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Vaginal progesterone in women with an asymptomaticsonographic short cervix in the midtrimester decreasespreterm delivery and neonatal morbidity: a systematic

review and metaanalysis of individual patient dataRoberto Romero, MD; Kypros Nicolaides, MD; Agustin Conde-Agudelo, MD, MPH; Ann Tabor, MD; John M. OBrien, 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 Alrevic, MD; Sonia S. Hassan, MD

OBJECTIVE: To determine whether the use of vaginal progesterone inasymptomatic women with a sonographic short cervix ( 25mm)inthemidtrimester 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 signicant reduction in the rate of preterm birth33weeks (relative risk [RR], 0.58; 95% condence interval [CI], 0.420.80), 35 weeks (RR, 0.69; 95% CI, 0.55 0.88), and 28 weeks(RR, 0.50; 95% CI, 0.300.81); respiratory distress syndrome (RR,0.48; 95%CI, 0.30 0.76);compositeneonatal morbidityandmortality

(RR, 0.57; 95% CI, 0.400.81); birthweight1500 g (RR, 0.55; 95%CI, 0.380.80); admission to neonatal intensive care unit (RR, 0.75;95% CI, 0.590.94); and requirement for mechanical ventilation (RR,0.66; 95% CI, 0.440.98). There were no signicant 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 asymptomaticwomenwith a sonographic short cervix reduces therisk of preterm birthand neonatal morbidity and mortality.

Key words: admission to neonatal intensive care unit, birthweight1500 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 HealthandHuman Development,National

Institutes of Health, Department of HealthandHuman Services,Bethesda, MD,and Detroit, MI (Drs Romero, Conde-Agudelo, and Hassan);Department of Obstetrics andGynecology, Kings College Hospital,London, UnitedKingdom (DrNicolaides); Department of FetalMedicine, CopenhagenUniversity Hospital, Rigshospitalet, Copenhagen, Denmark (Drs Taborand Rode); Faculty of Health Sciences,Universityof Copenhagen, Copenhagen, Denmark (Dr Tabor); PerinatalDiagnosticCenter, Central Baptist Hospital and Departmentof Obstetrics and Gynecology, University of Kentucky,Lexington, KY (Dr OBrien);Department of Obstetrics andGynecology, ZeynepKamilWomen and Children Diseases Education and Research Hospital, Uskudar, Istanbul, Turkey(Drs Cetingoz andCam); DepartamentodeObstetrcia e Ginecologia,Hospital do Servidor Publico Estadual Francisco Moratode Oliveiraand Schoolof Medicine,University of SoPaulo, SoPaulo, Brazil (DrFonseca); Columbia Laboratories Inc, Livingston, NJ (Dr Creasy); Department of Obstetrics and Gynecology,Medical University of Vienna, Vienna, Austria (DrKlein); Department of Obstetrics and Gynecology, Steve Biko Academic Hospital, and theUniversityof Pretoria,Pretoria, SouthAfrica (Dr Soma-Pillay); Departmentof Obstetricsand Gynecology, GovernmentMedical College andHospital, Maharashtra, India (Dr Fusey); Department for Womens and ChildrensHealth, Universityof Liverpool,Liverpool,UnitedKingdom (DrAlrevic); and Department of Obstetrics and Gynecology, Wayne State University/Hutzel Hospital,Detroit, MI (DrHassan). The majority of the authors report no conict of interest except as stated in this paragraph. J.M.OB. was involved in studies of progesterone gel

treatment 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.OB. serves on advisory boards and is a consultant for WatsonPharmaceuticals, a company with a nancial 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


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P reterm birth is the leading cause of perinatal morbidity and mortality worldwide 1 and contributes to 70% of neonatal mortality and approximately half of long-term neurodevelopmentaldisabilities.2 A recent systematic review

has estimated that 12.9 million births, or9.6% of all births worldwide, were pre-term, of which approximately 11.9 mil-lion (92.3%) were in Africa, Asia, LatinAmerica, and the Caribbean. 3 Duringthe last 25years, the preterm birth rate inthe United States increased 36%, from9.4% in 1981 to 12.8% in 2006.4 This in-creasehas been attributed toa higherfre-quency of indicated preterm births insingleton gestations and preterm deliv-ery in multiple gestations resulting, in

part, from the use of assisted reproduc-tive technologies.5-15

Spontaneous preterm labor/delivery isconsideredto beone of thegreatobstetri-cal syndromes, 16,17 a term that empha-sizes that obstetrical disorderswith a simi-lar phenotype are caused by multiplepathologic processes, 18 have a long sub-clinical phase, and may result from com-plex gene-environment interactions. 19-22

Progesterone is considered a key hor-mone for pregnancy maintenance, and a

decline of progesterone action is impli-cated in the onset of parturition. 23-26 If such a decline occurs in the midtrimes-ter, cervical shortening may occur, andthis would predispose to preterm deliv-ery. Therefore, an untimely decline inprogesterone action has been proposedas a mechanism of disease in the pre-term parturition syndrome. 27

Progesterone actions are mediated by genomic and nongenomic effects whichhave been studied in the uterine cervix,

myometrium,sperm,etc.28-101

A blockadeof progesterone action can lead to theclinical, biochemical, and morphologicchanges associated with cervical ripen-ing.28-101 A short cervix detected withtransvaginal ultrasound is a powerful pre-dictor ofpretermbirthin women withsin-gleton and twin gestations. 27,102-109 Theshorter the sonographic cervical length,thehigher theriskofspontaneous pretermbirth. 102-105,110-123 Moreover, a short cer-vix is associated with intraamniotic infec-

tionandinammation,andthismaymod-ify the response to interventions.

An interest in the role of progestogens(naturalandsynthetic) fortheprevention of preterm birth has existed for decades. 124-130

Recently, the administration of vaginal pro-

gesteronewasproposedforthepreventionof preterm birth inwomen with a sonographicshort cervixinthe midtrimesterbased on itsbiologic effects on the cervix, myome-trium, and chorioamniotic mem-branes. In 2007, Fonseca et al, 131 onbe-half of the Fetal Medicine Foundation of the United Kingdom, reported that theadministration of vaginal progesteronein women with a cervical length 15mm was associated with a signicant44% reduction in the rate of spontane-

ous preterm birth

34 weeks of gesta-tion. Similar ndings were reported by DeFranco et al 132 in a secondary analysisof a randomized clinical trial of vaginalprogesterone in women with a history of preterm birth in which the cervix wasmeasured. Hassan et al 133 reported thelargest randomized clinical trial to date,indicating that vaginal progesterone,when administeredto women with a cer-vical length of 10-20 mm, reduces therate of preterm birth at 33, 28, and

35 weeks, and this was associated witha signicant 61% reduction in the rate of respiratory distress syndrome (RDS). 133

Since the publication of the trial of Has-san et al,133 several trials evaluating vag-inal progesterone in women at high risk of spontaneous preterm birth, 134-136 in-cluding a subset of women with a shortcervix, have been published.

An individual patient data (IPD)metaanalysis is a specic type of system-atic reviewin which the original research

data for each participant in a study aresoughtdirectly from theinvestigators re-sponsible for that trial. 137 Such an ap-proach has been considered the goldstandard for summarizing evidenceacross clinical studies since it offers sev-eral advantages, both statistically andclinically, over conventional metaanaly-ses, which are based on published aggre-gate data.138 These advantages includestandardizing and updating of data sets,the ability to verify the quality of the data

and the appropriateness of the analyses,the improvement of consistency across

trials (eg, denition of outcomes), theperformance of subgroup analyses thatcould effectively identify groups of pa-tients who might benet from an inter-vention, the investigation of interactionbetween patient-level covariates and

treatment effects, and th e performanceof time-to-event analyses. 139-141

Using IPDfromrandomized controlledtrials,weperformedametaanalysis toeval-uate the efcacy and safety of vaginal pro-gesterone for the prevention of pretermbirth and neonatal morbidity and mortal-ity in asymptomatic women with a sono-graphic short cervix in the midtrimester.Wealsosoughttodeterminewhethertherewere clinical benets associated with theadministration of vaginal progesterone in

singleton and twin pregnancies.

M ATERIALS AND M ETHODS

Thestudywas conductedbasedon a pro-spectively prepared protocol, and is re-ported using the Preferred Reporting Itemsfor Systematic reviews and Meta-Analyses(PRISMA) guidelines for metaanalyses of randomized controlled trials 142 and sug-gested guidelines forIPDmetaanalyses. 141

Literature search

We searched MEDLINE, EMBASE, CI-NAHL, and LILACS (all from inceptionthrough December 31,2011); the CochraneCentral Register of Controlled Trials ( www.mrw.interscience.wiley.com/cochrane/cochrane_clcentral_articles_fs.html ) (1960through December 31, 2011); ISI Web of Science (www.isiknowledge.com ) (1960throughDecember31,2011);ResearchReg-isters of ongoing trials (www.clinicaltrials.gov , www.controlled-trials.com , www.centerwatch.com , www.anzctr.org.au ,www.

nihr.ac.uk , and www.umin.ac.jp/ctr ); andGoogle Scholar using a combination of key words and text words related to progesterone(progesterone, progestins, progesto-gen, progestagen, progestationalagent) and preterm birth (preterm,premature). Proceedings of the Society for Maternal-Fetal Medicine and interna-tional meetings on preterm birth, referencelists of identied studies, textbooks, previ-ously published systematic reviews, and re-view articles were also searched. Experts in

the eld were contacted to identify furtherstudies. Nolanguage restrictionwas used.

www.AJOG.org Reports of Major Impact

FEBRUARY 2012 American Journal of Obstetrics & Gynecology 124.e2
http://www.mrw.interscience.wiley.com/cochrane/cochrane_clcentral_articles_fs.htmlhttp://www.mrw.interscience.wiley.com/cochrane/cochrane_clcentral_articles_fs.htmlhttp://www.mrw.interscience.wiley.com/cochrane/cochrane_clcentral_articles_fs.htmlhttp://www.mrw.interscience.wiley.com/cochrane/cochrane_clcentral_articles_fs.htmlhttp://www.isiknowledge.com/http://www.isiknowledge.com/http://www.clinicaltrials.gov/http://www.clinicaltrials.gov/http://www.clinicaltrials.gov/http://www.controlled-trials.com/http://www.controlled-trials.com/http://www.centerwatch.com/http://www.centerwatch.com/http://www.centerwatch.com/http://www.anzctr.org.au/http://www.anzctr.org.au/http://www.nihr.ac.uk/http://www.nihr.ac.uk/http://www.nihr.ac.uk/http://www.umin.ac.jp/ctrhttp://www.umin.ac.jp/ctrhttp://www.umin.ac.jp/ctrhttp://www.nihr.ac.uk/http://www.nihr.ac.uk/http://www.anzctr.org.au/http://www.centerwatch.com/http://www.centerwatch.com/http://www.controlled-trials.com/http://www.clinicaltrials.gov/http://www.clinicaltrials.gov/http://www.isiknowledge.com/http://www.mrw.interscience.wiley.com/cochrane/cochrane_clcentral_articles_fs.htmlhttp://www.mrw.interscience.wiley.com/cochrane/cochrane_clcentral_articles_fs.htmlhttp://www.mrw.interscience.wiley.com/cochrane/cochrane_clcentral_articles_fs.html


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Study selectionWe included randomized controlled tri-als in which asymptomatic women witha sonographic short cervix (cervicallength of 25 mm) in the midtrimesterwere randomly allocated to receive vagi-

nal progesterone or placebo/no treat-ment for the prevention of pretermbirth. Trialswere included if theprimary aim of the study was to prevent pretermbirth in women with a sonographicshortcervix, or if the primary aim was to pre-vent preterm birth in women with risk factors other than a short cervix, butout-comes were available for patients with aprerandomization cervical length of

25 mm. Trials were excluded if they:(1) werequasirandomized; (2) evaluated

vaginal progesterone in women withthreatened preterm labor, second tri-mester bleeding, or premature ruptureof membranes; (3) evaluated the admin-istration of vaginal progesterone in therst trimester only to prevent miscarriage;or(4)did not reportclinical outcomes.Al-though there is no agreement on what is asonographic short cervix,wechose 25mmas the cutoff because this value corre-sponds approximately to the 10th percen-tile for cervical length in the midtrimes-

ter.103,110

Inaddition, thiscervical length isthemost commonly used in studies evalu-ating the predictive accuracy of cervicallength for preterm birth. 107,143

Two investigators (R.R. and A.C.-A.)independently reviewed all potentially relevant articles for eligibility. Disagree-ments regarding trial eligibility were re-solved by consensus.

Data collectionWe contacted the corresponding authors

to request access to thedata. Authors wereasked tosupplyanonymizeddata(withoutidentiers) about patient baseline charac-teristics, experimental intervention, con-trol intervention, cointerventions, andprespecied outcome measures for every randomly assigned subject and were in-vited to become part of the collaborativegroup with joint authorship of the nalpublication. Data provided by the investi-gators were merged into a master databasespecically constructed for the review.

Data were checked for missing informa-tion, errors, and inconsistencies by cross-

referencingthepublications of theoriginaltrials.Qualityandintegrity of therandom-ization processes were assessed by review-ing the chronological randomization se-quence and pattern of assignment, as wellas the balance of baseline characteristics

across treatment groups. Inconsistenciesormissingdatawerediscussedwiththeau-thors and corrections were made whendeemed necessary.

Outcome measuresThe prespecied primary outcome mea-sure was preterm birth 33weeksofges-tation. Secondary outcome measures in-cluded preterm birth 37, 36, 35,

34, 30, and 28 weeks of gestation;spontaneous preterm birth 33 and

34 weeks of gestation; RDS; necrotiz-ing enterocolitis; intraventricularhemorrhage (all grades); proven neo-natal sepsis; retinopathy of prematurity;bronchopulmonary dysplasia; periven-tricular leukomalacia; fetal death; neo-natal death; perinatal mortality, a com-posite neonatal morbidity and mortality outcome (dened as the occurrence of any of the following events: RDS, intra-ventricular hemorrhage, necrotizing en-terocolitis, proven neonatal sepsis, or

neonatal death); Apgar score

7 at 5minutes; birthweight 1500 g and2500 g; admission to the neonatal in-

tensive care unit (NICU); use of me-chanical ventilation; congenital anoma-ly; any maternal adverse event; vaginaldischarge;vaginal pruritus;discontinua-tion of treatment because of adverseevents; threatened preterm labor; andneurodevelopmental disability at 18-24months of age. Neonatal morbiditieswere dened as in the original

study.131,133,134,136,144

Assessment of risk of biasWe assessed the risk of bias using the cri-teria recently outlined in the CochraneHandbook for Systematic Reviews of In-terventions. 137 Seven domains related torisk of bias were assessed in each in-cluded trial since there is evidence thatthese issuesare associated with biasedes-timates of treatment effect: (1) randomsequence generation; (2) allocation con-

cealment; (3) blinding of participantsand personnel; (4) blinding of outcome

assessment; (5) incomplete outcomedata; (6) selective reporting; and (7)other bias. Review authors judgmentswere categorized as low, high, orunclear risk of bias. The assessmentsconsidered the risk of material bias

rather than any bias. Material bias isdened as a bias of sufcient magnitudeto have a notable impact on t he results orconclusions of the trial. 137 The risk of bias in each trial included was assessedindividually by 2 reviewers (R.R. andA.C.-A.). In addition, methods of ran-dom sequence generation, allocationconcealment, and blinding were con-rmed with the authors of the trials. Any differences of opinion regarding assess-ment of risk of bias were resolved by

discussion.Statistical analysisStatistical analyses were based on an in-tent-to-treat basis and included all ran-domized women and their fetuses/infants.Forbaseline data, maternal outcomes,andgestational age at birth-related outcomes,the unit of analysis was the pregnancy,whereas forneonatal outcomes, theunitof analysis wasthe neonate. Toassesssafetyof vaginal progesterone, all patients exposed

to progesterone were included. This in-cluded all studies and patients, even thosein which the cervical length was not mea-sured. IPD were combined in a 2-stage ap-proach in which outcomes were analyzedin theoriginal trial and then summary sta-tisticsweregenerated using standard sum-mary data metaanalysis techniques to giveanoverallmeasure of effect (summary rel-ativerisk [RR] with 95% condence inter-val [CI]). 145 Heterogeneity of the resultsamongstudieswas testedwith thequantity

I 2

, which describes the percentage of totalvariation across studies that can be attrib-uted to heterogeneity rather thanchance.146 A value of 0% indicates no ob-served heterogeneity, whereas I 2 values of

50% indicate a substantial level of heter-ogeneity. 146 We planned to use a xed ef-fects model if substantialstatistical hetero-geneity was not present. Random effectsmodels were also used to test the robust-nessofresults.Thenumberneededtotreat(NNT) for benet or harm with the 95%

CI was calculated for outcomes for whichthere was a statistically signicant reduc-




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R ESULTSStudy selection, details, and qualityThe searches yielded 2611 citations, of which 10 were considered for potentialinclusion ( Figure 1). Five studies wereexcluded.125,153-156 Three of these studies

evaluated vaginal progesterone in womenat high risk for preterm birth (previouspreterm birth, 125,154 uterine malforma-tion, 125 cervical insufciency,125 andtwins155 ) but none of them measured orcollected data on cervical length. Two of these studies125,154 reported that prophy-lactic administration of vaginal progester-one reduced the risk of preterm birth inwomen with a previous preterm birth,whereas the study by Norman et al 155

found that vaginal progesterone did notreduce the risk of the composite outcomedelivery or fetal death 34 weeks of gesta-tion inwomenwitha twingestation.The 2remaining studies evaluated vaginal pro-gesteroneasanadjuncttotocolytictherapy after threatened preterm labor. 153,156 Fivestudies, which provided data for 775women(723 [93.3%] with singleton preg-nanciesand 52 [6.7%] with twin pregnan-cies) and 827 fetuses/infants (723 [87.4%]from singleton pregnancies and 104[12.6%] from twin pregnancies), met theinclusion criteria. 131,133,134,136,144

The main characteristics of studies in-cluded in this IPD metaanalysis areshown in Table 1. All studies were dou-ble-blind, placebo-controlled trials, of which 4 were multicenter, conducted insites from both developed and develop-ingcountries.Two trials werespecically designed to evaluate the administrationof vaginal progesterone in women with asonographic shortcervix, 131,133 oneeval-uated the use of vaginal progesterone inwomen with a history of spontaneouspreterm birth, 144 another assessed vagi-nal progesterone in women with a twingestation, 134 and the remaining trial ex-amined the use of progesterone inwomen with a prior spontaneous pre-term birth, uterine malformations, ortw in gestations. 136 Two of these stud-ies134,144 reported data of planned sec-ondary analyses for women with a shortcervix in additional reports. 132,135 Data

from the trials by OBrien et al,144

Cetin-goz et al,136 and Rode et al134 relevant to T A B L E 1

C h a r a c t e r i s t

i c s o

f s t u

d i e s

i n c

l u d e d

( c o n t i n u e

d )

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p o p u

l a t i o n

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/ e x c

l u s i o n c r

i t e r

i a

N o o

f w o m e n w

i t h C L

< 2 5 m m

/ f e t u s e s o r

i n f a n t s

I n t e r v e n t i o n

C o

i n t e r v e n t i o n s

P r i m a r y o u t c o m e

V a g

i n a

l

p r o g e s t e r o n e

g r o u p

P l a c e

b o

g r o u p

R o d e e t a l

, 1 3 4

2 0 1 1

D e n m a r k , A u s t r i a

W o m e n w i t h a t w i n

p r e g n a n c y

I n c l u s i o n : w o m e n w i t h a d i a m n i o t i c t w i n

p r e g n a n c y a n d c h o r i o n i c i t y a s s e s s e d b y u l t r a s o u n d

1 6 w k o f g e s t a t i o n

E x c l u s i o n : h i g h e r o r d e r m u l t i p l e p r e g n a n c i e s ,

k n o w n a l l e r g y t o p r o g e s t e r o n e o r p e a n u t s a s a c t i v e

t r e a t m e n t c o n t a i n e d p e a n u t o i l , h i s t o r y o f

h o r m o n e - a s s o c i a t e d t h r o m b o e m b o l i c d i s o r d e r s ,

r u p t u r e o f m e m b r a n e s

, p r e g n a n c i e s t r e a t e d f o r o r

w i t h s i g n s o f t w i n - t o - t w i n t r a n s f u s i o n s y n d r o m e ,

i n t e n t i o n a l f e t a l r e d u c t i o n , k n o w n m a j o r s t r u c t u r a l

o r c h r o m o s o m a l f e t a l a b n o r m a l i t y

, k n o w n o r

s u s p e c t e d m a l i g n a n c y i n g e n i t a l s o r b r e a s t s ,

k n o w n l i v e r d i s e a s e

7 / 1 4

1 4 / 2 8

V a g i n a l p r o g e s t e r o n e

p e s s a r y ( 2 0 0 m g / d )

o r p l a c e b o f r o m 2 0 -

2 3 6 / 7 t o 3 3 6 / 7 w k

o f g e s t a t i o n

C e r v i c a l c e r c l a g e ( 2

[ 2 8 . 6 % ] i n v a g i n a l

p r o g e s t e r o n e g r o u p a n d 2

[ 1 4 . 3 % ] i n p l a c e b o g r o u p )

P r e t e r m b i r t h 3 4

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C L

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R o m e r o .

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I P D m e t a a n a

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.




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women with a cervical length of 25mm before randomization were pro-vided by the authors for inclusion in this

review. The 2 trials131,133

specically de-signed to evaluate the use of vaginal pro-

gesterone in women with a short cervix screened a total of 56,711 women, of which 1146 (2.0%) had a sonographic

short cervix as dened by the authors forthe purposes of each study. Of these

women, 715 (62.4%) were randomized;708 mothers with their 732 infants pro-vided data for the metaanalysis ( 90%of total sample size of the IPD meta-analysis). The other 3 studies provideddata for 67 women and 95 infants.

Twostudies used vaginal prog esteron ecapsules or pessaries 200 mg/d, 131,134 2used vaginal progesterone gel 90 mg/d,133,144 and the other used vaginal pro-gesterone suppositories 100 mg/d. 136

The treatment was initiated at 24 weeksof gestation in 2 trials,131,136 between20-23 weeks of gestation in 2 trials, 133,134

and between 18-22 weeks of gestation in1 trial.144 Three studies 131,134,136 re-ported that participating women re-ceived study medication from enroll-

ment until 34 weeks of gestation, and 2studies133,144 from enrollment until 366/7 weeks of gestation. In 3 stud-ies,131,133,134 cervical cerclage was al-lowed after randomization. In the study by Cetingozet al, 136 cervical cerclage wasnot performed in any women. The pri-mary outcome was preterm birth 33weeks ofgestation for1 trial, 133 32weeksof gestation for 1 trial,144 34 weeks for 1trial,134 37weeks for1 trial,136 andspon-taneous preterm birth 34 weeks for the

remaining study.131

Allofthe5studiesincludedinthisIPDmetaanalysis had high methodologicalquality and were considered to be at low risk of bias (Figure 2). One study did notreport the method of random sequencegeneration in the article but reported,upon request, having used a table of ran-dom numbers. 131 All 5 studies had ade-quate allocation concealment and usedidentical placebo to blind patients andclinical staff to treatment allocation.

There was blinding of outcome assess-ment and adequate handling of incom-plete outcome data in all studies. Onestudy 136 didnot reportseveral secondary neonatal outcomes of interest to thepresent study, but they were provided tothe investigators (R.R. and A.C.-A.) withthedatabaseandincluded into themeta-analyses. Overall, there was no obviousrisk of other biases for the 5 trials.

Primary outcome

Treatment with vaginal progesterone inpatients with a sonographic short cervix

FIGURE 2Methodological quality summary: risk of biases for each included study

Romero. Vaginal progesteroneto prevent preterm birthin women with a shortcervix:an IPDmetaanalysis.Am J Obstet Gynecol 2012.




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was associated with a signicant reduc-tion in the risk of preterm birth 33weeks of gestation (12.4% vs 22.0%; RR,0.58; 95% CI, 0.420.80; I 2 0%; 775women) ( Figure 3). The number of pa-tients with a short cervix who needed tobe treated with vaginal progesteronerather than with placebo to prevent 1case of preterm birth 33 weeks of ges-tation was 11 (95% CI, 823).

Secondary outcomesPatients allocated to receive vaginal pro-gesteronehad a signicantly lower risk of preterm birth 35 weeks of gestation(20.4% vs 30.5%; RR, 0.69; 95% CI,0.550.88; I 2 0%; NNT for benet 11;95% CI, 727), 34 weeks (16.0% vs27.1%;RR, 0.61;95%CI, 0.470.81; I 2

0%; NNT for benet 9; 95% CI, 719),30 weeks (7.5% vs 13.2%; RR, 0.58;95% CI, 0.38 0.89; I 2 0%; NNT forbenet 18; 95% CI, 1269), and 28weeks (5.4% vs 11.1%; RR, 0.50; 95% CI,0.300.81; I 2 0%; NNT for benet 18;95%CI,1347)comparedto thoseallocatedtoplacebo ( Table2). Moreover,vaginal pro-gesteroneadministrationwasassociatedwitha signicantly reduced risk of spontaneouspreterm birth 33and 34 weeks of gesta-tion. The reduction in the risk of preterm

birth 36weeksofgestationwas marginally signicant (RR, 0.82; 95% CI, 0.671.00).

Treatmentwithvaginalprogesteronewasas-sociated with an overall nonsignicant re-duction in the risk of perinatal mortality (3.4%vs5.3%;RR,0.63;95%CI,0.341.18;I 2 41%).This reductionappeared tobeat-tributable to a reduction in neonatal death(1.9%vs3.6%;RR,0.55;95%CI,0.261.19;I 2 43%) rather than fetal death (1.5% vs1.7%;RR,0.82;95%CI,0.282.42;I 2 0%).

Infants whose mothers received vaginalprogesterone also had a signicantly lowerrisk of RDS (6.1% vs 12.5%; RR, 0.48; 95%CI,0.300.76; I 2 0%; NNT for benet15;95% CI, 1133), composite neonatal mor-bidity and mortality (9.7% vs 17.3%; RR,0.57; 95% CI, 0.400.81; I 2 0%; NNT forbenet 13; 95% CI, 1030), birthweight

1500g (8.8% vs16.5%;RR, 0.55; 95% CI,0.380.80; I 2 6%; NNT for benet 13;95%CI,1030),admissiontoNICU(20.7%vs29.1%;RR, 0.75; 95% CI, 0.590.94; I 2

0%;NNTforbenet14;95%CI,857),andmechanical ventilation (8.5% vs 12.3%; RR,0.66; 95% CI, 0.440.98; I 2 0%; NNT forbenet 24; 95% CI, 15408) than infantswhosemothers had receivedplacebo.

There was no evidence of an effect of vaginal progesterone on necrotizing en-terocolitis, intraventricularhemorrhage,proven neonatal sepsis, retinopathy of

prematurity, bronchopulmonary dys-plasia,periventricular leukomalacia, Ap-

gar score 7 at 5 minutes, birthweight2500 g, or threatened preterm labor.In addition, the rates of maternal adverse

effects,discontinuationoftreatmentbecauseof adverse effects, and congenital anomaliesdidnotdiffer signicantly between thevagi-

nal progesterone and placebo groups. Onestudy 134 reported that the mean Ages andStagesQuestionnairescores(atoolthatmea-sures neurodevelopmental disability) at 18monthsofage were193 42.6 forinfants inthe progesterone group and 194 40.6 forinfants in the placebo group ( P .89).

Effect of vaginal progesterone insingleton and twin gestationsTable3 showstheeffectofvaginal progester-oneontheriskofpretermbirthandperinatal

outcomes in singleton and twin gestationsseparately. According to the interaction P values (all .10), therewas noevidencethatwomen with singleton pregnancies benetmore or less from the use of vaginal proges-teronethan womenwith twin pregnancies.

Among singletongestations, the adminis-tration of vaginal progesterone was associ-ated with a statistically signicant reductionin the risk of preterm birth 33, 35, and

28 weeks of gestation; RDS; compositeneonatal morbidity and mortality; Apgar

score 7 at5 minutes;birthweight 1500 g;and admission to theNICU.Among twin gestations, the adminis-

tration of progesterone did not signi-cantly reduce the risk of preterm birth

33 weeks of gestation (RR, 0.70; 95%CI, 0.341.44). However, it signicantly decreased the risk of composite neonatalmorbidity and mortality (RR, 0.52; 95%CI, 0.290.93). There were no signi-cant differences in other outcomemeasures among the vaginal progester-

one and placebo groups. The effects of vaginal progesterone on adverse peri-natal outcome in twins were testedwith 2 methods: one that assumed in-dependence of the twins, and anotherthat did not make such assumption.The results of both analyses were sim-ilar, with a slightly wider CI when themethod which assumed nonindepen-dence was employed ( Table 4). Thebenecial effects on composite neona-tal morbidity and mortality in twinsre-

mained statistically signicant (RR,0.56; 95% CI, 0.300.97).

FIGURE 3Effect of vaginal progesterone on pretermbirth < 33 weeks of gestation

0.01 0.1 0.2 0.5 1 2 5

Cetingoz 2011

Hassan 2011 0.55 (0.33-0.92)

Rode 2011

O'Brien 2007

Fonseca 2007

Combined 0.58 (0.42-0.80)

Relative risk (fixed)(95% CI)

Vaginalprogesterone

n/NPlacebo

n/NRelative risk

(95% CI)

Heterogeneity: I 2= 0%

Favors vag inal progesterone Favors p lacebo

StudyWeight

(%)

0.58 (0.36-0.92)

0.40 (0.05-3.13)

1.20 (0.40-3.63)

0.33 (0.04-2.91)

22/125 38/125 45.4

1/12 4/19 3.7

3/7 5/14 4.0

21/235 36/223 44.1

1/9 2/6 2.9

48/388 85/387 100.0

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Importantly,vaginalprogesteronewasas-sociated with a signicant reduction in the

risk ofpreterm birth 33weeksofgestationin both women with a singleton gestation

with no previous preterm birth (RR, 0.60;95%CI,0.390.92)aswellasinwomenwith

a singleton gestation and at least 1 previousspontaneous preterm birth 37 weeks of

gestation (RR, 0.54; 95% CI, 0.300.98).Moreover,vaginalprogesteronesignicantly

decreased the risk of composite neonatalmorbidity and mortality in women with a

TABLE 2Effect of vaginal progesterone on secondary outcome measures a

Outcome No. of trials

No. of events/total no.

Pooled RR (95% CI) I 2 (%) NNT (95% CI)Vaginalprogesterone Placebo

Preterm birth 37 wk 5 144/388 165/387 0.89 (0.751.06) 0 ................................................................................................................................................................................................................................................................................................................................................................................Preterm birth 36 wk 5 108/388 136/387 0.82 (0.671.00) 0 ................................................................................................................................................................................................................................................................................................................................................................................

Preterm birth 35 wk 5 79/388 118/387 0.69 (0.550.88) 0 11 (727)................................................................................................................................................................................................................................................................................................................................................................................

Preterm birth 34 wk 5 62/388 105/387 0.61 (0.470.81) 0 9 (719)................................................................................................................................................................................................................................................................................................................................................................................

Preterm birth 30 wk 5 29/388 51/387 0.58 (0.380.89) 0 18 (1269)................................................................................................................................................................................................................................................................................................................................................................................

Preterm birth 28 wk 5 21/388 43/387 0.50 (0.300.81) 0 18 (1347)................................................................................................................................................................................................................................................................................................................................................................................

Spontaneous preterm birth 33 wk 5 39/388 71/387 0.57 (0.400.81) 0 13 (929)................................................................................................................................................................................................................................................................................................................................................................................

Spontaneous preterm birth 34 wk 5 51/388 87/387 0.62 (0.460.84) 0 12 (828)................................................................................................................................................................................................................................................................................................................................................................................

Respiratory distress syndrome 5 25/411 52/416 0.48 (0.300.76) 0 15 (1133)................................................................................................................................................................................................................................................................................................................................................................................

Necrotizing enterocolitis 5 5/411 6/416 0.88 (0.302.64) 0 ................................................................................................................................................................................................................................................................................................................................................................................Intraventricular hemorrhage 5 6/411 9/416 0.74 (0.272.05) 0 ................................................................................................................................................................................................................................................................................................................................................................................

Proven neonatal sepsis 5 12/411 20/416 0.64 (0.321.29) 13 ................................................................................................................................................................................................................................................................................................................................................................................

Retinopathy of prematurity 5 6/411 3/416 1.56 (0.465.28) 0 ................................................................................................................................................................................................................................................................................................................................................................................

Bronchopulmonary dysplasia 2 4/249 5/231 0.76 (0.212.79) NA ................................................................................................................................................................................................................................................................................................................................................................................

Periventricular leukomalacia 2 0/249 0/231 Not estimable NA ................................................................................................................................................................................................................................................................................................................................................................................

Fetal death 5 6/411 7/416 0.82 (0.282.42) 0 ................................................................................................................................................................................................................................................................................................................................................................................

Neonatal death 5 8/411 15/416 0.55 (0.261.19) 43 ................................................................................................................................................................................................................................................................................................................................................................................

Perinatal death 5 14/411 22/416 0.63 (0.341.18) 41 ................................................................................................................................................................................................................................................................................................................................................................................

Composite neonatal morbidity/mortalitya 5 40/411 72/416 0.57 (0.400.81) 0 13 (1030)................................................................................................................................................................................................................................................................................................................................................................................

Apgar score 7 at 5 min 5 15/408 27/412 0.57 (0.321.02) 16 ................................................................................................................................................................................................................................................................................................................................................................................Birthweight 1500 g 5 36/410 68/413 0.55 (0.380.80) 6 13 (1030)................................................................................................................................................................................................................................................................................................................................................................................

Birthweight 2500 g 5 140/410 162/413 0.91 (0.761.08) 0 ................................................................................................................................................................................................................................................................................................................................................................................

Admission to NICU 5 85/411 121/416 0.75 (0.590.94) 0 14 (857)................................................................................................................................................................................................................................................................................................................................................................................

Mechanical ventilation 5 35/411 51/416 0.66 (0.440.98) 0 24 (15408)................................................................................................................................................................................................................................................................................................................................................................................

Congenital anomaly 7 30/1967 34/1954 0.89 (0.551.44) 0 ................................................................................................................................................................................................................................................................................................................................................................................

Any maternal adverse event 3 86/624 80/595 1.04 (0.791.38) 0 ................................................................................................................................................................................................................................................................................................................................................................................

Vaginal discharge 4 244/1065 248/1057 1.00 (0.871.15) 33 ................................................................................................................................................................................................................................................................................................................................................................................

Vaginal pruritus 4 54/1065 50/1057 1.08 (0.741.57) 0 ................................................................................................................................................................................................................................................................................................................................................................................

Discontinuation of treatment because ofadverse events

5 28/1083 28/1061 1.01 (0.611.69) 0

................................................................................................................................................................................................................................................................................................................................................................................

Threatened preterm labor 5 115/384 139/383 0.83 (0.681.02) 16 ................................................................................................................................................................................................................................................................................................................................................................................

Low ASQ developmental andsocioemotional score at 18 mo of ageb

1 19/503 18/488 1.02 (0.541.93) NA

................................................................................................................................................................................................................................................................................................................................................................................ ASQ, Ages and Stages Questionnaire; CI, condence interval; NA, not applicable; NICU, neonatal intensive care unit; NNT, number needed to treat; RR, relative risk.a Occurrence of any of the following events: respiratory distress syndrome, intraventricular hemorrhage, necrotizing enterocolitis, proven neonatal sepsis, or neonatal death; b ASQ score

115 points.

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singleton gestation and at least 1 previousspontaneous preterm birth 37 weeks of gestation(RR,0.41;95%CI,0.170.98),andin women with a twin gestation and nopre-vious preterm birth (RR, 0.52; 95% CI,0.290.93).

Subgroup and sensitivity analysesSubgroupanalyses of theeffectof vaginalprogesterone on primary outcomes arepresented in Table 5. There was no evi-dence that women in any one of the pre-specied subgroups benet more or lessfrom the use of vaginal progesteronethan those in any other subgroup (all P for interaction .30). However, the useof vaginal progesterone was associatedwith a statistically signicant reduction

in the risk of preterm birth 33 weeksand composite neonatal morbidity and

mortality in both women with no previ-ous spontaneous preterm birth andwomen with at least 1 previous sponta-neous preterm birth 37 weeks of gesta-tion, women with a sonographic cervicallength between 10-20 mm, women aged20-34 years, and Caucasian women.

No signicant differences were notedforpreterm birth 33 weeks of gestationand composite neonatal morbidity andmortality between subgroups based onthe daily dose of progesterone. A signi-cant decrease in the risk of preterm birth

33 weeks of gestation and compositeneonatal morbidity and mortality wasfound in women whoreceived either 90-100or 200mg/d of vaginal progesterone.

The effect of vaginal progesterone onthe risk of preterm birth 33 weeks of

gestation and composite neonatal mor-bidity/mortality did not change whensensitivity analysis was limited to the 2trials131,133 inwhichtheprimaryaimwasto evaluate the effect of vaginal proges-terone in women with a short cervix (pooled RR, 0.57; 95% CI, 0.400.80 forpretermbirth 33weeksandpooledRR,0.54; 95% CI, 0.350.82 for compositeneonatal morbidity/mortality). In addi-tion, the results of the metaanalyses didnot change signicantly when randomeffects models were used for pretermbirth 33 weeks (RR, 0.59; 95% CI,0.430.81) or for composite neonatalmorbidity/mortality (RR, 0.59; 95% CI,0.410.83). Sensitivity analyses based on

trial quality were not performed becauseall trials were considered at low risk for

TABLE 3Effect of vaginal progesterone on preterm birth and perinatal outcomes in singleton and twin gestations

Outcome

Singleton pregnancy Twin pregnancy

InteractionP value

No. of

trials

No. of events/total No.

Pooled RR

(95% CI)

No. of

trials

No. of events/total No.

Pooled RR

(95% CI)

Vaginal

progesterone Placebo

Vaginal

progesterone Placebo

Primary outcome.......................................................................................................................................................................................................................................................................................................................................................................

Preterm birth 33 wk 4 41/365 72/358 0.56 (0.400.80) 3 7/23 13/29 0.70 (0.341.44) .55................................................................................................................................................................................................................................................................................................................................................................................

Secondary outcomes.......................................................................................................................................................................................................................................................................................................................................................................

Preterm birth 37 wk 4 127/365 141/358 0.91 (0.751.10) 3 17/23 24/29 0.91 (0.681.23) .88.......................................................................................................................................................................................................................................................................................................................................................................

Preterm birth 35 wk 4 67/365 100/358 0.67 (0.510.87) 3 12/23 18/29 0.91 (0.571.46) .24.......................................................................................................................................................................................................................................................................................................................................................................

Preterm birth 28 wk 4 20/365 39/358 0.51 (0.310.85) 3 1/23 4/29 0.44 (0.111.85) .83.......................................................................................................................................................................................................................................................................................................................................................................

Respiratory distress syndrome 4 17/365 37/358 0.47 (0.270.81) 3 8/46 15/58 0.48 (0.211.09) .68.......................................................................................................................................................................................................................................................................................................................................................................

Necrotizing enterocolitis 4 5/365 6/358 0.88 (0.292.62) 3 0/46 0/58 Not estimable NA .......................................................................................................................................................................................................................................................................................................................................................................

Intraventricular hemorrhage 4 5/365 7/358 0.68 (0.222.13) 3 1/46 2/58 1.00 (0.1010.11) .74.......................................................................................................................................................................................................................................................................................................................................................................

Proven neonatal sepsis 4 11/365 14/358 0.80 (0.371.74) 3 1/46 6/58 0.33 (0.061.67) .30.......................................................................................................................................................................................................................................................................................................................................................................Retinopathy of prematurity 4 5/365 3/358 1.51 (0.405.69) 3 1/46 0/58 1.42 (0.0542.22) .91.......................................................................................................................................................................................................................................................................................................................................................................

Fetal death 4 6/365 7/358 0.82 (0.282.40) 3 0/46 0/58 Not estimable NA .......................................................................................................................................................................................................................................................................................................................................................................

Neonatal death 4 6/365 11/358 0.53 (0.201.39) 3 2/46 4/58 0.68 (0.232.02) .69.......................................................................................................................................................................................................................................................................................................................................................................

Perinatal death 4 12/365 18/358 0.64 (0.311.31) 3 2/46 4/58 0.68 (0.232.02) .90.......................................................................................................................................................................................................................................................................................................................................................................

Composite neonatal morbidity/ mortalitya

4 29/365 49/358 0.59 (0.380.91) 3 11/46 23/58 0.52(0.290.93) .69

.......................................................................................................................................................................................................................................................................................................................................................................

Apgar score 7 at 5 min 4 11/362 23/354 0.48 (0.240.95) 3 4/46 4/58 1.03 (0.382.81) .20.......................................................................................................................................................................................................................................................................................................................................................................

Birthweight 1500 g 4 28/364 53/355 0.52 (0.340.81) 3 8/46 15/58 0.69 (0.341.39) .47.......................................................................................................................................................................................................................................................................................................................................................................

Birthweight 2500 g 4 102/364 117/355 0.86 (0.691.07) 3 38/46 45/58 1.11 (0.921.35) .11.......................................................................................................................................................................................................................................................................................................................................................................

Admission to NICU 4 59/365 87/358 0.67 (0.500.91) 3 26/46 34/58 0.98 (0.701.35) .12.......................................................................................................................................................................................................................................................................................................................................................................

Mechanical ventilation 4 28/365 43/358 0.65 (0.411.01) 3 7/46 8/58 0.68 (0.301.56) .88................................................................................................................................................................................................................................................................................................................................................................................CI , condence interval; NA, not applicable; NICU , neonatal intensive care unit; RR , relative risk.a Occurrence of any of the following events: respiratory distress syndrome, intraventricular hemorrhage, necrotizing enterocolitis, proven neonatal sepsis, or neonatal death.





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biases. No funnelplots showedasymme-try, either visually or in terms of statisti-cal signicance (P .10 for all, by Eggertest).

C OMMENTPrincipal ndings of this studyVaginal progesterone administration toasymptomatic women with a sonographicshort cervix in the midtrimester was asso-ciatedwith:(1)asignicant42%reductionin the rate of preterm birth 33 weeks(primary outcome); (2) a signicant re-duction in the risk of preterm birth 35,

34, 30, and 28weeks and a trend fora reduction in the rate of preterm birth

36 weeks; (3) a signicant reduction in

the riskof spontaneous pretermbirth 33and 34 weeks; (4) a signicantly lowerrate of RDS (6.1% vs 12.5% in the placebogroup); (5) a signicant 43% decrease incomposite neonatal morbidity and mor-tality; (6) a signicantly lower rate of ad-mission to NICU (20.7% vs 29.1%) anduse of mechanical ventilation (8.5% vs12.3%); (7) a signicantly lower rate ofne-onates with a birthweight 1500 g (8.8%vs 16.5%); and (8) a nonsignicant differ-ence in therate of maternal adverseevents

(13.8%vs13.4%),discontinuation ofther-apy because of adverse events (2.6% vs2.6%), congenital anomalies (1.5% vs1.7%),and neurodevelopmental disability at 18 months of age (3.8% vs 3.7%). Fur-thermore, most results remained signi-cant when the analyses were restricted topatients with a singleton gestation. In pa-tients with a twin gestation, there was anonsignicant trend toward reduction of therateofpretermbirth 33weeks ofges-tation.However, there wasa signicant re-

duction in the risk of composite neonatalmorbidity/mortality (pooled RR, 0.52;95% CI, 0.290.93). Importantly, the re-duction in the rates of preterm birth 33weeksofgestationandcompositeneonatalmorbidity and mortality was observed inboth women with no previous spontane-ous preterm birth and women with a his-toryofspontaneous pretermbirth.Finally,there was no difference in efcacy when adose of either 90-100 or 200 mg/d of vagi-nal progesterone was used.

The major effect of vaginal progester-one was to reduce the rate of early pre-

term birth; however, our results indicatethat a fraction of late preterm births(34-36 6/7 weeks) can also be preventedwith the administration of vaginal pro-gesterone. Further studies are requiredto explore the reasons for the differentialeffect in early vs late preterm births. Onepossibility is that vaginal progesteronewas stopped at 36 6/7 weeks of gestationin the largest trial, but at 34 weeks of ges-tation in the trial of Fonseca et al. 131

Nonetheless, the importance of preventingearly preterm birth stems from their dispro-portionate contribution to serious perinatalmorbidity and long-term neurodevelop-mental disability.

A decrease in the rate of preterm birthhas been considered a surrogate endpointfor neonatal morbidity and mortality, andindeed, in some trials, a reduction in therate of preterm birth has not been accom-

paniedby a demonstrable reduction in thefrequency of neonatal morbid events. It

has been argued that a preventive strat-egy for preterm birth should accom-plish both a reduction in preterm birthand neonatal morbidity. Hassanet al133 demonstrated that the signi-cant reduction in the rate of pretermbirth at 33 weeks was associated witha signicant reduction in the rate of RDS by 61%, whereas Fonseca et al131

reported a nonsignicant reduction inthe risk of RDS by 41%. However, inthis IPD metaanalysis, we found thatvaginal progesterone signicantly de-creased the risk of RDS by 52%.

There was no signicant difference intheriskof adverse maternalevents,discon-tinuation of treatment because of adverseevents, and congenital anomalies betweenvaginal progesterone and placebo groups.Only 1 study of twin gestations 134 exam-ined developmental and socioemotional

scores at18 months of age, and found thatthere wasno differencebetweeninfantsex-

TABLE 4Effect of vaginal progesterone on adverse perinatal outcomesin twins according to analytical method used

Outcome

Pooled RR (95% CI)

Assuming independenceof newborns

Adjustment for the lack

of independenceof newborns

Respiratory distress syndrome 0.48 (0.211.09) 0.58 (0.251.39)..............................................................................................................................................................................................................................................

Necrotizing enterocolitis Not estimable Not estimable..............................................................................................................................................................................................................................................

Intraventricular hemorrhage 1.00 (0.1010.11) 1.00 (0.0518.19)..............................................................................................................................................................................................................................................

Proven neonatal sepsis 0.33 (0.061.67) 0.44 (0.044.67)..............................................................................................................................................................................................................................................

Retinopathy of prematurity 1.42 (0.0542.22) 1.36 (0.0358.74)..............................................................................................................................................................................................................................................

Fetal death Not estimable Not estimable..............................................................................................................................................................................................................................................

Neonatal death 0.68 (0.232.02) 0.48 (0.063.74)..............................................................................................................................................................................................................................................

Perinatal death 0.68 (0.232.02) 0.48 (0.063.74)..............................................................................................................................................................................................................................................

Composite neonatal morbidity/ mortalitya

0.52 (0.290.93) 0.56 (0.300.97)..............................................................................................................................................................................................................................................

Apgar score 7 at 5 min 1.03 (0.382.81) 0.88 (0.164.75)..............................................................................................................................................................................................................................................

Birthweight 1500 g 0.69 (0.341.39) 0.73 (0.291.83)..............................................................................................................................................................................................................................................

Birthweight 2500 g 1.11 (0.921.35) 1.13 (0.911.40)..............................................................................................................................................................................................................................................

Admission to NICU 0.98 (0.701.35) 0.89 (0.601.31)..............................................................................................................................................................................................................................................

Mechanical ventilation 0.68 (0.301.56) 0.60 (0.221.65)..............................................................................................................................................................................................................................................CI , condence interval; NICU , neonatal intensive care unit; RR , relative risk.a Occurrence of any of the following events: respiratory distress syndrome, intraventricular hemorrhage, necrotizing enterocolitis

proven neonatal sepsis, or neonatal death.

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posed to vaginal progesterone and thoseexposed to placebo. These results are con-sistentwith thoseofanunpublished obser-vation in a trial of singleton gestations ex-posed to vaginal progesterone. 157

Subgroup analysesSubgroup analyses did not indicate thatvaginal progesterone has differential ef-cacy in the main clinical subgroups of in-

terest. For example, patients with a sono-graphic short cervix with or without a

history of preterm birth seem to benetfrom vaginal progesterone for the reduc-tion of preterm birth. On the other hand,there was some suggestion that patientswith a singleton gestation, sonographiccervical length between10-20 mm,history of preterm birth, age 20-34 years, Cauca-sian, and body mass index 30 kg/m2

might derive a larger benet from the use

of vaginal progesterone than those withother characteristics. Although such anal-

ysis was prespecied, subgroup analysesshould, of course, be interpreted cau-tiouslybecause of theriskforfalse-positiveand false-negative results. 149,150

An important question is the range of cervical length in which vaginal proges-terone is effective. Fonseca et al131 notedthat vaginal progesterone reduced therate of spontaneous preterm delivery at

34 weeks of gestation by only 15% inwomen with a cervical length of 1-5 mm

TABLE 5Subgroup analyses of effect of vaginal progesterone on preterm birth< 33 weeks of gestation and composite neonatal morbidity/mortality a

Subgroup

Preterm birth < 33 wk of gestation Composite neonatal morbidity/mortality a

n RR (95% CI)

InteractionP value n RR (95% CI)

InteractionP value

Patient characteristics.......................................................................................................................................................................................................................................................................................................................................................................

Cervical length, mm .32 .93..............................................................................................................................................................................................................................................................................................................................................................

10 79 0.83 (0.491.41) 90 0.62 (0.281.38)..............................................................................................................................................................................................................................................................................................................................................................

10-20 653 0.52 (0.350.76) 680 0.54 (0.350.84)..............................................................................................................................................................................................................................................................................................................................................................

21-25 43 0.50 (0.102.41) .68 57 0.55 (0.261.19) .40.......................................................................................................................................................................................................................................................................................................................................................................

Obstetric history..............................................................................................................................................................................................................................................................................................................................................................

With no previous preterm birth 606 0.61 (0.420.89) 658 0.62 (0.430.91)..............................................................................................................................................................................................................................................................................................................................................................

With 1 previous preterm birth 169 0.54 (0.300.98) 169 0.41 (0.170.96).......................................................................................................................................................................................................................................................................................................................................................................

Maternal age, y .85 .31..............................................................................................................................................................................................................................................................................................................................................................

20 63 0.66 (0.212.14) 66 1.05 (0.254.37)..............................................................................................................................................................................................................................................................................................................................................................

20-34 620 0.58 (0.410.84) 659 0.48 (0.310.73)..............................................................................................................................................................................................................................................................................................................................................................

35 92 0.49 (0.201.15) 102 0.89 (0.332.36).......................................................................................................................................................................................................................................................................................................................................................................

Race/ethnicity .44 .68..............................................................................................................................................................................................................................................................................................................................................................

Caucasian 269 0.39 (0.220.69) 291 0.57 (0.350.93)..............................................................................................................................................................................................................................................................................................................................................................

Black 287 0.74 (0.461.19) 293 0.60 (0.321.12)..............................................................................................................................................................................................................................................................................................................................................................

Asian 157 0.53 (0.211.34) 159 0.87 (0.203.78)..............................................................................................................................................................................................................................................................................................................................................................

Other 41 0.60 (0.191.92) 42 0.20 (0.031.57).......................................................................................................................................................................................................................................................................................................................................................................

Body mass index, kg/m2 .70 .58..............................................................................................................................................................................................................................................................................................................................................................

18.5 58 0.35 (0.101.20) 62 0.26 (0.051.34)..............................................................................................................................................................................................................................................................................................................................................................18.5-24.9 359 0.63 (0.361.10) 390 0.62 (0.371.03)..............................................................................................................................................................................................................................................................................................................................................................

25.0-29.9 187 0.68 (0.391.19) 200 0.76 (0.391.47)..............................................................................................................................................................................................................................................................................................................................................................

30 159 0.49 (0.260.92) 163 0.46 (0.211.03)................................................................................................................................................................................................................................................................................................................................................................................

Trial characteristics.......................................................................................................................................................................................................................................................................................................................................................................

Daily dose of vaginal progesterone, mg .57 .92..............................................................................................................................................................................................................................................................................................................................................................

90-100 504 0.53 (0.330.85) 511 0.58 (0.350.95)..............................................................................................................................................................................................................................................................................................................................................................

200 271 0.63 (0.410.96) 316 0.56 (0.340.94)................................................................................................................................................................................................................................................................................................................................................................................CI , condence interval; RR , relative risk.a Occurrence of any of the following events: respiratory distress syndrome, intraventricular hemorrhage, necrotizing enterocolitis, proven neonatal sepsis, or neonatal death.





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and 25% in patients with a cervicallength of6-10mm, but the effect sizewas75%in patientswith a cervical lengthbe-tween 11-15 mm. One possible explana-tion for this observation is that womenwith a veryshort cervix are more likely to

have intraamniotic inammation andmay be less responsive to progester-one. 158,159 These observations are inkeeping with the rationale for excludingpatients with a cervical length of 10mm in the study reported by Hassan etal.133 A subgroup analysis of this IPDmetaanalysis suggests that progesteronemight be less effective in patients with acervical length of 10 mm. However,there was no statistically signicant differen-tial effectaccording to cervical length (inter-

action P value of .32 for preterm birth 33weeks of gestation and .93 for compositeneonatal morbidity/mortality). Therefore,this result is subject toall limitations ofanal- ysisofsubgroups.149,150

Fonseca et al131 and Hassan et al 133 re-ported that vaginal progesterone was as-sociated with a nonstatistically signi-cant reduction in the rate of pretermbirth 34 weeks and preterm birth 33weeks, respectively, in patients with ashort cervix and history of spontaneous

preterm birth. Some have interpretedsuch ndings as suggesting that vaginalprogesterone does not reduce the rate of preterm birth in these women. This isnot a correct interpretation of the resultsof the trials, because the number of pa-tients with a prior preterm birth in eachindividual trial was small. Indeed, pa-tients with a history of preterm birth

37 weeks of gestation represented only 15% and 21% of those enrolled in thetrials of Fonseca et al131 and Hassan et

al,133

respectively. Moreover, the pri-mary objective of both trials was to testwhether vaginal progesterone would re-duce the rate of preterm birth in womenwith a sonographic short cervix, and notin a particular subgroup. Although th

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