Randomised comparison of the nitric oxide donor isosorbide mononitrate with prostaglandin E2 gel for cervical ripening prior to the induction of labour at term

ISRCTN	ISRCTN58088708
DOI	https://doi.org/10.1186/ISRCTN58088708
Protocol serial number	01/02A
Sponsor	The Sir Jules Thorn Charitable Trust (UK)
Funder	The Sir Jules Thorn Charitable Trust (UK)

Submission date: 18/12/2002
Registration date: 18/12/2002
Last edited: 10/09/2009

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Pregnancy and Childbirth

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Plain English summary of protocol

Not provided at time of registration

Contact information

Dr Jane Norman
Scientific

Department of Obstetrics & Gynaecology
Level 3 - QEB
Glasgow Royal Infirmary
10 Alexandra Parade
Glasgow
G31 2ER
United Kingdom

Phone	+44 (0)141 211 4708
Email	goua21@udcf.gla.ac.uk

Study information

Primary study design	Interventional
Study design	Randomised controlled trial
Secondary study design	Randomised controlled trial
Scientific title
Study objectives	Double blind trial comparing isosorbide mononitrate with prostaglandin E2 for pre-induction cervical ripening in nulliparous women. Women were randomised to receive vaginally either IMN tablets (40mg) or PGE2 gel (2mg), up to two doses 16 hrs apart. The aims of the study were to test the following hypotheses: 1. IMN (40mg) is as effective as PGE2 gel (dinoprostone 2 mg) for cervical ripening prior to the induction of labour at term. 2. IMN (40mg) is associated with a lower incidence of uterine hyperstimulation than PGE2 gel (dinoprostone 2mg) for cervical ripening prior to the induction of labour at term. 3. IMN (40mg) is associated with a zero incidence of abnormal fetal heart rate (FHR) patterns, vaginal bleeding, uterine hypertonus and hypotension requiring treatment, and thus would be safe to use in an outpatient setting.
Ethics approval(s)	Not provided at time of registration
Health condition(s) or problem(s) studied	Obstetrics and gynaecology
Intervention	Randomised to one of two treatment groups on up to two occasions: 1. Isosorbide mononitrate tablet 40 mg administered vaginally (n = 200) 2. Prostaglandin gel (dinoprostone) 800 ug administered vaginally (n = 200). Each treatment given on up to two occasions: after recruitment and 16 h later. If Bishop score found to be more than 6, cervical ripening agent will be withheld and fetal membranes ruptured to induce labour. Women who go into labour during the ripening process will be managed according to an 'active management of labour' protocol, and further ripening agents withheld.
Intervention type	Other
Primary outcome measure(s)	The study examined primary outcomes of safety and efficacy. The cervical ripening effect of each agent was assessed as change in modified Bishop score at each treatment insertion (16 hours and 24 hours) over pre-randomisation modified Bishop score. Frequency and duration of uterine contractions was assessed at 2, 4, 6, 16, 18, 20, 22 and 24 hours, in order to calculate the incidence of uterine hyperstimulation (defined as uterine tachysystole [more than 5 uterine contractions per 10 minutes for at least 20 minutes] with or without FHR changes). 14 We also recorded the frequency of events during ripening that would be hazardous for mother or baby if cervical ripening had been performed on an outpatient basis (any of: abnormal FHR patterns, maternal hypotension requiring treatment, uterine hypertonus or vaginal bleeding). Abnormal FHR patterns were assessed by cardiotocography performed from 30 minutes prior to drug administration until one hour after, and then at 6, 15.5, 17 and 24 hours or continuously once uterine contractions ensued. Cardiotocograph tracings were rated normal, suspicious or pathological according to the Royal College of Obstetricians and Gynaecologists guidelines on the use of electronic fetal monitoring.13 On conclusion of the trial, the abnormal FHR patterns were reviewed by an independent Obstetrician whilst blind to treatment allocation. Hypotension requiring treatment was assessed by maternal pulse and blood pressure measurements at 1, 2, 6, 16, 17 and 24 hours using an automated device (Dinamap®, Critikon Company, Tampa, Fla). Vaginal bleeding during the cervical ripening period (first drug treatment to 24 hours) was prospectively ascertained by examination or patient enquiry. All primary outcomes were ascertained during the first 24 hour study period, during treatment solely with either IMN or PGE2, and prior to rescue treatment with PGE2 where applied.
Key secondary outcome measure(s)	1. The incidence of maternal side effects over the preceding 6 hours (assessed by a structured questionnaire at 6, 16 and 22 hours) 2. The timings and maternal outcomes of the subsequent labour 3. Fetal outcomes 4. Maternal satisfaction with cervical ripening treatment (measured by a visual analogue score [VAS] prior to discharge from hospital), 5. Preference for inpatient or outpatient cervical ripening 6. Any events requiring hospital admission or referral.
Completion date	30/11/2003

Eligibility

Participant type(s)	Patient
Age group	Adult
Sex	Female
Target sample size at registration	400
Key inclusion criteria	Consenting pregnant women admitted to Glasgow Royal Maternity Hospital for cervical ripening prior to the induction of labour at term who fulfil the criteria: 1. Singleton fetus 2. Cephalic presentation greater than or equal to 38 completed weeks gestation 3. Modified cervical (Bishop) score of less than or equal to 6
Key exclusion criteria	1. Patients with any of the contraindications listed in the British National Formulary to PGE2 (active cardiac, pulmonary, renal or hepatic disease, placenta praevia or unexplained vaginal bleeding during pregnancy and ruptured membranes, major cephalopelvic disproportion or fetalmalpresentation, history of Caesarean section or major uterine surgery, untreated pelvic infection and fetal distress) or IMN (hypersensitivity to nitrates, hypotensive conditions and hypovolaemia, hypertrophic obstructive cardiomyopathy, aortic or mitral stenosis, cardiac tamponade, constrictive pericarditis, marked anaemia and closed-angle glaucoma). 2. Other exclusion criteria were delivery mandatory within the next 48 hours in the maternal or fetal interest, one or more births >23 weeks gestation, age <16 years, or ruptured fetal membranes.
Date of first enrolment	01/10/2001
Date of final enrolment	30/11/2003

Locations

Countries of recruitment

United Kingdom
Scotland

Study participating centre

Department of Obstetrics & Gynaecology

Glasgow
G31 2ER
United Kingdom

Results and Publications

Individual participant data (IPD) Intention to share	No
IPD sharing plan summary	Not provided at time of registration
IPD sharing plan

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Results article	results	01/04/2006		Yes	No