T h e NE W E NGL A ND JOU R NA L o f M E DICINE

ORIGINAL ARTICLE
1
4
Copyright
2016
Massachusett
A
Rand
s Medical
Society.

omiz
ed
Trial
of a
Cervi
cal
From the Harris
Birthright Research Pessa
Cen-ter for Fetal
Medicine,
College,
Kings
London
ry to
(K.H.N., A.S.,
L.C.P., A.Z., E.S.,
Preve
J.R.C.), and the
Department of nt
Fetal Medicine,
Medway Maritime
Hospital,
Preter
Gillingham
both in the
(G.P.)
m
United
Department
Kingdom;
of Singl
Perinatology,
University Medical
Center Ljubljana,
eton
Slo-venia
Fetal
(N.T.);
Medicine
Birth
Unit, Hospi-tal
Clinico Universidad Kypros H.
de Chile, Santiago, Nicolaides,
Chile (M.P.-C.); and
Pregnancy M.D., Argyro
Research Center, Syngelaki,
Royal Womens Ph.D., Liona
Hospital, Mel-
bourne, VIC,
C. Poon, M.D.,
Australia. (R.P.-D.). Gemma
Address reprint Picciarelli,
requests to Dr.
Nicolaides at the
M.D., Natasa
Harris Birthright Tul, M.D.,
Research Center Aikaterini
for Fetal Medicine,
Zamprakou,
Kings College
Hospital, Den-mark M.D., Evdoxia
Hill, London SE5 Skyfta, M.D.,
9RS, United King- Mauro
dom, or at
kypros@fetalmedici
Parra-Cordero
ne.com. , M.D.,
Ricardo
N Engl Palma-Dias,
J Med M.D., Ph.D.,
2016;37
and Jesus
4:1044-
52.
Rodriguez
DOI: Calvo, M.D.
10.1056
/NEJMo
a15110
 weeksTR
ABS 6 AC
wasT no significant
days of difference between the
BACKGROU gestatio pessary group (465
ND n. participants) and the
Preterm birthParticip control group (467
is the leadingants in participants) in the rate
cause ofeither of spontaneous
neonatal andgroup delivery before 34
infant deathwho had weeks (12.0% and
and ofa 10.8%, respectively;
disability cervical odds ratio in the
among length pessary group, 1.12;
survivors. Itof 15 95% confidence
is unclearmm or interval, 0.75 to 1.69;
whether aless, at P=0.57). There were
pessary randomi no significant
inserted zation differences in the rates
around theor at of perinatal death
cervix re- subsequ (3.2% in the pessary
duces the riskent group and 2.4% in the
of preterm visits, control group, P=
singleton received 0.42), adverse neonatal
birth. treatme outcome (6.7% and
nt with 5.7%, respectively; P=
METHODS vaginal 0.55), or neonatal
We conductedprogeste special care (11.6% and
a multicenter,rone. 12.9%, respectively; P
randomized, The =0.59). The incidence
controlled primary of new or increased
trial out- vaginal discharge was
comparing come significantly higher in
pessary was the pessary group than
placement spontan in the control group.
with eous
expectant CONCLUSIONS
delivery Among girls and
management before
(control) in34 women with singleton
girls andweeks pregnancies who had a
women whoof short cervix, a cervical
were pregnantgestatio pessary did not result
with in a lower rate of
n. spontaneous early
singletons
(singleton RESUL preterm delivery than
pregnancies) TS the rate with expectant
and who hadIn an management. (Funded
a cervical intentio by the Fetal Medicine
length of 25 n-to- Founda-tion; Current
mm or less at treat Controlled Trials
20 weeks 0 analysis number,
days to 24, there ISRCTN01096902.)
374;1 .orgon on
1 March .
NEJM.
ORG 27, C
MAR 2016. op
CH For yr
17,
2016
personal ig
use ht
only.
TheNewEnglandJournalofMedicine
Downloadedfrom No 20
other 16
uses M
1044
N ENGL J
without as
MED permissi sa
chusetts s
Medical reserved
Society.All .
CERVICAL PESSARY TO PREVENT PRETERM SINGLETON BIRTH
randomized
trials involving age

P
M
women with me
E
singleton nt
RETERM T
BIRTH ISpregnancies H
(co
who had a short ntr
cervix, both of O
ol)
D in
RESPONSIBLE FORwhich were
more than 70% of allpublished after S girl
neonatal and infant
deaths.1 In addition,the start of the TRIAL s
the risk of cerebralcurrent trial, DESIGN AND an
palsy among childrenprovided con- PARTICIPANT
born preterm is 10 d
times as high as thattradictory S wo
among 2those born atresults This was an
term. The risks of me
perinatal death andregarding the open-label, n
illness are inverselyeffect of a pes-
related to gestational randomized wit
age at delivery.1,3,4sary on the rate trial com- h
The risk of pretermof spontaneous
birth is inversely paring pessary sin
related to cervicaldelivery before placement with
length as measured by34 weeks; in -
ultrasonography 5,6 at expectant man- gle
mid gestation. one trial,
Randomized,involving 380 ton
controlled trials pre
involv-ing womenwomen, the rate
who were pregnantof this outcome gn
with singletons anc
(singletonwas
pregnancies) and who ies.
had a short cervicalsignificantly We
length have shownlower with a
that the prophylactic co
use of progesteronepessary than
results in awith no pessary nd
significantly lower uct
rate of preterm(6% vs. 27%),15
delivery and ed
neonatal death thanbut in the
the
the7-10
rate withsecond trial,
placebo. Meta- tria
analyses of trials ofinvolving 108 l at
cervical cerclage inwomen, there
women with sin- 16
gleton pregnancies was no
who had a shortsignificant ma
cervix have not shown ter
a significantly lowereffect (9.4% and
rate of preterm5.5%, nit
delivery overall than y
the rate with norespectively).16
cerclage, although hos
they have shown We
benefit in the sub-performed this pit
group of women who als
had a previoustrial to test the
pretermhypothesis that in
delivery.11,12 En
among girls and
An alternative gla
women with
approach for the nd,
prevention of singleton preg-
Slo
preterm birth is thenancies who
ve
transvaginal have a short
nia
placement of acervix, the
,
silicone pessary insertion of a
Por
around the cervix; cervical pessary
tu-
this device is thoughtwould result in gal
to support the cervixa lower rate of ,
and change itsspontaneous Ch
direction toward thedelivery before ile,
sacrum, thereby34 weeks of Au
reducing the directgesta-tion than str
pressure from thethe rate with ali
uterine contents onexpectant
a,
the cervicalmanagement.
Ital
canal.13,14 Two
y, Albania, Germany,manuscript. The the operator as
and Belgium. Allfirst author to whether the
females 16 years oftakes par-ticipant
age or older who wereresponsibility should receive
pregnant withfor the accuracy a cervical
singletons, whoand pessary or the
under-went routinecompleteness of pregnancy
ultrasonographic the data and for should be
examination at 20the fidelity of managed
weeks 0 days to 24the trial and this expectantly.
weeks 6 days ofreport to the Con-sequently,
gestation, and whoprotocol, the trial
were found to have aavailable with personnel had
cervical length of 25the full text of no role in the
mm or less werethis article at random
eligible for the trial.NEJM.org. assignment.
Exclu-sion criteria A
were a maternal ageRANDOMIZATI PROCEDURE Qui
of less than 16 years,ON S ck
Tak
fetal death, major fetalParticipants Gestational age
e is
defect, cervicalwere randomly was determined ava
cerclage in situ,assigned in a from the mea- ilab
painful regular uterine1:1 ratio to surement of le
contrac-tions, andeither the fetal crown at

ruptured membranespessary group rump length at NE

11 to 13 JM.
diagnosed be-foreor the control org
randomization. Allgroup, with the weeks.17
participants in the trialuse of a Web- Cervical length
provided writtenbased was measured
informed consent. Theapplication. In by trans-
trial was approved bythe random- vaginal
the National Researchsequence ultrasonographi
Ethics Com-mittee ingeneration, c examination
the United Kingdomthere were no at 20 to 24
and by the local ethics restrictions, weeks as
described
committee at eachsuch as block
participating hospital. size or previously,18 by
operators with
Neither the trialstratifica-tion
certification of
sponsor (the Fetalaccording to
competence in
Medicine site. At each
the tech-nique
Foundation) nor thecenter, those
(Fetal
company that makeswho agreed to Medicine
the pessary had anyparticipate in Foundation
role in the design ofthe trial were Certificate of
the trial, theregistered with Competence in
collection, analysis,a central Cervical
or interpretation ofcomputer Assessment).
the data, or theprogram, which
writing of thethen instructed
374;11 20
N ENGL J MED NEJM.ORG 16
MARCH 17,
ew Medici
o 2016
T Engla ne n Massachusetts
h nd M Medical
Downloadedfrom
e Journ
nejm.org a Society.All
N alof r rightsreserved.
T h e NE W E NGL A ND JOU R NA L o f M E DICINE
c measurement who had a
of cervical cervical length
At length, of 15 mm or
randomization, assessment of less at
participants adverse events, randomization
underwent aand collection or at subse-
speculum of vaginal quent visits
examination, swabs. If after were given
and a high26 weeks the capsules
vaginal swabcervical length containing nat-
was obtained forwas less than ural
bacteriologic 10 mm, progesterone
examination; ifglucocorticoid (200 mg) and
the resultss were were
showed administered instructed to
infection, for fetal lung introduce one
appropriate maturation. At capsule into
antibiotic the time of the vagina
therapy wasrandomization, before going to
given. A pessarythe sleep every
certified byparticipants night up to 33
Euro-pean were informed weeks 6 days
Conformity that increased of gestation.7
(CE0482, vaginal The
MED/CERT discharge was cervical
ISO 9003/ ENa possible pessary was
46003; Dr.symptom
removed by
Arabin, Witten,related to vaginal
Germany) wasinsertion of the
examination at
inserted throughpessary. At 37 weeks of
the vagina witheach follow-up
gestation in
the woman invisit, we asked
asymp-tomatic
the recumbentthe
participants.
position andparticipants in
was placedboth
Earlier
groups removal was
upward aroundwhether they
under-taken in
the cervix.13,15had noted an
the following
The research-increase in the
circumstances:
team mem-bersseverity or medically
who inserted thefrequency of
indicated
pessaries hadvaginal
induction of
received discharge and labor or
practical whether any elective
training in theother symp- cesarean
placement of thetoms had
section;
device. developed
preterm labor,
Participants since the
prelabor
in the controlbeginning of
rupture of
group receivedtreat-ment. If
mem-branes,
the samebacterial
obstetrical careculture showed or active
as those in thepathogenic vaginal
pessary group.results, bleeding; or at
the
All theappropriate the par-
participants ticipants
antibiotic
had follow-uptherapy request.
was
visits every 4given without Quality
weeks until 34removal of the control of
weeks ofpessary. screening,
gestation forPartici-pants in handling of
ultrasonographi either group data, and
verification of care (admission
adherence torecords of all to the neonatal
protocols at theparticipants intensive care
various centerswho delivered unit,
were before 34 mechanical
performed byweeks of ventilation,
the trial co-gestation were phototherapy,
ordinators. examined to treatment for
Data ondeter-mine proven or
pregnancy whether the suspected
outcomes werebirth was sepsis, or blood
obtained frommedically transfu-sion),
hospital indicated or and major
maternity spontaneous. maternal
records or theSpontaneous complication
participants births included attrib-utable to
general those with the pessary
medical spontaneous (maternal
practitioners. onset of labor death, serious
The and those with cervical or
rupture of vaginal trauma,
membranes or
before labor. chorioamnioniti
s).
OUTCOME
MEASURES STATISTICAL
The primary ANALYSIS
outcome was The trial was
spontaneous one of two
delivery before randomized
34 weeks (238 trials that used
days) of essentially the
gestation. same protocol:
Second-ary one involving
outcome participants
measures were with singleton
birth weight pregnancies
(mean, <2.5 kg who had a
and <1.5 kg), short cervix
perinatal (fetal and the other
or neonatal) involving
death, a partici-pants
composite of with twin
major adverse pregnancies,
events in the irrespective of
neonate before cervical
discharge from length.
the hospital Calculation of
(any grade of the sample size
intraventricular assumed a
hemorrhage, logistic-
the respiratory regression
distress analysis of the
syndrome, any probability of
retinopathy of spontaneous
prematurity, or delivery before
necrotizing 34 weeks.
enterocolitis), a After adjusting
com-posite of for the effect
indicators of of cervical
neonatal special length, on the
assumption thatthe singleton- group would
the pessarypregnancy be 44%, 23%,
would have antrial, it was and 3.6%,
effect assumed that respectively,
equivalent to7% of the with an overall
an odds ratio ofparticipants rate of 6%;
0.5, wewould have a these values
calculated thatcervical length were obtained
enrollment ofof 1 to 10 mm, from our
1600 7% would unpublished
participants have a cervical research
with singletonlength of 11 to involving
pregnancies 15 mm, and more than
would give the86% would 50,000
study a powerhave a cervical pregnant
of 85% to showlength of 16 to women.
a treat-ment25 mm and Enrollment
effect at a two-that the risks in the
sided alphaof spontaneous singleton-
level of 5%. Indelivery before pregnancy
the computer34 weeks in trial
simulations forthe control
TheNewEnglandJournalofMedicine
permission.
1046
Downloadedfromnejm.orgonCopyright
March27, 2016
N ENGL J 2016.For Massachusetts
MED 374;11
NEJM.ORG personaluse Medical
MARCH Society.All
only.Noother
17, 2016 useswithout rightsreserved.
Thank you for evaluating
BCL easyConverter Desktop
This Word document was converted from PDF with an evaluation
version of BCL easyConverter Desktop software that only
converts the first 3 pages of your PDF.
CTRL+ Click on the link below to purchase

Activate your software for less than $20

http://www.pdfonline.com/easyconverter/