Plain English Summary
Background and study aims
Every year in England and Wales there are 700,000 births and thus hundreds of thousands of delighted parents. However, many couples are not so fortunate; in the same period of time: 15% of couples experience sub-fertility; 25% (500,000) of conceptions fail to implant; 15% (300,000) of pregnancies end in early miscarriage; 2% of couples suffer recurrent miscarriages (three or more losses). We have shown that failure of the lining of the womb (endometrium) to prepare adequately for pregnancy a process known as decidualisation is an underlying factor in these clinical problems.
During decidualisation, the endometrial lining becomes transformed into a secretory lining in preparation for accepting the embryo. Decidualisation is a characteristic of the endometrium of the pregnant uterus. Decidualisation is a process that occurs in early pregnancy. It is an adaption of the uterus to enable implantation of the embryo.
The blood thinning agent, Heparin, has been used in an attempt to improve reproductive success. However, heparin has always been given by daily sub-cutaneous injections causing bruising, pain and occasionally bleeding. These injections are given for weeks. Heparin also has the ability to increase activity of growth factors in the endometrium thereby improving decidualisation and increase successful implantation of the pregnancy.
We would like administer Heparin as a single dose by flushing it directly into the womb prior to pregnancy, during the window of implantation (5-7 days after ovulation). We wish to study whether this new method of administration enhances decidualisation and minimises the adverse effects of heparin.
Who can participate?
Women 18 years or older but younger than 45 years who are able to give informed consent and had previous unsuccessful in vitro fertility (IVF) treatment (no live birth after transfer of two good quality embryos) or had recurrent miscarriages (3 or more miscarriages) in the past.
What does the study involve?
Patient will be recruited with informed written consent. The patient will have a minimum of 24 hours to review the patient information sheet and consent form. If the patient consents, she will be asked to use barrier contraception for the month in which the study occurs.
These patients will be asked to attend 5 to 7 days after ovulation (as assessed by a home ovulation kit) and they will be randomized (after a negative pregnancy test) to either receive locally administered low molecular weight heparin (intervention group) OR locally administered saline (control group). After administration, they will mobilize and after four hours, bloods for Anti-Xa (assessing systemic heparin activity) will be taken. The patient will then go home with a side effect diary. 24 hours later the patient will re-attend and an endometrial biopsy (sampling of lining of the womb) will be taken together with a full blood count and liver function tests. All of these procedures will performed in outpatient and you will go home afterwards
A telephone consultation will follow 14 days later to ask about period heaviness and duration. Participant questionnaire and side effects diaries will be sent by pre-paid envelope back to principal investigator.
What are the possible benefits and risks of participating?
There is no immediate medical benefit to you from taking part, however, the information that we gain from this study may help us to treat women in the future. We do not expect any commercially significant results to be gained from this research. It is possible that the action of taking an endometrial biopsy may help the endometrium to respond correctly to an implanting embryo, however, the medical evidence for this is currently limited and there is no guarantee that the biopsy may help. You will be informed of the results by letter and you will be invited to a patient information evenings at the end of study
Women who are pregnant cannot take part in this study and who could possibly be pregnant. Sampling the lining of the womb (endometrial biopsy) may be uncomfortable or slightly painful, but leaves no long term effects because your womb lining regenerates every month.
There is a very small risk of bleeding with the use of heparin which is a blood thinning agent. For this reason, we will take a blood test 4 and 24 hours after administration. If you have any bruises which appear suddenly, please call us immediately as this might indicate a problem with bleeding. We have an antidote against the blood thinning agent which will reverse its effect. There is a very small risk of infection but we will perform pelvic swabs prior to any intervention in the study if not done recently.
Where is the study run from?
The study will be conducted at University of Warwick. The patients will be seen in outpatients at Centre of Reproductive Medicine at University Hospitals Coventry and Warwickshire NHS Trust.
When is study starting and how long is it expected to run for?
The proposed date of starting the study is 1st January 2013. However, this depends upon ethical and MHRA approval. Duration of the study will be 12 months from the ethics approval to collect samples from patients. A further 12 months will be required to analyse the data.
Who is funding the study?
Biomedical Research Unit, University Hospitals Coventry and Warwickshire NHS Trust
Who is the main contact?
Professor Siobhan Quenby
s.quenby@warwick.ac.uk
Trial website
Contact information
Type
Scientific
Primary contact
Prof Siobhan Quenby
ORCID ID
Contact details
Clinical Sciences Research Laboratory
Warwick Medical School
University of Warwick
University Hospitals Coventry and Warwickshire NHs Trust
Clifford Bridge Road
Coventry
CV2 2DX
United Kingdom
+44 (0)24 7696 8657
s.quenby@warwick.ac.uk
Additional identifiers
EudraCT number
2012-003682-18
ClinicalTrials.gov number
Protocol/serial number
HEP001QUEN
Study information
Scientific title
Endometrial flushing of low molecular weight heparin improves decidualisation - a prospective randomised control pilot study
Acronym
Study hypothesis
To assess the effects of local low molecular weight heparin administration on endometrial decidualisation in a non-conception menstrual cycle.
Added 25/09/2013: study participation was completed in July 2013. All 40 participants were recruited and the study is not recruiting any more participants.
Ethics approval
NRES Committee West Midlands - Edgbaston, 05/11/2012, ref: 12/WM/0347
Study design
Prospective randomized pilot study
Primary study design
Interventional
Secondary study design
Randomised controlled trial
Trial setting
Hospitals
Trial type
Treatment
Patient information sheet
Not available in web format, please use the contact details below to request a patient information sheet
Condition
Previous at least one unsuccessful IVF treatment, Recurrent Miscarriages
Intervention
Patient will be recruited with informed written consent. The patient will have a minimum of 24 hours to review the patient information sheet and consent form. If the patient consents, she will be asked to use barrier contraception for the month in which the study occurs.These patients will be asked to attend 5 to 7 days after ovulation (as assessed by a home ovulation kit) and they will be randomized (after a negative pregnancy test) to either receive locally administered low molecular weight heparin (intervention group) OR locally administered saline (control group). After administration, they will mobilize and after four hours, bloods for Anti-Xa (assessing systemic heparin activity) will be taken. The patient will
then go home with a side effect diary. 24 hours later the patient will re-attend and an endometrial biopsy will be taken together with a full blood count and liver function tests.
A telephone consultation will follow 14 days later to ask about period heaviness and duration. Participant questionnaire and side effects diaries will be sent by pre-paid envelope back to principal investigator.
Intervention type
Other
Phase
Not Applicable
Drug names
Primary outcome measures
Measurement of effective decidualisation will include the density of uterine natural killer cell by immunohistochemistry
Secondary outcome measures
1. To assess the effect of locally administered heparin on other markers of decidualisation including endometrial stromal cell culture, genome wide expression profile, induction of other decidualisation protein markers including prolactin, Prokinectin, IGFBPs (insulin Like Growth Factor Binding Proteins), HBEGF (Heparin Binding Epidermal Growth Factor)
2. To identify any potential side effects of local endometrial administration of heparin
3. To assess patient acceptability of this method of administration
Overall trial start date
01/01/2013
Overall trial end date
31/12/2013
Reason abandoned
Eligibility
Participant inclusion criteria
1. Women attending the Centre for Reproductive Medicine, University Hospitals of Coventry and Warwickshire NHS Trust, Coventry who had previous one unsuccessful IVF treatment (defined as failure to achieve live birth after transfer of two good quality embryos)
2. Women with recurrent miscarriages (defined as 3 or more unexplained miscarriages)
3. Women 18 years of age or older but younger than 45 years old
4. Able and willing to give informed consent
Participant type
Patient
Age group
Adult
Gender
Female
Target number of participants
40
Participant exclusion criteria
1. Women who had unprotected sexual intercourse during the month when endometrial flushing is planned
2. Women having a vaginal infection, these women will be eligible for inclusion once treatment of the infection has been completed
3. Pregnancy
4. Breast feeding
5. Women with weight of < 45 kg (due to higher risk of bleeding)
6. Women with bleeding disorders
7. Women with severe hypertension
8. Women with Known Renal or Liver Diseases
9. Women who had recent stroke
10. Women taking Warfarin for any medical condition
11. Women taking systemic steroids, systemic salicylates, acetylsalicylic acid, NSAIDS including Ketorolac, dextran and clopidogrel or any immunosuppressant medications
12. Women with Diabetes Mellitus (due to potential risk of hyperkalaemia)
13. Women with hypersensitivity to Heparin, Pork, Beef or other Animal products
14. Women with Peptic Ulcers
15. Women undergoing Tubal Patency testing, Hysteroscopy or Laparoscopy at the time when endometrial flushing is planned
Recruitment start date
01/01/2013
Recruitment end date
31/12/2013
Locations
Countries of recruitment
United Kingdom
Trial participating centre
Clinical Sciences Research Laboratory
Coventry
CV2 2DX
United Kingdom
Sponsor information
Organisation
University of Warwick (UK)
Sponsor details
c/o Dr Peter Hedges
Research Support Services
University House
Kirby Corner Road
Coventry
Cv4 8UW
United Kingdom
Sponsor type
University/education
Website
Funders
Funder type
Hospital/treatment centre
Funder name
University Hospitals Coventry and Warwickshire NHS Trust - Biomedical Research Unit (UK)
Alternative name(s)
Funding Body Type
Funding Body Subtype
Location
Results and Publications
Publication and dissemination plan
Not provided at time of registration
Intention to publish date
Participant level data
Not provided at time of registration
Results - basic reporting
Publication summary