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Randomized study of pessary vs standard
management in women with increased chance
of premature birth
Study Protocol
Chief Investigator: Professor Kypros Nicolaides
Director
Harris Birthright Research Centre for Fetal Medicine
King’s College Hospital
London
SE5 9RS
Telephone: 00442032998256
Fax: 00442077339534
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Version 3
ISRCTN01096902
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Date 3 July 2008
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TRIAL SUMMARY
Title
Study location
Study objectives
Study design
Study population
Main inclusion criteria
Main exclusion criteria
Randomized study of pessary vs standard management in women with
increased chance of premature birth
UK and non-UK obstetrics departments
To assess the usefulness of pessary in reducing the risk of premature
birth in:
1. in women with singleton pregnancies and short cervix (cervical length
of 25 mm or less at 21-24 weeks)
2. women with twin pregnancies
Randomized, multi-centre study
1. Women with singleton pregnancies and with a cervical length of 25 mm
or less
2. Women with twin pregnancies
Major fetal abnormalities (defined as those that are lethal or require
prenatal or postnatal surgery), fetal death, severe twin to twin transfusion
syndrome or severe fetal growth restriction in one of the fetuses (in the
case of twin pregnancy) diagnosed before randomization.
Painful regular uterine contractions, history of ruptured membranes, or
prophylactic cerclage before randomization.
Patients who are unconscious, severely ill, mentally handicapped or
under the age of 16 years.
Planned number of
participants
Planned number of
centres
Investigational product
Summary of outcome
measures
Primary
Secondary
Singleton pregnancies:
Twin pregnancies:
1,600
1,180
10-15
Cerclage pessary (CE0482, MED/CERT ISO 9003 / EN 46003)
Spontaneous delivery before 34 weeks of gestation.
Birth weight (mean, less than 2.5 Kg and less than 1.5 Kg)
Fetal or neonatal death, major adverse outcomes before discharge from
the hospital (intraventricular hemorrhage, respiratory distress syndrome,
retinopathy of prematurity, or necrotizing enterocolitis)
Need for neonatal special care (admission to a neonatal intensive care
unit, ventilation, phototherapy, treatment for proven or suspected sepsis,
or blood transfusion).
Duration of study period
Major maternal complications attributable to the pessary (maternal death,
chorioamnionitis, serious cervical or vaginal trauma)
4 years
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BACKGROUND
Prematurity is responsible for more than half of all neonatal deaths1 and whilst
advances in neonatal care have dramatically improved survival of extremely
premature infants, there remains a significant risk of handicap and disability in
survivors and an associated social and economic burden.2-4 Although all births before
37 weeks of gestation are defined as preterm, most damage and death occurs in
infants delivered before 34 weeks.2,3
Premature birth rates have not decreased in the last 20 years and in most developed
countries continue to rise despite advances in knowledge of the risk factors and
mechanisms related to preterm labour.5 There are essentially two reasons for this
failure to reduce premature birth: firstly, the absence of an effective screening test to
identify the women at high-risk and secondly, the lack of an effective intervention to
prevent this complication.
Screening for premature birth
The most widely adopted approach to identifying pregnancies at high risk of
spontaneous premature birth has been the use of obstetric history and maternal
demographic characteristics.
Singleton pregnancy
In our screening studies involving more than 60,000 singleton pregnancies the rate of
delivery before 34 weeks was 1.8%, which was the same as in all maternities in
England in 2005-6.1 In two-thirds of cases the deliveries were spontaneous (1.2% of
the total) and in one-third they were iatrogenic. In 3% of our cases the women had a
previous premature birth and this group accounted for only 15% of the spontaneous
deliveries before 34 weeks. An effective method of antenatal screening for
spontaneous early premature birth is sonographic measurement of cervical length at
20-25 weeks of gestation. The risk of spontaneous early delivery is inversely related
to cervical length (Table 1). The group with cervix of 1-15 mm accounted for 28% of
all spontaneous deliveries before 34 weeks and those with cervix of 16-25 mm
accounted for 21%.
Table 1
Cervical length (mm)
1-10
11-15
16-25
26-30
31-35
36-40
>40
Prevalence
0.6%
0.5%
7.1%
16.6%
27.4%
26.9%
21.0%
Risk
44%
23%
3.6%
1.3%
0.8%
0.6%
0.4%
Twin pregnancy
The rate of spontaneous premature birth before 34 weeks is about 13% in twin
pregnancies.6 In a study of more than 1000 twin pregnancies attending for routine
antenatal care we found that the risk of premature birth increases with decreasing
cervical length at 22-24 weeks but even for women with a long cervix the risk is still
substantially higher than in singleton pregnancies (Table 2).6 The study also showed
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that monochorionic and dichorionic twins have a similar incidence of early preterm
delivery, once severe twin-to–twin transfusion syndrome has been excluded.
Table 2
Cervical length (mm)
1-10
11-15
16-20
21-25
26-30
31-35
36-40
Prevalence
1.9%
0.9%
3.3%
8.4%
15.4%
21.0%
49.1%
Risk
95.0%
70.0%
55.6%
38.0%
14.3%
8.7%
3.2%
Prevention of premature birth
Singleton pregnancy
The traditional policy for prevention of premature birth is tocolytic administration in
those presenting in preterm labor. Although such administration of tocolytics has been
used for several decades, systematic reviews of randomized studies have not reported
improved neonatal outcome with administration.8
The prophylactic administration of progesterone beginning in mid-gestation to women
who previously had a premature birth and in those with a short cervix has been
shown to reduce the rate of spontaneous preterm birth before 34 weeks.9-11
Twin pregnancy
Potential methods for the prevention of preterm delivery include bed rest, cervical
cerclage and prophylactic administration of progesterone. Randomized studies
reported that, in twin pregnancies, bed rest was associated with a significant increase,
rather than decrease, in the rate of early preterm delivery.13 Furthermore, randomized
studies in twin pregnancies have reported that cerclage in those with a short cervix
doubles the risk of premature birth,14 and prophylactic administration of progesterone in
women with a history of premature birth does not reduce the risk of premature birth.15
Cerclage pessary
There is some evidence that the rate of premature birth in women at risk can be
dramatically reduced by the insertion of a vaginal pessary (cerclage pessary,
CE0482, MED/CERT ISO 9003 / EN 46003).16 The pessary consists of flexible
silicone and is designed for the treatment of pregnant women. It is used to support
the cervix and change its direction towards the sacrum. This is widely used and
Germany and other European countries for the prevention of premature birth and has
been widely used for several decades in the treatment of utero-vaginal prolapse. In a
retrospective matched analysis study of twin pregnancies found at routine ultrasound
examination to have a cervical length below the 10th centile, 23 twin pregnancies
were treated with a pessary and 23 did not have a pessary.16 There were no
significant differences in demographic characteristics between the two groups. The
rate of spontaneous delivery before 32 weeks was 0% in the pessary group and 30%
in the controls (p<0.001). In the same study, 12 singleton pregnancies were treated
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with a pessary and 12 did not have a pessary. The rate of spontaneous delivery
before 36 weeks was 0% in the pessary group and 50% in the controls (p<0.001).16
There are several other observational or case controlled studies dating from 1959 on
the use of pessaries for the prevention of premature birth with encouraging results in
the absence of serious side effects.17-19
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STUDY OBJECTIVES
The aim of the study is to determine the effect of cerclage pessary on the incidence
of spontaneous delivery between randomization (at 20+0-24+0 weeks) and 33+6 weeks
in asymptomatic women with singleton pregnancies found at routine mid-trimester
screening to have a cervix of <25 mm in length and in twin pregnancies.
4
STUDY DESIGN
The trial will be conducted in compliance with the protocol, Good Clinical Practice
(GCP) and applicable regulatory requirements.
This will be a multicentre trial in the UK and other countries. During routine
ultrasound scan at 20+0-24+6 weeks of gestation for examination of fetal anatomy and
growth, all women with twin pregnancy or with singleton pregnancy found to have a
cervix of <25 mm in length and where the fetuses are found to be alive with no major
abnormalities, severe twin to twin transfusion syndrome or severe fetal growth
restriction in one of the fetuses (FGR) (in the case of twin pregnancy), will be invited
to participate in a randomized trial of standard management vs vaginal insertion of a
cerclage pessary. For singleton pregnancy, in both arms the patients with cervical
length <15 mm will be given prophylactic progesterone (200 mg vaginal capsule per
night up to 34 weeks).
An information leaflet concerning the study will be given to the women when they
attend for their routine 11-13 weeks scan and again at the time of the 20-24 weeks
scan. Women with vaginal discharge will have bacteriological investigation and if
there is an infection they will be treated with the appropriate antibiotic; if they are
allocated to the pessary group the pessary will be inserted after completion of the
treatment. In the case of twin pregnancies, the diagnosis of severe TTTS will be
based on the presence of the anhydramnios / polyhydramnios sequence or in the
absence of anhydramnios the finding of absent or reversed flow in the waveform from
the ductus venosus or umbilical artery of at least one of the fetuses. The diagnosis of
severe FGR will be based on the finding of estimated fetal weight below the 10th
centile and absent or reversed flow in the waveform from the ductus venosus or
umbilical artery of at least one of the fetuses.
Written informed consent to participate in the study, randomization and insertion of
the pessary (in those allocated to this group) will be carried out within 5 days after the
20+0-24+6 weeks scan. In centres offering routine scans at 20 and 22 weeks
randomization and insertion of the pessary will be carried out at 22 weeks. Before
placement of the pessary a speculum examination will be carried out to inspect the
cervix for any pathology such as ectropion, and perform a high vaginal swab for
bacteriological examination (and measurement of fibronectin or other biochemical
markers of preterm delivery in some centres depending on availability of funding).
Gestational age will be determined from the menstrual history and confirmed from the
measurement of fetal crown–rump length (of the bigger fetus in twin pregnancies) at
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a first-trimester scan or the head circumference (of the bigger fetus in twin
pregnancies) at a second-trimester scan.
Follow-up visits for ultrasound assessment of fetal growth, cervical length and
bacteriological investigations will be carried out every four weeks until 33+6 weeks of
gestation. If after 26 weeks the cervical length is less than 10 mm steroids (two IM
injections of betamethasone 12 mg 24 hours apart) will be given.
At the time of randomization, the patients will be informed that a symptom related to
the insertion of the pessary could include increased vaginal discharge. At each
follow-up visit, we will ask the patients and record their answer (in both arms of the
study) as to whether they have noted an increase in severity or frequency of this
symptom and whether they had developed any new symptoms since the beginning of
treatment.
Adherence will be checked by the sonographers carrying out the follow up scans.
The general practitioners and obstetricians of the women will be informed in writing
about the women’s participation in the study, and the hospital notes of those
receiving a pessary will be marked with a sticker labelled “cervical pessary.” The
participants, general practitioners, obstetricians and midwifes of the patients will be
unaware of the results of cervical assessment.
The study will commence after approved by the Multi-Centre Research Ethics
Committee of the Medicine Control Agency in the United Kingdom, as well as the
local ethics committees of the participating hospitals.
The sponsor of the study, the Fetal Medicine Foundation, will have no role in study
design, data analysis, data interpretation, or the writing of the report.
Exclusion Criteria
1. Major fetal abnormalities (defined as those that are lethal or require prenatal or
postnatal surgery), fetal death, or (in the case of twin pregnancy) severe twin-totwin transfusion syndrome or selective FGR diagnosed before randomization.
2. Painful regular uterine contractions, history of ruptured membranes, or
prophylactic cerclage before randomization.
3. Patients who are unconscious, severely ill, mentally handicapped or under the
age of 16 years.
Subject withdrawal:
The pessary will be removed if the women request or there are any adverse events
not responding to alternative treatment (such as offensive vaginal discharge or not
responding to antibiotic therapy).
Such women will not be replaced and their data will be included because the analysis
will be based on the principle of intention to treat.
The follow-up for subjects withdrawn from the investigational product will be the
same as those in the standard expectant arm of the trial.
Quality control and handling of data
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Information on the characteristics of the patients, including demographic data,
measurements for calculation of body-mass index, and obstetrical and medical
histories, will be obtained from the patients at the first hospital visit and will be
recorded directly on the CRFs. These will then be entered into a computer database
and on the subject screening log in the study site file.
Data on pregnancy outcomes will be obtained from the hospital maternity records or
the patients’ general medical practitioners. The obstetrical records of all patients
delivering before 34 weeks will be examined to determine whether the delivery was
medically indicated or spontaneous. Spontaneous deliveries will include those with
spontaneous onset of labour and those with rupture of membranes before labour.
Quality control of screening, handling of data, and verification of adherence to
protocols at the different centres will be performed on a regular basis by the trial
coordinators.
The sonographers who will perform the scans will have received extensive training
and passed a practical examination administered by an expert to demonstrate their
competence in cervical assessment (Fetal Medicine Foundation Certificate of
Competence in Cervical Assessment). The obstetricians introducing the pessaries
will receive training on selecting the appropriate size and introducing the device.
Measurement of cervical length
The women will be asked to empty their bladder, placed in the dorsal lithotomy
position and the transvaginal probe will be placed in the anterior fornix of the vagina.
A sagittal view of the cervix will be obtained and the calipers will be used to measure
the distance between the triangular area of echodensity at the external os and the Vshaped notch at the internal os. Each examination should be performed over a period
of about three minutes. In about 1% of cases dynamic cervical changes, due to
uterine contractions, are observed. In such cases the shortest measurement will be
recorded.
Cerclage pessary
Transvaginal sonography will be carried out and the length of the cervix measured. If
there is offensive vaginal discharge bacterial swabs will be performed and
appropriate antibiotic therapy will be given before insertion of the pessary. The
pessary will be inserted by a doctor with the woman in the recumbent position. The
smaller upper ring will be placed around the cervix with care being taken for this not
to be too tight and the lower larger ring will be placed in the fornix. The pessary will
be removed by a simple vaginal examination at 37 weeks or earlier before medically
indicated preterm induction of labor or elective cesarean section. The pessary will
also be removed in women in preterm labor not responding to tocolytic therapy. In
monochorionic twins some obstetricians advise that delivery is carried out at around
36 weeks.
Women reporting increased vaginal discharge will be examined by a doctor for
evidence of infection and the appropriate investigations (swab) and therapy instituted
without the need to remove the pessary.
The pessaries will be purchased from the company (Dr. Arabin GmbH & Co, Witten,
Germany) which will provide no financial support and will have no involvement in
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study design, data collection, data handling, data analysis, study interpretation, the
drafting of the manuscript, or the decision to publish.
Progesterone capsules for singleton pregnancy
In both arms, each study participant with cervical length of 15 mm or less will be
given a pack of Cyclogest vaginal capsules which contain 200mg natural
Progesterone PhEur. Each woman will be instructed to introduce one capsule into
her vagina before going to sleep every night up to 33+6 weeks. Adherence will be
checked by counting the capsules at each follow-up visit.
5
ENDPOINTS
Outcome measures
The primary outcome measure will be spontaneous delivery before 34 weeks of
gestation.
The secondary outcome measures will be:
 Birth weight (mean, less than 2.5 Kg and less than 1.5 Kg)
 Fetal or neonatal death
 Major adverse outcomes in the neonate before discharge from the hospital
(intraventricular hemorrhage, respiratory distress syndrome, retinopathy of
prematurity, or necrotizing enterocolitis)
 Need for neonatal special care (admission to a neonatal intensive care unit,
ventilation, phototherapy, treatment for proven or suspected sepsis, or blood
transfusion)
 Major maternal complications attributable to the pessary (maternal death,
chorioamnionitis, serious cervical or vaginal trauma)
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RANDOMIZATION
The patients will be assigned to group A (expectant management) or group B
(pessary). A computer-generated random-number list will be created. Whenever a
patient agrees to participate the doctor in each centre will access through the internet
a secure site within the website of the Fetal Medicine Foundation, enter their name
and password, register their patient and the system will then allocate the patient to
group A or B.
7
ADVERSE EVENTS
Any unfavourable and intended sign, symptom or illness that develops or worsens
during the period of the study is classified as an adverse event (AE), whether or not it
is considered to be related to the study treatment. Adverse events include unwanted
side effects, sensitivity reactions, abnormal laboratory results, injury or inter-current
illnesses, and may be expected or unexpected.
Furthermore, if an adverse event:



results in death
is life threatening
requires hospitalisation or prolongation of existing hospitalisation
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results in persistent or significant disability or incapacity
or is considered by the investigator to be an important medical event
then it is classified as a serious adverse event (SAE) and must be reported to the trial
coordinator and the trial sponsor. A serious adverse reaction which is not expected is
classified as a suspected unexpected serious adverse reaction (SUSAR).
Procedure for reporting AEs, SAEs and SUSARs
Adverse events should be recorded by the treating researcher within the CRF at
each visit and also in the participant’s hospital case notes.
If an adverse event is considered to be a serious adverse event, it must be
documented and reported to the trial coordinator, when attributed to the treatment or
not. SAEs will be reported to the Data Monitoring Committee and all events will be
followed until resolution.
All suspected adverse reactions that are both unexpected and serious are subject to
expedited reporting. If the trial coordinator is notified of a SAE which qualifies as a
SUSAR, then details will immediately be passed to the sponsor. The sponsor will
report all SUSARs which are fatal or life-threatening to the ethics committee not later
than 7 days after the sponsor is first made aware of the reaction.
An annual safety report for the trial will be submitted to REC, including listings of all
suspected serious adverse reactions.
8
STATISTICS
Sample-size
Singleton pregnancy
The sample-size calculation presented here is based on detecting a treatment effect
that produces a one-third reduction in the overall incidence of spontaneous delivery
between randomization and 33+6 weeks from an anticipated 6% in the expectant
management group. Using logistic regression analysis, with adjustment for cervical
length, a total sample of 1,600 patients has an 85% power of detecting this difference
at a (two-tailed) significance level of 5% (see page 16).
On the assumption that 70% of women with singleton pregnancies fulfilling the entry
criteria agree to participate in the study and provide follow-up data, we would need to
approach 2,286 such women. Since the prevalence of pregnancies with cervical
length <25 mm is about 8% we would need to examine about 29,000 pregnancies.
The power calculations were undertaken by computer simulation assuming the
distribution of cervical lengths and risks in the expectant group presented in the
Table 1 above. An R program used for these simulations is available on request.
Twin pregnancy
The sample-size calculation presented here is based on detecting a treatment effect
that produces a one-third reduction in the overall incidence of spontaneous delivery
between randomization and 33+6 weeks from an anticipated 13% in the expectant
management group. Using logistic regression analysis, with adjustment for cervical
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length, a total sample of 1,180 patients has 85% power of detecting this difference at
a (two-tailed) significance level of 5% (see page 17).
On the assumption that 70% of women with twin pregnancies fulfilling the entry
criteria agree to participate in the study and provide follow-up data, we would need to
approach 1,700 such women. Since the prevalence of twin pregnancies is about 2%
we would need to examine 85,000 pregnancies. The power calculations were
undertaken by computer simulation assuming the distribution of cervical lengths and
risks in the expectant group presented in Table 2. An R program used for these
simulations is available on request.
Interim analysis
If treatment with pessary has important clinical effects, then these may become
apparent before the target sample size is achieved. To accommodate this, interim
analysis will be carried out after primary outcome data are available on the first 200
patients. The need for additional interim analyses will be determined by the data
monitoring committee.
At the time of interim analyses, data monitoring committee will advise the Chair of the
Trial Steering Committee if, in its view, the randomized comparisons in the trial have
provided both:
a) Proof beyond reasonable doubt that the treatment with pessary is clearly
indicated or clearly contraindicated in terms of efficacy which outweighs any
serious adverse effects of treatment or vice versa. (Appropriate criteria of
proof beyond reasonable doubt cannot be specified but for example, a
difference of at least three standard errors in an interim analysis would be
needed to justify closing or modifying the trial prematurely).
And
b) Evidence that might reasonably be expected to influence the management of
patients by many clinician who are informed of the results of any other
studies.
Statistical analysis and reporting
Results will be presented according to the CONSORT statement.20
Baseline Data
Baseline data on (LIST) for the pessary and placebo groups will be summarized for
by the median and the interquartile range. Continuous data will be summarised in
terms of means, standard deviations, minimum, maximum and quartiles. Attribute
data will be summarised on terms of frequency counts and proportions.
Primary Analysis
The primary analysis will be an intention to treat comparison of the treatment
assigned at randomisation. Incidence of spontaneous delivery before 34 weeks
gestation will be analysed using logistic regression allowing for cervical length as a
covariate. The treatment effect will be tested at the two-tailed 5% level. A 95%
confidence interval, allowing for cervical length, centre and previous history, will be
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produced for the odds ratio of pessary/no pessary. Odds ratios will be converted to
relative risks stratified by cervical length.
Interactions of cervical length, centre and previous history with treatment will be
tested and if significant at the 5% level, their effects will be presented.
Secondary Analysis
The risk of spontaneous preterm birth from randomization until 34 weeks will be
assessed using Kaplan–Meier analysis,21 where gestational age will be the time
scale, spontaneous delivery will be the event, and elective deliveries will be treated
as censored. For the purposes of this analysis, all pregnancies will be considered to
be no longer at risk for the event at the start of the 34th week. Hazard ratios will be
estimated with the use of the Cox proportional-hazards model, with a formal test of
the proportional-hazards assumption.21-23 Logistic regression will be used to assess
the risk of adverse events in the offspring.
9
TRIAL MANAGEMENT
Trial Steering Committee
The Trial Steering Committee will provide overall supervision of the trial, especially
trial progress, adherence to protocol, patient safety and consideration of new
information relevant to the study. The committee will comprise the following:
Professor Steve Thornton
Professor of Obstetrics and Gynaecology
Associate Dean (Research) WMS
Clinical Sciences Research Institute
Room B020
University of Warwick
Warwick Medical School
Coventry, CV4 7AL
Professor Zarko Alfirevic
Professor of Fetal and Maternal Medicine
Reproductive and Developmental Medicine
Liverpool Women’s Hospital
Crown Street, Liverpool, L8 7SS
Dr Neil Sebire
Consultant Paediatric Pathologist
Department of Histopathology
Camelia Botnar Laboratories
Great Ormond Street Hospital
Great Ormond Street
London, WC1N 3JH
Data monitoring committee
The data monitoring committee will be independent to the trial organizers and will
monitor the progress of the trial, perform the interim and final analysis of results. The
committee will be headed by Professor David Wright, Professor of Applied Statistics,
School of Mathematics and Statistics, University of Plymouth. The members of the
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committee will be selected by Professor Wright from members of his team at the
University of Plymouth.
Local principal investigator
At each site a Consultant in Obstetrics and Gynaecology will act as the principal
investigator and will have overall responsibility for the conduct of the study at his/her
study site. S/he will oversee recruitment of subjects and ensure that the study is
conducted locally according to both the protocol and the principles of GCP.
10
REGULATORY ISSUES
Study sponsor
The study will be sponsored by King’s College Hospital NHS Foundation Trust.
Ethics
The study is approved by King’s College Hospital Research Ethics Committee (REC)
and will be subject to Site Specific Assessment (SSA) at individual study sites.
R&D approval
The study received R&D approval from King’s College Hospital and will be subject to
local R&D approval at all sites.
11
PROTOCOL AMENDMENTS
Any substantial amendment to this protocol requires approval by the main REC prior
to implementation.
12
FUNDING
This study is supported by a grant from the Fetal Medicine Foundation (U.K. Charity
No: 1037116).
13
INDEMNITY
This is an NHS-sponsored research study. If an individual suffers negligent harm as
a result of participating in the study, NHS indemnity covers NHS staff and those
people responsible for conducting the trial who have honorary contracts with the
relevant NHS Trust.
14
PUBLICATION POLICY
Following analysis of study data, the results of the study will be published in scientific
journals and presented in congresses.
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ACCESS TO SOURCE DATA/DOCUMENTS
The investigators / institutions will permit trial-related monitoring, audits, IRB/IEC
review, and regulatory inspections, and also to provide direct access to source
data/documents.
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REFERENCES
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15. Rouse DJ, Caritis SN, Peaceman AM, Sciscione A, Thom EA, Spong CY, Varner
M, Malone F, Iam JD, Mercer BM, Thorp J, Sorokin Y, Carpenter M, Lo J, Ramin
S, Harper M, Anderson G; National Institute of Child Health and Human
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2007; 357:454-61.
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pessaries an option in patients with a sonographically detected short cervix? J
Perinat Med 2003; 31:122–133.
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17. Cross RG: Treatment of habitual abortion due to cervical incompetence. Lancet
1959;2:12718. Ludmir J, JR Mantione,RH Debbs, HM Sehdev: Is pessary a valid treatment for
cervical change during the late midtrimester. J Soc Gynecol Investig 2002;9:1119. Newcomer J: Pessaries for the treatment of incompetent cervix and premature
delivery. Obstet Gynecol Survey 2000;55:443.
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21. Hosmer DW Jr, Lemeshow S. Applied logistic regression. 2nd Ed. New York:
John Wiley, 2000.
22. Hosmer DWLS. Applied survival analysis: regression modeling of time to event
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Additional Comments: Logistic Regression Model
Singleton pregnancy
0.8
0.6
0.4
0.2
0.0
Probability of delivery prior to 34 weeks
1.0
Below is the fitted logistic regression model (black curve) showing the probability of
delivery before 34 weeks as a function of cervical length. The points show the
proportions from Table 1 (see Table 3). The orange curve shows the probabilities
under the assumption of an effect equivalent to an odds ratio of 0.5. The blue curve
shows the relative risk. Using a logistic regression analysis, including the effect of
cervical length and testing the treatment effect at the two sided 5% level, the
proposed sample of 1,600 has power of 85%. [See function power.cl]
0
10
20
30
40
CL (mm)
Table 3
OR = 0.5
Overall
Cervical
length
(mm)
0 - 10
11 - 15
16-25
26-30
31-35
36-40
>40
s
Prevalence
Risk
0.60%
0.50%
7.10%
16.60%
27.40%
26.90%
21.00%
44%
23%
3.60%
1.30%
0.80%
0.60%
0.40%
Per 1000
6
5
71
166
274
269
210
1001
16
Target Popn
Expected
Events
2.6
1.2
2.6
2.2
2.2
1.6
0.8
Per 1000
73
61
866
1000
Expected
Events
32.2
14.0
31.2
Version 3: 3 July 2008
REC ref 08/H0808/3
Twin pregnancies
0.8
0.6
0.4
0.2
0.0
Probability of delivery prior to 34 weeks
1.0
Below is the fitted logistic regression model (black curve) showing the probability of
delivery before 34 weeks as a function of cervical length. The points show the
proportions from Table 2 (see Table 4). The orange curve shows the probabilities
under the assumption of an effect equivalent to an odds ratio of 0.5 Using a logistic
regression analysis, including the effect of cervical length and testing the treatment
effect at the two sided 5% level, the proposed sample of 1,180 has power of 85%.
[See function power.cl]
0
10
20
30
40
CL (mm)
Table 4
OR = 0.5
Control
CL
1-10
11-15
16-20
21-25
26-30
31-35
36-40
Total
x
20
7
20
35
24
20
17
143
n
21
10
36
92
168
229
536
1092
Risk
0.952
0.700
0.556
0.380
0.143
0.087
0.032
odds
20.000
2.333
1.250
0.614
0.167
0.096
0.033
17
odds
10.00
1.17
0.63
0.31
0.08
0.05
0.02
Treatment
Expected
Risk
x
0.91
19.1
0.54
5.4
0.38
13.8
0.23
21.6
0.08
12.9
0.05
10.5
0.02
8.6
92
RR
0.95
0.77
0.69
0.62
0.54
0.52
0.51
0.64
OR
0.5
0.5
0.5
0.5
0.5
0.5
0.5