Cervical Occlusion improves pregnancy outcomes in
women with cervical insufficiency.
A randomised, controlled and observational trial with
cerclage, with and without cervical occlusion
Niels Jørgen Secher, principal investigator, MD
Professor
Department of Obstetrics and Gynecology
Copenhagen University Hospital, Hvidovre, Denmark
E-mail: njsecher@dadlnet.dk
Co-Investigators
Tom Weber, MD, ass. professor
Department of Obstetrics and Gynecology
Copenhagen University Hospital, Hvidovre, Denmark
C. D. McCormack, BSc, MBChB, FCOG (SA) FRANZCOG
Women’s and Children’s Hospital,
Adelaide, Australia
Merete Hein, MD, Ph.D
Department of Obstetrics and Gynecology
Aarhus University Hospital, Skejby, Denmark
Rikke Bek Helmig, MD, Ph.D
Department of Obstetrics and Gynecology
Aarhus University Hospital, Skejby , Denmark
Study protocol 1
April 2006
1
Please note: This protocol is meant to be a working document that is being revised
according to the progress and experiences during the Trial, and after input from study
participants. The core protocol will be finalized following full consultation with all
participants in the trial.
2
SUMMARY
Preterm birth is the single most important cause of neonatal mortality, morbidity and
later, neurological handicap. The birth of a preterm baby carries substantial cost in
human and socio-economic terms (1). A strong risk factor for preterm birth is a prior
history of cervical insufficiency / incompetence, based on a history of repeated,
painless, mid-trimester losses or preterm delivery. The incompetence / insufficiency
may be demonstrated on ultrasound as a shortening of the cervical length.
Previous studies have indicated that intrauterine infection caused by ascending infection
from the vagina, leads to preterm delivery as well as to spastic cerebral palsy (2, 3). In
recent years the importance of the cervical mucus plug as a gate-keeper protecting the
feto-placental unit against ascending infection from the vagina, has been demonstrated
(4).
Preliminary studies have indicated that the combination of a cervical cerclage against
insufficiency, and occlusion of the external cervical os (to retain the mucus plug) protects
against extreme preterm labour, and improve pregnancy outcomes.
Surgical treatment has previously consisted of the vaginal placement of a single
circumferential cervical suture, despite limited evidence of a positive effect. The current
protocol is a large pragmatic randomised-control, multicentre trial, to confirm or refute the
anticipated benefits of circumferential cerclage plus cervical occlusion, compared with a
single circumferential cerclage, in cases where a clinician considers that a suture is
indicated, either because of previous history or because of a shortening of the cervix on
ultrasound. Additionally, the trial will allow us the opportunity to obtain a more detailed
characterisation of the group of women considered clinically to be at repeated risk of
preterm labour.
Keywords: Labour/premature – randomised controlled trials – cerclage – cervical
incompetence, cervical insufficiency – pregnancy complications – mucus plug – cervical
occlusion.
BACKGROUND
There is little worldwide data on the prevalence of preterm birth, but estimates range from
5 % in some developed countries, to 25 % in some developing countries. Rates of
preterm birth have been stable at around 5-10 % for the last 30 years in most developed
countries (5, 6). The main precipitating factor is probably infection, but other causes
include multiple pregnancy, intrauterine growth restriction, excessive stress, heavy
manual work, low socio-economic status, and smoking. One third of preterm births are
associated with PPROM (Preterm, prelabour rupture of membranes), one-third with a
medical indication (such as maternal hypertension) for delivery (induced labour or
elective caesarean section) and one third because of spontaneous onset of labour.
Preterm birth is normally defined as a delivery at less than 37 completed weeks (WHO),
but clinically the transition in terms of need for neonatal special or intensive care is
between 34 and 37 weeks.
Infants born preterm are at increased risk of a range of adverse neonatal outcomes,
including chronic lung disease, severe brain injury, retinopathy of prematurity, necrotising
enterocolitis, and neonatal sepsis. In later life, preterm infants are at increased risk of
motor and sensory impairment, learning difficulties and behavioural problems. (7)
It is possible that as many as 40 % of the survivors of preterm birth will not be able to
become fully independent adults (8). The costs of preterm birth are substantial, are
inversely proportional to gestational age at birth, and persist into mid-childhood.
3
Thus, the cumulative direct cost of hospital care up to the age of 5 years in infants born at
less than 31 weeks is about £14,000, in addition to other indirect costs born by the Health
Services (1). Preterm birth also imposes an economic burden on other sectors and on
individuals.
In preterm labour, the high frequency of finding organisms in the amniotic fluid that are
also present in the vagina is strongly supportive of ascending infection having a
significant causal association. The organisms most often associated with
chorioamnionitis, neonatal sepsis, and meningitis after membrane rupture are group B
streptococcus and Escherichia coli.
The high risk of developmental disabilities with motor problems, and also cognitive
limitations, may be at least partly due to white matter damage caused by the
inflammation or infection that is associated with preterm labour (9, 10, 11, 12, 13, 2).
It is possible that the early loss of the protective cervical mucus plug could predispose to
intrauterine infections and consequently preterm delivery.
There are convincing data showing that increased intrauterine cytokine production in the
amniotic fluid is not only associated with preterm labour, but also contributes to the
mechanism of cervical incompetence. (14)
In one Swedish study, bacterial invasion was found in the amniotic fluid in 13 % of
women with spontaneous preterm labour, and 34 % with preterm prelabour rupture of the
amniotic membranes (PPROM) (3). The levels of the cytokines IL-8 and IL-6 were
increased in the amniotic fluid, if delivery occurred in up to 7 days after PPROM,
compared to delivery after 7 days. In a recent study, the diagnosis of intra-amniotic
infection by proteomic profiling methods was reported to be a promising method of
detecting preterm birth (15).
Cervical incompetence / insufficiency:
Some workers have defined cervical incompetence as a history of painless dilatation of
the cervix, resulting in ruptured membranes and second or early third trimester delivery
(12-24 weeks) and the passage without resistance of size 9 Hegar dilatators. Another
suggested definition is recurrent second or early third trimester losses, caused by the
inability of the cervix to retain a pregnancy until term. The cause can be a weak cervix,
either due to congenital causes, or previous cervical trauma (conisation, abortion and
delivery). Premature dilatation can be followed by infection, but in some cases ascending
infection from the vagina seems to be the primary cause of such dilatation. Measuring the
cervical length by ultrasound has been directly correlated with the duration of pregnancy.
In a recent study of 2567 singletons pregnancies, a cervical length of 5 mm, 15 mm and
50 mm at 23 week of gestation, decreased the risk of labour from  34 weeks from 78 %
to 4 % and 0,5 % respectively (16).
The incidence of diagnosed cervical insufficiency varies widely between departments and
countries. Part of the variation in incidence rates is due to difficulties in diagnosis and
registration of cervical insufficiency. In Denmark between 1980 – 1990, cervical
insufficiency was diagnosed in 4.6 /1000 women. In such women, the actual
miscarriage/pregnancy loss rate was 17.6 % (17).
"The cervical plug factor"
The cervical mucus plug is a well-characterised structure that fills the cervical canal
during pregnancy. The plug presents a local defence mechanism, and is an extremely
dense and compact structure, which not only acts as an effective mechanical barrier
between the vagina and uterus, but also protects the feto-maternal unit from ascending
infection during a pregnancy. When micro-organisms enter the cervical canal, they
encounter the innate immune system with neutrophils, granulocytes and macrophages
being the most important cells involved (18). Lactoferritin, lysozymes, secretory leukocyte
protease inhibitors, and calprotectin and defensins are important antibacterial, antifungal
and antiviral products of the cervical mucus plug.
4
The high immunoglobulin levels and phagocytes in the cervical mucus plug suggest a
considerable potential for adaptive immune protection (19, 20). Thus the mucus plug is a
‘gate-keeper’ protecting the feto-placental unit against ascending infections from the
vagina. Cervical occlusion keeps a plug which might otherwise be lost due to cervical
damage or malformation ‘in-situ’, and allows a reaccumulation of mucus in situations
where the plug has already started to dissipate.
Cerclage
A transvaginal cervical cerclage may be inserted prophylactically before pregnancy,
during the first trimester, or therapeutically, later in pregnancy, after detection of cervical
changes. A prophylactic cerclage is considered a primary prevention and is called a
primary cerclage. A therapeutic cerclage is called a secondary cerclage, unless the
membranes are exposed to the vagina, when it is called a tertiary cerclage (21).
The largest study so far reported was of 1290 women randomised to a circumferemtial
McDonald suture (MRC/RCOG study 1993). It reported a lower rate of preterm deliveries
before 33 weeks gestation, 13 % when cervical sutures were inserted, compared with 17
% in the control group. This meant that 24 sutures had to be inserted to prevent one
delivery before 33 weeks (22). Meta analyses of other trials of cervical cerclage for
prevention of preterm delivery have failed to show a lower rate of preterm delivery before
28 and 34 weeks in women assigned to cervical cerclage (21, 23, 24, 25, 26). However,
there is some evidence of a positive role for cerclage in women considered to be at very
high risk, with more than one second trimester loss. (27).
In a recent paper, no benefits of cervical cerclage were found in the prevention of preterm
delivery in women already diagnosed (using ultrasound) with short cervices (15 mm or
less), relative risk = 0, 84 (0, 54 -1, 31) (26). The disruption of the uterine cervix, as
documented by funnelling, is a significant risk factor for adverse perinatal outcomes (i.e.,
preterm labour and chorio-amnionitis) (28). However, a combination of poor obstetric
history and progressive shortening of the cervix in a small study of Althuisius 2002,
showed that all 19 women with a cervical suture, delivered after 34 weeks, in contrast to
only 7 out of 16 without a suture. Tertiary cerclage with bed rest reduces preterm birth
before 34 weeks of gestation, while bed rest alone does not (21).
The transabdominal placement of a cervical suture was first proposed as an alternative, if
transvaginal placement was difficult. Now the most common indication for its use is in
cases with previous failed transvaginal cerclages (29, 30).
In a study of abdominal (117 women) versus vaginal cerclage (40 women) after a failed
transvaginal cerclage, Zaveri (30) found that the likelihood of perinatal death caused by
delivery before 24 weeks was 6 % (3.8 – 8.2) after transabdominal cerclage and 12.5 %
(2.7 – 22.7) after transvaginal cerclage.
If there are no benefits from cerclage, it could be because:
1)
2)
3)
4)
5)
They do not work,
Incorrect insertion techniques are used,
Selection of patients is incorrect.
The cervix is so weak that it cannot be corrected with a suture
Failure of the protective mechanism of the cervical plug, possibly due to ascending
genital infections.
Double cerclage / cervical occlusion
In most cases, it is impossible to determine whether weakness of the cervix or ascending
infection is the primary cause in cases with a previous history of an apparently
incompetent cervix. The double cerclage deals with both problems.
5
The cervical resistance is increased by placing a circumferential cervical suture
(e.g. McDonald, Shirodkar or transabdominal) and the cervical plug is retained by
occlusion of the cervical canal.
The results from King Faisal Hospital, Riyadh, Saudi Arabia:
In women with a previous poor obstetric history and at least one failed single cerclage,
McCormack and Secher used the double cerclage on their patients, who then acted as
their own controls.
Success or ‘Take home baby rate’:
21 patients had 144 pregnancies, and 41 single sutures.
Total number of successful singles (vaginal) prior to the use of the double
cerclage = 8 out of 41 = 19,.5%%.= take home baby rate
Total abortions 27/41 = 65.9%
Total live births 14/41 = 34.2%
Total survival of livebirths 8/ 14= 57,1%
Total number of occlusions 24, including 3 repeat procedures
Total abortions 4/24 = 16.7 %
Total Live births 20/24 = 83.3 % = take home baby rate
Total survival of livebirths –20/20= 100%
PROPOSED TRIAL
Aim of the trial / primary objectives
The primary objectives are to evaluate the effect of double cerclage compared with single
cerclage on the incidence of live born infants as well as the gestational age, in women
with a history of cervical insufficiency or short cervix with or without a previously failed
cerclage.
The investigation
Design
Randomisation will be centralised and provided by the telephone randomisation service
at the Perinatal Epidemiological Research Unit at Aarhus University.
The data will be entered into a spreadsheet on a computer during the telephone call
using block randomisation, stratified on major prognostic variables such as history of
cervical incompetence, shortening of the cervix in high risk pregnancies, and previous
failed cerclage. The study will be discussed with the eligible women and their partners
(if appropriate) and an information sheet will be given. A consent form will be signed
before the woman will be included in the study.
The allocation will not be made before all details have been given by telephone, and the
woman is determined to be eligible.
The women will be randomised in two groups:
I) Prophylactic trial –primary cerclage
1) History of cervical incompetence / insufficiency. (Delivery 15 - < 36
weeks
2) Congenital short cervix (secondary to maternal administration of
diethyl stilbestrol, DES) or traumatic/surgical damage rendering the
vaginal approach difficult (e.g. conisation)
3) Cervical suture applied in previous pregnancy, successful outcome
4) Previous failed cerclage
6
II) Therapeutic trial
5) Secondary cerclage: Short cervix, without the membranes being
exposed to the vagina.
6) Tertiary cerclage: Short cervix, membranes exposed to the vagina
Observational 7) Repeat / Requested Cervical Occlusion**
** If only a few women participate in the randomisation, the external validity
of the study could be decreased. Therefore, women eligible for the study
who refuse to participate, as they wish to choose the operation method
themselves, will participate in an observational study.
The women will be randomised between normal (single) and double cerclage, or if single
cerclage does not seem appropriate, then between abdominal cerclage or double
cerclage. If the women fulfil more than one criteria, they will belong to the group with the
highest numbers.
Stratification of randomisation
In order to avoid the possibility of chance allocation of all women at a single centre to
either a single or a double suture (which could introduce bias if the techniques used at
different centres are significantly different), random allocation will be stratified by centre,
in blocks of ten. Within the centre, (where they might for example use McDonald,
Shirodkar and abdominal sutures according to clinical indication), to avoid the possibility
that by chance all the McDonald sutures might be double and all the Shirodkars single
(which would introduce bias), random allocation will be stratified by type of primary suture
(i.e McDonald, Shirodkar or abdominal), in blocks of ten. This will ensure that within each
block of ten, there will be five double and five single sutures.
The data entry form sent to Mette Krøll, secretary, Department of Obstetrics and
Gynecology 537, Copenhagen University Hospital Hvidovre, Kettegaard Alle 30, 2650
Hvidovre, by fax + 45 36 32 33 61, or by E-mail at: mette.kroell@hh.hosp.dk.
After delivery, a follow-up form is to be completed after discharge of both mother and
child, or six weeks after delivery, if the mother and child are still in hospital. The
completed data forms are sent to: Mette Krøll, secretary, Department of Obstetrics and
Gynecology 537, Copenhagen University Hospital Hvidovre, Kettegaard Alle 30, 2650
Hvidovre, by fax + 45 36 32 33 61, or by E-mail at: mette.kroell@hh.hosp.dk.
Steering Committee
The trial will be supervised by the Trial Steering Committee,
This consists of the Project Management Group and one chairman from each of the
participating centres.
The specific tasks of the Steering Committee are:
1) To approve the core protocol.
2) To approve necessary changes in the protocol based on considerations of feasibility
and practicality.
3) To receive the report from the Data Monitoring Committee.
4) To resolve any problems brought to it by the coordinating centres.
5) To approve study reports and papers for publication.
The Data Monitoring and Safety Committee
To maintain confidentiality, a Data Monitoring Committee consisting of an obstetrician, a
paediatrician and a statistician/datamanager (Professor Philip Steer, London, ass.
professor Tine Brink Henriksen, Denmark, datamanager Jakob Hjort, Denmark) has been
set up. This committee is independent of the trial organizers. During the period of
recruitment, the interim results of the trial will be assessed after every hundred patients
recruited.
7
If the interim results show that there is evidence beyond reasonable doubt (p<0.01) that
double cerclage is clearly indicated or contraindicated, or if it is evident that no clear
outcome will be obtained, the Data Monitoring and Safety Committee will advise the
Steering Committee of this and the Steering Committee will stop the trial. Otherwise, the
Data Monitoring and Safety Committee will advise that the trial should continue. The
interime results will not be revealed to anyone outside the Data Monitoring and Safety
Committee.
INCLUSION CRITERIA:
a) The physician in charge considers that a cerclage is indicated.
b) Gestational age between 12 and 27 completed weeks
c) Previous late mid-trimester miscarriage, or spontaneous preterm labour and delivery
before 28 weeks with or without previous cerclages.
d) Previous cerclage because of short cervix
e) Confirmed gestational age defined as: Gestational age estimated by ultrasound at
less than or equal to 22+0 weeks, and / or certain LMP.
f) Vaginal infection treated before cerclage
g) Ability to read and understand the relevant national language
h) Consent obtained in accordance with specifications of the local research ethics
committee
i)  18 years of age and legally competent
Exclusion criteria:
1) Demonstrated cervical infection.
1) Obstetrical complications in the current pregnancy
2) Multiple pregnancies
3) History of a significant abruptio placenta in a previous pregnancy
MEASUREMENT OF OUTCOMES:
Primary endpoints:
Delivery of live born infants discharged alive from the hospital = take-home baby rate
Secondary endpoints:
Mean and distribution of gestational age at delivery
Incidence of preterm birth (< 34+0 dage)
Tertiary endpoints:
Number of days in neonatal unit
Treatment regime
The cervical cerclage (Mc Donald or Shirodkar) as well as the abdominal suture will be
done with the same material and technique as normally used by the participating
department. The external os will be closed with a continuous nylon 2-0 / 3-0 suture.
Local guidelines concerning antibiotics, Heparin, bed rest, tocolytics etc. are followed and
recorded in the follow-up form.
Sample size
There is a huge variation in cervical sutures between hospitals and internationally, with a
higher "success rate" in departments using cervical sutures frequently. The commonly
reported seriously preterm/miscarriage rate with primary suture alone is about 15 % (Roy
Farquharson personal communication, 22). With the use of the double suture, we expect
that we can halve this failure rate. 604 randomised women are required in total with an 
of 0,05 and a power of 80 % to show that outcomes at these rates are significantly
different (Fisher exact test). We are aiming for a total sample size of 650 women in order
to reduce still further the possibility of a type 2 error. We expect the duration of the study
is 2½ years. If needed, the Data Monitoring and Safety Committee will perform
conditional sample size calculation.
8
BENEFITS
Preterm birth (5-10 % of all births) is the most important cause of neonatal mortality/morbidity and later neuro-developmental handicaps. Prevention of preterm birth saves
lives, decreases later handicaps and improves living conditions for the child and family.
Ethical implications
Each centre needs the approval of the protocol by the local research ethics committee.
A copy of these approvals will be send to the Data Co-ordinating Centre. The study will
be performed according to the guidelines of the current version of the Declaration of
Helsinki, and according to the guidelines for the conduct of pragmatic trials (Perinatal
Epidemiology Unit, Oxford).
Patient information and consent
The woman herself and her partner (if appropriate) will be informed about the purpose of
the study. The woman will be allowed time to consider the study and consult her primary
care providers. The participation in the trial is free and has no influence on the other
therapies that the woman will receive. It is the attending obstetrician's responsibility to
obtain formal consent. The local research ethics committee will determine how consent is
to be recorded in each of the participating centres. Only women more than 18 years old
and legally competent will take part in the study.
PROJECT MANAGEMENT STRUCTURE
Organisation of the trial
Department of Obstetrics and Gynaecology, Hvidovre Hospital, Copenhagen, Denmark
will be responsible for the overall conduct of the trial, including internal and external
communication. The randomisation and monitoring of the project will be performed in
corporation with the randomisation unit in the Perinatal Epidemiological Research Unit at
Aarhus University.
Management group
Niels Jørgen Secher, Professor (Principal Investigator) and Tom Weber, Department of
Obstetrics and Gynecology 537, Hvidovre Hospital, Kettegaard Alle 30, 2650 Hvidovre
Dr. C D McCormack, Women’s and Children’s Hospital, Adelaide, Australia
Merete Hein, Ph.D, Aarhus University Hospital, Skejby, Denmark, and Rikke Bek Helmig,
Ph.D, Aarhus University Hospital, Skejby Denmark.
Data Co-ordinating Centre
The Department of Obstetrics and Gynecology, Hvidovre Hospital, Copenhagen,
Denmark will be responsible for the day to day running of the trial. The functions include:
1) Recruitment of participating centres
2) Data collection and management
3) Data entry and cleaning
4) Data analysis
5) Collection of adverse event data and submission to the Project Management
Group
6) Organising and servicing the Data Monitoring Committee
7) To represent the collaborators' views at the Steering Committee meetings
Time table
The study expects to start in June 2006, with around 20 participating centres caring for a
total of 60,000 deliveries per year. With these numbers, it will take about 2½ years to
complete the study
9
Publication Policy
A writing committee comprised of members of the project management group and the
Steering Committee will be responsible for the final report of the trial.
To safeguard the scientific integrity of the trial, data from the final report should not be
presented in public, either in whole or in part, by any member of the Advisory Group,
Steering Committee, DMC or by any collaborator, without the written agreement of the
trial Steering Committee.
For the success of the trial depends on the collaboration of a large number of doctors,
midwives and nurses. For this reason, chief credit for the main results will be given not to
the committees or central organisers, but to all who have wholeheartedly collaborated in
the study.
Funding
The study has been supported by the Elsass Foundation with 215.000 Dkk (29.000
EUR). We will apply for further funding.
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PARTICIPATING DEPARTMENTS
Country: Clinical centres (number of expecting women enrolled):
SWEDEN: Universitetssjukhuset MAS in Malmö, Per Olofsson (15). GERMANY: Womens
Hospital - University of Marburg, Stephan Schmidt (5).
SWITZERLAND: Universitätshospital Basel, Irene Hösli (5). UNITED KINGDOM: Liverpool
Women's Hospital, Roy Farquharson (20). Chelsea and Westminster Hospital in London,
Philip Steer (30). SOUTH AFRICA: The Pretoria Academic Hospital Complex, Hennie
Lombaard (10). AUSTRALIA: Women’s and Children’s Hospital, Adelaide, Dee
McCormack (8). INDIA: All India Institute of Medical Sciences in New Delhi, Suneeta Mittal
(20). SPAIN: Hospital Materno-Infantil Valle Hebron in Barcelona, Lluis Cabero (15).
SAUDI ARABIA: King Faisal Specialist Hospital & Research Centre, Wesam Kurdi (20).
DENMARK: Hvidovre Hospital, Copenhagen. N. J. Secher, Tom Weber (8). Roskilde
Amtssygehus, Copenhagen, Jens Lyndrup (5). Rigshospitalet, Copenhagen, Jens
Langhoff-Roos (15). Skejby University Hospital, Aarhus, Lone Hvidman (15). Glostrup
Amtssygehus, Copenhagen, Henrik Nyholm (5). Holbæk, Lone Krebs (3). Horsens
sygehus, Bente Sørensen (5), Gentofte Amtssygehus, Copenhagen, Lise Helmsøe-Zinck
(3). Aalborg, Margrethe Møller (5), Odense University Hospital, Odense, Carsten
Henriques (11). Kolding, Jens Jørgen Jørgensen (5), Viborg, Anni Holmskov (5). Hillerød,
Copenhagen, Nini Møller (4). Herlev Amtssygehus, Copenhagen, Morten Lebech (5).
Total: 242 women enrolled per year.