Expectant management compared with physical examination–indicated cerclage (EM-PEC) in selected women with a dilated cervix at 140/7-256/7 weeks: results from the EM-PEC international

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xpectant management compared with physical examination–ndicated cerclage (EM-PEC) in selected women with a dilatedervix at 140/7-256/7 weeks: results from the EM-PECnternational cohort studyeonardo Pereira, MD; Amanda Cotter, MD; Ricardo Gómez, MD; Vincenzo Berghella, MD; Witoon Prasertcharoensuk, MD;uha Rasanen, MD; Surasith Chaithongwongwatthana, MD; Suneeta Mittal, MD; Sean Daly, MD; Jim Airoldi, MD;orge E. Tolosa, MD, MSCE

BJECTIVE: The objective of the study was to compare pregnancy out-omes in selected women with a dilated cervix who underwent expect-nt management or physical examination–indicated cerclage.

TUDY DESIGN: This was a historical cohort study conducted byhe Global Network for Perinatal and Reproductive Health. Womenetween 140/7 and 256/7 weeks’ gestation with a dilated cervix were

dentified at 10 centers by ultrasound or digital examination. Pri-ary outcome was time from presentation until delivery (weeks).econdary outcomes were neonatal survival, birthweight greater

han 1500 g and preterm birth less than 28 weeks. Multivariateegression was used to assess the likelihood of neonatal outcomesnd control for confounders.

ESULTS: Of 225 women, 152 received a physical examination–ndicated cerclage, and 73 were managed expectantly without cer-

See Journal Club, page 551

atal steroid use differed between groups. In the adjusted analyses,erclage was associated with longer interval from presentation untilelivery, improved neonatal survival, birthweight greater than500 g and preterm birth less than 28 weeks, compared with ex-ectant management. Similar results were obtained in the analyses

imited to women dilated between 2 and 4 cm (n � 122).

ONCLUSION: In this study, the largest cohort reported to date,hysical examination–indicated cerclage appears to prolong gesta-

ion and improve neonatal survival, compared with expectant man-gement in selected women with cervical dilation between 140/7

nd 256/7 weeks. A randomized, controlled trial should be con-ucted to determine whether these potential benefits outweigh theisks of cerclage placement in this population.

lage. Cervical dilation, gestational age at presentation, and ante- Key words: cerclage, premature cervical dilation, preterm birth

ite this article as: Pereira L, Cotter A, Gomez R, et al. Expectant management compared with physical examination-indicated cerclage (EM-PEC) in selectedomen with a dilated cervix at 140/7-256/7 weeks: results from the EM-PEC international cohort study. Am J Obstet Gynecol 2007;197:483.e1-483.e8.

rom the Division of Maternal-Fetal Medicine, Oregon Health & Science University, and the Global Network for Perinatal andeproductive Health, Portland, OR (Drs Pereira and Tolosa); the Division of Maternal-Fetal Medicine, Leonard L. Miller School ofedicine, University of Miami, Miami, FL (Dr Cotter); the Center for Perinatal Diagnosis and Research, Sotero del Río Hospital, Pontificianiversidad Catolica de Chile, Puente Alto, Chile (Dr Gómez); the Division of Maternal-Fetal Medicine, Department of Obstetrics andynecology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA (Dr Berghella); the Department of Obstetrics andynecology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand (Dr Prasertcharoensuk); the Department of Obstetrics andynecology, Faculty of Medicine, University of Oulu, Oulu, Finland (Dr Rasanen); the Department of Obstetrics and Gynecology, Facultyf Medicine, Chulalongkorn University, Bangkok, Thailand (Dr Chaithongwongwatthana); the Department of Obstetrics and Gynecology,ll India Institute of Medical Sciences, New Delhi, India (Dr Mittal); the Department of Obstetrics and Gynecology, Coombe Women’sospital, Dublin, Ireland (Dr Daly); and the Department of Obstetrics and Gynecology, St. Luke’s Hospital, Bethlehem, PA (Dr Airoldi).

resented at the 26th Annual Meeting of the Society for Maternal-Fetal Medicine, Jan. 30 through Feb. 4, 2006, Miami Beach, FL.

eceived September 20, 2006; revised March 14, 2007; accepted May 24, 2007.

eprints not available from the authors.

his work was supported in part by The Rockefeller Foundation, The United States Agency for International Development, The International Clinicalpidemiology Network, and Thomas Jefferson University.

002-9378/$32.002007 Mosby, Inc. All rights reserved.

oi: 10.1016/j.ajog.2007.05.041

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4

reterm birth is the most significantproblem in obstetrics. It accounts

or 70-80% of neonatal mortality and in-reased morbidity in both developed andeveloping countries.1 Current strate-ies and significant resources targetingrematurity prevention have been

argely unsuccessful, and the rate of pre-erm birth in the United States and otherountries has steadily increased duringhe past 25 years.2,3 Of all women at riskor preterm birth, those experiencingecond-trimester cervical dilation have aarticularly poor prognosis, with areater than 90% rate of pretermirth.4-7 Physical examination–indi-ated cerclage, defined as a cerclagelaced because of cervical dilation, re-ardless of cervical length, obstetric his-ory, or risk factors for preterm birth, haseen suggested as a therapy for theseomen.6,7

Despite this exceedingly high rate ofreterm birth, women with prematureervical dilation have been relatively un-erstudied, compared with the thou-ands of women enrolled into random-zed, controlled trials (RCTs) of cerclageased on either historical risk factors8-11

r a shortened cervix determined by ul-rasound.12-15 These trials demonstratedittle or no benefit associated with cer-lage.16 In contrast, 3 nonrandomizedtudies4-6 and 1 small RCT7 of womenith cervical dilation have all reported a

eduction in preterm birth associatedith physical examination–indicated

erclage in women with a dilated cervixhen compared with bed rest. However,iven the disappointing results of theforementioned RCTs in women withistorical risk factors or a shortened cer-ix, the bias inherent in nonrandomizedtudies, and practical concerns about in-raoperative complications, subclinicalhorioamnionitis,17 and neonatal cere-ral palsy18 in pregnancies complicatedy premature cervical dilation, the opti-al management of these patients re-ains unclear.Our study was conducted with 2 main

bjectives. The first was to estimate fetalnd maternal outcomes associated withhysical examination–indicated cer-lage, compared with expectant manage-
ent in women with cervical dilation be- v
83.e2 American Journal of Obstetrics & Gynecol

ween 140/7 and 256/7 weeks’ gestation.he secondary objective of this study was

o determine the sample size and feasibil-ty of an adequately powered RCT of cer-lage, compared with expectant manage-ent in women with premature cervical

ilation.

ATERIALS AND METHODShe expectant management comparedith physical-exam indicated cerclage

tudy was the first phase of a multicen-ered study of women with prematureervical dilation conducted by the Globaletwork for Perinatal and Reproductiveealth (GNPRH; www.gnprh.org), dur-

ng which a historical cohort of womenith cervical dilation between 140/7 and56/7 weeks’ gestation between January998 and December 2005 was identified.ollowing a meeting of investigators,ata collection instruments were devel-ped and pilot tested. Ten participatingenters reported on all pregnancies atach institution during which womenresenting for care between 140/7 and56/7 weeks’ gestation were found to haveervical dilation of the internal os onlinical examination, a finding that madehem eligible to receive a clinically indi-ated cerclage. Centers were not re-uired to participate for the entire 7 yeartudy period, but they were instructed toeport on all eligible pregnancies duringheir participating study time. The pur-ose of this study was to identify thistrictly defined cohort and compare out-omes in women undergoing cerclagelacement with those undergoing ex-ectant management. The primary out-ome of this historical cohort study wasime from presentation until delivery.he secondary outcomes were neonatal

urvival, birthweight greater than 1500 g,reterm birth before 28 weeks, and ges-ational age at delivery.

Approval by the institutional reviewoard was obtained at each participatingenter. Participating centers were all uni-ersity teaching or tertiary care centersith neonatal intensive care units with

he ability to administer surfactant and
asopressors and provide ventilator sup- s
ogy NOVEMBER 2007

ort to neonates. This study cohort wasot identified by routine digital exami-ation of all pregnant women at all cen-

ers. All of the women followed up in thistudy were initially identified in 1 of 2ays: (1) those found to have a short-

ned cervix or suspected cervical dilationn ultrasound or (2) those identified byigital examination performed becausef a history of prior second trimester

oss, history of preterm birth, or subjec-ive complaints of pressure or discharge.ll subjects identified by ultrasound un-erwent sterile speculum and digital ex-mination to confirm cervical dilation.

To be eligible for the study, subjectsad to be between 140/7 and 256/7 weeks’estation with cervical dilation of 1 cm orreater by digital examination. Womenith preterm prelabor rupture of mem-ranes (PPROM), active labor, vaginalleeding, or chorioamnionitis at time ofresentation and those with a closed cer-ix on digital examination were ex-luded. PPROM was defined by grossupture of amniotic fluid with anhydr-mnios on ultrasound, visualizing amni-tic fluid on sterile speculum exam, theresence of a Nitrazine positive vaginalool of fluid with a ferning pattern onicroscopy, or a positive amniocentesis

ye study. Active labor was defined as theresence of regular uterine contractionsor more in 10 minutes with cervical

hange. Chorioamnionitis was definedy the following: (1) positive amnioticuid culture (aerobic and anaerobic bac-

eria, ureaplasma, or mycoplasma); (2)he combination of positive amnioticuid Gram stain, amniotic fluid leuko-yte count greater than 50 cells/mm3,nd/or amniotic fluid glucose 14 mg/dLr less; (3) interleukin-6 greater than 2g/mL at centers at which this test wasvailable; or (4) clinical chorioamnioni-is as defined by Gibbs et al.19

Subjects were not randomly assignedo a particular management strategy.linical management was made case by

ase between the physician and patientfter an informed discussion. Physicalxamination–indicated cerclage wasvailable at all centers participating inhis study. In centers at which termina-ion of pregnancy was available, those
ubjects opting for induction of labor or
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ermination were observed for maternalomplications but not included in thenalysis of perinatal outcomes. Allomen in whom perinatal outcomes are

eported were managed either by physi-al examination–indicated cerclage orxpectantly (bed rest without cerclage).n all patients, the use of additional mea-ures such as antibiotics, amniocentesis,nd Trendelenberg positioning was re-orded at each center but were not stan-ardized. Intraoperative cerclage tech-iques such as reduction of membranesy sponge stick or Foley bulb, choice ofuture material, method of cerclagelacement, and the use of perioperative

ndomethacin, other tocolytic agents, orntibiotics were recorded in all cases.

Demographic characteristics and riskactors for preterm birth were recorded.he position of amniotic membranes asssessed during sterile speculum exami-ation (ie, not visible, visible, or pro-

apsed through the cervix), the degree ofervical dilation at time of presentation,nd details of clinical management suchs the use of amniocentesis to excludehorioamnionitis, treatment of subse-uent preterm labor, and administrationf antenatal steroids were recorded on allubjects.

All data collection forms were sent tohe coordinating study center of theNPRH located at Oregon Health andcience University in Portland, Ore-on. Data were entered into an SPSSata document (SPSS Inc, Chicago,L). Statistical analysis was performedith the SPSS statistical package (ver-

ion 14.0). Comparison of categoricalariables was achieved by �2 analysis,hereas the Mann-Whitney U test wassed to compare nonparametric con-

inuous variables.Multivariate regression was used to as-

ess the likelihood of neonatal outcomes

TABLE 1Demographic characteristics of th

Age (y) (� SD)...................................................................................................................

Previous preterm birth (%)...................................................................................................................

Previous second-trimester miscarriage (%)

hile controlling for confounders. Theollowing independent variables were in-luded in the multivariate regressionnalyses: gestational age at presentation,ervical dilation at presentation, institu-ion, and antenatal steroid use. The fol-owing dependent variables were in-luded: interval in weeks fromresentation to delivery, neonatal sur-ival, birthweight greater than 1500 g,nd preterm birth at less than 28 weeks.

ESULTSuring the study period, a total of 483omen between 140/7 and 256/7 weeks’estation with suspected cervical dilationcm or greater were identified. Of these83 women, 25 were excluded because ofervical dilation less than 1 cm. An addi-ional 160 were found to have contrain-

FIGURE 1Flow diagram of all identified wom

Subjects between 1with suspected c

N

Cervical diN

Contraindications to cerclage N = 160

PPROM N =75Active labor/vaginal bleeding N =63Amniocentesis positive for chorioamnionitis N =14Clinical chorioamnionitis N = 8

EligibleN

Termination of pregnancyN = 10

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Lost to follow upN = 20 Final

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AnalyzedN= 152

ereira. EM-PEC in selected women with a dilated cervix. AJOG 2

bserved cohortCerclage group(n � 152)

Exgr

30.1 (� 6.2) 28.........................................................................................................................

57 (37.5%) 28.........................................................................................................................

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NOVEMBER 2007 America

ications to cerclage (Figure 1). Of the98 remaining subjects, 10 opted for in-uction of labor or surgical termination.hese patients were followed up for theevelopment of any maternal complica-ions but were excluded from this analy-is. Women with multifetal gestationsere excluded (36 twins, 4 triplets), andf the remaining 248 singletons, out-omes were available in 90.7% (20omen in the cerclage group and 3omen in the expectant group were lost

o follow-up), leaving 225 women in thenal cohort. Statistical analysis was con-ucted on these 225 women, 73 whoere managed without cerclage and 152ho underwent cerclage placement at

he obstetrician’s discretion.Women who received a cerclage were

.0 years older on average (Table 1). Al-

between 140/7-256/7 weeks6/7 weeks gestation al dilation > 1 cm3

Cervical dilation < 1 cmN = 25

confirmed

erclage8

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Lost to follow upN = 3ort

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tant management(n � 73)

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� 6.7) .03..................................................................................................................

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hough there were similar rates of priorreterm birth in both groups, women re-eiving cerclage were more likely to havead a previous second-trimester miscar-iage. The 4 US centers accounted for2% of subjects, whereas 7% of the co-ort was from South America, 10% fromurope, and 11% from Asia (Figure 2).Subjects undergoing cerclage pre-

ented 4 weeks earlier in gestation on av-rage (Table 2). Median cervical dilationas the same in both groups; however,

he incidence of antenatal steroid ad-

FIGURE 2Recruitment by center

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TABLE 2Characteristics of the observed co

Gestational age at diagnosis (wks)...................................................................................................................

Cervical dilation at diagnosis (cm)...................................................................................................................

Amniocentesis performed to exclude subclinichorioamnionitis (n)

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

Antenatal steroids administered (n)...................................................................................................................

Antenatal antibiotics administered (n)...................................................................................................................

* Values are median (interquartile range).


inistration was lower in the group re-eiving cerclage. The use of amniocente-is and antibiotics did not differ betweenhe 2 groups. The distribution of cervicalilation in all women is displayed in Fig-re 3.Indomethacin was the most com-only administered tocolytic in this co-

ort (30.2% of subjects); its use was notifferent between the cerclage and ex-ectantly managed groups. In this co-ort, tocolytic use was not associatedith increased gestational age at delivery

Philadelphia38%Miami 26%

Santiago 7%

Portland 6%

Khon Kaen 6%

Oulu 5%

Dublin 5%

Bangkok 4%

Bethlehem 2%

Philadelphia

Delhi

rtCerclage group(n � 152)

19.1 (15.5, 22.7)*.........................................................................................................................

1.8 (1, 3.8)*.........................................................................................................................

23 (15.1%)

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

37 (24.3%).........................................................................................................................

85 (56.3%).........................................................................................................................

ogy NOVEMBER 2007

29.7 vs 29.5 weeks, P � .82) or birth-eight (1724 vs 1783 g, P � .73).With regard to the status of amnioticembranes in women undergoing cer-

lage, in 85 (56%) amniotic membranesere not visible on speculum examina-

ion, in 39 (25%) membranes were visi-le on sterile speculum examination athe level of the external os, in 22 (15%)

embranes were prolapsed into the va-ina, and in 6 (less than 4%) membranetatus was unknown.

Unadjusted analysis of the primaryutcome showed a significant increase inregnancy prolongation (median 12.4 vs.6 weeks, P � .001) and gestational aget delivery (median 33.0 vs 25.9 weeks, P

.003) in the cerclage group, comparedith the expectant group. Unadjusted

nalysis failed to demonstrate a differ-nce in neonatal survival (66.2% vs8.9%, P � .29), and there appeared toe a differential distribution of gesta-ional ages at delivery (Figure 4). How-ver, after adjustment for gestational age

FIGURE 3Distribution of cervical dilationbetween groups

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Cervical dilation at time of presentation (cm)

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60

40

20

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ExpectantManagement

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Expectant group(n � 73) P value

23.1 (20.2, 26.0)* �.001..................................................................................................................

2.0 (1, 4.5)* .104..................................................................................................................

7 (9.6%) .252

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

40 (55.8%) �.001..................................................................................................................

43 (58.9%) .711..................................................................................................................

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nd cervical dilation at presentation, fe-al number, institution, and steroid use,he primary outcome of pregnancy pro-ongation as well as neonatal survival,irthweight, and preterm birth at lesshan 28 weeks were all improved by clin-cally-indicated cerclage in a multivari-te regression (Tables 3 and 4).

Institution of origin was controlled foro account for the different race/ethnicistributions among the populations inhis study. In the adjusted analysis, these of physical examination–indicatederclage was associated with a greaterhan 10-fold increase in neonatal sur-ival and a 92% reduction in pretermirth prior to 28 weeks. More than 67%49 of 73) of women who were expect-ntly managed delivered prior to 28eeks, compared with 38% (57 of 152)f women who received a cerclage. Thiseneficial association occurred regard-

ess of the patient’s obstetric history. Inhis cohort, a history of prior pretermirth was not associated with a difference

n interval from presentation to deliveryr an increased rate of preterm birth at

ess than 28 weeks. In women managedxpectantly, the overall rate of pretermirth at less than 28 weeks was 67.1%67.9% in women with prior pretermirth, 66.7% in women with no priorreterm birth, P � .916).In a small group of women presentingith cervical dilation greater than 4 cm

n � 8), only 1 underwent cerclage (6 cmt 22 weeks after negative amniocentesiselivered at 35 weeks), and 7 were ex-ectantly managed (all 7 deliveredithin 1 week).We performed a separate analysis re-

tricted only to women with cervical di-ation between 2 and 4 cm. We chosehese cut-offs for a restricted analysis ofxpectant management to physical ex-mination–indicated cerclage because inultiparous women, slight cervical dila-

ion of 1 cm may be a normal variant,hereas in many women dilated greater

han 4 cm, cerclage may no longer be aiable option. When restricting the anal-sis to women dilated 2-4 cm (n � 122),esults for pregnancy prolongation, ges-ational age at delivery, neonatal sur-ival, birthweight, and preterm birth at
ess than 28 weeks were all similar to that
f the entire cohort, although the confi-ence interval for pregnancy prolonga-ion in this subgroup crossed 1 (Tables 3nd 4).

Compared with women with cervicalilation less than 2cm, cerclage seemedo provide more benefit to women withervical dilation 2 cm or greater (oddsatio for neonatal survival 5.80 (1.23,7.44), compared with 11.20 (2.16,8.02) and for preterm birth at lesshan 28 weeks 0.18 (0.04,0.76), com-ared with 0.07 (0.02, 0.35), respec-ively. When tocolytic use was in-

FIGURE 4Distribution of deliveries by gestat

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TABLE 3Multivariate linear regression of thplacement and time interval from

Linear regression

Cerreg(95

Interval from presentation to delivery(wks)

1.8

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

CI, confidence interval.

* Expectant management group is the reference group.† Analysis of all patients, adjusted for the following variablesinstitution, and antenatal steroid use.‡ Analysis of all patients dilated 2-4 cm, adjusted for the foll
at presentation, institution, and antenatal steroid use.

luded in the regression model, noignificant effect was observed for anyf the measured outcomes. Data onutcome of multifetal pregnancies,aternal morbidities related to cer-

lage placement, and neonatal morbid-ties related to prematurity will be re-orted in a separate manuscript.

OMMENTespite international efforts aimed at re-ucing the incidence of preterm deliv-ry, this entity remains the major cause

al age in weeks

t delivery (weeks)

403530252015

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nagement

association between cerclagesentation to delivery*

e (all cases)†

sion coefficientI)

Cerclage(2-4 cm dilated)‡

regression coefficient(95% CI)

.14, 2.45) 1.31 (0.29, 2.32)

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

tational age at presentation, cervical dilation at presentation,

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f perinatal morbidity and mortalityorldwide. With the exception of 2 re-

ently completed trials of serial proges-erone administration,20,21 most antena-al interventional trials have not beenuccessful in reducing the incidence ofreterm birth.22-24

In our study, placement of a cerclagen a very specific population (ie, thoseith cervical dilation in the absence of

abor, bleeding, PPROM or any signs ofhorioamnionitis clinically or by amnio-entesis) resulted in a favorable prolon-ation of pregnancy by 10 weeks, com-ared with expectant management. Thebserved benefits of physical examina-ion–indicated cerclage also includedmproved neonatal survival, higherirthweight, and a lower rate of earlyreterm birth before 28 weeks in the ad-

usted analysis. These findings are con-istent with the findings of 2 retrospec-ive case series of cerclage with controls,hich included 37 and 70 women,4,5 1rospective nonrandomized study of 46omen6 and 1 RCT in 23 women re-orted by Althuisius et al in 2003.7

The exclusion of women with pretermontractions, PPROM, or abnormal am-iocentesis results are importanttrengths of our study, intended to min-mize the number of women with sub-linical chorioamnionitis. The preva-ence of subclinical chorioamnionitis inomen with preterm cervical dilationas been reported to be more than5%,17 and clinical signs of infection areate markers of intraamniotic infection.

TABLE 4Multivariate logistic regression ofplacement and neonatal outcomes

Logistic regression

CcO

Neonatal survival 1...................................................................................................................

Birthweight greater than 1500 g...................................................................................................................

PTB less than 28 wks...................................................................................................................

CI, confidence interval; OR, odds ratio; PTB, preterm birth.

* Expectant management group is the reference group for all† Analysis of all patients and adjusted for the following variableinstitution, and antenatal steroid use.‡ Analysis of all patients dilated 2-4 cm, adjusted for the follat presentation, institution, and antenatal steroid use.

his may account for the consistent in- s


rease in maternal infectious morbidityssociated with cerclage8,16 and couldheoretically result in higher rates of neo-atal cerebral palsy if cerclage is used in

he setting of unrecognized chorioam-ionitis. Our study would have been fur-

her strengthened if all women had un-ergone amniocentesis.Other major strengths of our study are

he robust sample size (the largest toate), the inclusion of women from var-

ous race/ethnic groups, and the fact thatt describes the use of an interventionommonly performed at most secondaryr tertiary facilities in the world. The in-lusion of both expectantly managed pa-ients and those receiving cerclage dur-ng the same time period and at the samenstitutions is another strength. Thisends validity to the observed outcomes,specially after controlling for importantonfounders. The consistency betweenur findings and previously reportedtudies further supports a possible ther-peutic role for cerclage in this group ofomen.However, observational studies such

s ours are limited by multiple sources ofias, which cannot be completely ac-ounted for by statistical methods andan exaggerate potential therapeuticenefits. In this study, all women at all

nstitutions were not screened for cervi-al dilation. Instead, women with cervi-al dilation were identified in 1 of 2 ways:1) those found to have a shortened cer-ix or suspected cervical dilation on ul-rasound or (2) those identified by

association between cerclage

lageqa (alls)*†

95% CI)

Cerclage (2-4cm dilated)*‡ OR(95% CI)

3 (3.36, 33.00) 9.30 (1.75, 49.60)..................................................................................................................

8 (3.56, 26.36) 7.73 (1.68, 35.65)..................................................................................................................

8 (0.03, 0.23) 0.09 (0.02, 0.42)..................................................................................................................

els.

stational age at presentation, cervical dilation at presentation,

g variables: gestational age at presentation, cervical dilation

creening digital examination per- g

ogy NOVEMBER 2007

ormed because of a history of prior sec-nd-trimester loss, history of pretermirth, or subjective complaints of pres-ure or discharge. This may have biasedesults by selecting a cohort of womenho were more likely to miscarry or suf-

er early preterm birth than a cohort ofnselected low-risk, asymptomaticomen found to have a dilated cervix byniversal screening digital examina-

ions. Furthermore, minor cervical dila-ion (ie, less than 2 cm) may not reflect ahange from baseline in multiparous pa-ients, and in this subgroup, perhaps theisk for preterm birth is less. A prospec-ive study in which all women arecreened may find less benefit to cerclagef the natural history in women undergo-ng expectant management is better.

In this study, the gestational ages dif-ered between women who were expect-ntly managed and those undergoingerclage. The use of cerclage at an earlierestational age (median 19.1 weeks),ompared with the expectantly managedroup (median 23.1 weeks) likely reflectshe decision making of physicians whoould be expected to demonstrate a re-

uctance to perform surgery as thehreshold of viability is approached. De-ision making of the physicians alsoikely accounts for a reluctance to at-empt cerclage placement in the face ofdvanced cervical dilation because ofoncerns about intraoperative complica-ions. As a case in point, only 1 of 8 sub-ects with a cervical dilation greater than

cm had cerclage attempted. Thus, ifervical changes occur as a continuumith only a proportion of women pro-ressing from cervical shortening toarly and then advanced cervical dilationnd ultimately preterm birth (Figure 5),hen the reluctance of physicians to placeerclage in the setting of more advancedervical dilation likely biases the resultsf this study, overrepresenting the ap-arent benefit of cerclage because someubjects receiving earlier cerclage wouldever have progressed to more advancedegrees of cervical dilation or pretermirth.This bias may also explain, in part, the

ifferential distribution of gestationalges at delivery observed between the 2

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xpectantly delivered in a normal distri-ution, whereas those receiving cerclagead a bimodal distribution of deliverywith most patients delivering either fol-owing surgery, ie, less than 25 weeks’estation, or else at longer than 34eeks) (Figure 4).Interestingly, when analyzing our data

o consider the effect of obstetric history,e did not see an association betweenrior preterm birth and pregnancy out-ome. In fact, there was no associationith obstetric history and interval to de-

ivery or preterm birth at less than 28eeks for the entire cohort or when pa-

ients receiving cerclage or expectantanagement were analyzed separately.e hypothesize that because cervical di-

ation prior to 26 weeks, especially ad-anced dilation, is never a normal vari-nt, that once women progress to thisoint, their risk for preterm birth is soigh (67% at less than 28 weeks in ouropulation) that prior history does not

nfluence outcome, this in contrast toomen with a short cervix, the majorityf whom will carry to term unless theyave a history suggestive of cervical

nsufficiency.16

One might expect that cerclage, if ef-ective in pregnancy prolongation,ould demonstrate greater benefit when

pplied to women at highest risk torogress to preterm birth (ie, those withore advanced cervical dilation as sug-

ested in Figure 5). Our data support thisbservation, demonstrating a more than-fold difference in neonatal survivalodds ratio 11.2 vs 5.8) and preterm birtht less than 28 weeks (odds ratio 0.07 vs.18) in women with cervical dilation 2m or greater, compared with cervicalilation less than 2 cm who under-ent cerclage compared to expectantanagement.The risk of intraoperative membrane

upture with placement of cerclage inomen with cervical dilation has been

eported between 4% and 19%.25-27 In-reases in maternal and neonatal mor-idities may also be expected if cerclagelacement occurs in the presence of un-ecognized chorioamnionitis. Because ofhese potential adverse events, an ade-uately powered RCT to assess the ben-
fits and risks of physical examination– p
ndicated cerclage urgently needs to beone, a sentiment recently echoed in theditorial by Alfirevic.28

An RCT of cerclage in this setting ap-ears to be difficult but feasible. The neo-atal survival in expectantly managedatients in our study was 59% (43 of 73).his falls within the wide range in neo-atal survival previously reported in 2tudies (17-71%),6,7 both of which ob-erved a 60% reduction in neonatal mor-ality associated with cerclage. Assumingn expected neonatal mortality rate of0% and a more conservative 50% re-uction with cerclage to 20%, 180 sub-

ects would need to be randomized for andequately powered study. If 50% of eli-ible subjects at our 10 network centersgree to be randomized, then a multicen-ered RCT would be expected to take 5-6ears.To combat the rising rate of preterm

irth, it is critical that we shift our treat-ent paradigm toward etiology-specific

iagnosis and establish targeted thera-ies aimed at specific groups of at-riskomen. In this context, a multicenteredCT of physical examination–indicatederclage, compared with expectant man-gement in women with premature cer-ical dilation is essential and should be

FIGURE 5Inherent bias of cerclage procedur

Obstetricpopulation

Short cerv< 25mm

No premature cervic

CCt

his figure demonstrates the source of bias inharlier in the continuum of cervical change becaurogress to the next stage.ereira. EM-PEC in selected women with a dilated cervix. AJOG 2

erformed. f o


CKNOWLEDGMENThe GNPRH would like to acknowledge theontributions of the following individuals atach site for their efforts that made this studyossible: Thomas Jefferson University, Phila-elphia, PA: Jennifer Kolecki, MD, Ameness, MD, Jason Baxter, MD; Oregon Healthnd Science University, Portland, OR: Sophiaothberger MD, MPH, Heidi Printz, PhD,atherine Gesteland, MD, MPH; University ofulu, Oulu, Finland: Marja Vaarasmaki, MD;niversity of Miami, Miami, Florida: Lorenmarkusky, MD; Center for Perinatal Diagno-is and Research, Sotero del Río Hospital,ontifica Universidad Católica de Chile,uente Alto, Chile: Luis Medina, MD; Khonaen University, Khon Kaen, Thailand: Pisakeumbiganon, MD; Chulalongkorn University,angkok, Thailand: Sompop Limpongsa-urak, MD; All India Institute of Medical Sci-nces, New Delhi, India: J B Sharma MD, Nu-ur Gupta, MD; Coombe Women’s Hospital,ublin, Ireland: Etaoin Kearney, MD; and St.uke’s Hospital, Bethlehem, Pennsylvania:lbert Sarno, MD.

EFERENCES. Lawn J, McCarthy BJ, Ross SR. The healthyewborn: a reference manual for program man-gers. Atlanta (GA): Centers for Disease Controlnd Prevention, CARE, 2001. p. 1.20.. Hamilton BE, Martin JA, Ventura SJ. Births:reliminary data for 2005. Nat Vit Stat Rep006;55:1-18.. Lumley J. Defining the problem: the epidemi-

Early Cervical Dilation < 3 cm

Advanced Cervical Dilation > 4 cm

Preterm birth

ffacement

premature cervical dilation

Delivery at term

No further cervical dilation

ically-indicatedlage more likely employed

Expectant managementmore likely to be employed

t when clinicians perform cerclage proceduresnly a proportion of the population will naturally

es

ix

al e

No

linerc

o be

erense o

007

logy of preterm birth. BJOG 2003;110:3-7.


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4

. Novy MJ, Gupta A, Wothe DD, Gupta S,ennedy KA, Gravett MG. Cervical cerclage in

he second trimester of pregnancy: a historicalohort study. Am J Obstet Gynecol001;184:1447-54.. Olatunbosun OA, Al-Nuaim L, Turnell RW.mergent cerclage compared with bed rest fordvanced cervical dilatation in pregnancy. Inturg 1995;80:170-4.. Daskalakis G, Papantoniou N, Mesogitis S,ntsaklis A. Management of cervical insuffi-iency and bulging fetal membranes. Obstetynecol 2006;107:221-6.. Althuisius SM, Dekker GA, Hummel P, vaneijn HP. Cervical incompetence prevention

andomized cerclage trial: emergency cerclageith bed rest versus bed rest alone. Am J Ob-tet Gynecol 2003;189:907-10.. MRC/RCOG Working Party on Cervical Cer-lage. Final report of the MRC/RCOG multicen-re randomised trial of cervical cerclage. Br Jbstet Gynaecol 1993;100:516-23.. Althuisius SM, Dekker GA, van Geijn HP,ekedam DJ, Hummel P. Cervical incompe-

ence prevention randomized cerclage trialCIPRACT): study design and preliminary re-ults. Am J Obstet Gynecol 2000;183:823-9.0. Lazar P, Gueguen S, Dreyfus J, Renaud R,ontonnier G, Papiernik E. Multicentred con-

rolled trial of cervical cerclage in women atoderate risk of preterm delivery. Br J Obstetynaecol 1984;91:731-5.1. Rush RW, Isaacs S, McPherson K, Jones L,halmers I, Grant A. A randomized controlled

rial of cervical cerclage in women at high risk ofpontaneous preterm delivery. Br J Obstetynaecol 1984;91:724-30.2. Althuisius SM, Dekker GA, Hummel P,
ekedam DJ, van Geijn HP. Final results of the t

ervical incompetence prevention randomizedrial (CIPRACT): therapeutic cerclage with bedest versus bed rest alone. Am J Obstetynecol 2001;185:1106-12.3. Rust O, Atlas RO, Jones KJ, Benham BN,alducci J. A randomized trial of cerclage ver-us no cerclage among patients with ultrasono-raphically detected second-trimester pretermilatation of the internal os. Am J Obstet Gy-ecol 2000;183:830-5.4. Berghella V, Odibo AO, Tolosa JE. Cerclage

or prevention of preterm birth in women with ahort cervix found on transvaginal ultrasoundxamination: a randomized trial. Am J Obstetynecol 2004;191:1311-7.5. To MS, Alfirevic Z, Heath VC, et al. Fetaledicine Foundation Second Trimestercreening Group. Cervical cerclage for preven-

ion of preterm delivery in women with shortervix: randomised controlled trial. Lancet004;363:1849-53.6. Drakeley AJ, Roberts D, Alfirevic Z. Cervicalerclage for preventing pregnancy loss inomen. Cochrane Database Syst Rev 2003:D003253 (also printed in Obstet Gynecol003;102:621-7).7. Gomez R, Romero R, Nien JK, et al. A shortervix in women with preterm labor and intactembranes: a risk factor for microbial invasionf the amniotic cavity. Am J Obstet Gynecol005;192:678-89.8. Goldenberg RL, Hauth JC, Andrews WW.

ntrauterine infection and preterm delivery.Engl J Med 2000;342:1500-7.

9. Gibbs R, Blanco J, St Clair P, Castaneda Y.uantitative bacteriology of amniotic fluid fromomen with clinical intra-amniotic infection at

erm. J Infect Dis 1982;145:1-8. 2

ogy NOVEMBER 2007

0. Meis PJ, Klebanoff M, Thom E, et al, for theICHHD Maternal-Fetal Medicine Units Net-ork. Prevention of recurrent preterm deliveryy 17 alpha-hydroxyprogesterone caproate.Engl J Med 2003;348:2379-85.

1. da Fonseca EB, Bittar RE, Carvalho MHB,ugaib M. Prophylactic administration of pro-esterone by vaginal suppository to reduce the

ncidence of spontaneous preterm birth inomen at increased risk: a randomized place-o-controlled double-blind study. Am J Obstetynecol 2003;188:419-24.2. Canadian Preterm Labor Investigatorsroup. Treatment of preterm labor with the be-

a-adrenergic agonist ritodrine. N Engl J Med992;327:308.3. Cox SM, Sherman ML, Leveno KJ. Ran-omized investigation of magnesium sulfate forrevention of preterm birth. Am J Obstet Gy-ecol 1990;163:767.4. Carey JC, Klebanoff MA, for the NICHDFMU Network. Metronidazole treatment in-

reased the risk of preterm birth in asymptom-tic women with trichomonas. Am J Obstet Gy-ecol 2000;183:S13.5. Higuchi M. Hirano H. Maki M. Emergencyervical cerclage using a metreurynter in pa-ients with bulging membranes. Acta Obstetynecol Scand 1992;71:34-8.6. Wong GP, Farquharson DF, Dansereau J.mergency cervical cerclage: a retrospectiveeview of 51 cases. Am J Perinatol993;10:341-7.7. Barth WH Jr, Yeomans ER, Hankins GD.mergent cerclage. Surg Gynecol Obstet990;170:323-6.8. Alfirevic Z. Cerclage: we all know how to do

t but can’t agree when to do it. Obstet Gynecol
006;107:219-20.

Documents

Expectant management compared with physical examination–indicated cerclage (EM-PEC) in selected women with a dilated cervix at 140/7-256/7 weeks: results from the EM-PEC international