Beruflich Dokumente
Kultur Dokumente
13061
www.bjog.org
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
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.
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.
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-
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
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)
Analysis
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)
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).
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
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
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.
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
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
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.
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1 Centro de Investigación en Salud Poblacional –Population Health 2 Hamilton BE, Martin JA, Ventura SJ. Births: preliminary data for
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