A Randomized Trial of Pessary in Singleton Pregnancies With a Short Cervix
Phase: PHASE3
Conditions: Short Cervix, Preterm Delivery
Sponsor: The George Washington University Biostatistics Center

 
 
 
A Randomized Trial of Pessary in Singleton 
Pregnancies with a Short Cervix  
(TOPS) 
  
IDE# G160176 
 
 
 
Protocol 
 
 
 
 
Eunice Kennedy Shriver  
National Institute of Child Health and Human Development (NICHD) 
Maternal-Fetal Medicine Units (MFMU) Network  
 
 
 
 
 
 
Prepared by the 
 
Biostatistical Coordinating Center for the NICHD MFMU Network 
 
The Biostatistics Center 
George Washington University 
6110 Executive Boulevard, Suite 750 
Rockville, MD 20852 
(301) 881-9260 
 
 
 
 
June 15, 2020 
 
 
 

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Table of Contents 
1 
INTRODUCTION ............................................................................................................................................... 3 
1.1 
STUDY ABSTRACT .......................................................................................................................................... 3 
1.2 
PRIMARY HYPOTHESIS ................................................................................................................................... 3 
1.3 
PURPOSE OF THE STUDY PROTOCOL ............................................................................................................... 3 
2 
BACKGROUND .................................................................................................................................................. 4 
2.1 
INTRODUCTION ............................................................................................................................................... 4 
2.2 
CERVICAL LENGTH AND THE RISK OF PRETERM BIRTH .................................................................................. 4 
2.3 
PROGESTERONE FOR SHORT CERVIX .............................................................................................................. 4 
2.4 
CERVICAL SUPPORT FOR SHORT CERVIX IN SINGLETON PREGNANCIES - CERCLAGE ..................................... 5 
2.5 
CERVICAL SUPPORT FOR SHORT CERVIX IN SINGLETON PREGNANCIES - PESSARY ........................................ 6 
2.6 
SAFETY AND ACCEPTABILITY OF THE ARABIN PESSARY ................................................................................ 6 
2.7 
RATIONALE FOR A RANDOMIZED CLINICAL TRIAL ......................................................................................... 6 
3 
STUDY DESIGN ................................................................................................................................................. 8 
3.1 
PRIMARY RESEARCH QUESTION ..................................................................................................................... 8 
3.2 
SECONDARY RESEARCH QUESTIONS .............................................................................................................. 8 
3.3 
DESIGN SUMMARY ......................................................................................................................................... 8 
3.4 
ELIGIBILITY CRITERIA .................................................................................................................................... 8 
3.5 
INFORMED CONSENT CRITERIA .................................................................................................................... 11 
3.6 
RANDOMIZATION METHOD AND MASKING................................................................................................... 11 
4 
STUDY PROCEDURES ................................................................................................................................... 12 
4.1 
SCREENING FOR ELIGIBILITY AND CONSENT ................................................................................................ 12 
4.2 
RANDOMIZATION .......................................................................................................................................... 12 
4.3 
BASELINE PROCEDURES ............................................................................................................................... 12 
4.4 
PATIENT MANAGEMENT AND FOLLOW-UP ................................................................................................... 13 
4.5 
ADVERSE EVENT REPORTING ....................................................................................................................... 14 
4.6 
STUDY OUTCOME MEASURES AND ASCERTAINMENT ................................................................................... 14 
5 
STATISTICAL CONSIDERATIONS ............................................................................................................. 17 
5.1 
DATA RELEVANT TO THE PRIMARY OUTCOME ............................................................................................. 17 
5.2 
SAMPLE SIZE AND POWER ............................................................................................................................ 17 
5.3 
FEASIBILITY ................................................................................................................................................. 17 
5.4 
INTERIM ANALYSIS....................................................................................................................................... 18 
5.5 
ANALYSIS PLAN ........................................................................................................................................... 18 
6 
DATA COLLECTION ...................................................................................................................................... 20 
6.1 
DATA COLLECTION FORMS .......................................................................................................................... 20 
6.2 
WEB DATA ENTRY SYSTEM ......................................................................................................................... 20 
6.3 
CENTRALIZED DATA MANAGEMENT SYSTEM .............................................................................................. 21 
6.4 
PERFORMANCE MONITORING ....................................................................................................................... 21 
7 
STUDY ADMINISTRATION .......................................................................................................................... 22 
7.1 
ORGANIZATION AND FUNDING ..................................................................................................................... 22 
7.2 
COMMITTEES ................................................................................................................................................ 22 
8 
STUDY TIMETABLE....................................................................................................................................... 24 
8.1 
TRAINING AND CERTIFICATION .................................................................................................................... 24 
8.2 
RECRUITMENT AND DATA COLLECTION PERIOD .......................................................................................... 24 
8.3 
FINAL ANALYSIS .......................................................................................................................................... 25 
APPENDIX A 
DESIGN SUMMARY ................................................................................................................ 26 

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APPENDIX B 
SAMPLE INFORMED CONSENT FORMS .......................................................................... 27 
B.1. 
SAMPLE INFORMED CONSENT FORM FOR SCREENING (WITHOUT COMMON RULE 2018 CHANGES) .............. 27 
B.2. 
SAMPLE INFORMED CONSENT FORM FOR SCREENING (WITH COMMON RULE CHANGES) ............................. 30 
B.3. 
SAMPLE INFORMED CONSENT FORM FOR RCT (WITHOUT COMMON RULE 2018 CHANGES) ........................ 34 
B.4. 
SAMPLE INFORMED CONSENT FORM FOR RCT (WITH COMMON RULE 2018 CHANGES) ............................... 42 
REFERENCES .......................................................................................................................................................... 51 
TABLE 1. CUTOFFS FOR USING LMP TO DETERMINE GESTATIONAL AGE FOR SURE LMP .......................... 9 
TABLE 2. SAMPLE SIZE FOR VARIOUS OUTCOME RATES AND EFFECT SIZES ............................................... 17 
TABLE 3. CALCULATION OF POTENTIAL NUMBER OF WOMEN WITH SHORT CERVIX DETECTABLE PER 
YEAR.................................................................................................................................................................... 25 
FIGURES 
FIGURE 1. TIMETABLE ............................................................................................................................................. 24 

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1 Introduction 
1.1 Study Abstract 
Preterm birth is the primary driver of perinatal morbidity and mortality affecting approximately 11% of 
all newborns in the United States.1  Of the 4 million neonatal deaths that occur annually around the world, 
more than a quarter are the result of preterm birth.2  A short cervix by ultrasound has been noted to be one 
of the strongest predictors of subsequent preterm birth and investigators have focused efforts in finding a 
treatment for women with a short cervix that will reduce the risk of preterm delivery.  Although vaginal 
progesterone and cerclage have been shown to reduce the risk, results have not been uniformly positive, 
and a low-cost, simple and effective method would be of great value, especially globally.  The cervical 
pessary is such a treatment.  This randomized trial will evaluate whether a cervical pessary can reduce the 
risk of preterm birth before 37 weeks in women with a short cervix.  
1.2 Primary Hypothesis 
In women with a singleton gestation who show ultrasound evidence of short cervical length, placement of 
a cervical pessary reduces the risk of preterm birth less than 37 weeks.  
1.3 Purpose of the Study Protocol 
This protocol describes the background, design and organization of the randomized clinical trial and may 
be viewed as a written agreement among the study investigators.  The Data and Safety Monitoring 
Committee (DSMC) and the Network Advisory Board review the protocol.  Before recruitment begins, 
the protocol is approved by the Eunice Kennedy Shriver National Institute of Child Health and Human 
Development (NICHD) Maternal-Fetal Medicine Units (MFMU) Network Steering Committee, and the 
Institutional Review Board (IRB) of each clinical center.  Any changes to the protocol during the study 
period require the approval of the Steering Committee and the IRBs; major changes also require the 
approval of the DSMC. 
A manual of operations supplements the protocol with detailed specifications of the study procedures. 
 

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2 Background 
2.1 Introduction 
Preterm birth remains the paramount clinical challenge in obstetrics and continues to be a major cause of 
infant mortality.  Despite the scale of this issue, effective treatments for women presenting with preterm 
labor beyond administering corticosteroids for fetal lung maturation have remained elusive.  Historically, 
efforts have focused on ameliorating the consequences of prematurity rather than preventing its 
occurrence.3  Although this approach has improved neonatal outcomes, tremendous economic burden 
occurs as a direct result of the hospitalization of these neonates as well as the long-term costs associated 
with caring for these children. 
The failure of these efforts has led researchers to explore interventions earlier in pregnancy and to identify 
women at increased risk for preterm delivery in whom such interventions could be beneficial.  Success in 
preventing preterm birth has been achieved by identifying women with a history of prior preterm birth 
and providing exogenous progesterone.4,5  However, while history of a prior spontaneous preterm birth 
remains one of the most powerful predictors of recurrent preterm birth, its utility is limited.  First, 40% of 
pregnancies occur in nulliparous women who do not have an obstetrical history. An additional 50% of 
women are multiparous with only prior term birth.  Although their risk of preterm birth is low, they still 
represent a significant percentage of the women who deliver prematurely.  Petrini and colleagues in an 
analysis of the impact of universal screening for a history of prior preterm birth and treatment with 
progesterone noted that the impact on the overall preterm delivery rate was limited as it would only 
change by 0.3%.6   
2.2 
Cervical Length and the Risk of Preterm Birth 
A short cervix during pregnancy, as measured by endovaginal ultrasound, was first reported to be a 
significant risk factor for preterm delivery by Andersen et al. in 1990.7  This study found that in an 
unselected population of 113 gravidas, a cervix of less than 39 mm before 30 weeks gestation was a 
significant risk factor for early delivery.  Moreover, the authors found the risk of preterm delivery to be 
inversely proportional to cervical length and that the risk increased significantly with shorter cervical 
measurements.   
Subsequently, multiple studies have confirmed this finding, including the Preterm Prediction Study 
conducted by the MFMU Network from 1992-1995.  The Prediction Study was a prospective 
observational cohort study evaluating associations between various markers and subsequent spontaneous 
preterm delivery.  A total of 2915 women with a singleton gestation and 151 with a twin gestation had a 
cervical length measurement at 22-24 weeks of gestation by trained and certified sonographers.  In the 
singleton cohort, the mean cervical length was 35 mm with a standard deviation of 8 mm.8 A cervical 
length of 25 mm was approximately the 9th percentile for singletons and has now become the adopted 
cutoff for the diagnosis of short cervical length in singleton gestations.  In an unselected population, short 
cervical length (≤ 20 mm) at 23 weeks of gestation demonstrated a sensitivity of 58% with a false positive 
rate of 7% and a positive predictive value of 11% for spontaneous preterm birth ≤ 32 weeks.9   
After the success of progesterone in women with previous preterm birth, the next logical step was to 
evaluate whether progesterone would prevent preterm delivery in women with a short cervix.  
2.3 Progesterone for Short Cervix 
In 2007, Fonseca et al. reported a randomized trial of 413 women with a short cervix (<15 mm) who were 
assigned to either 200-mg capsules of micronized progesterone administered vaginally daily or placebo.  
Vaginal progesterone was associated with a reduction in the primary outcome, spontaneous preterm birth 

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less than 34 weeks, (Relative Risk [RR] 0.56, 95% Confidence Interval [CI] 0.36 to 0.86).10  The rate of 
preterm birth < 37 weeks was not reported.   
In a randomized multinational trial of 659 women with a prior preterm birth, O’Brien et al. found no 
overall difference in the rate of preterm birth between progesterone and placebo.11  However, in a small 
pre-specified subgroup analysis of 46 women with a cervical length of < 28 mm, the investigators found 
that there was a reduction in the rate of preterm birth < 32 weeks (0% vs. 29.6%, P = 0.014).  There was 
no difference in preterm birth at any other gestational age cutoff.   
Hassan et al. randomized 465 women with a short cervix (10 - 20mm) to either vaginal progesterone gel 
or placebo in a multinational trial of progesterone to prevent preterm delivery.12  This study demonstrated 
a relative risk of 0.55 for the primary outcome, preterm birth <33 weeks (95% CI, 0.33–0.92) but there 
was no difference in the rate of preterm birth <37 weeks (RR 0.89, 95% CI 0.68 to1.16).   
An individual participant data meta-analysis that included these trials of vaginal progesterone showed a 
significant reduction in preterm birth < 35 weeks (RR, 0.69; 95% CI, 0.55–0.88).13  
In contrast with these positive findings, the MFMU Network examined the impact of 17-α hydroxy-
progesterone caproate in nulliparous women with a short cervix (< 30 mm) and found no difference in the 
rate of preterm birth less than 37weeks.14  Moreover, the FDA did not approve a New Drug Application 
for vaginal progesterone used to prevent preterm birth.  In their reanalysis of the Hassan trial, the FDA 
concluded that there was considerable heterogeneity and a lack of efficacy among the US participants 
such that the data did not support the efficacy of progesterone gel.15  Most recently the OPPTIMUM trial 
of vaginal progesterone conducted in the UK and Sweden did not show a benefit for women at high risk 
of preterm delivery.  The definition of high risk included short cervix ≤ 25 mm as well as previous 
spontaneous preterm birth ≤ 34 weeks, or fetal fibronectin positive in conjunction with obstetrical risk 
factors.16  Approximately one-third of the women had short cervical length.  There was no differential 
effect between women with or without a short cervix as evidenced by a negative interaction test. 
Nevertheless, the strategy of routine screening of cervical length and treatment with vaginal progesterone 
if the cervix is found to be short has been adopted by many in the obstetrical community.  The American  
College of Obstetricians and Gynecologists  (ACOG) Practice Bulletin stated that universal cervical 
length screening in women without a prior preterm birth may be considered.17  The Society for Maternal-
Fetal Medicine (SMFM) made a similar statement in 2012.18  Several decision analyses have suggested 
that routine screening coupled with treatment with progesterone will result in a marked decreases in the 
rates of preterm birth < 34 weeks and substantial cost savings.19,20  From a survey of the MFMU Network 
in 2014, 17 of the component 35 sites (at 14 centers) at that time (49%) were not measuring cervical 
length as part of the routine prenatal ultrasound, 7 sites were doing universal transvaginal cervical length 
screening and the remainder were measuring cervical length abdominally, with reflexive transvaginal 
cervical length measurement if the abdominal cervical length was below a cutoff of 30-35 mm.    
2.4 Cervical Support for Short Cervix in Singleton Pregnancies - Cerclage 
Besides progesterone, another strategy to prevent preterm delivery in high-risk women with a short cervix 
is to provide cervical support by means of a cerclage or pessary. The cerclage has been shown to be 
effective in preventing preterm delivery.  In a meta-analysis of four prior randomized controlled trials of 
women with prior preterm birth and a short cervix (< 25 mm), Berghella noted a decrease in the rate of 
preterm birth < 35 weeks.21   Owen, in a prospective randomized trial of cerclage in women with a prior 
preterm birth, found a decrease in the rate of preterm birth < 35 weeks in the subgroup of women with 
cervical length less than 15 mm.22  

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2.5 Cervical Support for Short Cervix in Singleton Pregnancies - Pessary  
Vaginal pessaries have been used for many decades to treat uterine or vaginal vault prolapse but their use 
to prevent preterm birth dates back to the original case series reported by Cross in 1959.23   In the late 
1970s, a German doctor, Hans Arabin, designed a pessary made of flexible silicone.24  The Arabin 
pessary has some theoretical benefits over cerclage in that the insertion is non-surgical and may 
mechanically tilt the cervix lowering mechanical stresses rather than a cerclage which simply encloses the 
cervix.  Subsequent case reports and series have suggested that the Arabin pessary may offer benefit 
amongst women at risk for preterm birth.25   
In the Spanish trial (PECEP) published in 2012, 385 women with a singleton pregnancy and a short 
cervix (< 25 mm) were randomized to either pessary or expectant management.  A significant reduction 
was observed in the primary outcome, spontaneous preterm birth < 34 weeks (OR 0.18; 95% CI 0.08 to 
0.37).26  A similar difference was seen in spontaneous preterm birth < 37 weeks (OR 0.19; 95% CI 0.12 to 
0·30) and in a composite of adverse neonatal outcomes (OR 0.14; 95% CI 0.04-0.39).   
However, an international trial published by Nicolaides et al. showed that the Arabin pessary was not 
effective in preventing preterm birth < 34 weeks or < 37 weeks in 935 singleton pregnancies with cervical 
length less than or equal to 25 mm (OR 1.12; 95% CI 0.75 to 1.69). Preterm birth < 37 weeks was not 
reported.27   
A small trial from Hong Kong in 108 women also showed no difference for preterm birth < 34 weeks (OR 
1.04; 95% CI 0.94–1.12) or < 37 weeks (OR 0.96; 95% CI 0.81–1.14).28   However, this trial was stopped 
before 10% of the planned sample size had accrued without a pre-specified stopping rule or conditional 
power analysis.   
2.6 Safety and Acceptability of the Arabin Pessary 
In the PECEP trial, 192 women were treated with the Arabin pessary.26 While all women reported an 
increase in the amount of vaginal discharge, there were no serious adverse effects associated with the use 
of the pessary, including no increase in infection, rupture of membranes, or need for removal due to 
discomfort.  Only 14% of patients required pessary repositioning at any point during pregnancy and only 
one patient (0.5%) requested pessary removal. There was no increase in the occurrence of adverse 
neonatal outcomes.  
In the trial by Nicolaides et al., the pessary group had a higher rate than the control group of increased or 
new vaginal discharge (46.8% vs. 13.8%, P<0.001) and pelvic discomfort (11.4% vs. 3.4%, P<0.001).  
Ten percent (47 women) asked for the pessary to be removed, approximately half (25) because of 
discomfort and the remainder because of discharge (19) and vaginal bleeding (3). There appeared to be no 
provision in the protocol for replacing or repositioning the pessary.  There was no difference in vaginal 
infection between the groups.27   
In the Hong Kong trial, 53 women were treated with the Arabin pessary.28  Women in the pessary group 
experienced significantly more side effects (55.6% versus 27.3%) than in the expectant management 
group.  Nearly all of the side effects reported were vaginal discharge and this accounted for the difference 
between the groups (25 women versus 12). There were no differences in vaginal infection, ruptured 
membranes or adverse neonatal outcomes. The pessary dislodged in 2 patients and required replacement.  
2.7 
Rationale for a Randomized Clinical Trial 
Although the rate of preterm birth among singleton pregnancies has slowly declined since its peak in  
2005,29 it remains the single largest cause of perinatal mortality and reduction of the preterm birth rate 
remains a public health priority.  While short cervical length is one of the most powerful predictors of 

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subsequent preterm birth, the best treatment to reduce subsequent preterm birth remains unknown.  
Although some studies have shown a benefit to vaginal progesterone, some clinicians feel that the data 
are less than conclusive.  In addition, some women may be reluctant to use a hormone-based treatment 
due to fear with regard to unknown, long-term effects.  The Arabin pessary is a promising low–cost, non-
surgical intervention that appears to be well-tolerated.  Since it is not associated with hormone exposure, 
if shown effective it may offer a safe, simple and medication-free intervention.  To date, however, the two 
larger trials to date have conflicting results.  The results of an adequately powered and appropriately 
conducted trial from the United States will be important in determining whether the Arabin pessary is a 
useful intervention for the prevention of subsequent preterm birth in women with singleton gestation.   
 
 

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3 Study Design 
3.1 Primary Research Question  
This randomized trial will address the primary research question: 
In women with a singleton gestation and short cervical length less than or equal to 20 mm at 16 weeks 0 
days to 23 weeks 6 days of gestation, does treatment with a cervical pessary reduce the risk of  preterm 
birth prior to 37 weeks of gestation? 
3.2 Secondary Research Questions 
Secondary research questions that this study will address are: 
 
Does treatment with the Arabin cervical pessary for women with a short cervix (≤ 20mm) compared 
with usual care alter any of the secondary outcomes listed in Section 4.6, including: 
o Preterm birth less than 28 weeks, 32 weeks, or 35 weeks? 
o Neonatal morbidity or mortality? 
o Special care nursery admission? 
o Lower genital tract or urinary tract infection? 
o Physician interventions including labor inhibition, cerclage, and bed rest? 
o Alter the rates of inflammatory markers in cervicovaginal fluid? 
 
What is the acceptability of and compliance with the Arabin pessary as an adjunctive with vaginal 
progesterone? 
 
Are there specific subgroups in which treatment with the pessary is more efficacious? (See Section 
5.5 for a discussion of subgroup analyses.) 
 
 
3.3 Design Summary 
The study is an unblinded randomized controlled multi-center clinical trial of 850 women with a singleton 
gestation and ultrasound evidence of short cervical length, defined as less than or equal to 20 mm, 
randomized to one of two arms at participating MFMU Network clinical centers. 
 
Usual care.  Women will receive vaginal progesterone if they meet the criteria per local standard 
of care.  
 
Arabin cervical pessary.  If the local usual care is to receive vaginal progesterone for a short 
cervix, women randomized to the pessary will also receive progesterone.    
3.4 Eligibility Criteria  
3.4.1 Inclusion Criteria 
1. Singleton gestation.  Twin gestation reduced to singleton either spontaneously or therapeutically, 
is not eligible unless the reduction occurred before 13 weeks 6 days project gestational age (see 
below). Higher order multifetal gestations reduced to singletons are not eligible. 

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2. Gestational age at randomization between 16 weeks 0 days and 23 weeks 6 days based on clinical 
information and evaluation of the earliest ultrasound as described in Gestational Age 
Determination in Section 3.4.2 below.   
3. Cervical length on transvaginal examination of less than or equal to 20 mm by a study certified 
sonographer.  There is no lower cervical length threshold. 
3.4.2 Gestational Age Determination 
Gestational age is determined using criteria proposed by the American Congress of Obstetrics and 
Gynecology, the American Institute of Ultrasound in Medicine and the Society for Maternal-Fetal 
Medicine and is denoted  as the “project gestational age”.30  The “project EDC”, which is based on the 
project gestational age, cannot be revised once a determination has been made.  If the pregnancy is 
conceived by in-vitro fertilization, project gestational age is calculated from the date of embryo transfer 
and the embryo age at transfer.  If the pregnancy is conceived spontaneously (including ovulation 
induction and artificial insemination) information from the earliest dating ultrasound and the last 
menstrual period are used to determine project gestational age.  If no dating ultrasound has been 
performed previously, one must be performed before the patient can be randomized.   
Table 1. Cutoffs for Using LMP to Determine Gestational Age for Sure LMP 
Gestational age at first ultrasound by LMP 
Ultrasound method of 
measurement 
Ultrasound agreement with 
LMP 
Up to 8 weeks 6 days 
CRL 
± 5 days 
9 weeks 0 days to 13 weeks 6 days 
CRL 
± 7 days 
14 weeks 0 days to 15 weeks 6 days 
Per institution 
± 7 days 
16 weeks 0 days to 21 weeks 6 days 
Per institution 
± 10 days 
22 weeks 0 days to 23 weeks 6 days 
Per institution 
± 14 days 
 
3.4.3 Cervical Length Determination 
The length of the cervix will be measured according to the transvaginal ultrasound method described by 
Iams et al.31   With a real-time ultrasound probe placed in the anterior fornix of the vagina while the 
woman’s bladder is empty, the appropriate sagittal view will be obtained by the location of the triangular 
area of echodensity at the external os, a V-shaped notch at the internal os, and a faint line of echodensity 
or echolucency between the two.  After the initial image is obtained once the probe is in place, the probe 
will be withdrawn until the image blurs, and then the probe will be reapplied with only enough pressure to 
restore the image.  The cervix will be measured three times along the line made by the interface of the 
mucosal surfaces, with calipers placed at the external and internal os.  Dynamic change in cervical length 
will be considered by observing for spontaneous dynamic change or by applying mild fundal pressure for 
15-30 seconds and then re-measuring the cervical length.  The final cervical measurement reported will be 
the shortest best measure that clearly meets the above criteria – an averaging approach will not be used.  
All cervical length measurements employed for enrollment will be performed by a sonographer who has 
been trained and certified in transvaginal cervical length measurement.  If the initial screening 
measurement has been obtained by a non-accredited sonographer it will need to be repeated by a 
credentialed sonographer.  Credentialed sonographers will have documentation of education and 
proficiency in appropriate technique and competency in cervical assessment.  Required documentation 
includes a Fetal Medicine Foundation Certificate of Competence in cervical assessment, or certification 

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through the Perinatal Quality Foundation’s Cervical Length Education and Review (CLEAR) program, or 
sonographer participation in a previous NICHD study.   
An advisory committee of ultrasound experts will be assembled to review a random sampling of 
approximately 10-15% of enrollment vaginal ultrasound cervical length measurements as validation of 
appropriate imaging techniques. 
3.4.4 Exclusion Criteria 
1. Cervical dilation (internal os) 3 cm or greater on digital examination or evidence of prolapsed 
membranes beyond the external cervical os either at the time of the qualifying cervical ultrasound 
examination or at a cervical exam immediately before randomization.   
2. Fetal anomaly or imminent fetal demise.  This includes lethal anomalies, or anomalies that may 
lead to early delivery or increased risk of neonatal death e.g., gastroschisis, spina bifida, serious 
karyotypic abnormalities.  An ultrasound examination from 14 weeks 0 days to 23 weeks 6 days 
by project EDC must be performed prior to randomization to evaluate the fetus for anomalies.  
3. Previous spontaneous preterm birth between 16 weeks 0 days and 36 weeks 6 days.  This includes 
induction for pPROM in a prior pregnancy. 
4. Planned treatment with intramuscular 17-α hydroxy-progesterone caproate 
5. Placenta previa, because of risk of bleeding and high potential for indicated preterm birth. A low 
lying placenta is acceptable. 
6. Active vaginal bleeding greater than spotting at the time of randomization, because of potential 
exacerbation due to pessary placement.  
7. Symptomatic, untreated vaginal or cervical infection because of potential exacerbation due to 
pessary placement.  Patients may be treated and if subsequently asymptomatic, randomized.  
8. Active, unhealed herpetic lesion on labia minora, vagina, or cervix due to the potential for 
significant patient discomfort or increasing genital tract viral spread.  Once lesion(s) heal and the 
patient is asymptomatic, she may be randomized.  History of herpes is not an exclusion. 
9. Rupture of membranes due to likelihood of pregnancy loss and preterm delivery as well as the 
risk of ascending infection which could be increased with pessary placement. 
10. More than six contractions per hour reported or documented prior to randomization.  It is not 
necessary to place the patient on a tocodynamometer. 
11. Known major Mullerian anomaly of the uterus (specifically bicornuate, unicornuate, or uterine 
septum not resected) due to increased risk of preterm delivery which is unlikely to be affected by 
progesterone. 
12. Any fetal/maternal condition which would require invasive in-utero assessment or treatment, for 
example significant red cell antigen sensitization or neonatal alloimmune thrombocytopenia.  
13. Major maternal medical illness associated with increased risk for adverse pregnancy outcome or 
indicated preterm birth (treated hypertension requiring more than one agent, treatment for 
diabetes prior to pregnancy, chronic renal insufficiency defined by creatinine >1.4 mg/dL, 
carcinoma of the breast, conditions treated with chronic oral glucocorticoid therapy). Lupus, 
uncontrolled thyroid disease, and NYHA stage II or greater cardiac disease are also excluded. 
Patients with seizure disorders, HIV, and other medical conditions not specifically associated 
with an increased risk of indicated preterm birth are not excluded.  Prior cervical 
cone/LOOP/LEEP is not an exclusion criterion. 
14. Planned cerclage or cerclage already in place since it would preclude placement of a pessary. 

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15. Planned indicated delivery prior to 37 weeks. 
16. Allergy to silicone  
17. Participation in another interventional study that influences gestational age at delivery or neonatal 
morbidity or mortality. 
18. Participation in this trial in a previous pregnancy.  Patients who were screened in a previous 
pregnancy, but not randomized, may be included.  
19. Prenatal care or delivery planned elsewhere unless the study visits can be made as scheduled and 
complete outcome information can be obtained. 
3.5 
Informed Consent Criteria 
Written informed consent must be obtained from patients before they can be screened for the study by 
cervical ultrasound unless the ultrasound is clinically indicated or part of routine clinical care.  Patients 
who are eligible for the study because of the ultrasound results will be asked to sign another consent form 
to participate in the trial.  Full disclosure of the nature and potential risks of participating in the trial is to 
be made.   
Each center will develop its own consent form(s) according to the requirements of its own institutional 
review board using the model screening and study consent forms in Appendix B.  Each center will also 
develop its own patient research authorization documents, as required by the HIPAA Privacy Rule, 
following the guidelines of its own institution.  A copy of the signed screening consent form and, if 
applicable, the consent form for the study will be provided to the patient.   
Women who are not fluent in English will be enrolled by a person fluent in their language, if possible.  
Both verbal and written informed consent and authorization will be obtained in that language; if this is not 
possible the patient will be excluded. 
3.6 Randomization Method and Masking 
Consenting women will be assigned to one of the two arms by using an internet based randomization 
system maintained centrally by the Biostatistical Coordinating Center (BCC).   
The simple urn method will be used to generate the randomization sequences because it provides a high 
probability of balance in treatment assignments, it is unpredictable, and it allows an explicit 
randomization analysis to be conducted with relative ease.  Randomization will be stratified by clinical 
site to assure balance between the two arms with respect to anticipated differences in the clinic 
populations and possible differences in patient management. 
 

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4  Study Procedures 
4.1 
Screening for Eligibility and Consent 
All women with singleton gestation presenting for prenatal care before approximately 24 weeks 
gestational age are potentially eligible for screening. Women, who are identified with a short cervix 
through clinical or research screening will be approached for inclusion into this trial. The measurement 
must have been made by a certified sonographer.  Patients who have had a documented short cervical 
length (≤ 20 mm) by non-study certified personnel are eligible for inclusion in the study but would still 
have to undergo cervical length screening by an official study sonographer. 
If the cervical length is 20 mm or less, consent for the trial will be obtained and the patient will be 
screened for eligibility.  If an obstetrical ultrasound examination to evaluate the fetus for anomalies has 
not been performed at 14 weeks of gestation or later, one must be performed before randomization.  The 
results of this ultrasound must be reviewed to check for exclusion criteria, and if it is the patient’s first 
ultrasound with dating parameters, gestational age.  The results of the dating and/or anatomy ultrasounds 
may be made available to the patient’s physician.  
Immediately prior to randomization a speculum examination will be performed (followed by a digital 
exam if necessary) to rule out cervical dilation and cervical infection, as well as an evaluation of preterm 
premature rupture of the membranes (pooling, nitrazine, ferning).  A cervicovaginal fluid sample, vaginal 
Gram stain, and vaginal pH will be collected to assess for local inflammation and vaginitis.     
4.2 
Randomization   
Eligible and consenting patients will be randomized by certified research staff using an internet based 
randomization system maintained by the BCC.  The patient will be assigned either to pessary or usual 
care.   
4.3 
Baseline Procedures 
In addition to information collected for eligibility, project gestational age, and project EDC determination, 
the following information will be obtained at randomization from a patient interview followed by a 
review of her chart: 
 
Demographic information: age, race, insurance status 
 
Medical history: pre-pregnancy weight, current weight, height, chronic disease history 
 
Obstetrical history including outcome of all prior pregnancies and history of vaginal bleeding in 
the current pregnancy 
 
Social history: marital status, years of education, alcohol use, tobacco use and other maternal 
drug use 
 
 Complications during this pregnancy including sexually transmitted infections and vaginal 
infections. 
 
Current and planned progesterone treatment per usual care at the participating site. 
Women randomized to pessary will be evaluated by an accredited obstetric care provider (nurse, nurse 
practitioner, nurse midwife, or physician) who has been trained in the proper technique of pessary sizing 
and placement.  The provider will fit the patient for and place an Arabin pessary according to standard 
techniques so that it encircles the cervix and rests in the anterior and posterior fornices.  Care to ensure 

JUNE 15, 2020 
13 
 
that the entirety of the cervix is contained within the pessary will be assessed through a vaginal digital 
examination. Women will be provided with written education regarding anticipated symptoms with a 
pessary and indications for physician assessment. The patient will be instructed to present to the research 
center on the next business day if the pessary should be spontaneously expulsed.   
All women will be provided with education regarding the warning symptoms of preterm labor. 
4.4 
Patient Management and Follow-up 
All patients will receive a phone call from a research nurse to assess compliance and symptoms within 
one week of randomization.  If a patient in the pessary group is experiencing discomfort she will be asked 
to come in to assess the pessary for fit and possible replacement with a different size. 
All patients will have monthly study visits (in-person or virtual) with a research nurse/provider for 
compliance, symptoms related to treatment, review of recent hospitalization(s), and any additional 
treatment received for preterm labor, such as corticosteroids or tocolytics since their last visit.  Data on 
ongoing progesterone treatment will be collected.  
A second set of cervicovaginal fluid samples will be collected if an in-person study visit occurs between 
24 to 32 weeks by project gestational age. The second samples will include a cervicovaginal fluid sample, 
vaginal Gram stain and vaginal pH (without a speculum exam) to assess for local inflammation and 
vaginitis.  The samples will be evaluated not only for their potential individual association with outcomes, 
but also to examine any potential interval changes that may be associated with the assigned treatment 
arm.  Women randomized to pessary will have at least one in-person visit to undergo a digital 
examination to ensure appropriate pessary placement. 
At the second study visit after randomization, patients randomized to pessary will be asked to complete a 
questionnaire summarizing their experience with the pessary.  The questionnaire will be administered 
again at 37 weeks gestation. 
Therapy will be continued until 36 weeks 6 days, at which time all patients should have a final study visit 
scheduled.  Women in the pessary arm will have the device removed at this visit. 
The pessary may be removed as necessary to evaluate vaginal bleeding contractions, preterm labor, or 
other conditions.  The pessary will be reinserted if symptoms resolve and the cervix is less than 3 cm 
dilated. A patient will be instructed to call if the pessary comes out (fully or partially), becomes dislodged 
or if she removes it herself so that arrangements for a replacement pessary can be made. If the patient is 
uncomfortable, a replacement pessary may be inserted or the original pessary may be reinserted or 
repositioned.   
Indications for pessary removal are as follows: 
1. Painful, regular uterine contractions occurring at least every 10 minutes in order to facilitate 
accurate assessment of cervical dilation and effacement, especially if cervical examination with 
the pessary in place suggests dilation or progressive cervical shortening. 
2. Confirmed rupture of membranes — the initial assessment for rupture can be performed with the 
pessary in place, but once confirmed, the pessary should be removed.  
3. Confirmed diagnosis of clinical chorioamnionitis. 
4. Active vaginal bleeding greater than spotting — if the bleeding ceases and there are no other 
contraindications, the pessary can be replaced. 
5. Development of significant cervical edema with a cervical herpetic lesion. 
6.  Cervical laceration or significant edema. 

JUNE 15, 2020 
14 
 
7. At the patient’s request because of significant discomfort or other reasons. 
If a patient presents with symptoms of vaginitis, she should be treated as per local clinical standards.  No 
attempt will be made to alter or mandate clinical management of the subjects, which includes 
corticosteroids, tocolytics and magnesium sulfate.  In rare instances an exam-indicated rescue cerclage 
may be placed at the discretion of the provider.  Sexual intercourse is not expressly prohibited in this 
study.  However, the use of serial cervical length ultrasounds, prophylactic tocolytic drugs or cerclage is 
discouraged.  
Neonates will be followed to 28 days after the expected date of delivery or to discharge, whichever is 
longer.  Maternal and neonatal records will be reviewed and a follow-up telephone interview conducted to 
capture neonatal and maternal outcomes.   
4.5 
Adverse Event Reporting 
Detailed information concerning adverse events will be collected and evaluated throughout the conduct of 
the protocol.  
The NICHD Program Scientist and the BCC will be notified within seventy-two hours of any maternal or 
neonatal death by email/phone/fax, if the event occurred in a MFMU Network hospital.  For any maternal 
or neonatal death occurring outside a MFMU Network hospital, the adverse event must be reported to the 
NICHD and the BCC within twenty-four hours of being notified.  These and other adverse events deemed 
serious, unexpected and definitely, possibly or probably related, will be immediately (within twenty-four 
hours of notification) forwarded by the BCC to the DSMC Chair, NIH representative, and any other 
DSMC member who requests notification.  If a death is reported, a copy of the patient’s medical record 
will be made.   
Adverse events which do not qualify under the above definition must be reported to the BCC within 7 
days of being notified.  These adverse events will be collected and sent to the Chair, NIH representative, 
and any other requesting DSMC member on a monthly basis.  The Chair decides whether the adverse 
event reports should be disseminated to the rest of the committee and whether a follow-up call or meeting 
is required.  NICHD representatives may also request follow-up of specific events.  All adverse events 
will be considered along with other interim safety data in the DSMC deliberations. 
An IDE safety report will be completed for any suspected adverse reaction to the pessary that is both 
serious and unexpected.   
4.6 Study Outcome Measures and Ascertainment 
4.6.1 Primary outcome  
The primary outcome is delivery or fetal demise prior to 37 weeks 0 days (as determined by the project 
gestational age). 
4.6.2 Maternal Secondary Outcomes 
1. Interval from randomization to delivery or fetal demise 
2. Gestational age at delivery  
3. Preterm delivery or fetal demise prior to 28 weeks, 32 weeks or 35 weeks 
4. Preterm premature rupture of membranes (pPROM) 
5. Spontaneous preterm delivery (following preterm labor or pPROM)  
6. Indicated preterm delivery   

JUNE 15, 2020 
15 
 
7. Cesarean delivery 
8. Chorioamnionitis 
9. Maternal antepartum hospitalization days 
10. Maternal antibiotic or antifungal use for vaginal infection 
11. Vaginal infection as assessed by local clinical diagnosis 
12. Treatment for preterm labor, including cervical cerclage 
13. Side effects including symptomatic vaginal discharge or discomfort 
14. Discontinuation of pessary treatment and reason 
4.6.3 Fetal and Neonatal Secondary outcomes  
1. Fetal or neonatal death 
2. Duration of ventilator support 
3. Duration of supplemental oxygen 
4. Seizures requiring treatment 
5. Small for gestational age defined as < 5th percentile weight for gestational age, assessed specifically 
by sex and race of the infant based on United States birth certificate data 
6. Intraventricular hemorrhage (IVH) grades III or IV as determined by cranial ultrasounds performed as 
part of routine clinical care and classified based on the Papile classification system 
7. Retinopathy of prematurity (ROP).  This diagnosis will be reached when an ophthalmologic 
examination of the retina has been performed and ROP is diagnosed at Stage I (demarcation line in 
the retina) or greater. 
8. Respiratory distress syndrome (RDS) defined as the presence of clinical signs of respiratory distress 
(tachypnea, retractions, flaring, grunting, or cyanosis), with an oxygen requirement and a chest x-ray 
that shows hypoaeration and reticulogranular infiltrates. 
9. Bronchopulmonary dysplasia (BPD) defined as oxygen requirement at 28 days of life or at 36 weeks 
project gestational age for infants born before 32 weeks. 
10. Necrotizing Enterocolitis (NEC), defined as modified Bell Stage 2 or 3 where stage 2 represents 
clinical signs and symptoms with pneumatosis intestinalis on radiographs and stage 3 is defined as 
advanced clinical signs and symptoms, pneumatosis, impending or proven intestinal perforation. 
11. Hyperbilirubinemia.  Peak total bilirubin of at least 15 mg% or the use of phototherapy  
12. Neonatal infectious morbidity 
 
Sepsis (within 72 hours and > 72 hours after birth).  The diagnosis of sepsis will require 
the presence of a clinically ill infant in whom systemic infection is suspected with a 
positive blood, CSF, or catheterized/suprapubic urine culture; or, in the absence of 
positive cultures, clinical evidence of cardiovascular collapse or an unequivocal 
radiograph confirming infection.  
 
Suspected sepsis.  The diagnosis of suspected sepsis will include infants with suspicious 
clinical findings of infection, but no positive cultures or radiographs. 
 
Pneumonia.  The diagnosis of pneumonia will be confirmed by radiograph or positive 
blood culture. 

JUNE 15, 2020 
16 
 
13. Composite neonatal outcome comprised of fetal or neonatal death or RDS, Grade 3 or 4 IVH, PVL, 
Stage 2 or 3 NEC, BPD, Stage III or higher ROP, or early onset sepsis.  Occurrence of any of the 
individual components  is considered indicative of the outcome 
14. Length of hospital stay, need for NICU or intermediate care admission and length of stay 
 

JUNE 15, 2020 
17 
 
5 Statistical Considerations 
5.1 
Data Relevant to the Primary Outcome 
Hassan, who used a screening cervical length of between 10-20 mm, found a rate of preterm birth < 37 
weeks of 26.7% in women treated with progesterone.12  Because of the exclusion of women with cervical 
lengths between 0-9 mm it is highly plausible that the rate will be higher in the current trial. In an 
individual patient data meta-analysis of vaginal progesterone trials by Romero et al., the pooled preterm 
birth rate for singleton pregnancies was 34.7% for women with a short cervix of < 25 mm.   However, 
Conde-Agudelo et al. in a systematic review and indirect comparison meta-analysis that contained 
overlapping but not exactly the same trials reported a rate of preterm birth<37 weeks of 45.3%.32  Goya et 
al reported a 59% rate of spontaneous preterm delivery < 37 weeks for women with short cervix ≤ 25 mm 
in the expectant management group.33  
5.2 
Sample Size and Power 
A one-third reduction in preterm birth < 37 weeks was selected as being clinically meaningful.  If it is 
conservatively assumed that the rate of preterm birth <37 weeks  in the progesterone arm is between 28% 
and 35%, then a sample of 850 women is sufficient to detect a 33% reduction in preterm birth at 90% 
power.  In addition this sample size yields more than 80% power to detect a 30% reduction, assuming  a 
type 1 error of 5% 2-sided.  
Table 2. Sample Size for Various Outcome Rates and Effect Sizes 
 
PTB rate in Usual care 
arm (%)  
Total sample size for 30% 
reduction  
Total sample size  for 
33.3% reduction  
Power=80% ( α=0.05; β=0.2)  
28  
810  
640  
30  
740  
590 
32  
680  
540  
35  
600  
480  
Power=90% (α=0.05; β=0.1)  
28  
1080  
850  
30  
990  
790  
32  
900  
720  
35  
800  
640  
5.3 
Feasibility 
The feasibility of answering the primary research question will be addressed after the first 150 patients 
have been randomized and delivered.  The primary outcome rate in the usual care group will be presented 
to the Data and Safety Monitoring Committee (DSMC) without any comparison by group.  The DSMC 
would be charged with making a recommendation regarding potential revision of the sample size in 
addition to addressing the feasibility of answering the primary research question.   

JUNE 15, 2020 
18 
 
5.4 
Interim Analysis 
The DSMC meets in person at least once per year and more often if recommended by the committee.  
Before each of the annual meetings, a formal detailed report will be written by the Biostatistical 
Coordinating Center (BCC) which presents all baseline variables, protocol adherence, side effects, all 
adverse events reported, as well as center performance in terms of recruitment, data quality, loss to 
follow-up and protocol violations.   
Once sufficient patients have been accrued into the trial, the report will also include a formal interim 
analysis evaluating the primary outcome by treatment group.  For this evaluation, a cohort of patients is 
chosen consisting of all patients randomized before a certain date so that the analysis cohort does not 
depend on gestational age at delivery.   
The main statistical issue relevant to interim analysis is the problem of performing multiple tests of 
significance on accumulating data.   For this trial, the group sequential method of Lan and DeMets will be 
used to characterize the rate at which the type I error is spent.34  This method is flexible with regard to the 
timing of the interim analyses.  It is expected that an interim analysis will be conducted at approximately 
50% of the final sample size of 850.  
Asymmetric stopping boundaries will be used for the Lan-DeMets procedure.  The upper boundary which 
describes the stopping rule for benefit will be based on 1-sided type I error of .025 and the Lan-DeMets 
generalization of the O’Brien-Fleming boundary.  The lower boundary will be based on a less stringent 
stopping rule: 1-sided type I error of .05 and the Lan-DeMets generalization of the Pocock type boundary.  
It is often useful to calculate conditional power given the observed data to date, and conditional on the 
future data showing the originally assumed design effect.  If this conditional power is low (under 10 
percent) the DSMC may consider termination for futility if the accrual rate is slow with confidence that 
the Type II error is not greatly inflated.35 
It is recognized that any decision to terminate the study would not be reached solely on statistical grounds 
but on a number of complex clinical and statistical considerations.  
5.5 
Analysis Plan 
All statistical analyses will be based upon the total cohort of patients randomized into the trial.  Although 
data on some patients may be missing, all relevant data available from each patient will be employed in 
the analyses.  Patients will be included in the treatment group to which they were randomly assigned 
regardless of compliance. 
The primary analysis will consist of a simple comparison of binomial proportions.  The relative risk and 
confidence interval will be reported.  The individual components of the composite outcome will also be 
examined.  If the treatment groups are found to differ on a pre-treatment factor known to be a risk factor 
for the outcome, the statistical analysis will adjust for these differences.  An evaluation of treatment by 
center interaction will be included.  An analysis adjusting by center also will be performed to ensure that 
center differences do not change the conclusion.   
If the two groups show a difference in the incidence of the primary outcome, interactions will be 
evaluated and subgroup analyses conducted to determine whether the effect prevails throughout particular 
subgroups of patients.  Indeed, NIH guidelines require investigators to evaluate consistency between the 
genders and across racial subgroups (see Section 5.5.1).  It should be noted, however, that subgroup 
analyses have been greatly abused, particularly when there is no overall treatment difference.36  There is a 
strong temptation to search for a specific subpopulation in which the therapy is nevertheless effective.  
Yusuf et al. concluded “the overall ‘average’ result of a randomized clinical trial is usually a more reliable 
estimate of the treatment effect in the various subgroups examined than are the observed effects in 
individual subgroups.”37  Thus subgroup analyses will be interpreted with care.   

JUNE 15, 2020 
19 
 
It is generally acknowledged that subgroup analysis that is pre-specified in the protocol has more validity 
than ad-hoc comparisons.  The following factors will be considered for subgroup analysis, if there is a 
significant interaction between the factor of interest and the treatment effect. 
 
Race/ethnicity (see below) 
 
Gestational age at randomization (< 20 weeks and ≥ 20 weeks) 
 
Cervical length at randomization (< 15 and ≥ 15 - 20 mm) 
 
Treatment with vaginal progesterone (as planned per usual care locally) 
 
Screening to randomization interval 
 
Debris/funneling on randomization ultrasound 
 
Obesity by BMI category 
 
Parity 
 
Bacterial vaginosis/Nugent score at enrollment—Nugent ≥ 7 with pH  > 4.4 
 
Prior cervical surgery including LOOP/ LEEP 
Loss to follow-up will be defined as no information regarding pregnancy prior to 37 weeks.  Those 
defined as lost to follow-up will not be included in the primary analysis.  It is expected that the loss to 
follow-up rate will be very low.  For trials conducted by the MFMU Network, the loss to follow-up rate 
has typically been under 2 percent.  However, a sensitivity analysis will be performed including patients 
lost to follow-up with different assumptions regarding their outcome, to determine whether the results are 
robust.   
Since many of the secondary endpoints are dichotomous variables like the primary outcome, standard 
statistical methods for rates and proportions will be appropriate.  The Wilcoxon rank sum test will be used 
to compare continuous variables, and survival analysis methodology may be used to compare time-to-
event variables.  
In general, analyses of data will be conducted to address the primary and secondary research questions of 
the trial, and other interrelationships among elements of study data of interest to the investigators and of 
relevance to the objectives of the study. 
5.5.1 Racial/Ethnic Subgroup Analysis 
The racial/ethnic composition of women recruited into the MFMU Network trials varies.  Assuming for 
this trial that the composition is 50% African-American and 15% Hispanic, similar to the SCAN trial 
there is >90% and approximately 50% power respectively to detect a 50% reduction in the primary 
outcome in the separate subgroups.    
 

JUNE 15, 2020 
20 
 
6 Data Collection 
6.1 
Data Collection Forms 
Data will be collected on standardized forms on which nearly all responses have been pre-coded.  Each 
form is briefly described below: 
 
TO01 Screening Log. 
 
TO01A Eligibility Checklist 
 
TO02 Eligibility and Randomization Form is completed for all patients eligible for the study. 
 
TO03A Pessary Accountability Log lists the specific pessary(ies) given to each patient. 
 
TO04 Baseline Form is completed for all randomized patients.  This form includes detailed 
demographic and social data, medical and obstetrical history, and current pregnancy 
complications. 
 
TO04A Previous Pregnancy Outcome Form. 
 
TO05 Study Visit Form documents monthly study visits, possible side effects and compliance 
 
TO07 Unscheduled Visit or Hospitalization Form is completed for all patients who had an 
unscheduled emergency room, Labor & Delivery, clinic visit or hospitalization between the 
scheduled monthly visits, including the delivery admission. 
 
TO08 Maternal Delivery and Outcome Form documents specific pregnancy complications since 
randomization, in addition to labor, delivery and postpartum information.  
 
TO09 Neonatal Baseline Form records date and time of birth, delivery data and status at 
delivery, for each fetus/infant. 
 
TO10 Neonatal Outcome Form records outcome data for all infants admitted to the NICU or 
special care nursery. 
 
TO11 Patient Status Form documents loss to follow up/withdrawal status, last date of contact 
for lost to follow-up patients, side effects since the last dose. 
 
TO12 Adverse Event Form records serious and non-serious adverse events. 
 
TO13A Women’s Views on the Arabin Pessary, a patient questionnaire.  
 
TO14  Pessary Removal Form documents the position of the pessary at the time of  removal. 
 
 
6.2 
Web Data Entry System 
For this protocol, web data entry screens corresponding to the study forms listed above will be developed 
and maintained by the staff of the BCC.  Clinical center staff will enter data into the MySQL database 
located at the BCC through a web data management system (MIDAS).  The data are edited on-line for 
missing, out of range and inconsistent values.  A Users’ Manual documenting this system is provided to 
the centers by the BCC.  

JUNE 15, 2020 
21 
 
6.3 
Centralized Data Management System 
Daily data conversions from the MySQL database create up-to-date SAS datasets.  Data are reviewed 
weekly using edit routines similar to those implemented on-line during data entry, as well as additional 
checks for data consistency within or across forms.  A database of resulting potential data problems is 
generated in MIDAS for initial review by BCC staff who then evaluate the comments keyed in 
association with edits on missing or unusual values.  Valid edits will be flagged in MIDAS for resolution 
at the clinical centers.   
At regular intervals, specialized data reviews comparing data availability and consistency across forms 
are run by the BCC staff on the entire database or on a specific subset of data.  These reports are also 
submitted to the centers for correction or clarification. 
An audit trail, consisting of all prior versions of each data form as entered in the computer for each 
patient, is maintained so that the succession of corrections can be monitored. 
6.4 
Performance Monitoring 
The BCC will present regular reports to the TOPS Subcommittee, the Steering Committee, and the Data 
and Safety Monitoring Committee.  These include: 
 
Monthly Recruitment Reports - reports of the number of women screened and enrolled by month 
and by clinical center are provided monthly to the TOPS Subcommittee and all other members of 
the Steering Committee.  Weekly or bi-weekly reports are provided electronically if needed. 
 
Quarterly Steering Committee Reports - reports detailing recruitment, baseline patient 
characteristics, data quality, incidence of missing data and adherence to study protocol by clinical 
center, are provided quarterly to the TOPS Subcommittee and all other members of the Steering 
Committee. 
 
Data and Safety Monitoring Committee Reports - for every meeting of the DSMC, a report is 
prepared which includes patient recruitment, baseline patient characteristics, center performance 
information with respect to data quality, timeliness of data submission and protocol adherence (in 
addition to safety and efficacy data).  The reports also include adverse events, loss to follow-up 
and all outcome variables as described previously in this protocol. 

JUNE 15, 2020 
22 
 
7 Study Administration 
7.1 
Organization and Funding 
The study is funded by the Eunice Kennedy Shriver National Institute of Child Health and Human 
Development (NICHD).  The study is conducted by the NICHD Maternal-Fetal Medicine Units (MFMU) 
Network, consisting of twelve clinical centers, the Biostatistical Coordinating Center (BCC) and the 
NICHD, and is administered under cooperative agreements between each of the centers and the NICHD.  
Each of the funded institutions is represented by a Principal Investigator.  A complete description of the 
organization of the MFMU Network is provided in the MFMU Network Policy Manual.   
7.1.1 Participating Clinical Centers 
The participating Principal Investigators of the clinical centers have agreed to abide by the study protocol, 
to have comparable staff, facilities and equipment and to ensure the proper conduct of the study at each of 
their centers including: recruitment and treatment of patients as specified in the protocol, accurate data 
collection and the transmission of information to the Steering Committee. 
7.1.2 Biostatistical Coordinating Center 
The BCC is responsible for all aspects of biostatistical design, data management, interim and final 
statistical analyses, and preparation of publications based on the study results.  The Principal Investigator 
of the BCC reports to the Steering Committee and the Data and Safety Monitoring Committee. 
7.1.3 NICHD 
In addition to its role as funding agency, the NICHD participates in the activities of the Network, 
including the development of protocols, administration and conduct of the studies and preparation of 
publications. 
7.1.4 Network Advisory Board 
Appointed by the NICHD, the members of the Network Advisory Board consist of a group of experts 
who are not affiliated with research being conducted by the Network and represent the disciplines of 
maternal-fetal medicine, neonatology and biostatistics/epidemiology.  The role of the board includes the 
review and prioritization of proposed studies, in addition to the identification of scientifically and 
clinically important questions and ideas that might be conducted by the Network.  The NICHD Project 
Scientist convenes and attends the meetings. 
7.2 
Committees 
7.2.1 Steering Committee 
This committee consists of fifteen members.  The Principal Investigator from each of the twelve clinical 
centers, the BCC, and the NICHD MFMU Network Project Scientist are all voting members. The Chair of 
the Steering Committee may vote to break a tie.  The Chair, a person independent of the participating 
institutions, is appointed by NICHD.  The Steering Committee has the responsibility for identifying topics 
for Network studies, designing and conducting study protocols and monitoring study implementation, 
recruitment and protocol adherence.  The committee receives recommendations from the Data and Safety 
Monitoring Committee and the Network Advisory Board. 
7.2.2 Protocol Subcommittee 
The subcommittee consists of a chair (who is an investigator from one of the clinical centers), 
investigators from one or more other clinical centers, BCC staff, nurse coordinators, outside consultants 

JUNE 15, 2020 
23 
 
(if appropriate), and the NICHD Network Project Scientist.  The Protocol Subcommittee is responsible 
for the preparation and conduct of the study, and reporting the progress of the study to the Steering 
Committee. 
7.2.3 Publications Committee 
The Publications Committee is a standing committee of the Steering Committee.  The functions of this 
committee are to develop publication policies and to review all manuscripts and abstracts prior to 
submission.  The goals of this committee are fair and appropriate authorship credit and high quality 
publications. 
7.2.4 Data and Safety Monitoring Committee 
The Data and Safety Monitoring Committee (DSMC), a group of individuals not affiliated with any of the 
participating institutions, was established by the NICHD.  Before the trial can begin, the protocol must be 
approved by the committee.  During the conduct of the study, the committee is charged with monitoring 
the emerging results for efficacy and safety, in addition to center performance and protocol adherence.  
Recommendations by the committee can include protocol modification, early termination for efficacy, or 
for unexpected safety problems.  Recommendations are made to the NICHD and disseminated to the 
Steering Committee. 

JUNE 15, 2020 
24 
 
8 Study Timetable 
 
Figure 1. Timetable 
 
 2016               2017                   2018                  2019                   2020                    2021  
  2022 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.1 
Training and Certification 
A preliminary training with the nurse coordinators was held on January 2016 and a final training was 
conducted for research staff in July 2016, in addition to CLEaR or Fetal Medicine Foundation 
certification of individual sonographers not previously certified.  Physicians and staff at each study site 
will also have to undergo training in the appropriate techniques of pessary sizing and placement prior to 
receiving approval to begin enrollment.  Each participating center must be certified to start the trial before 
recruitment at that center can begin.  The certification requirements are designed to ensure that personnel 
involved in the trial are committed to the study and proficient in study procedures, and that the center has 
satisfied regulatory requirements.  Each center is required to obtain IRB approval for the study before 
they are certified to begin the trial.  The trial is expected to start in August/September 2016, if approved. 
8.2 
Recruitment and Data Collection Period  
Approximately 160,000 women deliver at MFMU Network centers annually.  It is conservatively 
hypothesized that that 1.5% of the women will have a short cervix < 20 mm.  In the MFMU SCAN trial 
of nulliparous singletons, 2 % of those screened had a cervical length ≤ 20mm before 23 weeks. In an 
analysis of the MFMU Network Prediction Study, 2.2% of parous women with a low–risk history had 
cervical length ≤ 20mm  at 22-24 week ultrasound.38  In Hassan et al., 2.3% of women had a cervical 
length between 10 and 20 mm.12     
Training/Certification  
Recruitment 
Follow-up  
Data processing  

JUNE 15, 2020 
25 
 
A survey of the MFMU Network sites in 2014 showed that in approximately 50% of the delivery 
population the cervix is not routinely measured, in 20% of the population universal routine transvaginal 
cervical length screening is conducted and in 30% the cervix is measured or evaluated by abdominal scan 
with reflexive transvaginal screening if it is short. If it is assumed that 80% of women receive an 
ultrasound at 16-23 weeks, and that there is a 20% detection rate for short cervix  where cervical length is 
not measured routinely, 100% detection with routine transvaginal cervical length screening and a 90% 
rate when there is abdominal scan with reflexive transvaginal cervical length measurement, then with 
160,000 deliveries per year approximately 1100 potentially eligible women would be available for 
recruitment annually.   
Table 3. Calculation of Potential Number of Women with Short Cervix Detectable per Year 
Approach (% detection) 
Percent of 
Delivery 
Population 
Short Cx 
(1.5%)  
With Ultrasound 
(80%) at 15-23 
wks 
Detected 
No Screening (detection 
rate 20%) 
50 
1200 
960 
192 
Cervical Measurement 
(detection rate 100%) 
20 
480 
384 
384 
Abdominal Measurement 
(detection rate 90%) 
30 
720 
576 
518 
 
 
 
 
1094 
 
Assuming that only 75% of these women are accessible and eligible and that only 50% consent to the 
study, this would translate to an enrollment rate of 410 women per year, or 34 per month.   Thus 
enrollment could be achieved within 30 months, even assuming a gradual start-up.  If the percentage of 
women accessible and eligible cervix is only 50%, enrollment could still be achieved in just over 3 years.   
8.3 
Final Analysis 
After a three-month period for completion of data entry for the trial and close-out of the delivery and 
primary outcome, the data set will be locked and available for the primary and other main analysis.   
 
 

 
26 
 
Appendix A 
Design Summary 
A Randomized Trial of Pessary in Singleton Pregnancies with a Short Cervix 
OBJECTIVE:  To determine whether pessary reduces the risk of preterm birth in women with a singleton gestation and a short cervix. 
ORGANIZATION 
 
SCHEDULED EVALUATIONS / DATA COLLECTION 
Clinical Centers: 
 
 
Subcommittee: 
Magee, UAB, Ohio State, Utah, Brown, Columbia, Case 
Western, UT-Houston, UNC, Northwestern, UTMB-Galveston, 
UPenn 
Matthew Hoffman, MD (Chair) 
Pre-Randomization: 
 
Randomization: 
 
Cervical length measurement by trained sonographer 
 
Pregnancy, exposure and medical history 
 
Vaginal sample, vaginal Gram stain and vaginal pH 
DESIGN 
Post-randomization: 
 
 
 
 
 
 
 
Delivery: 
 
Phone call to assess patient symptoms and 
compliance within 7 days of randomization  
 
Every four weeks: study visit to  assess symptoms 
and compliance 
 
Study visit between 24 and 32wks: vaginal sample, 
vaginal Gram stain and vaginal pH 
 
Digital exam to ensure appropriate pessary 
placement (pessary group) 
 
Patient questionnaire 8 weeks after randomization 
and again at 37 wks gestation. 
 
Pessary group: assessed for fit or replacement, as 
needed 
 
Delivery and neonatal data 
Major Eligibility 
Criteria: 
 
Singleton gestation 
 
Gestational age  160 to 236  wks  
 
Cervical length ≤ 20.0 mm   
Groups: 
 
 
Usual Care (may include vaginal progesterone) 
 
Arabin Pessary + Usual Care 
Random Allocation:  
Standard urn design; 1:1 allocation 
MANAGEMENT PROTOCOL 
Both Groups: 
 
Pessary Group: 
 
 
Vaginal progesterone per usual care and rescue 
cerclage if needed 
 
Placement management from randomization to   < 37 
wks   
Level of Masking: 
Unmasked 
Stratification: 
 
Clinical site 
Sample Size: 
 
850 
OUTCOME MEASURES 
Assumptions: 
 
 
 
 
 
Outcome event=delivery < 370 weeks gestation or 
fetal loss 
 
Usual care  group event rate =28%  
 
Pessary group event rate =18.67% (33.3% reduction) 
 
Type I error = 2.5% (two sided with one comparison) 
 
Power =90% 
Primary: 
 
Secondary: 
 
Delivery or fetal loss prior to 37 wks 
 
 
Randomization to delivery interval 
 
Gestational age at delivery 
 
Neonatal morbidity and mortality 
 
Lower genital tract or urinary tract infection 
 
Physician interventions including bedrest, cerclage, 
labor inhibition therapy 
Interim Analysis: 
 
Lan-DeMets group sequential method 
TIMETABLE 
 
 
Enrollment: 
Data Collection: 
Closeout/Analysis 
 
September 2016 to October 2019 
 
September 2016 to October 2019  
 
October 2019 to September 2021 

 
 
JUNE 15, 2020 
 
27 
 
Appendix B 
Sample Informed Consent Forms 
B.1. Sample Informed Consent Form for Screening (without Common Rule 2018 
changes) 
Research Study Title:  A Randomized Trial of Pessary in Singleton Pregnancies with a Short Cervix 
(TOPS)  
Sponsor:    Eunice Kennedy Shriver National Institute of Child Health and Human Development 
(NICHD) of the National Institutes of Health (NIH) 
 
Principal Investigator:  _______________________________Phone (____)  ___ - ____ 
  
Introduction 
You are invited to be screened to see if you are eligible to take part in a research study.  This consent 
form provides the information about the risks and benefits of being screened for this research study.  You 
can choose whether or not you will take part in the study.  If you agree to be screened for this study, you 
will need to sign this consent form.  This process is known as informed consent.  Please tell the study 
doctor or study staff if you are taking part in another research study. 
This consent form may contain words that you do not understand.  Please ask the study staff to explain 
any words or information that you do not clearly understand.   
 
Research Purpose 
Women who have a short cervix (which is the lower, narrow part of the womb) are more likely to deliver 
preterm.  Babies born preterm have a greater chance of having serious, long-term health problems or 
dying.   
The purpose of this research study is to find out whether a pessary lowers the risk of a baby being born 
too soon to women with a short cervix.  One study has been done to date in the US to find out if placing a 
pessary in women with a short cervix helps the pregnancy to last longer.  That study did not show that the 
pessary delayed or prevented preterm birth but the study was too small to have a reliable result.  Studies 
done in other countries have had differing results.  A pessary is a soft silicone device that goes around the 
cervix to give the cervix support.   
Procedures 
If you consent to screening for this study, your cervix will be measured by a vaginal ultrasound.  The 
ultrasound exam will take about 10 minutes.  If the length of your cervix measures 20 mm (about ¾ of an 
inch) or less, a member of the research staff may contact you to talk about taking part in a study in which 
you will be randomized (like flipping a coin) into one of two treatment groups:  1) pessary or 2) non-
pessary.  The pessary group will have a pessary placed around the cervix.  The non-pessary group will 
continue to receive the standard obstetric care provided by the doctor or nurse. You and your doctor or 
nurse will be informed of the results of your screening ultrasound examination. 
Possible Risks 
Vaginal ultrasounds have been used in pregnancy for many years and have not been shown to cause any 
harm to the mother or the unborn baby. It is widely used to look at the cervix.  A vaginal ultrasound is 
like having a pelvic exam.  Therefore, you may have mild discomfort during the exam. 
Benefits 

 
 
JUNE 15, 2020 
 
28 
 
The screening may not benefit you directly.  If your ultrasound shows that you have a short cervix, you 
may be eligible for the randomized study. 
Alternatives 
The alternative is not to participate in the screening. 
Costs 
There will be no additional cost to you for taking part in the screening.  
Right to Withdraw From the Research Study 
You are free to withdraw your consent and stop participating at any time.     
Confidentiality 
You have the right to privacy.  All information obtained from this research that can identify you will 
remain confidential within the limits of the law.  The results of your vaginal ultrasound will be sent to the 
data coordinating center, the George Washington University Biostatistics Center in Rockville, Maryland, 
with a unique code.  Only the research study staff at this medical center for this study will have access to 
the key to the code that can identify you. 
Certificate of Confidentiality 
This research is covered by a Certificate of Confidentiality from the NIH. The researchers with this 
Certificate may not disclose or use information, documents, or biospecimens that may identify you in any 
federal, state, or local civil, criminal, administrative, legislative, or other action, suit, or proceeding, or be 
used as evidence, for example, if there is a court subpoena, unless you have consented for this use. 
Information, documents, or biospecimens protected by this Certificate cannot be disclosed to anyone else 
who is not connected with the research except, if there is a federal, state, or local law that requires 
disclosure (such as to report child abuse or communicable diseases but not for federal, state, or local civil, 
criminal, administrative, legislative, or other proceedings); if you have consented to the disclosure or if it 
is used for other scientific research, as allowed by federal regulations protecting research subjects. 
The Certificate cannot be used to refuse a request for information from personnel of the United States 
federal or state government agency sponsoring the project that is needed for auditing or program 
evaluation by the NIH or to meet the requirements of the Food and Drug Administration (FDA). If you 
want your research information released to an insurer, medical care provider, or any other person not 
connected with the research, you must provide consent to allow the researchers to release it. 
Questions 
If you have questions about the procedures of this research study, please contact ________________ by 
telephoning (___) ___-____ during the workday. 
If you have any questions about the informed consent process or any other rights as a research subject, 
please contact __________________, Director of the Office of Human Research, at (____) ___-____.  
_______________  who is your representative. 
Signatures 
By signing this form you show that you have read this informed consent form, the study has been 
explained to you, your questions have been answered, and you agree to take part in the screening for this 
study.   
 
______________________              _______________________  
______________ 
Participant (Print Name)                    Signature  
 
          Date 

 
 
JUNE 15, 2020 
 
29 
 
    
_______________________              ________________________ 
_______________ 
Person Obtaining Consent                  Signature  
 
          Date 
   (Print Name) 
ASSENT FOR FEMALES UNDER 18 YEARS of AGE (if required by Center IRB): 
 
I agree __________ 
 
 
I do not agree__________ to participate in this study.   
 
This has been explained to me by ________________________ 
 
_____________________________                   _____________________ 
Signature of Minor 
 
 
 
Date 
 
_____________________________                  _____________________ 
Print Name of Subject                                           Age 
 
Please provide either one or both parental signatures as instructed by your IRB. 
 
_____________________________                    _____________________ 
Signature of Mother/Guardian                                          Date 
 
_____________________________                  _____________________ 
Signature of Father/Guardian                                 
Date 
 
 
A witness unrelated to the study is necessary if the participant can comprehend but cannot read (i.e., 
blind), or cannot sign (e.g., unable to use hands) the consent form. 
 
 
______________________                 ________________________ 
_______________ 
Witness’ Name                                               Signature 
 
 
        Date 
(Print Name) 
 
 

 
 
JUNE 15, 2020 
 
30 
 
B.2. Sample Informed Consent Form for Screening (with Common Rule changes) 
Research Study Title:  A Randomized Trial of Pessary in Singleton Pregnancies with a Short Cervix 
(TOPS)  
Sponsor:    Eunice Kennedy Shriver National Institute of Child Health and Human Development 
(NICHD) of the National Institutes of Health (NIH) 
 
Principal Investigator:  _______________________________Phone (____)  ___ - ____ 
  
Key Information 
This screening study is being done to find out whether you have a short cervix which may make you 
eligible for a research study. Women with a short cervix have an increased risk of a baby being born too 
soon.   
If you consent, your cervix will be measured by transvaginal ultrasound between 16,0 and 23,6 weeks of 
pregnancy.  You and your doctor or nurse will be informed of the results of your screening ultrasound 
examination.  If you have a short cervix, research staff may contact you to talk about taking part in a 
research study.  
This screening may not benefit you directly. A possible risk of the vaginal ultrasound is mild discomfort 
during the exam. Participation in this research study is voluntary and if you do not take part, you will 
receive the routine care usually provided to pregnant women. 
 
 
Introduction 
You are invited to be screened to see if you are eligible to take part in a research study.  This consent 
form provides the information about the risks and benefits of being screened for this research study.  You 
can choose whether or not you will take part in the study.  If you agree to be screened for this study, you 
will need to sign this consent form.  This process is known as informed consent.  Please tell the study 
doctor or study staff if you are taking part in another research study. 
This consent form may contain words that you do not understand.  Please ask the study staff to explain 
any words or information that you do not clearly understand.   
 
Research Purpose 
Women who have a short cervix (which is the lower, narrow part of the womb) are more likely to deliver 
preterm.  Babies born preterm have a greater chance of having serious, long-term health problems or 
dying.   
The purpose of this research study is to find out whether a pessary lowers the risk of a baby being born 
too soon to women with a short cervix.  One study has been done to date in the US to find out if placing a 
pessary in women with a short cervix helps the pregnancy to last longer.  That study did not show that the 
pessary delayed or prevented preterm birth but the study was too small to have a reliable result.  Studies 
done in other countries have had differing results.  A pessary is a soft silicone device that goes around the 
cervix to give the cervix support.   
 
 

 
 
JUNE 15, 2020 
 
31 
 
Procedures 
If you consent to screening for this study, your cervix will be measured by a vaginal ultrasound.  The 
ultrasound exam will take about 10 minutes.  If the length of your cervix measures 20 mm (about ¾ of an 
inch) or less, a member of the research staff may contact you to talk about taking part in a study in which 
you will be randomized (like flipping a coin) into one of two treatment groups:  1) pessary or 2) non-
pessary.  The pessary group will have a pessary placed around the cervix.  The non-pessary group will 
continue to receive the standard obstetric care provided by the doctor or nurse. You and your doctor or 
nurse will be informed of the results of your screening ultrasound examination. 
Possible Risks 
Vaginal ultrasounds have been used in pregnancy for many years and have not been shown to cause any 
harm to the mother or the unborn baby. It is widely used to look at the cervix.  A vaginal ultrasound is 
like having a pelvic exam.  Therefore, you may have mild discomfort during the exam. 
Benefits 
The screening may not benefit you directly.  If your ultrasound shows that you have a short cervix, you 
may be eligible for the randomized study. 
Alternatives 
The alternative is not to participate in the screening. 
Costs 
There will be no additional cost to you for taking part in the screening.  
Right to Withdraw From the Research Study 
You are free to withdraw your consent and stop participating at any time.     
Confidentiality 
You have the right to privacy.  All information obtained from this research that can identify you will 
remain confidential within the limits of the law.  The results of your vaginal ultrasound will be sent to the 
data coordinating center, the George Washington University Biostatistics Center in Rockville, Maryland, 
with a unique code.  Only the research study staff at this medical center for this study will have access to 
the key to the code that can identify you. 
Certificate of Confidentiality 
This research is covered by a Certificate of Confidentiality from the NIH. The researchers with this 
Certificate may not disclose or use information, documents, or biospecimens that may identify you in any 
federal, state, or local civil, criminal, administrative, legislative, or other action, suit, or proceeding, or be 
used as evidence, for example, if there is a court subpoena, unless you have consented for this use. 
Information, documents, or biospecimens protected by this Certificate cannot be disclosed to anyone else 
who is not connected with the research except, if there is a federal, state, or local law that requires 
disclosure (such as to report child abuse or communicable diseases but not for federal, state, or local civil, 
criminal, administrative, legislative, or other proceedings); if you have consented to the disclosure or if it 
is used for other scientific research, as allowed by federal regulations protecting research subjects. 
The Certificate cannot be used to refuse a request for information from personnel of the United States 
federal or state government agency sponsoring the project that is needed for auditing or program 
evaluation by the NIH or to meet the requirements of the Food and Drug Administration (FDA). If you 
want your research information released to an insurer, medical care provider, or any other person not 
connected with the research, you must provide consent to allow the researchers to release it. 
 
 

 
 
JUNE 15, 2020 
 
32 
 
Questions 
If you have questions about the procedures of this research study, please contact ________________ by 
telephoning (___) ___-____ during the workday. 
If you have any questions about the informed consent process or any other rights as a research subject, 
please contact __________________, Director of the Office of Human Research, at (____) ___-____.  
_______________  who is your representative. 
Signatures 
By signing this form you show that you have read this informed consent form, the study has been 
explained to you, your questions have been answered, and you agree to take part in the screening for this 
study.   
 
______________________              _______________________  
______________ 
Participant (Print Name)                    Signature  
 
          Date 
    
_______________________              ________________________ 
_______________ 
Person Obtaining Consent                  Signature  
 
          Date 
   (Print Name) 
ASSENT FOR FEMALES UNDER 18 YEARS of AGE (if required by Center IRB): 
 
I agree __________ 
 
 
I do not agree__________ to participate in this study.   
 
This has been explained to me by ________________________ 
 
_____________________________                   _____________________ 
Signature of Minor 
 
 
 
Date 
 
_____________________________                  _____________________ 
Print Name of Subject                                           Age 
 
Please provide either one or both parental signatures as instructed by your IRB. 
 
_____________________________                    _____________________ 
Signature of Mother/Guardian                                          Date 
 
_____________________________                  _____________________ 
Signature of Father/Guardian                                 
Date 

 
 
JUNE 15, 2020 
 
33 
 
 
 
A witness unrelated to the study is necessary if the participant can comprehend but cannot read (i.e., 
blind), or cannot sign (e.g., unable to use hands) the consent form. 
 
 
______________________                 ________________________ 
_______________ 
Witness’ Name                                               Signature 
 
 
        Date 
(Print Name) 

 
 
JUNE 15, 2020 
 
34 
 
B.3. Sample Informed Consent Form for RCT (without Common Rule 2018 
changes)  
 Research Study Title:  A Randomized Trial of Pessary in Singleton Pregnancies with a Short Cervix 
(TOPS)  
Sponsor:    Eunice Kennedy Shriver National Institute of Child Health and Human Development 
(NICHD) of the National Institutes of Health (NIH) 
 
Principal Investigator:  ______________________________Phone  (____)  ___ - ____ 
 
Introduction 
You are invited to take part in a research study.  Before you decide to be a part of this study, you need to 
understand the risks and benefits.  This consent form provides information about the research study.  A 
member of the research team will be available to answer your questions.  Please ask the study staff to 
explain any words or information that you do not clearly understand.  You can choose whether or not you 
will take part in the study.  If you agree to take part, you need to sign this consent form.  This process is 
known as informed consent.  
 
You have been asked to take part in this research study because you are between 16 weeks 0 days and 23 
weeks 6 days pregnant with one baby and a vaginal ultrasound showed that your cervix is shorter than 
usual (less than or equal to 20 mm, which is about ¾ of an inch).  The cervix is the lower, narrow part of 
your womb.  
Please tell the study doctor or study staff if you are taking part in another research study. 
Research Purpose 
Women who have a short cervix are more likely to deliver preterm.  Babies born preterm have a greater 
chance of having serious, long-term health problems or dying.   
The purpose of this research study is to find out whether a pessary lowers the risk of a baby being born 
too soon to women with a short cervix.  One study has been done to date in the US to find out if placing a 
pessary in women with a short cervix helps the pregnancy to last longer.  That study did not show that the 
pessary delayed or prevented preterm birth but the study was too small to have a reliable result.  Studies 
done in other countries have had differing results.  A pessary is a soft silicone device that goes around the 
cervix. 
The Arabin pessary has not been approved by the FDA for treating pregnant women who have a short 
cervix and are at risk for preterm delivery.  For this reason, the pessary is considered to be an 
‘investigational’ device and is being used for research purposes only.  
You will be in the study from the time of randomization (between 16-23 weeks of pregnancy) until one 
month after your expected date of delivery or until your baby is discharged from the hospital, whichever 
is the longest. 
This research study is funded by the Eunice Kennedy Shriver National Institute of Child Health and 
Human Development (NICHD).   Twelve medical centers across the country are part of this research 
study, and in all, 850 women with singleton pregnancies who have a short cervix will be enrolled. 
Procedures 
If you are eligible and decide to participate in this study, you will be asked to sign this consent form.  If 
you consent, you will be randomized (like tossing a coin) to one of two treatment groups: 1) pessary or 2) 

 
 
JUNE 15, 2020 
 
35 
 
non-pessary.  The pessary group will have a pessary placed around the cervix.  The non-pessary group 
will continue to receive the standard obstetric care provided by the doctor or nurse.   
All study participants will receive standard obstetric care should they develop symptomatic preterm labor.  
This care may include the following:  
 
Corticosteroids which helps preterm babies breathe easier 
 
Magnesium sulfate which may prevent cerebral palsy in preterm babies 
 
Certain medications that may decrease contractions 
 
Just before being randomized into one of the two treatment groups, an exam will be done with a 
“speculum”, a device which allows the doctor to look at the inside of your vagina and to look at your 
cervix to find out if it is opening or if you have an infection.  You have had a similar exam earlier in your 
pregnancy.  Opening of the cervix may allow the membranes (your bag of waters) to be exposed to the 
vagina which could increase the chances of infection, rupture of the membranes and preterm delivery.  If 
you have significant opening of your cervix, you do not qualify for this study.  Some infections of the 
cervix or vagina can increase the risk of complications, such as preterm birth, during pregnancy so it is 
important that we determine if an infection is present before beginning any treatment.  If you have an 
infection you will be treated before you can join the study.  You will need to have another speculum exam 
at that time.  If necessary, a digital exam (an exam where the physician uses his/her fingers) of the cervix 
may follow the speculum examination to better determine if your cervix is opening.   
During the exam, three vaginal samples will be collected.  The samples will be taken by placing a swab in 
your vagina and holding it there for about 30 seconds.  All vaginal swabs taken during the study will be 
tested at a later time to look at factors that may be linked to preterm birth.  You will not get results from 
these tests since they are for research purposes only.  
If you are randomized to the pessary group, a pessary will be placed around your cervix at your first study 
visit.  This will be done by a member of the research staff who will make sure that it fits around your 
cervix and is comfortable.  You will also be given information to take home with you about any 
symptoms you may have while the pessary is in place.  
No matter which treatment group you were randomized to a research nurse will call you within one week 
of your randomization visit to see how you are doing.   
If you are randomized to the pessary and feel discomfort in the pelvic area, you will be asked to come into 
the clinic.  You will have an exam to find out if the pessary should be moved or changed so that it feels 
better.  
After the first study visit, you will meet (either in-person or by video or phone) with a member of the 
research staff every four weeks until the 37th week of your pregnancy.  At each study visit, the research 
nurse will ask questions about your pregnancy, if you have had any symptoms, and if you are taking any 
medication.   
If you have an in-person study visit between 24 and 32 weeks of pregnancy, a second set of vaginal swabs 
will be taken at that time.  If you are in the pessary group, a vaginal exam will be done at an in-person 
visit to check that the pessary is in place. 
If you are randomized to the pessary group, during your second study visit after randomization (about 8 
weeks after randomization) you will be asked to complete a questionnaire about your feelings on the 
pessary.  You may be asked to answer these questions again around the 37th week of your pregnancy.   
If you were randomized to pessary, an in-person study visit will take place around the 37th week of your 
pregnancy to remove the pessary.   

 
 
JUNE 15, 2020 
 
36 
 
You will continue to receive standard care from your doctor while you are in this research trial.  There is 
a very small chance that your doctor may decide to place a rescue cerclage if your cervix opens too early 
in pregnancy.  A rescue cerclage is a stitch that is used to close the cervix when the membranes are 
bulging into the vagina.  About one month after your expected date of delivery or at the time your baby is 
discharged from the hospital, whichever is the longest, we will collect information about your pregnancy, 
labor, delivery, and the health of your baby.  We will review your medical records and your baby’s 
medical records and will contact you by telephone.   
After the study is done, researchers may want to contact you to do another follow-up study on you and 
your baby. 
Possible Risks 
If you are randomized to pessary, you may feel discomfort during the placement, or when it is taken out at 
the last visit, or if the pessary has to be moved or changed.  After placement, the pessary may become 
displaced or dislodged; should you experience any pain or discomfort please contact your provider.  You 
may have light vaginal bleeding or spotting at the time of pessary placement.  Vaginal intercourse may 
also be uncomfortable with the pessary in place.  The pessary may not reduce the risk of preterm birth. 
In studies of women pregnant with one baby, no serious side effects were associated with the pessary, 
including infection or rupture of membranes.   In one study some women (about 5%) asked for the 
pessary to be removed because of discomfort but it is not known if they were offered a replacement.   In 
the other two studies no women asked for the pessary to be removed because of discomfort.  Women did 
report an increase in vaginal discharge.  No risks from the pessary to the baby were found in either study. 
You may have vaginal itching, vaginal irritation, vaginal odor or vaginal burning, no matter which group 
you are randomized to.  If any of these symptoms occur, you can come into the clinic and your health care 
provider can determine if treatment is necessary.   
Although unlikely, it is possible that participating in this study may involve risks to you or your baby that 
are not expected. 
There is a risk of improper release or misuse of your personal information or specimens.  The chance of 
this happening is very small.  We have many protections in place to lessen this risk. 
Benefits 
If you decide to take part in this research study, you and your baby may or may not directly benefit from 
your participation.  If the study shows that treatment is successful, you and your baby may benefit if you 
are assigned to receive the pessary.  If the pessary is successful it may delay or prevent preterm delivery.  
In addition, if the study shows benefit, ultrasound testing and/or pessary may be made available to other 
women. Therefore, your participation can potentially benefit mothers and their babies in the future. 
Consent for Use/Disposal of Biospecimens  
By signing this consent form, you agree to have vaginal samples taken before receiving the pessary and/or 
usual care and at a later study visit between 26 and 30 weeks of pregnancy.  These samples may be used 
in the future to find out if there was an infection or other condition, such as the presence of certain 
substances in the fluid from your cervix, which may increase the risk of delivering a preterm baby. 
If you agree, any samples leftover after the study is finished may be used for future research.  The 
samples will be sent to a National Institutes of Health sample storage facility, where they will be kept 
indefinitely and without information identifying you.  The samples will only be shared with researchers 
approved by the National Institutes of Health.  An Institutional Review Board must also approve any 
future research using your samples. 
However if the researchers decide that there is no more use for your samples, you agree that they may be 
discarded. 

 
 
JUNE 15, 2020 
 
37 
 
Alternative Procedures  
The alternative to this study is not to participate and to continue receiving standard monitoring and care 
during pregnancy, labor and delivery. 
Costs 
There will be no cost to you to take part in the research study.  All research study related procedures will 
be provided at no cost to you or your insurance company.  The costs of your standard medical care will be 
billed to you or your insurance company in the usual manner. 
Compensation 
By signing this consent form, you acknowledge and agree that in the event that this research project 
results in the development of any marketable product, you will have no ownership interest in the product 
and no right to share in any profits from its sale or commercialization. 
(THIS SECTION WILL BE CENTER SPECIFIC.)  You will be paid $XX to compensate you for the 
time and travel associated with the research study. 
Payment for Injury or Harm 
(THIS SECTION WILL BE CENTER SPECIFIC.)  This medical institution and the NICHD have not 
made any provision for monetary compensation in the event of injury resulting from the research. In the 
event of such injury, treatment will be provided, but it is not provided free of charge.  Since this is a 
research study, payment for any injury resulting from your participation in this research study may not be 
covered by some health insurance plans. 
Right to Withdraw From the Research Study 
Your participation in this research study is voluntary.  You are free to withdraw your consent and stop 
taking part in this research study at any time.  Refusal to take part will involve no penalty or loss of 
benefits to which you are otherwise entitled.  Neither will your refusal affect your legal rights or quality 
of health care that you will receive at this hospital.  All of the information that has already been collected 
about you as part of the research study will continue to be used.  No new information about you will be 
collected for research study purposes unless the information concerns an adverse event (bad effect) 
related to the research study. 
Any significant new information which becomes available during your participation in this research, and 
which may affect your health, safety, or willingness to continue in this research study, will be given to 
you. 
Right of the Investigator to Withdraw 
The researchers of this institution or the National Institutes of Health can withdraw you from this study 
without your approval.  A possible reason for withdrawal could be the early termination of the study by 
the National Institutes of Health. 
Confidentiality 
You have the right to privacy.  All information obtained from this research that can be identified with you 
will remain confidential within the limits of the law.   
The medical information collected on you for this research study will come from your medical record and 
from information you give the nurse, such as your previous pregnancies, height, weight, and whether you 
drink or smoke.  Other information collected about you includes marital status, your level of education, 
type of medical insurance, and current pregnancy complications.  When your baby is born, data will be 
collected on your labor (such as when it starts) and delivery.  Information will also be collected on your 

 
 
JUNE 15, 2020 
 
38 
 
baby at delivery and on your baby’s hospital stay.  If we lose track of you, study staff may collect 
information from the internet including social network sites in order to find your contact information. 
The information collected for this research study will be submitted to the data coordinating center 
(George Washington University Biostatistics Center in Rockville, Maryland).  There the information will 
be put into a database with information from all of the participants.  Your information in the database will 
only be used for statistical analysis and may appear in scientific publications but will not identify you. 
The information sent to the data coordinating center does not include your name, address, social security 
number, hospital number, date of birth or any other personal identifiers.  Instead, the data center will use a 
unique code for each person consisting of a number and the first letter of your first name.  All vaginal 
samples will be labeled with a unique barcode consisting of a series of numbers.  The key to the code 
linking the data and samples to you will be kept here in a locked file.  Only the research study staff 
employed for this study at this hospital will have access to the key to the code. 
The following individuals and/or agencies will be able to look at and copy your research records: 
 
The investigator, study staff and other medical professionals who may be evaluating the study. 
 
Authorities from this institution, including the Institutional Review Board (IRB) which is a group of 
people who are responsible for making sure the rights of participants in research are respected. 
Members or staff of the IRB at this medical center may also contact you about your experience with 
this research.  You do not have to answer any questions the representative(s) of the board may ask. 
 
The United States Food and Drug Administration (FDA) and/or the Office for Human Research 
Protections (OHRP). 
 
The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) 
which sponsors this study, including persons or organizations working with the sponsors, such as the 
data coordinating center, the George Washington University Biostatistics Center in Rockville, 
Maryland. 
A copy of your medical chart or your baby’s medical chart also may be sent to research investigators at 
one of the other enrolling centers or the data coordinating center for review.  If your chart is sent, all 
identifying information, such as your name, address, social security number, hospital number, and date of 
birth first will be removed.  The results of this research study will be provided to the sponsor, NICHD 
(and/or their representatives). 
In addition, data from this study will be put in a public data set that will be available to other research 
investigators.  This public data set will not contain any identifying patient data. 
A description of this clinical trial will be available on http://www.clinicaltrials.gov, as required by U.S. 
Law.  This web site will not include information that can identify you.  At most, the web site will include 
a summary of the results.  You can search this web site at any time. 
Once the study is finished, you may request to have and review a copy of your personal health 
information collected during this study and placed in your medical record.  This right to review and copy 
your personal health information only extends to information that is placed in your medical record; it does 
not extend to information that is placed in your research record.  
We may want to use or share your biologic samples and data with other investigators either within or 
outside our institution so that other research studies can be done now or in the future.  Your samples and 
data will be de-identified (all identifying information removed) before being released to other researchers 
within or outside of this institution.  Such future testing and research may also lead to the development 
and use of information, products, tests, and treatments having commercial value.  You will not receive 
any financial compensation that may result from this testing or research as the specimens used have been 
de-identified and it will not be possible to determine if your specimen was used. 

 
 
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If you agree to let us keep your samples for future research, the samples will be stored until they are used 
up, or for as long as deemed useful for research purposes and may be stored in off-site facilities.  There 
will be no cost to you for any data or sample collection and storage. 
This permission does not end unless you cancel it, even if you withdraw from the study.  You can cancel 
this permission any time except where a healthcare provider has already used or released your health 
information, or relied on your permission to do something.  Even if you cancel this authorization, the 
researchers may still use and disclose protected health information (PHI) they already have obtained 
about you as necessary to maintain the integrity or reliability of the research.  However, no new PHI or 
new biological specimens will be collected from you after you revoke your authorization. 
To cancel your authorization, you will need to send a letter to Dr. ________ of the ________ stating that 
you are canceling your authorization.  This letter must be signed and dated and sent to this 
address:___________________.  If you are unable to write a letter ask one of the research staff to provide 
you with a letter that must be signed, dated, and sent to the above address.  A copy of this cancellation 
will be provided to the Study Doctor and his or her research team.  Not signing this form or later 
canceling your permission will not affect your health care treatment outside the study, payment for health 
care from a health plan, or ability to get health plan benefits. 
Your protected health information will be treated confidentially to the extent permitted by applicable laws 
and regulations.  Federal law may allow someone who gets your health information from this study to use 
or release it in some way not discussed in this section and no longer be protected by the HIPAA Privacy 
Rule. 
By signing this form you authorize the Study Doctor and members of the research team to use and share 
with others (disclose) your PHI for the purpose of this study.  If you do not wish to authorize the use or 
disclosure of your PHI, you cannot participate in this study because your PHI is necessary to conduct this 
study. 
Certificate of Confidentiality 
This research is covered by a Certificate of Confidentiality from the National Institutes of Health (NIH). 
The researchers with this Certificate may not disclose or use information, documents, or biospecimens 
that may identify you in any federal, state, or local civil, criminal, administrative, legislative, or other 
action, suit, or proceeding, or be used as evidence, for example, if there is a court subpoena, unless you 
have consented for this use. Information, documents, or biospecimens protected by this Certificate cannot 
be disclosed to anyone else who is not connected with the research except, if there is a federal, state, or 
local law that requires disclosure (such as to report child abuse or communicable diseases but not for 
federal, state, or local civil, criminal, administrative, legislative, or other proceedings); if you have 
consented to the disclosure, including for your medical treatment; or if it is used for other scientific 
research, as allowed by federal regulations protecting research subjects. 
The Certificate cannot be used to refuse a request for information from personnel of the United States 
federal or state government agency sponsoring the project that is needed for auditing or program 
evaluation by the NIH or for information that must be disclosed in order to meet the requirements of the 
federal Food and Drug Administration (FDA). You should understand that a Certificate of Confidentiality 
does not prevent you from voluntarily releasing information about yourself or your involvement in this 
research. If you want your research information released to an insurer, medical care provider, or any other 
person not connected with the research, you must provide consent to allow the researchers to release it. 
Questions   
The researchers are available to answer your questions about this research.  A representative of the 
Institutional Review Board is also available to answer questions about your rights as a participant in 

 
 
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40 
 
research or to answer your questions about an injury or other complication resulting from your 
participation in this research study. 
If you have questions or are hurt while taking part in this research study, you should contact 
________________ at (___) ___-____. 
If you have any questions about the informed consent process or any other rights as a research subject, 
please contact __________________, at (____) ___-____.  _______________ . 
Signatures 
By signing below, you indicate that you have read this consent form, the study has been explained to you, 
your questions have been answered, and you agree to take part in this study.  You do not give up any of 
your legal rights by signing this form.  A copy of this consent form will be given to you. 
Please initial below to indicate whether or not you give permission for future research of your samples. 
YES (initials)_____ I agree to have my samples, which will be kept confidential, stored and shared with 
other investigators doing research which is related to the health of mothers and children. 
NO (initials)_____ I do not agree to have my samples, which will be kept confidential, stored and shared 
with other investigators doing research which is related to the health of mothers and children. 
The investigator or study team may wish to contact you in the future to request permission for additional 
research. Please initial the appropriate statement to indicate whether or not you give permission for future 
contact. 
YES (initials)_____ I give permission to be contacted in the future for follow-up research. 
NO (initials)_____ I do not give permission to be contacted in the future for follow-up research.  
 
______________________              _______________________  
______________ 
Signature of Mother                                       Signature 
 
 
         Date 
(Print Name) 
______________________              _______________________  
______________ 
Signature of Father                                         Signature 
 
 
         Date 
(Print Name) 
_______________________              ________________________ 
_______________ 
Person Obtaining Consent                               Signature  
 
         Date 
(Print Name) 
ASSENT FOR FEMALES UNDER 18 YEARS of AGE (if required by Center IRB): 
 
I agree __________ 
 
 
I do not agree__________ to participate in this study.   
 
This has been explained to me by ________________________. 
 
_____________________________                   _____________________ 

 
 
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41 
 
Signature of Minor 
 
 
 
 
Date 
 
_____________________________                  _____________________ 
Print Name of Subject                                            
Age 
 
Please provide either one or both parental signatures as instructed by your IRB. 
 
_____________________________                    _____________________ 
Signature of Mother/Guardian                                          Date 
 
_____________________________                  _____________________ 
Signature of Father/Guardian                                 
Date 
 
A witness unrelated to the study is necessary if the participant can comprehend but cannot read (e.g., 
blind), or cannot sign (e.g., unable to use hands) the consent form. 
 
______________________                 ________________________ 
_______________ 
Witness’ Name                                               Signature 
 
 
        Date 
   (Print Name) 
Investigator Statement 
I certify that the research study has been explained to the above individual by me or my research staff 
including the purpose, the procedures, the possible risks and the potential benefits associated with 
participation in this research study.  Any questions have been answered to the Individual’s satisfaction. 
 
_______________________              ________________________ 
_______________ 
Investigator                                                      Signature  
 
         Date 
 (Print Name) 
 
 
 

 
 
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42 
 
B.4. Sample Informed Consent Form for RCT (with Common Rule 2018 changes) 
 Research Study Title:  A Randomized Trial of Pessary in Singleton Pregnancies with a Short Cervix 
(TOPS)  
Sponsor:    Eunice Kennedy Shriver National Institute of Child Health and Human Development 
(NICHD) of the National Institutes of Health (NIH) 
 
Principal Investigator:  ______________________________Phone  (____)  ___ - ____ 
 
Key Information 
This research is being done to find out whether a pessary lowers the risk of a baby being born too soon to 
women who have a short cervix.  A pessary is a soft, round, silicone device that is placed into the vagina 
to support the cervix. The cervix is the lower, narrow part of your womb. 
If you consent, you will be in the study from randomization (between 16,0 and 23,6 weeks of pregnancy) 
until one month after your expected date of delivery or until your baby is discharged from the hospital, 
whichever is the longest.  Just before randomization, an exam will be done with a speculum (a device 
which allows the doctor to look at the inside of your vagina and to look at your cervix) and vaginal 
samples will be collected. You will be randomly assigned (like tossing a coin) to pessary or no pessary.  
You will have monthly study visits (in-person or by video or phone) until the 37th week of pregnancy or 
delivery, whichever comes first.  After delivery, the research staff will collect medical information about 
you and your baby until you leave the hospital.  Around four weeks after your expected date of delivery, 
the research staff will give you a phone call to see how you and your baby are doing.  
There are risks to the study that are described in this consent. If you are in the pessary group, likely risks 
include discomfort during pessary placement, or when the pessary is removed or changed, light vaginal 
bleeding or spotting at the time of placement, or discomfort during vaginal intercourse.  For all groups, 
risks include vaginal itching, vaginal irritation, vaginal odor or vaginal burning. 
There are no known benefits from participating in this study. Participation in this research study is 
voluntary and if you do not take part, you will receive the routine care usually provided to pregnant 
women. 
 
Introduction 
You are invited to take part in a research study.  Before you decide to be a part of this study, you need to 
understand the risks and benefits.  This consent form provides information about the research study.  A 
member of the research team will be available to answer your questions.  Please ask the study staff to 
explain any words or information that you do not clearly understand.  You can choose whether or not you 
will take part in the study.  If you agree to take part, you need to sign this consent form.  This process is 
known as informed consent.  
 
You have been asked to take part in this research study because you are between 16 weeks 0 days and 23 
weeks 6 days pregnant with one baby and a vaginal ultrasound showed that your cervix is shorter than 
usual (less than or equal to 20 mm, which is about ¾ of an inch).  The cervix is the lower, narrow part of 
your womb.  
Please tell the study doctor or study staff if you are taking part in another research study. 
Research Purpose 

 
 
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43 
 
Women who have a short cervix are more likely to deliver preterm.  Babies born preterm have a greater 
chance of having serious, long-term health problems or dying.   
The purpose of this research study is to find out whether a pessary lowers the risk of a baby being born 
too soon to women with a short cervix.  One study has been done to date in the US to find out if placing a 
pessary in women with a short cervix helps the pregnancy to last longer.  That study did not show that the 
pessary delayed or prevented preterm birth but the study was too small to have a reliable result.  Studies 
done in other countries have had differing results.  A pessary is a soft silicone device that goes around the 
cervix. 
The Arabin pessary has not been approved by the FDA for treating pregnant women who have a short 
cervix and are at risk for preterm delivery.  For this reason, the pessary is considered to be an 
‘investigational’ device and is being used for research purposes only.  
You will be in the study from the time of randomization (between 16-23 weeks of pregnancy) until one 
month after your expected date of delivery or until your baby is discharged from the hospital, whichever 
is the longest. 
This research study is funded by the Eunice Kennedy Shriver National Institute of Child Health and 
Human Development (NICHD).   Twelve medical centers across the country are part of this research 
study, and in all, 850 women with singleton pregnancies who have a short cervix will be enrolled. 
Procedures 
If you are eligible and decide to participate in this study, you will be asked to sign this consent form.  If 
you consent, you will be randomized (like tossing a coin) to one of two treatment groups: 1) pessary or 2) 
non-pessary.  The pessary group will have a pessary placed around the cervix.  The non-pessary group 
will continue to receive the standard obstetric care provided by the doctor or nurse.   
All study participants will receive standard obstetric care should they develop symptomatic preterm labor.  
This care may include the following:  
 
Corticosteroids which helps preterm babies breathe easier 
 
Magnesium sulfate which may prevent cerebral palsy in preterm babies 
 
Certain medications that may decrease contractions 
 
Just before being randomized into one of the two treatment groups, an exam will be done with a 
“speculum”, a device which allows the doctor to look at the inside of your vagina and to look at your 
cervix to find out if it is opening or if you have an infection.  You have had a similar exam earlier in your 
pregnancy.  Opening of the cervix may allow the membranes (your bag of waters) to be exposed to the 
vagina which could increase the chances of infection, rupture of the membranes and preterm delivery.  If 
you have significant opening of your cervix, you do not qualify for this study.  Some infections of the 
cervix or vagina can increase the risk of complications, such as preterm birth, during pregnancy so it is 
important that we determine if an infection is present before beginning any treatment.  If you have an 
infection you will be treated before you can join the study.  You will need to have another speculum exam 
at that time.  If necessary, a digital exam (an exam where the physician uses his/her fingers) of the cervix 
may follow the speculum examination to better determine if your cervix is opening.   
During the exam, three vaginal samples will be collected.  The samples will be taken by placing a swab in 
your vagina and holding it there for about 30 seconds.  All vaginal swabs taken during the study will be 
tested at a later time to look at factors that may be linked to preterm birth.  You will not get results from 
these tests since they are for research purposes only.  
If you are randomized to the pessary group, a pessary will be placed around your cervix at your first study 
visit.  This will be done by a member of the research staff who will make sure that it fits around your 

 
 
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44 
 
cervix and is comfortable.  You will also be given information to take home with you about any 
symptoms you may have while the pessary is in place.  
No matter which treatment group you were randomized to a research nurse will call you within one week 
of your randomization visit to see how you are doing.   
If you are randomized to the pessary and feel discomfort in the pelvic area, you will be asked to come into 
the clinic.  You will have an exam to find out if the pessary should be moved or changed so that it feels 
better.  
After the first study visit, you will meet (either in-person or by video or phone) with a member of the 
research staff every four weeks until the 37th week of your pregnancy.  At each study visit, the research 
nurse will ask questions about your pregnancy, if you have had any symptoms, and if you are taking any 
medication.   
If you have an in-person study visit between 24 and 32 weeks of pregnancy, a second set of vaginal swabs 
will be taken at that time.  If you are in the pessary group, a vaginal exam will also be done at an in-
person visit to check that the pessary is in place. 
If you are randomized to the pessary group, during your second study visit after randomization (about 8 
weeks after randomization) you will be asked to complete a questionnaire about your feelings on the 
pessary.  You may be asked to answer these questions again around the 37th week of your pregnancy.   
If you were randomized to pessary, an in-person study visit will take place around the 37th week of your 
pregnancy to remove the pessary.   
You will continue to receive standard care from your doctor while you are in this research trial.  There is 
a very small chance that your doctor may decide to place a rescue cerclage if your cervix opens too early 
in pregnancy.  A rescue cerclage is a stitch that is used to close the cervix when the membranes are 
bulging into the vagina.  About one month after your expected date of delivery or at the time your baby is 
discharged from the hospital, whichever is the longest, we will collect information about your pregnancy, 
labor, delivery, and the health of your baby.  We will review your medical records and your baby’s 
medical records and will contact you by telephone.   
After the study is done, researchers may want to contact you to do another follow-up study on you and 
your baby. 
Possible Risks 
If you are randomized to pessary, you may feel discomfort during the placement, or when it is taken out at 
the last visit, or if the pessary has to be moved or changed.  After placement, the pessary may become 
displaced or dislodged; should you experience any pain or discomfort please contact your provider.  You 
may have light vaginal bleeding or spotting at the time of pessary placement.  Vaginal intercourse may 
also be uncomfortable with the pessary in place.  The pessary may not reduce the risk of preterm birth. 
In studies of women pregnant with one baby, no serious side effects were associated with the pessary, 
including infection or rupture of membranes.   In one study some women (about 5%) asked for the 
pessary to be removed because of discomfort but it is not known if they were offered a replacement.   In 
the other two studies no women asked for the pessary to be removed because of discomfort.  Women did 
report an increase in vaginal discharge.  No risks from the pessary to the baby were found in either study. 
You may have vaginal itching, vaginal irritation, vaginal odor or vaginal burning, no matter which group 
you are randomized to.  If any of these symptoms occur, you can come into the clinic and your health care 
provider can determine if treatment is necessary.   
Although unlikely, it is possible that participating in this study may involve risks to you or your baby that 
are not expected. 

 
 
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45 
 
There is a risk of improper release or misuse of your personal information or specimens.  The chance of 
this happening is very small.  We have many protections in place to lessen this risk. 
Benefits 
If you decide to take part in this research study, you and your baby may or may not directly benefit from 
your participation.  If the study shows that treatment is successful, you and your baby may benefit if you 
are assigned to receive the pessary.  If the pessary is successful it may delay or prevent preterm delivery.  
In addition, if the study shows benefit, ultrasound testing and/or pessary may be made available to other 
women. Therefore, your participation can potentially benefit mothers and their babies in the future. 
Consent for Use/Disposal of Biospecimens  
By signing this consent form, you agree to have vaginal samples taken before receiving the pessary and/or 
usual care and at a later study visit between 26 and 30 weeks of pregnancy.  These samples may be used 
in the future to find out if there was an infection or other condition, such as the presence of certain 
substances in the fluid from your cervix, which may increase the risk of delivering a preterm baby. 
If you agree, any samples leftover after the study is finished may be used for future research.  The 
samples will be sent to a National Institutes of Health sample storage facility, where they will be kept 
indefinitely and without information identifying you.  The samples will only be shared with researchers 
approved by the National Institutes of Health.  An Institutional Review Board must also approve any 
future research using your samples. 
However if the researchers decide that there is no more use for your samples, you agree that they may be 
discarded. 
Alternative Procedures  
The alternative to this study is not to participate and to continue receiving standard monitoring and care 
during pregnancy, labor and delivery. 
Costs 
There will be no cost to you to take part in the research study.  All research study related procedures will 
be provided at no cost to you or your insurance company.  The costs of your standard medical care will be 
billed to you or your insurance company in the usual manner. 
Compensation 
By signing this consent form, you acknowledge and agree that in the event that this research project 
results in the development of any marketable product, you will have no ownership interest in the product 
and no right to share in any profits from its sale or commercialization. 
(THIS SECTION WILL BE CENTER SPECIFIC.)  You will be paid $XX to compensate you for the 
time and travel associated with the research study. 
Payment for Injury or Harm 
(THIS SECTION WILL BE CENTER SPECIFIC.)  This medical institution and the NICHD have not 
made any provision for monetary compensation in the event of injury resulting from the research. In the 
event of such injury, treatment will be provided, but it is not provided free of charge.  Since this is a 
research study, payment for any injury resulting from your participation in this research study may not be 
covered by some health insurance plans. 
Right to Withdraw From the Research Study 
Your participation in this research study is voluntary.  You are free to withdraw your consent and stop 
taking part in this research study at any time.  Refusal to take part will involve no penalty or loss of 
benefits to which you are otherwise entitled.  Neither will your refusal affect your legal rights or quality 

 
 
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of health care that you will receive at this hospital.  All of the information that has already been collected 
about you as part of the research study will continue to be used.  No new information about you will be 
collected for research study purposes unless the information concerns an adverse event (bad effect) 
related to the research study. 
Any significant new information which becomes available during your participation in this research, and 
which may affect your health, safety, or willingness to continue in this research study, will be given to 
you. 
Right of the Investigator to Withdraw 
The researchers of this institution or the National Institutes of Health can withdraw you from this study 
without your approval.  A possible reason for withdrawal could be the early termination of the study by 
the National Institutes of Health. 
Confidentiality 
You have the right to privacy.  All information obtained from this research that can be identified with you 
will remain confidential within the limits of the law.   
The medical information collected on you for this research study will come from your medical record and 
from information you give the nurse, such as your previous pregnancies, height, weight, and whether you 
drink or smoke.  Other information collected about you includes marital status, your level of education, 
type of medical insurance, and current pregnancy complications.  When your baby is born, data will be 
collected on your labor (such as when it starts) and delivery.  Information will also be collected on your 
baby at delivery and on your baby’s hospital stay.  If we lose track of you, study staff may collect 
information from the internet including social network sites in order to find your contact information. 
The information collected for this research study will be submitted to the data coordinating center 
(George Washington University Biostatistics Center in Rockville, Maryland).  There the information will 
be put into a database with information from all of the participants.  Your information in the database will 
only be used for statistical analysis and may appear in scientific publications but will not identify you. 
The information sent to the data coordinating center does not include your name, address, social security 
number, hospital number, date of birth or any other personal identifiers.  Instead, the data center will use a 
unique code for each person consisting of a number and the first letter of your first name.  All vaginal 
samples will be labeled with a unique barcode consisting of a series of numbers.  The key to the code 
linking the data and samples to you will be kept here in a locked file.  Only the research study staff 
employed for this study at this hospital will have access to the key to the code. 
The following individuals and/or agencies will be able to look at and copy your research records: 
 
The investigator, study staff and other medical professionals who may be evaluating the study. 
 
Authorities from this institution, including the Institutional Review Board (IRB) which is a group of 
people who are responsible for making sure the rights of participants in research are respected. 
Members or staff of the IRB at this medical center may also contact you about your experience with 
this research.  You do not have to answer any questions the representative(s) of the board may ask. 
 
The United States Food and Drug Administration (FDA) and/or the Office for Human Research 
Protections (OHRP). 
 
The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) 
which sponsors this study, including persons or organizations working with the sponsors, such as the 
data coordinating center, the George Washington University Biostatistics Center in Rockville, 
Maryland. 

 
 
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A copy of your medical chart or your baby’s medical chart also may be sent to research investigators at 
one of the other enrolling centers or the data coordinating center for review.  If your chart is sent, all 
identifying information, such as your name, address, social security number, hospital number, and date of 
birth first will be removed.  The results of this research study will be provided to the sponsor, NICHD 
(and/or their representatives). 
In addition, data from this study will be put in a public data set that will be available to other research 
investigators.  This public data set will not contain any identifying patient data.  When the data set is 
shared, it will be done without obtaining additional permission from you. 
A description of this clinical trial will be available on http://www.clinicaltrials.gov, as required by U.S. 
Law.  This web site will not include information that can identify you.  At most, the web site will include 
a summary of the results.  You can search this web site at any time. 
Once the study is finished, you may request to have and review a copy of your personal health 
information collected during this study and placed in your medical record.  This right to review and copy 
your personal health information only extends to information that is placed in your medical record; it does 
not extend to information that is placed in your research record.  
We may want to use or share your biologic samples and data with other investigators either within or 
outside our institution so that other research studies can be done now or in the future.  Your samples and 
data will be de-identified (all identifying information removed) before being released to other researchers 
within or outside of this institution.  Such future testing and research may also lead to the development 
and use of information, products, tests, and treatments having commercial value.  You will not receive 
any financial compensation that may result from this testing or research as the specimens used have been 
de-identified and it will not be possible to determine if your specimen was used. This future research will 
not include whole genome (DNA) sequencing. 
If you agree to let us keep your samples for future research, the samples will be stored until they are used 
up, or for as long as deemed useful for research purposes and may be stored in off-site facilities.  There 
will be no cost to you for any data or sample collection and storage. 
This permission does not end unless you cancel it, even if you withdraw from the study.  You can cancel 
this permission any time except where a healthcare provider has already used or released your health 
information, or relied on your permission to do something.  Even if you cancel this authorization, the 
researchers may still use and disclose protected health information (PHI) they already have obtained 
about you as necessary to maintain the integrity or reliability of the research.  However, no new PHI or 
new biological specimens will be collected from you after you revoke your authorization. 
To cancel your authorization, you will need to send a letter to Dr. ________ of the ________ stating that 
you are canceling your authorization.  This letter must be signed and dated and sent to this 
address:___________________.  If you are unable to write a letter ask one of the research staff to provide 
you with a letter that must be signed, dated, and sent to the above address.  A copy of this cancellation 
will be provided to the Study Doctor and his or her research team.  Not signing this form or later 
canceling your permission will not affect your health care treatment outside the study, payment for health 
care from a health plan, or ability to get health plan benefits. 
Your protected health information will be treated confidentially to the extent permitted by applicable laws 
and regulations.  Federal law may allow someone who gets your health information from this study to use 
or release it in some way not discussed in this section and no longer be protected by the HIPAA Privacy 
Rule. 
By signing this form you authorize the Study Doctor and members of the research team to use and share 
with others (disclose) your PHI for the purpose of this study.  If you do not wish to authorize the use or 

 
 
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disclosure of your PHI, you cannot participate in this study because your PHI is necessary to conduct this 
study. 
Certificate of Confidentiality 
This research is covered by a Certificate of Confidentiality from the National Institutes of Health (NIH). 
The researchers with this Certificate may not disclose or use information, documents, or biospecimens 
that may identify you in any federal, state, or local civil, criminal, administrative, legislative, or other 
action, suit, or proceeding, or be used as evidence, for example, if there is a court subpoena, unless you 
have consented for this use. Information, documents, or biospecimens protected by this Certificate cannot 
be disclosed to anyone else who is not connected with the research except, if there is a federal, state, or 
local law that requires disclosure (such as to report child abuse or communicable diseases but not for 
federal, state, or local civil, criminal, administrative, legislative, or other proceedings); if you have 
consented to the disclosure, including for your medical treatment; or if it is used for other scientific 
research, as allowed by federal regulations protecting research subjects. 
The Certificate cannot be used to refuse a request for information from personnel of the United States 
federal or state government agency sponsoring the project that is needed for auditing or program 
evaluation by the NIH or for information that must be disclosed in order to meet the requirements of the 
federal Food and Drug Administration (FDA). You should understand that a Certificate of Confidentiality 
does not prevent you from voluntarily releasing information about yourself or your involvement in this 
research. If you want your research information released to an insurer, medical care provider, or any other 
person not connected with the research, you must provide consent to allow the researchers to release it. 
Questions   
The researchers are available to answer your questions about this research.  A representative of the 
Institutional Review Board is also available to answer questions about your rights as a participant in 
research or to answer your questions about an injury or other complication resulting from your 
participation in this research study. 
If you have questions or are hurt while taking part in this research study, you should contact 
________________ at (___) ___-____. 
If you have any questions about the informed consent process or any other rights as a research subject, 
please contact __________________, at (____) ___-____.  _______________ . 
Signatures 
By signing below, you indicate that you have read this consent form, the study has been explained to you, 
your questions have been answered, and you agree to take part in this study.  You do not give up any of 
your legal rights by signing this form.  A copy of this consent form will be given to you. 
Please initial below to indicate whether or not you give permission for future research of your samples. 
YES (initials)_____ I agree to have my samples, which will be kept confidential, stored and shared with 
other investigators doing research which is related to the health of mothers and children. 
NO (initials)_____ I do not agree to have my samples, which will be kept confidential, stored and shared 
with other investigators doing research which is related to the health of mothers and children. 
The investigator or study team may wish to contact you in the future to request permission for additional 
research. Please initial the appropriate statement to indicate whether or not you give permission for future 
contact. 
YES (initials)_____ I give permission to be contacted in the future for follow-up research. 
NO (initials)_____ I do not give permission to be contacted in the future for follow-up research.  

 
 
JUNE 15, 2020 
 
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______________________              _______________________  
______________ 
Signature of Mother                                       Signature 
 
 
         Date 
(Print Name) 
______________________              _______________________  
______________ 
Signature of Father                                         Signature 
 
 
         Date 
(Print Name) 
_______________________              ________________________ 
_______________ 
Person Obtaining Consent                               Signature  
 
         Date 
(Print Name) 
ASSENT FOR FEMALES UNDER 18 YEARS of AGE (if required by Center IRB): 
 
I agree __________ 
 
 
I do not agree__________ to participate in this study.   
 
This has been explained to me by ________________________. 
 
_____________________________                   _____________________ 
Signature of Minor 
 
 
 
 
Date 
 
_____________________________                  _____________________ 
Print Name of Subject                                            
Age 
 
Please provide either one or both parental signatures as instructed by your IRB. 
 
_____________________________                    _____________________ 
Signature of Mother/Guardian                                          Date 
 
_____________________________                  _____________________ 
Signature of Father/Guardian                                 
Date 
 
A witness unrelated to the study is necessary if the participant can comprehend but cannot read (e.g., 
blind), or cannot sign (e.g., unable to use hands) the consent form. 
 
______________________                 ________________________ 
_______________ 
Witness’ Name                                               Signature 
 
 
        Date 

 
 
JUNE 15, 2020 
 
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   (Print Name) 
Investigator Statement 
 
I certify that the research study has been explained to the above individual by me or my research staff 
including the purpose, the procedures, the possible risks and the potential benefits associated with 
participation in this research study.  Any questions have been answered to the Individual’s satisfaction. 
 
_______________________              ________________________ 
_______________ 
Investigator                                                      Signature  
 
         Date 
 (Print Name) 
 
 

 
 
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51 
 
References 
 
1. 
Hamilton BE, Martin JA, Osterman MJ, Curtin SC, Matthews TJ. Births: Final Data for 2014. 
Natl Vital Stat Rep 2015;64:1-64. 
2. 
Lawn JE, Kerber K, Enweronu-Laryea C, Cousens S. 3.6 million neonatal deaths--what is 
progressing and what is not? Semin Perinatol 2010;34:371-86. 
3. 
ACOG Practice Bulletin no. 127: Management of preterm labor. Obstet Gynecol 2012;119:1308-
17. 
4. 
Meis PJ, Klebanoff M, Thom E, et al. Prevention of recurrent preterm delivery by 17 alpha-
hydroxyprogesterone caproate. N Engl J Med 2003;348:2379-85. 
5. 
da Fonseca EB, Bittar RE, Carvalho MH, Zugaib M. Prophylactic administration of progesterone 
by vaginal suppository to reduce the incidence of spontaneous preterm birth in women at increased risk: a 
randomized placebo-controlled double-blind study. Am J Obstet Gynecol 2003;188:419-24. 
6. 
Petrini JR, Callaghan WM, Klebanoff M, et al. Estimated effect of 17 alpha-hydroxyprogesterone 
caproate on preterm birth in the United States. Obstet Gynecol 2005;105:267-72. 
7. 
Andersen HF, Nugent CE, Wanty SD, Hayashi RH. Prediction of risk for preterm delivery by 
ultrasonographic measurement of cervical length. Am J Obstet Gynecol 1990;163:859-67. 
8. 
Iams JD, Goldenberg RL, Meis PJ, et al. The length of the cervix and the risk of spontaneous 
premature delivery. National Institute of Child Health and Human Development Maternal Fetal Medicine 
Unit Network. N Engl J Med 1996;334:567-72. 
9. 
Heath VC, Southall TR, Souka AP, Elisseou A, Nicolaides KH. Cervical length at 23 weeks of 
gestation: prediction of spontaneous preterm delivery. Ultrasound in obstetrics & gynecology : the official 
journal of the International Society of Ultrasound in Obstetrics and Gynecology 1998;12:312-7. 
10. 
Fonseca E, Celik E, Parra M, Singh M, Nicolaides KH. Progesterone and the risk of preterm birth 
among women with a short cervix. N Engl J Med 2007;357:462-9. 
11. 
O'Brien JM, Adair CD, Lewis DF, et al. Progesterone vaginal gel for the reduction of recurrent 
preterm birth: primary results from a randomized, double-blind, placebo-controlled trial. Ultrasound 
Obstet Gynecol 2007;30:687-96. 
12. 
Hassan SS, Romero R, Vidyadhari D, et al. Vaginal progesterone reduces the rate of preterm birth 
in women with a sonographic short cervix: a multicenter, randomized, double-blind, placebo-controlled 
trial. Ultrasound Obstet Gynecol 2011;38:18-31. 
13. 
Romero R, Nicolaides K, Conde-Agudelo A, et al. Vaginal progesterone in women with an 
asymptomatic sonographic short cervix in the midtrimester decreases preterm delivery and neonatal 
morbidity: a systematic review and metaanalysis of individual patient data. Am J Obstet Gynecol 
2012;206:124 e1-19. 
14. 
Grobman WA, Thom EA, Spong CY, et al. 17 alpha-hydroxyprogesterone caproate to prevent 
prematurity in nulliparas with cervical length less than 30 mm. Am J Obstet Gynecol 2012;207:390 e1-8. 
15. 
Meeting of the Advisory Committee for Reproductive Health Drugs, Jan 20, 2012. (Accessed Jun 
8 2016, at http:// 
www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ReproductiveHealth
DrugsAdvisoryCommittee/UCM291316.pdf.) 
16. 
Norman JE, Marlow N, Messow CM, et al. Vaginal progesterone prophylaxis for preterm birth 
(the OPPTIMUM study): a multicentre, randomised, double-blind trial. Lancet 2016. 
17. 
Committee on Practice Bulletins-Obstetrics TACoO, Gynecologists. Practice bulletin no. 130: 
prediction and prevention of preterm birth. Obstet Gynecol 2012;120:964-73. 
18. 
Society for Maternal-Fetal Medicine Publications Committee waoVB. Progesterone and preterm 
birth prevention: translating clinical trials data into clinical practice. Am J Obstet Gynecol 2012;206:376-
86. 

 
 
JUNE 15, 2020 
 
52 
 
19. 
Cahill AG, Odibo AO, Caughey AB, et al. Universal cervical length screening and treatment with 
vaginal progesterone to prevent preterm birth: a decision and economic analysis. Am J Obstet Gynecol 
2010;202:548 e1-8. 
20. 
Werner EF, Han CS, Pettker CM, et al. Universal cervical-length screening to prevent preterm 
birth: a cost-effectiveness analysis. Ultrasound Obstet Gynecol 2011;38:32-7. 
21. 
Berghella V, Odibo AO, To MS, Rust OA, Althuisius SM. Cerclage for short cervix on 
ultrasonography: meta-analysis of trials using individual patient-level data. Obstet Gynecol 
2005;106:181-9. 
22. 
Owen J, Hankins G, Iams JD, et al. Multicenter randomized trial of cerclage for preterm birth 
prevention in high-risk women with shortened midtrimester cervical length. Am J Obstet Gynecol 
2009;201:375 e1-8. 
23. 
Cross RG. Treatment of habitual abortion due to cervical incompetence. Lancet 1959;274:127. 
24. 
Arabin H. Pessartherapie (Therapy with pessaries) In: G M, ed. Gynäkologie. Stuttgart-New 
York: Thieme; 1991:263–76. 
25. 
Arabin B, Halbesma JR, Vork F, Hubener M, van Eyck J. Is treatment with vaginal pessaries an 
option in patients with a sonographically detected short cervix? J Perinat Med 2003;31:122-33. 
26. 
Goya M, Pratcorona L, Merced C, Rodo C, Valle L, Romero A, et al. Cervical pessary in 
pregnant women with a short cervix (PECEP): an open-label randomised controlled trial. Lancet 
2012;379:1800-6. 
27. 
Nicolaides KH, Syngelaki A, Poon LC, et al. A Randomized Trial of a Cervical Pessary to 
Prevent Preterm Singleton Birth. N Engl J Med 2016;374:1044-52. 
28. 
Hui SY, Chor CM, Lau TK, Lao TT, Leung TY. Cerclage pessary for preventing preterm birth in 
women with a singleton pregnancy and a short cervix at 20 to 24 weeks: a randomized controlled trial. 
Am J Perinatol 2013;30:283-8. 
29. 
Gyamfi-Bannerman C, Ananth CV. Trends in spontaneous and indicated preterm delivery among 
singleton gestations in the United States, 2005-2012. Obstet Gynecol 2014;124:1069-74. 
30. 
Committee opinion no 611: method for estimating due date. Obstet Gynecol 2014;124:863-6. 
31. 
Iams J, Goldenberg RL, Meis PJ, Mercer BM, Moawad A, Das A, et al The length of the cervix 
and the risk of spontaneous premature delivery. National Institute of Child Health and Human 
Development Maternal Fetal Medicine Unit Network. N Engl J Med 1996;334:567-72. 
32. 
Conde-Agudelo A, Romero R, Nicolaides K, et al. Vaginal progesterone vs. cervical cerclage for 
the prevention of preterm birth in women with a sonographic short cervix, previous preterm birth, and 
singleton gestation: a systematic review and indirect comparison metaanalysis. Am J Obstet Gynecol 
2013;208:42 e1- e18. 
33. 
Goya M, Pratcorona L, Merced C, et al. Cervical pessary in pregnant women with a short cervix 
(PECEP): an open-label randomised controlled trial. Lancet 2012;379:1800-6. 
34. 
Lan K, DeMets, D. Discrete sequential boundaries for clinical trials. Biometrika 1983;70:659-63. 
35. 
Lan KK, Wittes, J. The B-value: A tool for monitoring data Biometrics 1988;44:579-85. 
36. 
Stallones RA. The use and abuse of subgroup analysis in epidemiological research. Prev Med 
1987;16:183-94. 
37. 
Yusuf S, Wittes J, Probstfield J, Tyroler HA. Analysis and interpretation of treatment effects in 
subgroups of patients in randomized clinical trials. JAMA 1991;266:93-8. 
38. 
Facco FL, Simhan HN. Short ultrasonographic cervical length in women with low-risk obstetric 
history. Obstet Gynecol 2013;122:858-62.