Prematurity in singletons
Study Protocol

Randomized study of pessary vs expectant management in women with singleton pregnancies and a short cervix

Background

Premature birth is responsible for more than half of all neonatal deaths 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. Although all births before 37 weeks of gestation are defined as preterm, most damage and death occurs in infants delivered before 34 weeks.

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. 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

In our screening studies involving more than 60,000 pregnancies the rate of delivery before 34 weeks was 1.8%. 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 (see table). 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%.

Prevention of premature birth

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.

Randomized studies in singleton pregnancies suggest that the risk of premature birth can be halved by the use of maternal prophylactic administration of progesterone in women with a history of premature birth and in those found to have a short cervix at 20-24 weeks gestation. Nevertheless, in women with a short cervix even after treatment with progesterone there is still a high risk for premature birth.

Vaginal pessary

There is some evidence that in singleton pregnancies with a short cervix the insertion of a vaginal pessary may reduce the rate of premature birth in the absence of serious side effects. 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 has been widely used for several decades in the treatment of utero-vaginal prolapse.

Aim of the randomized study

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.

Study design

The trial will be conducted in compliance with the protocol, Good Clinical Practice and applicable regulatory requirements.

This will be a multicentre trial in the UK and other countries. During routine ultrasound scan at 20⁺⁰ - 24⁺⁰ weeks of gestation for examination of fetal anatomy and growth, all women with singleton pregnancy found to have a cervix of 25 mm or less in length and where the fetus is found to be alive with no major abnormalities will be invited to participate in a randomized trial of standard management vs vaginal insertion of a cerclage pessary. In both arms the patients with cervical length 15 mm or less 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.

Written 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⁺⁰ 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.

Gestational age will be determined from the menstrual history and confirmed from the measurement of fetal crown-rump length at a first-trimester scan or the head circumference at a second-trimester scan.

Follow-up visits for ultrasound assessment of fetal growth and cervical length 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 betamethosone 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 labeled "cervical pessary."

The study has be approved by 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

• Major fetal abnormalities (defined as those that are lethal or require prenatal or postnatal surgery) 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.

Quality control and handling of data

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 entered into a computer database.

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 labor and those with rupture of membranes before labor.

Quality control of screening, handling of data, and verification of adherence to protocols at the different centers 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 V-shaped 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.

Vaginal 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. If there are any pregnancy complications, such as pre-eclampsia or poor fetal growth the attending obstetrician may advise an earlier delivery.

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. In all patients with premature rupture of membranes, vaginal blood loss and severe painful contractions the pessary will be removed.

The pessaries will be purchased from the German company in which they are manufactured. The company has not provided any financial support and will have no involvement in study design, data collection, data handling, data analysis, study interpretation, the drafting of the manuscript, or the decision to publish.

Randomization

The patients will be assigned to group A (standard 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.

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.

Outcome measures

The primary outcome measure will be spontaneous delivery from randomization to 33+6 weeks (237 days) 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 complication attributable to the pessary (maternal death, chorioamnionitis, serious cervical or vaginal trauma)

Sample-size

The sample-size calculation has been based on a reduction in the incidence of spontaneous delivery between randomization and 33⁺⁶ weeks from about 6% in group A (standard) by one third to 4% in group B (pessary), with a power of 85%. To detect this difference at a significance level of 5%, we need to randomize 1,600 patients.

Data Monitoring Committee

The Data Monitoring Committee will be independent to the trial organisers and will perform the interim and final analyses of results. The interim analyses will be carried out after randomization of the first 200 patients and at subsequent intervals as determined by the Data Monitoring Committee. This will be done to judge the progress of the trial and to ensure that the stopping rules had not been met. The stopping rules will be significant maternal or perinatal morbidity and mortality in one of the arms of the trial. The need for additional interim analyses will be determined by the Data Monitoring Committee.

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Vaginal scan: short cervix