Actualización  en  obstetricia:  prevención  de  parto  prematuro Montserrat González Rodríguez

Servicio de Obstetricia y Ginecología Hospital Universitario Infanta Elena

Valdemoro

Definiciones •  PARTO PRETERMINO: antes de las 37SG. Etiología

compleja y multifactorial. Factores inflamatorios, isquémicos, inmunológicos, mecánicos y hormonales

•  AMENAZA DE PARTO PRETERMINO: proceso clínico sintomático que sin tratamiento o, cuando este fracasa, puede conducir a un parto pretérmino

Prematuridad extrema < 28 SG Prematuridad severa 28+1-31+6SG Prematuridad moderada 32-33+6 SG Prematuridad leve 34- 36+6 SG

Etiología

•  Parto pretérmino espontáneo 31-40%

•  Infección intraamniótica •  Causa vascular •  Estrés •  Sobredistensión uterina

•  Rotura prematura de membranas 30-40% •  Finalización electiva 20-25%

Factores  de  riesgo

•  Parto pretérmino previo. Si < 28SG x 10 •  Raza negra •  IMC bajo •  Estrés laboral •  Tabaquismo •  Período intergenésico < 6meses •  Factores uterinos: conización previa,

malformaciones, incompetencia cervical

Consecuencias

La prematuridad es responsable de un importante porcentaje de morbi-mortalidad perinatal • Déficits neurosensoriales • Problemas pulmonares crónicos • Infecciones • Hemorragia ventricular • Enterocolitis necrotizante

Estrategias  de  prevención

Prevención

•  Prevención primaria factores de riesgo •  Prevención secundaria detección precoz y tratamiento •  Prevención terciaria secuelas

2012

Progesterona Vaginal progesterone in women with an asymptomaticsonographic short cervix in the midtrimester decreasespreterm delivery and neonatal morbidity: a systematicreview and metaanalysis of individual patient dataRoberto Romero, MD; Kypros Nicolaides, MD; Agustin Conde-Agudelo, MD, MPH; Ann Tabor, MD; John M. O’Brien, MD;Elcin Cetingoz, MD; Eduardo Da Fonseca, MD; George W. Creasy, MD; Katharina Klein, MD; Line Rode, MD;Priya Soma-Pillay, MD; Shalini Fusey, MD; Cetin Cam, MD; Zarko Alfirevic, MD; Sonia S. Hassan, MD

OBJECTIVE: To determine whether the use of vaginal progesterone inasymptomatic women with a sonographic short cervix (!25 mm) in themidtrimester reduces the risk of preterm birth and improves neonatalmorbidity and mortality.

STUDY DESIGN: Individual patient data metaanalysis of randomizedcontrolled trials.

RESULTS: Five trials of high quality were included with a total of 775women and 827 infants. Treatment with vaginal progesterone was as-sociated with a significant reduction in the rate of preterm birth !33weeks (relative risk [RR], 0.58; 95% confidence interval [CI], 0.42–0.80), !35 weeks (RR, 0.69; 95% CI, 0.55–0.88), and !28 weeks(RR, 0.50; 95% CI, 0.30–0.81); respiratory distress syndrome (RR,0.48; 95% CI, 0.30–0.76); composite neonatal morbidity and mortality

(RR, 0.57; 95% CI, 0.40–0.81); birthweight !1500 g (RR, 0.55; 95%CI, 0.38 – 0.80); admission to neonatal intensive care unit (RR, 0.75;95% CI, 0.59–0.94); and requirement for mechanical ventilation (RR,0.66; 95% CI, 0.44 – 0.98). There were no significant differences be-tween the vaginal progesterone and placebo groups in the rate of ad-verse maternal events or congenital anomalies.

CONCLUSION: Vaginal progesterone administration to asymptomaticwomen with a sonographic short cervix reduces the risk of preterm birthand neonatal morbidity and mortality.

Key words: admission to neonatal intensive care unit, birthweight!1500 g, mechanical ventilation, prematurity, preterm birth,progestin, respiratory distress syndrome, transvaginal ultrasound,uterine cervix, 17"-hydroxyprogesterone caproate

Cite this article as: Romero R, Nicolaides K, Conde-Agudelo A, et al. Vaginal progesterone in women with an asymptomatic sonographic short cervix in the midtrimesterdecreases preterm delivery and neonatal morbidity: a systematic review and metaanalysis of individual patient data. Am J Obstet Gynecol 2012;206:124.e1-19.

From the Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NationalInstitutes of Health, Department of Health and Human Services, Bethesda, MD, and Detroit, MI (Drs Romero, Conde-Agudelo, and Hassan);Department of Obstetrics and Gynecology, King’s College Hospital, London, United Kingdom (Dr Nicolaides); Department of FetalMedicine, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark (Drs Tabor and Rode); Faculty of Health Sciences,University of Copenhagen, Copenhagen, Denmark (Dr Tabor); Perinatal Diagnostic Center, Central Baptist Hospital and Department ofObstetrics and Gynecology, University of Kentucky, Lexington, KY (Dr O’Brien); Department of Obstetrics and Gynecology, Zeynep KamilWomen and Children Diseases Education and Research Hospital, Uskudar, Istanbul, Turkey (Drs Cetingoz and Cam); Departamento deObstetrícia e Ginecologia, Hospital do Servidor Publico Estadual “Francisco Morato de Oliveira” and School of Medicine, University of SãoPaulo, São Paulo, Brazil (Dr Fonseca); Columbia Laboratories Inc, Livingston, NJ (Dr Creasy); Department of Obstetrics and Gynecology,Medical University of Vienna, Vienna, Austria (Dr Klein); Department of Obstetrics and Gynecology, Steve Biko Academic Hospital, and theUniversity of Pretoria, Pretoria, South Africa (Dr Soma-Pillay); Department of Obstetrics and Gynecology, Government Medical College andHospital, Maharashtra, India (Dr Fusey); Department for Women’s and Children’s Health, University of Liverpool, Liverpool, UnitedKingdom (Dr Alfirevic); and Department of Obstetrics and Gynecology, Wayne State University/Hutzel Hospital, Detroit, MI (Dr Hassan).

The majority of the authors report no conflict of interest except as stated in this paragraph. J.M.O’B. was involved in studies of progesterone geltreatment for preterm birth prevention sponsored by Columbia Laboratories Inc, the manufacturer of the preparation used in the PREGNANT Trialand a previous trial of vaginal progesterone in women at risk for preterm delivery. J.M.O’B. serves on advisory boards and is a consultant for WatsonPharmaceuticals, a company with a financial interest in marketing vaginal progesterone gel for the prevention of preterm birth. He and others arelisted in the patent on the use of all progesterone compounds to prevent preterm birth (US Patent No. 7,884,093: Progesterone for the Treatmentand Prevention of Spontaneous Preterm Birth). G.W.C. is an employee of Columbia Laboratories Inc.

This research was supported, in part, by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health andHuman Development, National Institutes of Health, Department of Health and Human Services.

Reprints not available from the authors.

0002-9378/free • © 2012 Published by Mosby, Inc. • doi: 10.1016/j.ajog.2011.12.003

For Editors’ Commentary, see Table of Contents

See related editorial, page 101

Reports of Major Impact www.AJOG.org

124.e1 American Journal of Obstetrics & Gynecology FEBRUARY 2012

Vaginal progesterone in women with an asymptomaticsonographic short cervix in the midtrimester decreasespreterm delivery and neonatal morbidity: a systematicreview and metaanalysis of individual patient dataRoberto Romero, MD; Kypros Nicolaides, MD; Agustin Conde-Agudelo, MD, MPH; Ann Tabor, MD; John M. O’Brien, MD;Elcin Cetingoz, MD; Eduardo Da Fonseca, MD; George W. Creasy, MD; Katharina Klein, MD; Line Rode, MD;Priya Soma-Pillay, MD; Shalini Fusey, MD; Cetin Cam, MD; Zarko Alfirevic, MD; Sonia S. Hassan, MD

OBJECTIVE: To determine whether the use of vaginal progesterone inasymptomatic women with a sonographic short cervix (!25 mm) in themidtrimester reduces the risk of preterm birth and improves neonatalmorbidity and mortality.

STUDY DESIGN: Individual patient data metaanalysis of randomizedcontrolled trials.

RESULTS: Five trials of high quality were included with a total of 775women and 827 infants. Treatment with vaginal progesterone was as-sociated with a significant reduction in the rate of preterm birth !33weeks (relative risk [RR], 0.58; 95% confidence interval [CI], 0.42–0.80), !35 weeks (RR, 0.69; 95% CI, 0.55–0.88), and !28 weeks(RR, 0.50; 95% CI, 0.30–0.81); respiratory distress syndrome (RR,0.48; 95% CI, 0.30–0.76); composite neonatal morbidity and mortality

(RR, 0.57; 95% CI, 0.40–0.81); birthweight !1500 g (RR, 0.55; 95%CI, 0.38–0.80); admission to neonatal intensive care unit (RR, 0.75;95% CI, 0.59 – 0.94); and requirement for mechanical ventilation (RR,0.66; 95% CI, 0.44 – 0.98). There were no significant differences be-tween the vaginal progesterone and placebo groups in the rate of ad-verse maternal events or congenital anomalies.

CONCLUSION: Vaginal progesterone administration to asymptomaticwomen with a sonographic short cervix reduces the risk of preterm birthand neonatal morbidity and mortality.

Key words: admission to neonatal intensive care unit, birthweight!1500 g, mechanical ventilation, prematurity, preterm birth,progestin, respiratory distress syndrome, transvaginal ultrasound,uterine cervix, 17"-hydroxyprogesterone caproate

Cite this article as: Romero R, Nicolaides K, Conde-Agudelo A, et al. Vaginal progesterone in women with an asymptomatic sonographic short cervix in the midtrimesterdecreases preterm delivery and neonatal morbidity: a systematic review and metaanalysis of individual patient data. Am J Obstet Gynecol 2012;206:124.e1-19.

From the Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NationalInstitutes of Health, Department of Health and Human Services, Bethesda, MD, and Detroit, MI (Drs Romero, Conde-Agudelo, and Hassan);Department of Obstetrics and Gynecology, King’s College Hospital, London, United Kingdom (Dr Nicolaides); Department of FetalMedicine, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark (Drs Tabor and Rode); Faculty of Health Sciences,University of Copenhagen, Copenhagen, Denmark (Dr Tabor); Perinatal Diagnostic Center, Central Baptist Hospital and Department ofObstetrics and Gynecology, University of Kentucky, Lexington, KY (Dr O’Brien); Department of Obstetrics and Gynecology, Zeynep KamilWomen and Children Diseases Education and Research Hospital, Uskudar, Istanbul, Turkey (Drs Cetingoz and Cam); Departamento deObstetrícia e Ginecologia, Hospital do Servidor Publico Estadual “Francisco Morato de Oliveira” and School of Medicine, University of SãoPaulo, São Paulo, Brazil (Dr Fonseca); Columbia Laboratories Inc, Livingston, NJ (Dr Creasy); Department of Obstetrics and Gynecology,Medical University of Vienna, Vienna, Austria (Dr Klein); Department of Obstetrics and Gynecology, Steve Biko Academic Hospital, and theUniversity of Pretoria, Pretoria, South Africa (Dr Soma-Pillay); Department of Obstetrics and Gynecology, Government Medical College andHospital, Maharashtra, India (Dr Fusey); Department for Women’s and Children’s Health, University of Liverpool, Liverpool, UnitedKingdom (Dr Alfirevic); and Department of Obstetrics and Gynecology, Wayne State University/Hutzel Hospital, Detroit, MI (Dr Hassan).

The majority of the authors report no conflict of interest except as stated in this paragraph. J.M.O’B. was involved in studies of progesterone geltreatment for preterm birth prevention sponsored by Columbia Laboratories Inc, the manufacturer of the preparation used in the PREGNANT Trialand a previous trial of vaginal progesterone in women at risk for preterm delivery. J.M.O’B. serves on advisory boards and is a consultant for WatsonPharmaceuticals, a company with a financial interest in marketing vaginal progesterone gel for the prevention of preterm birth. He and others arelisted in the patent on the use of all progesterone compounds to prevent preterm birth (US Patent No. 7,884,093: Progesterone for the Treatmentand Prevention of Spontaneous Preterm Birth). G.W.C. is an employee of Columbia Laboratories Inc.

This research was supported, in part, by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health andHuman Development, National Institutes of Health, Department of Health and Human Services.

Reprints not available from the authors.

0002-9378/free • © 2012 Published by Mosby, Inc. • doi: 10.1016/j.ajog.2011.12.003

For Editors’ Commentary, see Table of Contents

See related editorial, page 101

Reports of Major Impact www.AJOG.org

124.e1 American Journal of Obstetrics & Gynecology FEBRUARY 2012

Pesario Articles

1800 www.thelancet.com Vol 379 May 12, 2012

Lancet 2012; 379: 1800–06

Published OnlineApril 3, 2012

DOI:10.1016/S0140-6736(12)60030-0

This online publication has been corrected. The corrected

version fi rst appeared at thelancet.com on May 11, 2012

See Comment page 1769

*Contributed equally

Maternal Fetal Medicine Unit, Department of Obstetrics,

Hospital Universitari Vall d’Hebron, Universitat

Autonoma de Barcelona, Barcelona, Spain (M Goya MD,

L Pratcorona MD, C Merced MD, C Rodó MD, J C Bello-Muñoz MD,

E Llurba PhD, T Higueras MD, E Carreras PhD, L Cabero PhD);

Maternal and Child Health and Development Network

(SAMID), Instituto Salud Carlos III, Madrid, Spain (M Goya,

E Llurba, E Carreras, L Cabero); Centre for Biomedical Research

on Rare Diseases (CIBERER), Instituto Salud Carlos III, Madrid, Spain (E Llurba);

Maternal Fetal Medicine Unit, Department of Obstetrics,

Hospital Universitario Materno Infantil de Canarias, Las Palmas de Gran Canaria, Canary Islands,

Spain (L Valle PhD, A Romero MD); Maternal Fetal Medicine Unit, Department of

Obstetrics, Hospital Son Llatzer, Balearic Islands, Spain

(M Juan MD); Maternal Fetal Medicine Unit, Department of

Obstetrics, Institut Universitari Dexeus, Barcelona, Spain

(A Rodríguez MD); Maternal Fetal Medicine Unit,

Department of Obstetrics, Hospital Sant Joan de Reus,

Reus, Tarragona, Spain (B Muñoz MD); and Maternal

Fetal Medicine Unit, Department of Obstetrics,

Hospital de Fuenlabrada, Madrid, Spain (B Santacruz MD)

Correspondence to:Dr Elena Carreras, Maternal Fetal

Medicine Unit, Department of Obstetrics, Hospital Universitari

Cervical pessary in pregnant women with a short cervix (PECEP): an open-label randomised controlled trialMaria Goya, Laia Pratcorona, Carme Merced, Carlota Rodó, Leonor Valle, Azahar Romero, Miquel Juan, Alberto Rodríguez, Begoña Muñoz, Belén Santacruz, Juan Carlos Bello-Muñoz, Elisa Llurba, Teresa Higueras, Luis Cabero*, Elena Carreras*, on behalf of the Pesario Cervical para Evitar Prematuridad (PECEP) Trial Group

SummaryBackground Most previous studies of the use of cervical pessaries were either retrospective or case controlled and their results showed that this intervention might be a preventive strategy for women at risk of preterm birth; no randomised controlled trials have been undertaken. We therefore undertook a randomised, controlled trial to investigate whether the insertion of a cervical pessary in women with a short cervix identifi ed by use of routine transvaginal scanning at 20–23 weeks of gestation reduces the rate of early preterm delivery.

Methods The Pesario Cervical para Evitar Prematuridad (PECEP) trial was undertaken in fi ve hospitals in Spain. Pregnant women (aged 18–43 years) with a cervical length of 25 mm or less were randomly assigned according to a computer-generated allocation sequence by use of central telephone in a 1:1 ratio to the cervical pessary or expectant management (without a cervical pessary) group. Because of the nature of the intervention, this study was not masked. The primary outcome was spontaneous delivery before 34 weeks of gestation. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00706264.

Findings 385 pregnant women with a short cervix were assigned to the pessary (n=192) and expectant management groups (n=193), and 190 were analysed in each group. Spontaneous delivery before 34 weeks of gestation was signifi cantly less frequent in the pessary group than in the expectant management group (12 [6%] vs 51 [27%], odds ratio 0·18, 95% CI 0·08–0·37; p<0·0001). No serious adverse eff ects associated with the use of a cervical pessary were reported.

Interpretation Cervical pessary use could prevent preterm birth in a population of appropriately selected at-risk women previously screened for cervical length assessment at the midtrimester scan.

Funding Instituto Carlos III.

IntroductionSpontaneous preterm birth, which arises in roughly 5–13% of pregnancies, is the leading cause of perinatal morbidity and mortality.1–4 However, the rates have not changed much over the past 10 years. Improvements in neonatal care have increased survival rates in very premature infants. Never theless, a major reduction in rates of mortality and morbidity in premature babies will only be achieved with increased precision in the identifi cation of women at risk of spontaneous preterm birth and through the develop ment of an eff ective prevention for this complication.

A strategy for the prevention of spontaneous preterm births in which therapeutic intervention is restricted to women with a previous preterm birth is likely to have a small eff ect on the overall rate of prematurity since only about 10% of spontaneous preterm births arise in women with such a history.5 Ultrasonographic measure-ment of cervical length at 20–23 weeks of gestation can increase the identifi cation of women at risk of either singleton or twin pregnancies.6–8 Asymptomatic women with a short cervical length (≤25 mm) are at increased risk of spontaneous early preterm delivery.

Cervical pessary is a silicone device that has been used in the past 50 years to prevent preterm birth.9 Most of

the reported studies were either retrospective or case controlled and the results showed that a cervical pessary can be used as a preventive strategy for patients at risk of preterm birth.10 No randomised controlled trials have been undertaken. We therefore assessed the eff ect of cervical pessary on the spontaneous early preterm birth rate in asymptomatic women.

MethodsParticipants and trial designA prospective, open-label, randomised clinical trial was undertaken in fi ve hospitals in Spain. Pregnant women (aged 18–43 years) with singleton pregnancies who were undergoing routine second trimester ultra sonography at 18–22 weeks of gestation were given the option of transvaginal ultrasonographic measurement of cervical length as a predictor of spontaneous preterm birth.11 Cervical length was measured according to the criteria of the Fetal Medicine Foundation.12 Women with a cervical length of 25 mm or less were invited to take part in the Pesario Cervical para Evitar Prematuridad (PECEP) trial. Exclusion criteria were major fetal abnormalities, painful regular uterine contractions, active vaginal bleeding, ruptured membranes, placenta praevia, and a history of cone biopsy or cervical cerclage in situ.

Prevención  primaria

Prevención  primaria Medicina Fetal •  Antecedente previo de parto pretérmino o RPM •  Historia obstétrica sugestiva de incompetencia cervical •  Episodio de APP en la gestación actual •  RPM < 24 SG •  Factores uterinos:

Cirugía previa: conización Malformaciones uterinas: útero doble Incompetencia cervical

Prevención  primaria

Maniobras preventivas: • Screening tratamiento de la bacteriuria asintomática • Deteccion y tratamiento de la vaginosis bacteriana en el 2T • Detección y tratamiento de Chlamydia trachomatis, ureaplasma y SBH • Valoración cervical ecográfica • Fibronectina fetal

Clindamicina  300  v.o    cada  12  horas    5  días

En el manejo clínico diario, tanto la ecografía como la fibronectina tiene una eficacia similar . Debido al mayor acceso y menor coste de la ecografía en nuestro ámbito, nosotros utilizaremos la medida de la longitud cervical (por ecografía transvaginal) como elemento predictor para el seguimiento de las pacientes.

<  25  mm

Eco  20  SG

Seguimiento  obstétrico

•  RPM < 24 SG: control ambulatorio

•  Metrorragias 2º y 3ª T excluyendo placenta previa tienen más riesgo de RPM, reevaluar el riesgo a la semana del ingreso

•  Incompetencia cervical: cerclaje

•  Antecedentes de 2 o más pérdidas fetales 2º o 3ºT o pretérmino menor de 34 SG o  Control ecográfico cada 2

semanas o  Cultivos en la semana 12-16

y 20-22

•  Ingreso previo por APP: a la semana del alta, controles cada 1-2 semanas

Longitud cervical: > 25mm antes de la 28 > 20 mm entre la 28-32

> 15 mm > 32 SG BAJO RIESGO

Progesterona

Se recomendará la utilización de progesterona 100 mg cada 24 horas en: • Pacientes con antecedentes de pretérmino y cérvix < 25 mm • Pacientes asintomáticas sin antecedentes con cérvix < 20mm • Hallazgo ecográfico de acortamiento cervical progresivo hasta las 34 SG.

Pesario  cervical •  Estudio  PCEP •  Cérvix  corto  asintomáticas •  Consulta •  Desplaza  el  eje  de  presión •  Comodidad •  Leucorrea •  Control  mensual.  No  cervicometría •  37SG

Articles

www.thelancet.com Vol 379 May 12, 2012 1801

Vall d’Hebron, Universitat Autonoma de Barcelona, Passeig de la Vall d’Hebron, 119-129, 08036 Barcelona, Spainecarreras@vhebron.net

Gestational age was judged from the menstrual history and confi rmed by measurement of fetal crown-rump length at a fi rst trimester scan, which was done routinely in all participating hospitals.

Trial coordinators regularly undertook quality control of screening, data handling, and verifi cation of adher ence to protocols at the diff erent centres. Obstetricians who did the scans had received extensive training and passed a practical examination administered by an expert to demonstrate their competence in cervical assessment. All the images of the cases included in the trial were reviewed centrally. All cases of preterm birth were reviewed and discussed centrally. Dr Arabin, Witten, Germany, very kindly provided, free of charge, advice, recommendations, and suggestions for the use of cervical pessaries in pregnant women. The central team then instructed the other centres about the use of the pessary (fi gure 1).

The ethics committees for all participating hospitals approved the protocol.

Randomisation and maskingAfter written informed consent was obtained from women, they were randomly allocated to the cervical pessary group or expectant management group in a 1:1 ratio. The randomisation sequence was computer generated by the Statistics Unit of the Vall d’Hebron Hospital Research Institute, Barcelona, Spain, with variable block sizes of two and four, stratifi ed for centre and parity, and implemented by use of central telephone. The recruiters or the trial coordinator did not have access to the randomisation sequence. The allocation code was disclosed after the patient’s initials were confi rmed. This study was open label because of the nature of the intervention.

InterventionsCervical and vaginal swabs were taken from all patients for bacteriological analysis. If visual evidence existed of infection, appropriate treatment was given and insertion of the pessary was delayed by 1 week. Vaginal examination was done to detect cervical dilation or visible membranes. The pessary was not removed if there was evidence of bacterial infection after device insertion; however, appro-priate antibiotic treatment was given. Patients allocated to the pessary group had the device inserted and were given detailed instructions about its subsequent manage-ment. Special emphasis was placed on the need to report any adverse symptoms immediately.

We used cervical pessaries certifi ed by European Conformity (CE0482, MED/CERT ISO 9003/EN 46003; Dr Arabin, lower larger diameter 65 mm, height 25 mm, and upper smaller diameter 32 mm) during the study.

Both groups were seen by the clinical team of the trial at each centre every month until delivery. Transabdominal ultrasonography was done for fetal biometries and wellbeing, clinical questionnaire was administered for confi rmation of correct device placement in the pessary group (fi gure 2), vaginal swab was taken for study of

bacteriological infection, and transvaginal ultra sono-graphy was done to measure cervical length (fi gure 3).

The pessary was removed during the 37th week of gestation. Indications for pessary removal before this time were active vaginal bleeding, risk of preterm labour with persistent contractions despite tocolysis, or severe patient discomfort.

Figure 2: Cervical pessaryThe smaller diameter of the pessary is fi tted around the cervix and the larger diameter faces the pelvic fl oor, thus rotating the cervix to the posterior vaginal wall and correcting the cervical angle.

Figure 3: Ultrasound visualisation of cervical length in women using a cervical pessary13

Pessary

Cervix

Pessary

Uterus

Vagina

B CA

Figure 1: Photograph of the silicone cervical pessary(A) Inner diameter. (B) Outer diameter. (C) Lateral view.

Articles

www.thelancet.com Vol 379 May 12, 2012 1801

Vall d’Hebron, Universitat Autonoma de Barcelona, Passeig de la Vall d’Hebron, 119-129, 08036 Barcelona, Spainecarreras@vhebron.net

Gestational age was judged from the menstrual history and confi rmed by measurement of fetal crown-rump length at a fi rst trimester scan, which was done routinely in all participating hospitals.

Trial coordinators regularly undertook quality control of screening, data handling, and verifi cation of adher ence to protocols at the diff erent centres. Obstetricians who did the scans had received extensive training and passed a practical examination administered by an expert to demonstrate their competence in cervical assessment. All the images of the cases included in the trial were reviewed centrally. All cases of preterm birth were reviewed and discussed centrally. Dr Arabin, Witten, Germany, very kindly provided, free of charge, advice, recommendations, and suggestions for the use of cervical pessaries in pregnant women. The central team then instructed the other centres about the use of the pessary (fi gure 1).

The ethics committees for all participating hospitals approved the protocol.

Randomisation and maskingAfter written informed consent was obtained from women, they were randomly allocated to the cervical pessary group or expectant management group in a 1:1 ratio. The randomisation sequence was computer generated by the Statistics Unit of the Vall d’Hebron Hospital Research Institute, Barcelona, Spain, with variable block sizes of two and four, stratifi ed for centre and parity, and implemented by use of central telephone. The recruiters or the trial coordinator did not have access to the randomisation sequence. The allocation code was disclosed after the patient’s initials were confi rmed. This study was open label because of the nature of the intervention.

InterventionsCervical and vaginal swabs were taken from all patients for bacteriological analysis. If visual evidence existed of infection, appropriate treatment was given and insertion of the pessary was delayed by 1 week. Vaginal examination was done to detect cervical dilation or visible membranes. The pessary was not removed if there was evidence of bacterial infection after device insertion; however, appro-priate antibiotic treatment was given. Patients allocated to the pessary group had the device inserted and were given detailed instructions about its subsequent manage-ment. Special emphasis was placed on the need to report any adverse symptoms immediately.

We used cervical pessaries certifi ed by European Conformity (CE0482, MED/CERT ISO 9003/EN 46003; Dr Arabin, lower larger diameter 65 mm, height 25 mm, and upper smaller diameter 32 mm) during the study.

Both groups were seen by the clinical team of the trial at each centre every month until delivery. Transabdominal ultrasonography was done for fetal biometries and wellbeing, clinical questionnaire was administered for confi rmation of correct device placement in the pessary group (fi gure 2), vaginal swab was taken for study of

bacteriological infection, and transvaginal ultra sono-graphy was done to measure cervical length (fi gure 3).

The pessary was removed during the 37th week of gestation. Indications for pessary removal before this time were active vaginal bleeding, risk of preterm labour with persistent contractions despite tocolysis, or severe patient discomfort.

Figure 2: Cervical pessaryThe smaller diameter of the pessary is fi tted around the cervix and the larger diameter faces the pelvic fl oor, thus rotating the cervix to the posterior vaginal wall and correcting the cervical angle.

Figure 3: Ultrasound visualisation of cervical length in women using a cervical pessary13

Pessary

Cervix

Pessary

Uterus

Vagina

B CA

Figure 1: Photograph of the silicone cervical pessary(A) Inner diameter. (B) Outer diameter. (C) Lateral view.

Prevención  secundaria

Definiciones  clásicas

•  Amenaza de parto pretérmino: presencia de d i n á m i c a u t e r i n a r e g u l a r a s o c i a d a a modificaciones cervicales progresivas desde la 22 a la 36+6SG.

•  Dinámica regular : contracciones uter inas persistentes ( al menos 4 en 20-30 minutos u 8 en una hora)

•  Modi f icaciones cerv ica les presenc ia de borramiento > 80% o dilatación cervical mayor o igual de 2 cm. 20-­‐‑30%

En  la  urgencia •  Anamnesis y revisión de historia clínica •  Exploración física •  Exploración obstétrica:

o  FCF o  Abdomen o  Espéculo

o  Cultivos previos a TV: frotis recto-vaginal, endocervical. o  Tacto vaginal

•  Ecografía transvaginal y obstétrica básica •  RCTG •  Analitica: H, bioqca, coag y PCR. Orina •  Amniocentesis? Glucosa , leucos y Gram. Cultivo

En presencia de dinámica regular se consideran pacientes de alto riesgo si uno o más de : Criterios clínicos: • Bishop > o = 5 • Parto pretérmino anterior ( espontáneo) antes de la 34 • Gestación múltiples Criterios ecográficos: • Longitud cervical < 25 mm antes de las 28+0 SG • Longitud cervical < 20 mm entre las 28+1-31+6 SG • Longitud cervical < 15 mm a las 32 SG o más Se consideran de bajo riesgo cuando no está presente NINGUNO

En ausencia de dinámica efectiva regular: es necesario valorar con precaución. Seguimiento clínico en 1-2 semanas NO SON TRIBUTARIOS DE TRATAMIENTO TOCOLITICO ya que pueden representar un extremo de la normalidad Restringir actividad laboral y estilo de vida hasta valorar evolución.

Tratamiento

•  Dinámica uterina en paciente de BAJO RIESGO: Reposo y observación 2-3 horas en urgencias Cede la dinámica y no modificaciones: alta y reposo

relativo 24 horas No cede la dinámica, pero no modifica cérvix,

ingreso y observación 12-24 h. NO tratamiento •  Dinámica uterina en paciente de ALTO RIESGO: Ingreso, tocolisis y corticoides, reposo absoluto 24

horas, RCTG/8-12 horas

La hidratación oral o intravenosa no reduce la incidencia de parto prematuro y no se recomienda su uso rutinario

Prevención  terciaria

•  Secuelas respiratorias •  Secuelas neurológicas

Obste  Gynecol  Clin  North  Am.  2012  Mar;39(1):47-­‐‑63. Antenatal  corticosteroids  in  the  management  of  preterm  birth:  are  we  back  where  we  started? Bonanno  C,  Wapner  RJ.  Source  Division  of  Maternal  Fetal  Medicine,  Department  of  Obstetrics  and  Gynecology,  Columbia  University  College  of  Physicians  and  Surgeons,  161  West  168th  Street,  New  York,  NY  10032,  USA.  cab90@columbia.edu

DOSIS  REPETIDAS

34 6

OBSTETRICS

Repeat antenatal glucocorticoids for womenat risk of preterm birth: a Cochrane Systematic ReviewChristopher J. D. McKinlay, MBChB; Caroline A. Crowther, MD; Philippa Middleton, MPH; Jane E. Harding, DPhil

Asingle course of antenatal glucocor-ticoids is recommended for all

women with threatened or planned pre-term birth at less than 35 weeks’ gesta-tion, with few exceptions.1 In a system-atic review of randomized trials, a singlecourse of antenatal glucocorticoids com-pared with placebo substantially reducedthe incidence of neonatal death, respira-tory distress syndrome, intraventricularhemorrhage, necrotizing enterocolitis,and early sepsis.2 Antenatal glucocorti-coid treatment increases the effective-

ness of postnatal surfactant therapy,3,4

reduces health care costs1 and is likely toreduce rates of disability.2,5 Glucocorti-coids play a key role in fetal organ matu-ration and differentiation in late gesta-tion, facilitating successful transitionfrom fetal to extrauterine life.6 Exoge-nous glucocorticoids prematurely in-duce these maturation pathways with ef-fects not only in the lungs but in manyother fetal tissues.7

It was previously common in manycenters to administer repeat doses of glu-cocorticoids to women who did not givebirth shortly after an initial course. Thispractice was supported by subgroupanalysis of randomized trials, which sug-gested that clinical benefit diminished ifbirth was delayed more than 7 days aftertreatment,2 and by laboratory evidencethat fetal surfactant production couldbe repetitively induced.7 Furthermore,studies in sheep suggested that fetal lungmaturation was maximal when gluco-corticoids were administered seriallyover several weeks.8,9

The effectiveness of repeat antenatalglucocorticoid treatment in humans wasconfirmed in a 2007 Cochrane system-atic review involving 5 trials and over2000 women.10 This review found that

infants exposed to repeat compared witha single course of antenatal glucocorti-coids had reduced neonatal lung diseaseand associated serious morbidity. It wasconcluded that these short-term benefitsjustified the use of repeat doses of gluco-corticoids in women at risk of pretermbirth.

Despite this evidence, the use of repeatantenatal glucocorticoids remains con-troversial. There is concern that pro-longed induction of tissue differentia-tion may result in inappropriate patternsof fetal organ growth with consequencesfor later health. In animal experiments,exposure to repeat or high-dose antena-tal glucocorticoids has been associatedwith reduced fetal growth and long-termadverse effects on brain development,neuroendocrine function, blood pres-sure, and glucose homeostasis.11 Thus, itis important that long-term effects areconsidered when evaluating the overallbenefit from repeat antenatal glucocorti-coid treatment.

Since the last update of the Cochranereview on repeat doses of antenatal glu-cocorticoids, several trials have reportedoutcomes for infants at 2 years of age anda number of new trials have been com-pleted. It is unlikely that further trials of

From the Liggins Institute (Drs McKinlay andHarding), University of Auckland, Auckland,New Zealand, and Australian Research Centrefor Health of Women and Babies (ARCH),Discipline of Obstetrics and Gynaecology (DrCrowther and Ms Middleton), The University ofAdelaide, Adelaide, Australia.

Received May 25, 2011; revised July 13, 2011;accepted July 25, 2011.

C.A.C. and J.E.H. are investigators in theAustralasian Collaborative Trial of RepeatDoses of Corticosteroids for the Prevention ofNeonatal Respiratory Disease (ACTORDS). Theother authors report no other conflicts ofinterest.

This study was supported by Auckland MedicalResearch Foundation; Health ResearchCouncil, New Zealand; Australian Departmentof Health and Ageing. This review is anabridged version of a Cochrane Reviewpreviously published in the Cochrane Databaseof Systematic Reviews 2011, Issue 6, doi:10.1002/14651858.CD003935.pub3 (http://www.thecochranelibrary.com!www.thecochranelibrary.com). CochraneReviews are regularly updated as newevidence emerges and in response tofeedback, and Cochrane Database ofSystematic Reviews should be consulted forthe most recent version of the review.

Presented at the 15th Annual Congress of thePerinatal Society of Australia and New Zealand,Hobart, Tasmania, Australia, April 10-13, 2011.

Reprints not available from the authors.0002-9378/$36.00© 2012 Mosby, Inc. All rights reserved.doi: 10.1016/j.ajog.2011.07.042

Administration of antenatal glucocorticoids to women at risk of preterm birth has majorbenefits for infants but the use of repeat dose(s) is controversial. We performed a system-atic review of randomized trials, using standard Cochrane methodology, to assess theeffectiveness and safety of 1 or more repeat doses given to women at risk of preterm birth7 or more days after an initial course. Ten trials were included involving over 4730 womenand 5700 infants. Treatment with repeat dose(s) compared with no repeat treatmentreduced the risk of respiratory distress syndrome (risk ratio, 0.83; 95% confidence inter-val, 0.75– 0.91) and serious neonatal morbidity (risk ratio, 0.84; 95% confidence interval,0.75– 0.94). At 2- to 3-year follow-up (4 trials, 4170 children), there was no evidence ofeither significant benefit or harm. Repeat doses of glucocorticoids should be considered inwomen at risk of preterm birth 7 or more days after an initial course, in view of the neonatalbenefits.

Key words: prenatal corticosteroids, repeat antenatal glucocorticoids, respiratorydistress syndrome, systematic review

Systematic Reviews www.AJOG.org

MARCH 2012 American Journal of Obstetrics & Gynecology 187

1

Corticoides antenatales para acelerar la maduración fetal (Actualizado julio 2012)

INTRODUCCIÓN El parto pretérmino es la causa más frecuente de mortalidad y morbilidad perinatal. Es el responsable del 75% de las muertes neonatales no vinculadas a malformaciones congénitas. Las principales complicaciones asociadas a la prematuridad son el síndrome de dificultad respiratoria (SDR), hemorragia intraventricular (HIV), enterocolitis necrotizante, displasia broncopulmonar, persistencia del conducto arterioso, retinopatía y sepsis. Los corticoides actúan en las células epiteliales y del mesénquima y modifican el desarrollo estructural y la diferenciación celular. Estimulan la diferenciación de las células epiteliales y los fibroblastos y la síntesis y secreción de surfactante en los neumocitos tipo II. Tras su administración se observa un incremento de la distensibilidad pulmonar fetal y del volumen máximo, una disminución de la permeabilidad vascular y una mayor depuración de agua. Inducen la síntesis de todos los componentes conocidos del surfactante e incrementan el porcentaje de fosfatidilcolina saturada. También promueven la diferenciación y maduración celular en otros órganos y sistemas como el intestino, encéfalo, páncreas y piel(1). BENEFICIOS DE LA ADMINISTRACIÓN DE CORTICOIDES En 1972, Liggins publicó el primer estudio randomizado sobre la utilidad de la betametasona en la prevención del SDR del recién nacido pretérmino, demostrando una reducción del SDR, con una mortalidad perinatal cinco veces menor en los neonatos de madres tratadas con betametasona(2). Publicaciones posteriores confirmaron la eficacia de los corticoides como inductores de la madurez pulmonar, hasta que un metaanálisis de 18 estudios, publicado en 1995, demostró que la administración de corticoides a la gestante con amenaza de parto pretérmino se asociaba no sólo a una disminución del SDR, sino también de la mortalidad neonatal, HIV y enterocolitis necrotizante, sin un aumento de la morbilidad infecciosa materno-fetal (NE: Ia-A)(3). Posteriormente, una revisión Cochrane con 21 estudios, además de confirmar los resultados anteriores, evidenció una disminución de

NOTA: Sustituye al protocolo de Pruebas de madurez fetal (2004) y al protocolo de Aceleración farmacológica de la madurez pulmonar fetal (2003).

Protocolos Asistenciales en Obstetricia

“Los   autores   de   la   revisión   concluyen   que   los   resultados   del  metaanálisis  apoyan   el  uso  de  dosis   repetida/s  de   corticoides  prenatales   en   las  mujeres  que  han   recibido  un  ciclo   inicial  de  corticoides  prenatales   siete  o  más  días  antes   y   todavía   presentan   riesgo   de   parto   pretérmino,   dado   que   esta  conducta   tiene  un  beneficio  clínicamente   relevante  a   corto  plazo,  en   forma  de  disminución  del  SDR  y  de  problemas  de   salud  graves  en   las    primeras  semanas  después  del  nacimiento.”

Corticoides

Los criterios para el empleo de ciclos múltiples de corticoides antenatales son: • Usarse sólo en aquéllos casos en que estén indicados. Hay que ser rigurosos en la valoración del riesgo y no pautarlos “por si acaso” • Empleo del menor número de dosis posible. Parece prudente no sobrepasar las 6 dosis en total • Ser conscientes del mayor efecto se obtiene cuando la dosis se ha puesto en los 7 días previos al parto

SOGC  Clinical  Practice  Guideline  May  2011  

•  RECOMENDACIONES: 1.- Se debe considerar la administración de sulfato de magnesio para neuroprotección fetal en aquellas mujeres con riesgo de PARTO INMINENTE antes de la 31+6 SG. Grado de recomendación I- A PARTO INMINENTE

o  Trabajo activo de parto con dilatación de 4 cm o más con o sin RPM

o  Parto programado por indicaciones materna o fetales

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Conclusión

•  La parálisis cerebral es permanente, puede dar lugar a secuelas severas para los niños y puede afectar significativamente a las familias y a la sociedad en general. El NNT para prevenir un caso de PC parece justificable y comparable al de la eclapmsia. Dada la relativa seguridad del MgSO4 para la madre, la falta de evidencia de riesgo en la mortalidad infantil y la familiaridad de la mayoría de los obstetras con su uso, el sulfato de magnesio debería ser considerado para la neuroprotección en el parto pretérmino.

Antibioterapia

No se ha demostrado beneficio Sólo tributarias si exposición franca de bolsa amniótica en vagina o signos de infección por amniocentesis. Ampicilina 1 gr / 6 horas + gentamicina 80 mg /8 h Sí debe hacerse profilaxis de SBH en los casos indicados con pauta de Penicilina como primera elección por su mayor espectro antimicrobiano.

Estudio  multicentrico  PESAPRO

Gracias