Cervical Pessary for Prevention of Preterm Birth in Individuals With a Short Cervix

Cervical Pessary for Prevention of Preterm Birth in Individuals
With a Short Cervix
The TOPS Randomized Clinical Trial
Matthew K. Hoffman, MD, MPH; Rebecca G. Clifton, PhD; Joseph R. Biggio, MD, MS; George R. Saade, MD;
Lynda G. Ugwu, PhD; Monica Longo, MD, PhD; Sabine Z. Bousleiman, MSN, MSPH; Kelly Clark, BSN, RN;
William A. Grobman, MD, MBA; Heather A. Frey, MD; Suneet P. Chauhan, MD; Lorraine Dugoff, MD;
Tracy A. Manuck, MD; Edward K. Chien, MD; Dwight J. Rouse, MD; Hyagriv N. Simhan, MD; M. Sean Esplin, MD;
George A. Macones, MD, MSCE; for the Eunice Kennedy Shriver National Institute of Child Health
and Human Development Maternal-Fetal Medicine Units (MFMU) Network
IMPORTANCE A short cervix as assessed by transvaginal ultrasound is an established risk
factor for preterm birth. Study findings for a cervical pessary to prevent preterm delivery
in singleton pregnancies with transvaginal ultrasound evidence of a short cervix have
been conflicting.
OBJECTIVE To determine if cervical pessary placement decreases the risk of preterm birth or
fetal death prior to 37 weeks among individuals with a short cervix.
DESIGN, SETTING, AND PARTICIPANTS We performed a multicenter, randomized, unmasked
trial comparing a cervical pessary vs usual care from February 2017 through November 5,
2021, at 12 centers in the US. Study participants were nonlaboring individuals with a singleton
pregnancy and a transvaginal ultrasound cervical length of 20 mm or less at gestations of 16
weeks 0 days through 23 weeks 6 days. Individuals with a prior spontaneous preterm birth
were excluded.
INTERVENTIONS Participants were randomized 1:1 to receive either a cervical pessary placed
by a trained clinician (n = 280) or usual care (n = 264). Use of vaginal progesterone was at the
discretion of treating clinicians.
MAIN OUTCOME AND MEASURES The primary outcome was delivery or fetal death prior to
37 weeks.
RESULTS A total of 544 participants (64%) of a planned sample size of 850 were enrolled in
the study (mean age, 29.5 years [SD, 6 years]). Following the third interim analysis, study
recruitment was stopped due to concern for fetal or neonatal/infant death as well as for
futility. Baseline characteristics were balanced between participants randomized to pessary
and those randomized to usual care; 98.9% received vaginal progesterone. In an
as-randomized analysis, the primary outcome occurred in 127 participants (45.5%)
randomized to pessary and 127 (45.6%) randomized to usual care (relative risk, 1.00;
95% CI, 0.83-1.20). Fetal or neonatal/infant death occurred in 13.3% of those randomized to
receive a pessary and in 6.8% of those randomized to receive usual care (relative risk, 1.94;
95% CI, 1.13-3.32).
CONCLUSIONS AND RELEVANCE Cervical pessary in nonlaboring individuals with a singleton
gestation and with a cervical length of 20 mm or less did not decrease the risk of preterm
birth and was associated with a higher rate of fetal or neonatal/infant mortality.
TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT02901626
JAMA. 2023;330(4):340-348. doi:10.1001/jama.2023.10812
Visual Abstract
Editorial page 323
Supplemental content
Author Affiliations: Author
affiliations are listed at the end of this
article.
Corresponding Author: Matthew K.
Hoffman, MD, MPH, Department of
Obstetrics and Gynecology,
Christiana Care Health Services,
4755 Ogletown-Stanton Rd,
Newark, DE 19718 (mhoffman@
christianacare.org).
Research
JAMA | Original Investigation
340 (Reprinted) jama.com
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P
reterm birth remains the most frequent cause of perina-
tal mortality,1,2
and children born prematurely are at
greater risk of chronic medical conditions3,4
and devel-
opmentaldelays.5
Theserisksareinverselyproportionaltoges-
tational age at birth.6
Improvements in survival have largely
been attributed to the use of antenatal corticosteroids7
and im-
proved neonatal care.8
Shortened cervical length (<25 mm) as
measured by transvaginal sonography in the second trimester
has been shown to correlate with the risk of preterm delivery9
andoccursinapproximately1.0%to2.5%ofthepopulation.10,11
Randomizedclinicaltrialshavedemonstratedthatintravaginal
progesterone decreases the risk of preterm birth among preg-
nancies with a shorter cervical length of 20 mm or less12,13
and
that cerclage uniquely benefits individuals with a short cervix
who also have a history of preterm birth.12
Nevertheless, these
treatments have been shown to result in a decrease in preterm
birthbefore34weeksofonlyapproximately45%13,14
andnodif-
ferences in preterm birth before 37 weeks. Therefore, addi-
tional treatments are needed to further reduce the rates of pre-
term birth in this at-risk population.
Cervical pessary placement is one treatment that has been
evaluated to prevent preterm birth in those with a singleton
pregnancyandashortcervicallength.Randomizedclinicaltrials
have differed on the effect of pessary placement, with some
studies15,16
showing lower rates of preterm birth before 34 and
37weeksandotherstudiesnotdemonstratingbenefit.17-19
Rea-
sons for these disparate outcomes have been hypothesized to
be the result of varying use of progesterone,15
inclusion of in-
dividuals with a prior preterm birth,15,17
and lack of adequate
training in pessary placement.
The randomized Trial of Pessary in Singleton Pregnan-
cies With a Short Cervix (TOPS) was performed to test the hy-
pothesis that nonlaboring individuals carrying a singleton ges-
tation, with no prior preterm birth history and a cervical length
of 20 mm or less (measured by transvaginal ultrasound) prior
to 24 weeks of gestation, would have a lower rate of preterm
birth or fetal death before 37 weeks of gestation with place-
ment of a cervical pessary.
Methods
Study Design and Participants
We conducted a multicenter, open-label, randomized clinical
trial comparing a pessary (Dr Arabin GmBH & Co) vs usual care
at12clinicalcentersparticipatingintheEuniceKennedyShriver
National Institute of Child Health and Human Development’s
Maternal-Fetal Medicine Units Network from February 2017
through November 5, 2021. The protocol (Supplement 1) was
approvedbyeachindividualcenter’sinstitutionalreviewboard
priortoparticipantenrollment.Anindependentdataandsafety
monitoring board was convened prior to study initiation, ap-
proved the protocol, and determined a schedule of ongoing
data oversight. The trial was performed under an FDA Inves-
tigational Device Exemption (IDE No. G160176). The statisti-
cal analysis plan is available in Supplement 2.
Individuals with nonlaboring, singleton pregnancies who
had a transvaginal cervical length of 20 mm or less at gesta-
tions of 16 weeks 0 days through 23 weeks 6 days were iden-
tified at each individual hospital per the local protocol for as-
sessment of cervical length.
Individuals were not eligible for the study if they had
a history of spontaneous preterm birth; a cervix that was di-
lated 3 cm or greater on digital examination; prolapse of
the membranes beyond the cervical os; preterm rupture
of membranes or evidence of preterm labor (>6 contractions
per hour); a major fetal or müllerian anomaly; a planned or
placed cerclage; or another medical condition that increased
the risk of medically indicated preterm birth (eTable 1
in Supplement 3). Race and ethnicity were self-reported by
participants.
Randomization and Masking
Individuals meeting eligibility requirements and accepting
trial participation were randomized in a 1:1 fashion to either
pessary or usual care using a secure web-based system devel-
oped by the data coordinating center (Figure 1). Randomiza-
tion sequences were generated by the data coordinating cen-
ter using the simple-urn method and stratified by site.20
Research staff had no role in determining the randomization
assignment.
Interventions
All research staff, sonographers, and pessary placers were
trained and certified for this study. The certification process
for sonographers included both demonstration of knowledge
of cervical length assessment and demonstration of appropri-
ate technique in accordance with Fetal Medicine Foundation
or Perinatal Quality Foundation standards. Pessary place-
ment was required to be performed by physicians who were
certified following standardized education and demonstra-
tion of competence by passing a standardized test.
Following individual written informed consent, eligibil-
ity confirmation via speculum pelvic examination was per-
formed, and vaginal swabs for bacterial analysis and cervico-
vaginal fluid collection were obtained.
Participants randomized to receive a pessary were posi-
tioned in lithotomy position. The pessary was placed on the
day of randomization around the cervix and then flexed
Key Points
Question Does placement of a cervical pessary reduce the rate of
preterm birth or fetal death before 37 weeks in nonlaboring
singleton pregnancies with a cervical length of 20 mm or less?
Findings In this randomized trial of 544 singleton pregnancies,
the rate of preterm birth or fetal death before 37 weeks did not
differ between those randomized to pessary (45.5%) and those
randomized to usual care (45.6%) (relative risk, 1.00; 95% CI,
0.83-1.20). Fetal or neonatal/infant death occurred more
frequently in those randomized to receive a pessary (13.3%) than
those randomized to receive usual care (6.8%) (relative risk, 1.94;
95% CI, 1.13-3.32).
Meaning Cervical pessary does not benefit singleton pregnancies
with a cervical length of 20 mm or less.
Cervical Pessary for Prevention of Preterm Birth in Individuals With a Short Cervix Original Investigation Research
jama.com (Reprinted) JAMA July 25, 2023 Volume 330, Number 4 341

posteriorly with digital pressure to alter the cervicouterine
angle.15
Pessary placers were allowed to choose from 3 differ-
ent sizes of pessary (nulliparous: internal diameter, 32 mm,
external diameter, 65 mm; multiparous: internal diameter,
32 mm, external diameter, 70 mm; and alternative: internal
diameter, 35 mm, external diameter 70 mm) based on partici-
pant obstetric history, anatomy, and tolerance and the ability
of the pessary, once placed, to maintain the correct position.
All participants were to be contacted within 1 week of
randomization to assess adherence and adverse effects of the
pessary. Participants were asked to return every 4 weeks for a
study visit, which initially was planned to occur in person
but, after the onset of the COVID-19 pandemic, could be con-
ducted virtually. An additional set of vaginal samples and a
pessary check were scheduled between 24 weeks and 32
weeks of gestation. In the event the pessary was dislodged or
removed, it was to be replaced by a trained placer. Pessary
position at the time of planned removal at 36 weeks and 6
days of gestation was noted. Medically indicated removal of
the pessary prior to study completion was required in the set-
ting of active labor, preterm premature rupture of mem-
branes, clinical chorioamnionitis, active vaginal bleeding, or
cervical edema or laceration. The pessary could also be
removed for other reasons at the discretion of treating obstet-
ric clinicians or due to participant request. The remainder of
obstetrical care, including the use of progesterone and
examination-indicated cerclage (ie, cerclage placed based on
physical examination changes following randomization),
was at the discretion of treating clinicians. Following deliv-
ery, maternal, fetal, and neonatal outcomes were abstracted
from medical records by certified research staff members.
Outcomes
The primary outcome was delivery or fetal death before
37 weeks 0 days of gestation. Prespecified secondary mater-
nal outcomes were preterm birth or fetal death before 35
weeks, 32 weeks, and 28 weeks of gestation; interval from
randomization to delivery or fetal death; gestational age at
delivery; preterm birth (before 37 weeks 0 days of gestation),
premature rupture of membranes; vaginal infection as
assessed by clinical diagnosis; maternal antibiotic or anti-
fungal prescription for vaginal infection; adverse effects;
and discontinuation of the pessary and reasons for its
removal. Prespecified secondary neonatal/fetal outcomes
included fetal or neonatal (birth to 28 days of life)/infant (>28
days of life to 1 year) death, duration of ventilator support,
duration of supplemental oxygen, seizures requiring treat-
ment, and small-for-gestational-age birth (less than the fifth
percentile for gestational age per the methods of Alexander
et al; written communication; Greg R. Alexander, RS, MPH,
ScD; 2000).21,22
The composite neonatal outcome included
the occurrence of any of the following: fetal death, neonatal/
infant death, respiratory distress syndrome, grade III/IV
intraventricular hemorrhage, periventricular leukomalacia,
stage 2 or 3 necrotizing enterocolitis, bronchopulmonary dys-
plasia, stage 3 or higher retinopathy of prematurity, or proven
Figure 1. Participant Flow in a Study of Cervical Pessary to Reduce Preterm Birth or Fetal Death
in Singleton Pregnancy
2105 Individuals identified with a cervical length
<20 mm at gestations of 16 wk 0 d to 23 wk 6 d
1561 Excluded
1086 Did not meet inclusion criteria
365 Prior preterm delivery ≥16 wk
350 Cerclage planned or placed
70 Cervical dilation ≥3 cm or prolapsed
membranes
28 Gestational age ≥23 wk 6 d
26 Diabetes requiring medication
20 Language barrier
18 Placenta previa
17 Known major fetal anomaly
155 Other reasons
475 Declined to participate
1 Lost to
follow-up
1 Lost to
follow-up
544 Randomizeda
279 Included in primary analysis
280 Randomized to receive a pessary
276 Received a pessary
as randomized
4 Did not receive a pessary
due to discomfort
264 Randomized to receive usual care
264 Received usual care
as randomized
263 Included in primary analysis a
Randomization was stratified
by site.
Research Original Investigation Cervical Pessary for Prevention of Preterm Birth in Individuals With a Short Cervix
342 JAMA July 25, 2023 Volume 330, Number 4 (Reprinted) jama.com

early sepsis. A complete list of prespecified outcomes is
shown in eTable 2 in Supplement 3.
Sample Size Calculation
Based on available literature at the time of protocol develop-
ment, we assumed the rate of preterm birth before 37 weeks
or fetal death in those randomized to usual care was 28% and
that a sample size of 850 would have at least 90% power to
detect a 33% reduction in preterm birth with a 2-sided type I
error of .05. We also determined that this sample size would
yield more than 80% power to detect a 30% reduction in pre-
term birth or fetal death prior to 37 weeks.
Statistical Analysis
The analyses were performed using a randomized approach.
Participants randomized to the pessary group who had a pes-
sary placed comprised the as-treated population. We com-
pared categorical baseline variables using χ2
and Fisher exact
tests. We compared continuous variables using Wilcoxon rank
sum tests. Unadjusted log-binomial models were used to as-
sess treatment effect for the primary outcome of delivery or
fetal death prior to 37 weeks. If the treatment groups were
found to differ on a pretreatment factor known to be a risk fac-
tor for the outcome, the statistical analysis adjusted for these
differences. Per protocol, prespecified subgroup analyses were
conducted only if there was a statistical difference in the pri-
mary outcome between the 2 treatment groups.
Categorical outcomes were evaluated using relative risks
and 95% confidence intervals. Quantile regression was used
to evaluate differences in medians for continuous outcomes.
Wedidnotperformsensitivityanalysesorimputationformiss-
ing data. A 2-tailed P < .05 was considered to indicate statis-
tical significance. Statistical analyses were performed using
SAS version 9.4 (SAS Institute Inc).
The timing of interim analyses was at the discretion
of the data and safety monitoring board and not prespecified
in the protocol. Three interim analyses were performed for
the primary outcome. For the interim analyses, we used a
group sequential method to control the type I error, with the
Lan-Demets characterization of the O’Brien-Fleming bound-
ary providing the stopping rule for benefit.23
The data and
safety monitoring board also used conditional power analysis
as a stopping guideline for futility. If the conditional power
was low given the observed data and assuming the alterna-
tive hypothesis for the remainder of the trial, termination for
futility could be considered. Although the protocol did not
specify stopping rules for safety, the data and safety monitor-
ing board reviewed maternal and neonatal safety outcomes
and considered them in their deliberations and recommenda-
tions for trial continuation or termination.
After adjusting the planned type I error rate of .05 for in-
terim analyses, the 2-tailed α value indicating statistical sig-
nificance for the primary outcome was .04756. We report 95%
confidence intervals throughout because the type I error ad-
justment for interim analyses was minimal. This trial is part
of the PROMPT collaborative, an international prospective in-
dividualpatientdatameta-analysisofpessarytrials(PROSPERO
2018 CRD42018067740).
Results
Trial Population
From February 2017 through November 5, 2021, 2105 indi-
viduals with a cervical length of 20 mm or less were identi-
fied by referral or institutional protocol for cervical length
screening and assessed for eligibility. A total of 1019 were
considered eligible and 544 provided consent and were ran-
domized (Figure 1; eTable 6 in Supplement 3). At the third
interim analysis, which included complete data for 511 par-
ticipants (60.1% of the planned sample size), the data and
safety monitoring board recommended termination of the
trial due to a safety concern of a higher frequency of fetal and
neonatal/infant death in the pessary group as well as futility.
Among the 280 participants randomized to receive a pessary,
4 were not able to tolerate the device at the time of the initial
pessary placement. A total of 264 participants were random-
ized to usual care. One participant in each study group was
lost to follow-up (Figure 1).
The characteristics of the participants were balanced be-
tweenthe2groups(Table1).Vaginalprogesteroneusewaspre-
scribed for 98.9% in each group. The proportions of individu-
als treated for vaginal infection prior to randomization did not
differ between groups.
Outcomes
Primary Outcome
The primary outcome of preterm birth before 37 weeks or fe-
tal death occurred in 127 participants (45.5%) randomized to
pessary and in 120 (45.6%) randomized to usual care (relative
risk in the pessary group, 1.00; 95% CI, 0.83-1.20) (Table 2).
Prespecified Secondary Outcomes
Rates of preterm birth or fetal death before 35 weeks, 32
weeks, and 28 weeks did not differ between participants ran-
domized to pessary and those randomized to usual care. The
proportion of individuals who remained pregnant across ges-
tational ages did not differ between the 2 groups (hazard
ratio in the pessary group, 1.9; 95% CI, 0.8-4.7) (Figure 2).
Other obstetrical outcomes were similar between the
2 groups except cerclage placement, which occurred in 13
participants (4.7%) randomized to pessary and 24 (9.1%)
randomized to usual care (relative risk, 0.51; 95% CI, 0.51-
0.98). Reviewers who were masked to study group evaluated
cerclage indications and determined cerclage placement
to be examination indicated in 32 participants and non–
examination indicated in 5 participants.
Medically indicated removal of the pessary occurred in
83.3% of participants, with the most common nonmedical rea-
son being participant request (n = 23 [8.3%]; 16 for discom-
fort, 1 for vaginal discharge, and 6 had no reason listed).
Suspected neonatal sepsis was less likely in the pessary
group compared with the usual care group (14.7% vs 20.1%;
relativerisk,0.67;95%CI,0.47-0.97);however,confirmedearly
and late sepsis did not differ between groups. All other neo-
natal outcomes and care were similar between the 2 groups
(Table 3).

In analyses of the as-treated population (5 patients in the
pessary group were not analyzed [4 did not receive the pes-
sary and 1 was lost to follow-up]; in the usual care group, 1 was
not analyzed due to being lost to follow-up), fetal or neonatal/
infant death occurred in 36 of 275 participants (13.1%) in the
pessary group compared with 18 of 263 (6.8%) in the usual care
group (relative risk, 1.91; 95% CI, 1.11-3.29; P = .02). More spe-
cifically, fetal death occurred in 17 (6.2%) of 275 pregnancies
in the pessary group and in 9 (3.4%) of 263 in the usual care
group (relative risk, 1.81; 95% CI, 0.82-3.99; P = .14), and there
were 19 neonatal/infant deaths (7.4%) among 258 pregnan-
cies in the pessary group and 9 neonatal/infant deaths (3.5%)
among 254 pregnancies in the usual care group (relative risk,
2.34; 95% CI, 1.04-5.25; P = .04). The median gestation at fe-
tal death was 20.5 weeks (IQR, 18.7-22.4 weeks) in the pes-
sary group and 20.1 weeks (IQR, 19.1-21.3 weeks) in the usual
Table 1. Baseline Participant Characteristics
Characteristics
Pessary
(n = 280)
Usual care
(n = 264)
Maternal age, mean (SD), y 29.9 (6.0) 29.1 (5.9)
Race and ethnicity, No. (%)a
American Indian or Alaska Native 1 (0.4) 0
Asian 12 (4.3) 16 (6.1)
Non-Hispanic Black 132 (47.1) 127 (48.1)
Hispanic 62 (22.1) 56 (21.2)
Native Hawaiian or Pacific Islander 0 1 (0.4)
Non-Hispanic White 61 (21.8) 53 (20.1)
More than 1 race 2 (1.0) 2 (1.0)
Not reported or unknown 10 (3.6) 9 (3.4)
Body mass index at first clinic visit,
median (IQR)b
28.8 (24.3-34.2) (n = 276) 28.6 (23.2-33.4) (n = 263)
<30 153 (55.4) 162 (61.6)
30.0-34.9 61 (22.1) 49 (18.6)
35.0-39.9 29 (10.5) 30 (11.4)
≥40.0 33 (12.0) 22 (8.4)
Cigarette use during pregnancy, No. (%) 30 (10.7) 21 (8.0)
Married or living with partner, No. (%) 167 (59.6) 168 (63.6)
Employed full- or part-time, No. (%) 191 (68.2) 172 (65.2)
More than 12 y of education, No./total (%) 176/280 (62.9) 155/263 (58.9)
Insurance, No. (%)
Private 145 (51.8) 137 (51.9)
Government 127 (45.4) 121 (45.8)
Self-pay 8 (2.9) 6 (2.3)
Prior cervical surgery, No. (%)c
33 (11.8) 31 (11.7)
Previous pregnancy regardless of outcome,
No. (%)
103 (36.8) 87 (33.0)
Total prior term deliveries, median (IQR) 0 (0-1) 0 (0-1)
Type of pregnancy, No. (%)
Spontaneous 257 (91.8) 245 (92.8)
In vitro fertilization 18 (6.4) 15 (5.7)
Ovulation induction/artificial insemination 5 (1.8) 4 (1.5)
Vaginal infection prior to enrollment, No. (%)d
57 (20.4) 55 (20.8)
Cervical length at screening, median (IQR), mm 13.3 (9.1-17.2) 13.7 (8.3-17.5)
<10 mm, No. (%) 80 (28.6) 82 (31.1)
Amniotic cavity debris on screening ultrasound,
No./total (%)
50/276 (18.1) 44 (16.7)
Gestation at enrollment, median (IQR), wk 21.7 (20.6-22.9) 21.9 (20.7-23.2)
Time from screening to randomization,
median (IQR), d
0 (0-3) 0 (0-3)
Current or planned progesterone use, No. (%) 277 (98.9) 261 (98.9)
Nugent score, No./total (%)e
0-3 (normal flora) 168/251 (66.9) 161/234 (68.8)
4-6 (intermediate) 39/251 (15.5) 34/234 (14.5)
7-10 (bacterial vaginosis) 44/251 (17.5) 39/234 (16.7)
a
Race and ethnicity are based on
participant self-report.
b
Calculated as weight in kilograms
divided by height in meters
squared.
c
Any cervical surgery, including
cervical cone, or loop electrosurgical
excision procedure.
d
Includes chlamydia, gonorrhea,
syphilis, trichomonas, bacterial
vaginosis, genital herpes, HIV,
hepatitis B, hepatitis C, hepatitis D,
pyelonephritis, cystitis, or
candidiasis diagnosed during the
current pregnancy.
e
The Nugent score is a summary
evaluation from the Gram stain of
vaginal swabs. It ranges from 0 to
10, with scores of 7 or higher
indicating bacterial vaginosis.

care group. A summary of fetal deaths is provided in eTable 3
in Supplement 3.
In a post hoc analysis comparing those who experienced
a fetal death (death prior to delivery or delivery prior to 20
weeks) or a neonatal/infant death (death following delivery at
or after 20 weeks) with those who did not, the average cervi-
cal length at screening was shorter among those with a death
and was more likely to be less than 10 mm (eTable 4 in Supple-
ment 3). The qualifying cervical length was detected at an ear-
lier mean gestational age than among those who did not have
Table 2. Preterm Delivery and Fetal Death and Maternal Secondary Outcomes
Outcomes
Pessary
(n = 279)
Usual care
(n = 263)
Absolute
median difference
(95% CI)
Unadjusted
relative risk
(95% CI)
Primary outcome
Preterm delivery or fetal death <37 wk,
No. (%)
127 (45.5) 120 (45.6) 1.00 (0.83-1.20)
Preterm delivery <37 wk, No. (%) 109 (39.1) 111 (42.2)
Fetal death <37 wk, No. (%)a
18 (6.5) 9 (3.4)
Secondary outcomes
Time from enrollment to delivery
or fetal death, median (IQR), d
105 (42-20) 103 (56-118) 2 (−4 to 8)
Gestational age at delivery,
median (IQR), wk
37.3
(27.4-39.1)
37.4
(29.6-39.1)
0.1 (−0.8 to1.1)
Preterm delivery or fetal death,
No. (%)
<28 wk 72 (25.8) 54 (20.5) 1.26 (0.92-1.71)
<32 wk 93 (33.3) 73 (27.8) 1.20 (0.93-1.55)
<35 wk 111 (39.8) 90 (34.2) 1.16 (0.93-1.45)
Preterm premature rupture
of membranes, No./total (%)
64/277 (23.1) 46/207 (17.8) 1.30 (0.92-1.82)
Spontaneous preterm delivery,
No. (%)
109 (39.1) 106 (40.3) 0.97 (0.79-1.19)
Indicated preterm delivery,
No. (%)
18 (6.5) 14 (5.3) 1.21 (0.61-2.39)
Cesarean delivery, No. (%) 86 (30.8) 80 (30.4) 1.01 (0.79-1.31)
Chorioamnionitis, No. (%) 18 (6.5) 16 (6.1) 1.06 (0.55-2.04)
Antepartum length of stay,
median (IQR), d
1 (0-1) 1 (0-1) 0 (0 to 0)
Vaginal infection, No./total (%)b
57/226 (25.2) 41/220 (18.6) 1.36 (0.95-1.94)
Antibiotic or antifungal treatment,
No./total (%)b
55/226 (24.3) 37/220 (16.8) 1.45 (0.99-2.06)
Treatment for preterm labor,
No./total (%)c
150/258 (58.1) 143/250 (57.2) 1.02 (0.88-1.18)
Cerclage placement, No. (%) 13 (4.7) 24 (9.1) 0.51(0.27-0.98)
Pessary removal reasons, No. (%) n = 276
Medically indicated 230 (83.3)
Final study visit 104 (37.7)
Preterm premature rupture
of membranes
53 (19.2)
Preterm labor 42 (15.2)
Delivery 9 (3.3)
Vaginal bleeding 7 (2.5)
Uterine contractions 7 (2.5)
Cervical dilation ≥3 cm 7 (2.5)
Confirmed clinical chorioamnionitis 1 (0.4)
Not medically indicated 46 (16.7)
Patient request (any reason) 23 (8.3)
Cerclage 7 (2.5)
Clinician request 5 (1.8)
Self-removed 4 (1.5)
Spontaneous dislodgement 3 (1.1)
Recruitment closure 2 (0.7)
Cervical erosion 1 (0.4)
Incontinence 1 (0.4)
a
Includes only delivery prior to 20
weeks or fetal deaths that occurred
prior to delivery, and not infant
deaths following delivery at or after
20 weeks.
b
Participants with at least 1 study
visit. Vaginal infection includes
chlamydia, gonorrhea, syphilis,
trichomonas, bacterial vaginosis,
genital herpes, HIV, hepatitis B,
hepatitis C, hepatitis D,
pyelonephritis, cystitis, or
candidiasis diagnosed during the
current pregnancy. Antibiotics
include those administered
after randomization and before
delivery via intravenous, oral, and
vaginal routes.
c
Treatment for preterm labor
includes cerclage, bed rest,
tocolysis, antenatal corticosteroids
for fetal lung maturity, and
magnesium sulfate for
neuroprotection.

a fetal or neonatal/infant death. Those who experienced a fe-
tal or neonatal/infant death were less likely to have had a prior
term delivery. The mean gestational age at delivery in those
who experienced a fetal or neonatal/infant death was 22.1
weeks (SD, 2.4 weeks) and there was a shorter time from ran-
domization to delivery. Similarly, preterm premature rupture
of membranes occurred more frequently among those receiv-
ing a pessary (50.0%) than among those receiving usual care
(17.4%) (P < .001).
Adverse Events
Participants in the pessary group who had a pessary placed
were more likely to report adverse effects (eTable 5 in Supple-
ment 3). Specifically, they were more likely to report vaginal
discharge, soreness, odor, itching, and leakage of fluid.
Discussion
The results of this trial demonstrate that in nonlaboring indi-
viduals with singleton pregnancies and a cervical length of
Table 3. Neonatal Outcomes Among Live Births
Outcomes
Pessary
(n = 279)
Usual care
(n = 263)
Absolute
median difference
(95% CI)
Unadjusted
relative risk
(95% CI)
Fetal or neonatal/infant death, No. (%) 37 (13.3) 18 (6.8) 1.94 (1.13-3.32)
Live births n = 261 n = 254
Ventilator or continuous positive airway pressure use,
No./total (%)
75/259 (29.0) 82/254 (32.3) 0.90 (0.69-1.17)
Ventilator or continuous positive airway pressure,
median (IQR), d
6 (0-43) [n = 97] 5 (0-41) [n = 104] 0 (−12 to 12)
Supplemental oxygen, median (IQR), d 7 (0-41) [n = 95] 6 (0-51) [n = 105] 1 (−12 to 14)
Seizures requiring treatment, No./total (%) 1/259 (0.4) 1/254 (0.4) 0.98 (0.06-15.7)
Small for gestational age (less than fifth percentile),
No./total (%)
5/256 (1.9) 6/257 (2.4) 0.82 (0.25-2.65)
Intraventricular hemorrhage grade 3 or 4, No./total (%) 4/258 (1.6) 7/254 (2.8) 0.56 (0.17-1.90)
Retinopathy of prematurity, No./total (%) 27/259 (10.4) 23/254 (9.1) 1.15 (0.68-1.96)
Respiratory distress syndrome, No./total (%) 67/259 (25.9) 69/254 (27.2) 0.95 (0.71-1.27)
Bronchopulmonary dysplasia, No./total (%) 14/260 (5.4) 19/254 (7.5) 0.72 (0.37-1.41)
Necrotizing enterocolitis stage 2 or 3, No./total (%) 7/259 (2.7) 6/254 (2.4) 1.14 (0.39-3.37)
Hyperbilirubinemia, No./total (%)a
84/259 (32.4) 82/253 (32.4) 1.00 (0.78-1.29)
Neonatal infectious morbidity, No./total (%) 53/259 (20.5) 65/254 (25.6) 0.80 (0.58-1.10)
Suspected sepsis 38 (14.7) 51 (20.1) 0.67 (0.47-0.97)
Early-onset sepsisb
5 (1.9) 2 (0.8) 2.45 (0.48-12.57)
Late-onset sepsisb
8 (3.1) 12 (4.7) 0.65 (0.27-1.58)
Pneumonia 2 (0.8) 4 (1.6) 0.49 (0.09-2.66)
Composite neonatal outcome, No./total (%)c
81/260 (31.2) 74/254 (29.1) 1.05 (0.81-1.37)
Hospital length of stay, median (IQR), d 3 (2-20) [n = 258] 3 (2-22) [n = 253] 0 (0 to 0)
Special care admission, No./total (%) 98/260 (37.7) 105/254 (41.3) 0.91 (0.74-1.13)
Special care length of stay, median (IQR), d 50 (10-99) [n = 97] 37 (11-88) [n = 104] 10 (−16 to 36)
Birth weight, median (IQR), g 2847 (1410-3300)
[n = 258]
2810 (1690-3290)
[n = 253]
35 (−194 to 264)
Congenital malformation, No./total (%) 4/259 (1.5) 2/253 (0.8) 1.95 (0.36-10.61)
a
Peak total bilirubin of 15 mg/dL or higher or phototherapy use.
b
Early-onset sepsis defined as diagnosis at or prior to 72 hours postbirth.
Late-onset sepsis defined as diagnosis after 72 hours postbirth.
c
Includes any of death, respiratory distress syndrome, intraventricular
hemorrhage grade 3 or 4, periventricular leukomalacia, necrotizing
enterocolitis stage 2 or 3, bronchopulmonary dysplasia, retinopathy of
prematurity stage 2 or higher, or early-onset sepsis.
Figure 2. Kaplan-Meier Plot of Continued Pregnancy Without Delivery
or Fetal Death
1.0
0.8
0.6
0.4
0.2
0
Proportion
of
participants
remaining
pregnant,
%
Gestational age, wk
16
263
279
18
278
262
20
272
260
22
263
253
24
244
242
26
221
226
28
207
209
30
196
196
32
186
190
34
177
176
36
164
162
38
123
119
40
25
20
42
0
0
No. at risk
Pessary
Pessary
Usual care
Usual care
Log-rank P =.92
The median time from randomization to delivery or fetal death was 105 days
(IQR, 42-120 days) in the pessary group and 103 days (IQR, 56-118 days) in the
usual care group.

20 mm or less, cervical pessary placement did not result in a
lowerfrequencyofpretermbirthorfetaldeathpriorto37weeks
of gestation. Pessary placement was associated with a higher
rate of fetal or neonatal/infant death. Other neonatal out-
comes,includingadverseeventsandcareutilization,wereoth-
erwise similar between the 2 groups. Per-protocol adherence
to the pessary was high, although adverse effects of vaginal
discharge, soreness, odor, and leakage of fluid were more com-
monly reported by individuals in the pessary group.
Our results differ from a 2012 clinical trial that found a sig-
nificant reduction in preterm birth prior to 34 weeks and prior
to37weeksinindividualswithshortcervicallengthoflessthan
25 mm randomized to receive a pessary.13
A key difference in
our trial was the routine use of progesterone for short cervix
and a requirement of a shorter cervical length (<20 mm). Al-
though 2 prior trials had larger sample sizes,15,17
the sample
size in this trial is larger than in other published randomized
trials of pessary for preterm birth prevention in singleton
gestations.13,14,16,24
Most randomized trials of pessary pub-
lished since 2012 have included routine provision of proges-
terone and, similar to our trial, did not demonstrate a reduc-
tion in preterm birth.17-19
However, in a trial by Saccone et al16
that included individuals with a cervical length of 25 mm or
less in which progesterone was provided to those with a cer-
vical length of 20 mm or less, lower rates of preterm birth be-
fore 34 weeks and 37 weeks were found in the pessary group.
Our study differs from other trials in that we excluded indi-
vidualswithahistoryofpretermbirth,requiredashorterquali-
fying cervical length (<20 mm), and randomized participants
at an earlier gestational age.
Inourtrial,cerclagewasmorecommoninparticipantsran-
domized to receive usual care. For most participants, cer-
clage was examination indicated; there is controversy regard-
ing this indication. This may have potentially advantaged the
usual care group. This study adds to the literature sugges-
tions that there is no incremental benefit of use of a cervical
pessary when progesterone is initially prescribed.
This trial raises a new concern, given the higher rate of fe-
tal or neonatal/infant death among individuals who received
a pessary; this finding has not been reported in other random-
ized trials. Our ability to detect this may be due to recruit-
ment of a particularly high-risk group of individuals with se-
vere cervical length shortening found early in gestation, which
was more common in those who experienced a fetal or neo-
natal/infant death. The overwhelming majority of fetal deaths
(death prior to delivery or delivery prior to 20 weeks) and
neonatal/infant deaths (death following delivery at or after
20 weeks) reflected periviable births, with both groups hav-
ing a median gestational age of 22.1 weeks.
Limitations
This trial has several limitations. First, the open-label design
has the potential to introduce bias. We attempted to mini-
mize bias to the greatest extent possible through the rigor of
the protocol and by selecting a primary outcome that was not
prone to ascertainment bias. However, the difference in cer-
clage placement may result from an unmeasured bias. Sec-
ond, our planned effect size differed from the trial results. The
final cohort had a shorter cervical length than anticipated, and
this likely contributed to the higher incidence of the primary
outcome. Third, we are unable to precisely report the num-
ber of individuals who had a short cervical length in the popu-
lation that may have potentially been eligible, as centers var-
ied in their approach to clinical screening (ranging from
universal screening to chance finding). In addition, referrals
from outside centers and screening occurring at private clini-
cians’ offices complicated quantification of screening logs in
a uniform fashion.
Conclusions
Thistrialdemonstratesthatcervicalpessaryplacementinnon-
laboring individuals with singleton gestations and a cervical
length of 20 mm or less did not decrease the rate of preterm
birth before 37 weeks. Furthermore, cervical pessary place-
ment was associated with a higher risk of fetal and neonatal/
infant mortality.
ARTICLE INFORMATION
Accepted for Publication: June 1, 2023.
Author Affiliations: Department of Obstetrics and
Gynecology, Columbia University, New York,
New York (Hoffman, Bousleiman); George
Washington University Biostatistics Center,
Washington, DC (Clifton, Ugwu); University of
Alabama at Birmingham, Birmingham (Biggio);
University of Texas Medical Branch at Galveston,
Galveston (Saade); Eunice Kennedy Shriver
National Institute of Child Health and Human
Development, Bethesda, Maryland (Longo);
University of North Carolina at Chapel Hill, Chapel
Hill (Clark, Manuck); Northwestern University,
Chicago, Illinois (Grobman); The Ohio State
University, Columbus (Frey); University of Texas
Health Science at Houston–Children’s Memorial
Hermann Hospital, Houston (Chauhan); Hospital of
the University of Pennsylvania, Philadelphia
(Dugoff); MetroHealth Medical Center, Case
Western Reserve University, Cleveland, Ohio
(Chien); Brown University, Providence, Rhode
Island (Rouse); The University of Pittsburgh,
Pittsburgh, Pennsylvania (Simhan); University of
Utah Health Sciences Center, Salt Lake City (Esplin);
University of Texas at Austin, Austin (Macones).
Author Contributions: Drs Clifton and Ugwu had
full access to all of the data in the study and take
responsibility for the integrity of the data and the
accuracy of the data analysis.
Concept and design: Hoffman, Clifton, Biggio,
Saade, Bousleiman, Clark, Grobman, Manuck,
Chien, Rouse, Esplin, Macones.
Acquisition, analysis, or interpretation of data:
Hoffman, Clifton, Biggio, Saade, Ugwu, Longo,
Bousleiman, Clark, Grobman, Frey, Chauhan,
Dugoff, Manuck, Chien, Rouse, Simhan, Esplin.
Drafting of the manuscript: Hoffman, Clifton,
Biggio, Ugwu, Chauhan, Manuck.
Critical revision of the manuscript for important
intellectual content: Hoffman, Clifton, Biggio,
Saade, Longo, Bousleiman, Clark, Grobman, Frey,
Chauhan, Dugoff, Manuck, Chien, Rouse, Simhan,
Esplin, Macones.
Statistical analysis: Clifton, Ugwu.
Obtained funding: Clifton, Saade, Grobman,
Manuck, Chien, Rouse, Simhan.
Administrative, technical, or material support:
Hoffman, Clifton, Biggio, Saade, Bousleiman, Clark,
Frey, Chauhan, Dugoff, Manuck, Chien, Rouse,
Simhan, Esplin.
Supervision: Hoffman, Clifton, Biggio, Saade, Longo,
Clark, Frey, Chauhan, Manuck, Chien, Simhan,
Macones.
Conflict of Interest Disclosures: Dr Clifton
reported receipt of grants from the National
Institutes of Health (NIH). Ms Clark reported receipt
of grants from the University of North Carolina at
Chapel Hill. Dr Frey reported receipt of grants from
Samsung Medison. Dr Chauhan reported receipt of
grants from McGovern Medical School. Dr Manuck
reported receipt of grants from the NIH, UNC
Health Foundation, and State of North Carolina

PFAS Collaboratory and being Director of the Libby
and Lucy Overman Fund to Support Prematurity.
Dr Simhan reported receipt of grants from
Organon. Dr Esplin reported holding stock in Sera
Prognostics. No other disclosures were reported.
Funding/Support: This work is funded by the
Eunice Kennedy Shriver National Institute of Child
Health and Human Development (NICHD)
(grants HD27915, HD53097, HD40500, HD40544,
HD27869, HD40560, HD34208, HD40485,
HD87230, HD40545, HD40512, HD87192, and
HD36801).
Role of the Funder/Sponsor: Staff from the NICHD
had input into the study design, data collection, and
data interpretation and reviewed and approved this
report. They similarly reviewed this report and
approved the manuscript.
Group Information: A complete list of the
members of the Eunice Kennedy Shriver National
Institute of Child Health and Human Development
Maternal-Fetal Medicine Units (MFMU) Network is
available in Supplement 4.
Disclaimer: The authors’ views do not necessarily
represent those of the NICHD. The content is solely
the responsibility of the authors and does not
necessarily represent the official views of the NIH.
Data Sharing Statement: See Supplement 5.
Additional Contributions: We thank the
participants of this trial; research staff at the clinical
sites; Elizabeth A. Thom, PhD, formerly of the
George Washington University Biostatistics Center,
for protocol development and oversight; and Uma
M. Reddy, MD, MPH, Columbia University, for
protocol development.
Additional Information: Dr Thom is deceased.
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