labour. 39 Volumenie JL, Luton D, De Spirlet M, Sibony O, Blot P, Oury JF.
Cochrane Database Syst Rev 2010:CD000940. Ultrasonographic cervical length measurement is not a better

ª 2014 Royal College of Obstetricians and Gynaecologists 11


Martinez de Tejada et al.

predictor of preterm delivery than digital examination in a 51 Di Renzo GC, Mattei A, Gojnic M, Gerli S. Progesterone and
population of patients with idiopathic preterm labor. Eur J Obstet pregnancy. Curr Opin Obstet Gynecol 2005;17:598–600.
Gynecol Reprod Biol 2004;117:33–7. 52 Baumbach J, Shi S-Q, Shi L, Balducci J, Coonrod DV, Garfield RE.
40 Leitich H, Kaider A. Fetal fibronectin—how useful is it in the Inhibition of uterine contractility with various tocolytics with and
prediction of preterm birth? BJOG 2003;110(Suppl 20):66–70. without progesterone: in vitro studies. Am J Obst Gynecol
41 Honest H, Bachmann LM, Gupta JK, Kleijnen J, Khan KS. Accuracy 2012;206:254.e251–5.
of cervicovaginal fetal fibronectin test in predicting risk of 53 Erny R, Pigne A, Prouvost C, Gamerre M, Malet C, Serment H, et al.
spontaneous preterm birth: systematic review. BMJ 2002;325:301. The effects of oral administration of progesterone for premature
42 Plaut MM, Smith W, Kennedy K. Fetal fibronectin: the impact of a labor. Am J Obstet Gynecol 1986;154:525–9.
rapid test on the treatment of women with preterm labor symptoms. 54 Tan PC, King AS, Vallikkannu N, Omar SZ. Single dose 17
Am J Obstet Gynecol 2003;188:1588–93; discussion 1593–5. a-hydroxyprogesterone caproate in preterm labor: a randomized
43 Largo RH, Pfister D, Molinari L, Kundu S, Lipp A, Duc G. trial. Arch Gynecol Obstet 2012;285:585–90.
Significance of prenatal, perinatal and postnatal factors in the 55 Noblot G, Audra P, Dargent D, Faguer B, Mellier G. The use of
development of AGA preterm infants at five to seven years. Dev micronized progesterone in the treatment of menace of preterm
Med Child Neurol 1989;31:440–56. delivery. Eur J Obstet Gynecol Reprod Biol 1991;40:203–9.
44 Simhan HN, Caritis SN. Prevention of preterm delivery. N Engl J Med 56 Arikan I, Barut A, Harma M, Harma IM. Effect of progesterone as a
2007;357:477–87. tocolytic and in maintenance therapy during preterm labor. Gynecol
45 Lan KKG, DeMets DL. Discrete sequential boundaries for clinical Obstet Invest 2011;72:269–73.
trials. Biometrika 1983;70:659–63. 57 Schumacher A, Costa SD, Zenclussen AC. Endocrine factors
46 Romero R, Nicolaides K, Conde-Agudelo A, Tabor A, O’Brien JM, modulating immune responses in pregnancy. Front Immunol
Cetingoz E, et al. Vaginal progesterone in women with an 2014;5:196.
asymptomatic sonographic short cervix in the midtrimester decreases 58 Mackenzie R, Walker M, Armson A, Hannah ME. Progesterone for
preterm delivery and neonatal morbidity: a systematic review and the prevention of preterm birth among women at increased risk: a
metaanalysis of individual patient data. Am J Obstet Gynecol systematic review and meta-analysis of randomized controlled trials.
2012;206:124.e1–19. Am J Obstet Gynecol 2006;194:1234–42.
47 Berghella V. Universal cervical length screening for prediction 59 Dodd JM, Crowther CA, Cincotta R, Flenady V, Robinson JS.
and prevention of preterm birth. Obstet Gynecol Surv 2012;67: Progesterone supplementation for preventing preterm birth: a
653–8. systematic review and meta-analysis. Acta Obstet Gynecol Scand
48 Owen J, Szychowski JM, Hankins G, Iams JD, Sheffield JS, 2005;84:526–33.
Perez-Delboy A, et al. Does midtrimester cervical length >/=25 mm 60 Sanchez-Ramos L, Kaunitz AM, Delke I. Progestational agents to
predict preterm birth in high-risk women? Am J Obstet Gynecol prevent preterm birth: a meta-analysis of randomized controlled
2010;203:393.e391–5. trials. Obstet Gynecol 2005;105:273–9.
49 Combs CA. Vaginal progesterone for asymptomatic cervical 61 Dodd JM, Flenady V, Cincotta R, Crowther CA. Prenatal
shortening and the case for universal screening of cervical length. administration of progesterone for preventing preterm birth.
Am J Obstet Gynecol 2012;206:101–3. Cochrane Database Syst Rev 2006:CD004947.
50 Mateus J. Clinical management of the short cervix. Obstet Gynecol
Clin North Am 2011;38:367–85.

12 ª 2014 Royal College of Obstetricians and Gynaecologists