The new england journal of medicine Original Article A Randomized Trial of a Cervical Pessary to Prevent Preterm Singleton Birth Kypros H. Nicolaides, M.D., Argyro Syngelaki, Ph.D., Liona C. Poon, M.D., Gemma Picciarelli, M.D., Natasa Tul, M.D., Aikaterini Zamprakou, M.D., Evdoxia Skyfta, M.D., Mauro Parra-Cordero, M.D., Ricardo Palma-Dias, M.D., Ph.D., and Jesus Rodriguez Calvo, M.D.​​ ABSTRACT BACKGROUND From the Harris Birthright Research Cen- Preterm birth is the leading cause of neonatal and infant death and of disability ter for Fetal Medicine, King’s College, among survivors. It is unclear whether a pessary inserted around the cervix re- London (K.H.N., A.S., L.C.P., A.Z., E.S., J.R.C.), and the Department of Fetal duces the risk of preterm singleton birth. Medicine, Medway Maritime Hospital, Gillingham (G.P.) — both in the United METHODS Kingdom; Department of Perinatology, We conducted a multicenter, randomized, controlled trial comparing pessary University Medical Center Ljubljana, Slo- venia (N.T.); Fetal Medicine Unit, Hospi- placement with expectant management (control) in girls and women who were tal Clinico Universidad de Chile, Santiago, pregnant with singletons (singleton pregnancies) and who had a cervical length of Chile (M.P.-C.); and Pregnancy Research 25 mm or less at 20 weeks 0 days to 24 weeks 6 days of gestation. Participants in Center, Royal Women’s Hospital, Mel- bourne, VIC, Australia. (R.P.-D.). Address either group who had a cervical length of 15 mm or less, at randomization or at reprint requests to Dr. Nicolaides at the subsequent visits, received treatment with vaginal progesterone. The primary out- Harris Birthright Research Center for Fetal come was spontaneous delivery before 34 weeks of gestation. Medicine, King’s College Hospital, Den- mark Hill, London SE5 9RS, United King- RESULTS dom, or at kypros@ fetalmedicine . com. In an intention-to-treat analysis, there was no significant difference between the N Engl J Med 2016;374:1044-52. pessary group (465 participants) and the control group (467 participants) in the DOI: 10.1056/NEJMoa1511014 Copyright © 2016 Massachusetts Medical Society. rate of spontaneous delivery before 34 weeks (12.0% and 10.8%, respectively; odds ratio in the pessary group, 1.12; 95% confidence interval, 0.75 to 1.69; P = 0.57). There were no significant differences in the rates of perinatal death (3.2% in the pessary group and 2.4% in the control group, P = 0.42), adverse neonatal outcome (6.7% and 5.7%, respectively; P = 0.55), or neonatal special care (11.6% and 12.9%, respectively; P = 0.59). The incidence of new or increased vaginal discharge was significantly higher in the pessary group than in the control group. CONCLUSIONS Among girls and women with singleton pregnancies who had a short cervix, a cervical pessary did not result in a lower rate of spontaneous early preterm delivery than the rate with expectant management. (Funded by the Fetal Medicine Founda- tion; Current Controlled Trials number, ISRCTN01096902.) 1044 n engl j med 374;11 nejm.org March 17, 2016 The New England Journal of Medicine Downloaded from nejm.org on March 16, 2016. For personal use only. No other uses without permission. Copyright © 2016 Massachusetts Medical Society. All rights reserved. Cervical Pessary to Prevent Preterm Singleton Birth reterm birth is responsible for agement (control) in girls and women with sin- more than 70% of all neonatal and infant gleton pregnancies. We conducted the trial at 16 Pdeaths.1 In addition, the risk of cerebral maternity hospitals in England, Slovenia, Portu- palsy among children born preterm is 10 times gal, Chile, Australia, Italy, Albania, Germany, and as high as that among those born at term.2 The Belgium. All females 16 years of age or older risks of perinatal death and illness are inversely who were pregnant with singletons, who under- related to gestational age at delivery.1,3,4 The risk went routine ultrasonographic examination at of preterm birth is inversely related to cervical 20 weeks 0 days to 24 weeks 6 days of gestation, length as measured by ultrasonography at mid- and who were found to have a cervical length of gestation.5,6 Randomized, controlled trials involv- 25 mm or less were eligible for the trial. Exclu- ing women who were pregnant with singletons sion criteria were a maternal age of less than 16 (singleton pregnancies) and who had a short years, fetal death, major fetal defect, cervical cervical length have shown that the prophylactic cerclage in situ, painful regular uterine contrac- use of progesterone results in a significantly tions, and ruptured membranes diagnosed be- lower rate of preterm delivery and neonatal fore randomization. All participants in the trial death than the rate with placebo.7-10 Meta-analyses provided written informed consent. The trial was A Quick Take of trials of cervical cerclage in women with sin- approved by the National Research Ethics Com- is available at gleton pregnancies who had a short cervix have mittee in the United Kingdom and by the local NEJM.org not shown a significantly lower rate of preterm ethics committee at each participating hospital. delivery overall than the rate with no cerclage, Neither the trial sponsor (the Fetal Medicine although they have shown benefit in the sub- Foundation) nor the company that makes the group of women who had a previous preterm pessary had any role in the design of the trial, delivery.11,12 the collection, analysis, or interpretation of the An alternative approach for the prevention of data, or the writing of the manuscript. The first preterm birth is the transvaginal placement of a author takes responsibility for the accuracy and silicone pessary around the cervix; this device is completeness of the data and for the fidelity of thought to support the cervix and change its the trial and this report to the protocol, available direction toward the sacrum, thereby reducing with the full text of this article at NEJM.org. the direct pressure from the uterine contents on the cervical canal.13,14 Two randomized trials Randomization involving women with singleton pregnancies who Participants were randomly assigned in a 1:1 had a short cervix, both of which were published ratio to either the pessary group or the control after the start of the current trial, provided con- group, with the use of a Web-based application. tradictory results regarding the effect of a pes- In the random-sequence generation, there were sary on the rate of spontaneous delivery before no restrictions, such as block size or stratifica- 34 weeks; in one trial, involving 380 women, the tion according to site. At each center, those who rate of this outcome was significantly lower with agreed to participate in the trial were registered a pessary than with no pessary (6% vs. 27%),15 with a central computer program, which then but in the second trial, involving 108 women, instructed the operator as to whether the par- there was no significant effect (9.4% and 5.5%, ticipant should receive a cervical pessary or the respectively).16 pregnancy should be managed expectantly. Con- We performed this trial to test the hypothesis sequently, the trial personnel had no role in the that among girls and women with singleton preg- random assignment. nancies who have a short cervix, the insertion of a cervical pessary would result in a lower rate of Procedures spontaneous delivery before 34 weeks of gesta- Gestational age was determined from the mea- tion than the rate with expectant management. surement of fetal crown–rump length at 11 to 13 weeks.17 Cervical length was measured by trans- Methods vaginal ultrasonographic examination at 20 to 24 weeks as described previously,18 by operators Trial Design and Participants with certification of competence in the tech- This was an open-label, randomized trial com- nique (Fetal Medicine Foundation Certificate of paring pessary placement with expectant man- Competence in Cervical Assessment). n engl j med 374;11 nejm.org March 17, 2016 1045 The New England Journal of Medicine Downloaded from nejm.org on March 16, 2016. For personal use only. No other uses without permission. Copyright © 2016 Massachusetts Medical Society. All rights reserved. The new england journal of medicine At randomization, participants underwent a records of all participants who delivered before speculum examination, and a high vaginal swab 34 weeks of gestation were examined to deter- was obtained for bacteriologic examination; if the mine whether the birth was medically indicated results showed infection, appropriate antibiotic or spontaneous. Spontaneous births included therapy was given. A pessary certified by Euro- those with spontaneous onset of labor and those pean Conformity (CE0482, MED/CERT ISO 9003/ with rupture of membranes before labor. EN 46003; Dr. Arabin, Witten, Germany) was inserted through the vagina with the woman in Outcome Measures the recumbent position and was placed upward The primary outcome was spontaneous delivery around the cervix.13,15 The research-team mem- before 34 weeks (238 days) of gestation. Second- bers who inserted the pessaries had received ary outcome measures were birth weight (mean, practical training in the placement of the device. <2.5 kg and <1.5 kg), perinatal (fetal or neonatal) Participants in the control group received the death, a composite of major adverse events in same obstetrical care as those in the pessary the neonate before discharge from the hospital group. All the participants had follow-up visits (any grade of intraventricular hemorrhage, the every 4 weeks until 34 weeks of gestation for respiratory distress syndrome, any retinopathy of ultrasonographic measurement of cervical length, prematurity, or necrotizing enterocolitis), a com- assessment of adverse events, and collection of posite of indicators of neonatal special care vaginal swabs.