CHOICE. Cervical Ripening at Home or In-Hospital - prospective cohort study and process evaluation.

• Chief Investigator: Dr Sarah Stock, University of Edinburgh
• Funder: National Institute for Health and Care Research (NIHR)

In most pregnancies labour starts on its own, but sometimes induction of labour (IOL) is needed. The first part of IOL is ‘cervical ripening’, where medication or a specialised balloon is used to prepare the cervix (neck of the womb) for labour. Cervical ripening used to be performed only in hospitals. However, about half of UK maternity units now offer ‘home cervical ripening’, where women have the procedure started off in hospital, then spend some time at home whilst waiting for the treatment to work. This may help reduce demands on maternity services and reduce the time women spend in hospital. Women may also prefer it. However, benefits are not proven. Home cervical ripening may be riskier for mother and babies, as some rare complications may not be detected when women are at home.  We aim to see if home cervical ripening is safe, acceptable to women and their partners, and cost-effective for the NHS. We will use routinely collected data from the electronic health records of women having IOL in 30 UK maternity units. We will use qualitative methods to assess the acceptability of home cervical ripening and explore women’s experiences of IOL.  

In Scotland, this study recruited in NHS Borders, Fife, Grampian, Highland, Lanarkshire and Tayside, it is now completed.

C-STICH2. Emergency Cervical Cerclage to Prevent Miscarriage and Preterm Birth: a Randomised Controlled Trial.

• Chief Investigator: Dr Katie Morris, Birmingham Women's and Children’s Hospital
• Funder: National Institute for Health and Care Research (NIHR)

The main aim of this project is to evaluate whether emergency cervical cerclage can improve outcome for mothers and babies in women who present with cervical dilatation and exposed, unruptured fetal membranes.

A cervical cerclage is the placement of a stitch to keep the neck of the womb closed. A stitch can be placed in a planned way because of a risk of preterm birth based on a woman’s pregnancy history or because the neck of the womb is shorter than normal on an ultrasound scan but still closed. Sometimes the neck of the womb can start to open and expose the bag of water around the baby. If this happens between 16 and 28 weeks of pregnancy, an emergency stitch is sometimes inserted to try to delay delivery. Prolonging the pregnancy so that the baby can be born when they are bigger and stronger may give them a better chance of surviving and suffering from fewer complications of prematurity. However, doctors do not know if an emergency cerclage works. There is some evidence it may prolong pregnancy but it is possible that it will also speed up delivery by causing infection or damage to the neck of the mother’s womb. It is therefore very important to undertake a study to decide if emergency cerclages delay delivery, and if they do, whether this benefits the baby (and mother). The best way to work out if emergency cerclage works, and is safe, is to ask women to be randomly allocated to either emergency cerclage or no cerclage. This is what we need to do to ensure we know what is best for future women and babies to prevent harm. This study will ask women who have an open neck of the womb with the bag of waters around the baby coming through, to have either an emergency stitch or no emergency stitch. Which treatment they will receive will be decided by a process that randomly allocates a woman to one group or the other. All women in the study, irrespective of their allocated group, will be able to have other treatments that may help prolong pregnancy such as antibiotics, progesterone and medicines that stop the womb contracting. The study team will collect information about what happens to the mother and baby from their medical notes and talk to women about their experiences of taking part in the study. Where appropriate families will be contacted at 2 years of age to assess how the babies are developing by a postal questionnaire completed by the carers.

For more information please visit https://www.birmingham.ac.uk/research/bctu/trials/womens/c-stich2/index.aspx

In Scotland, this trial is open to recruitment in NHS Grampian and Lothian.

MAP. Methods of Assessing Perinatal Anxiety: The Effectiveness of Different Approaches.

• Chief investigator: Professor Susan Ayers, University of London
• Funder: National Institute for Health and Care Research (NIHR)

Mental illness affects one in five women during pregnancy and the first year after birth. Depression and anxiety are most common but there is very little research on anxiety. Perinatal anxiety affects around 15% of women and leads to greater risk of premature birth, postnatal depression and long-term mental health and behaviour problems in their children. It is currently recommended that women are asked two questions about anxiety by their midwife. However, it is not known if these are the best questions to identify women who need treatment. To be useful the anxiety questionnaire must be: (1) acceptable to women; (2) effective at identifying women who require treatment and those who do not; (3) practical and easy to use in the NHS and other UK health services. This application is part of a larger study (MAP - Methods of Assessing Perinatal Anxiety: The Acceptability, Effectiveness and Feasibility of Different Approaches). The MAP study aims to identify the most effective, acceptable and feasible method for assessing anxiety in women during pregnancy and after birth. We will address each of these important points through three connected Work Packages (WPs). We will compare four different anxiety questionnaires in NHS services in England and Scotland. We selected the questionnaires by looking at reviews of all the available evidence.

For more information please visit https://blogs.city.ac.uk/map/

In Scotland, this study recruited in NHS Ayrshire & Arran, Grampian, Greater Glasgow & Clyde, Lanarkshire and Tayside, it is now completed.

OASI2. Evaluation of strategies for care bundle implementation.

• Chief investigator: Dr Ranee Thakar, Croydon University Hospital
• Funder: The Health Foundation

Obstetric anal sphincter injury (OASI) is the combined term for third and fourth degree perineal tearing sustained during childbirth. It can result in complications such as anal incontinence (involuntary loss of flatus and faeces) with significant psychosocial consequences to women, and long-term financial consequences for health systems.

The overarching aim of OASI2 is to sustainably reduce rates of severe perineal trauma following childbirth in Great Britain. This is achieved with the following two objectives:

1. Support the long-term sustainability of the OASI Care Bundle in units that have participated in the original OASI1 study.
2. Support the scale-up of the OASI Care Bundle in new units.

OASI2 involves testing different scale-up strategies of the OASI Care Bundle, a set of four evidence-based practices that when used together, have demonstrated effectiveness in reducing women’s risk of severe perineal tearing during childbirth.

For further details visit https://www.health.org.uk/funding-and-partnerships/programmes/oasi2-care-bundle

In Scotland, this project recruited in Ayrshire & Arran, Forth Valley, Grampian, Greater Glasgow & Clyde and Lothian, it is now in follow-up.

The Big Baby Trial. Induction of labour for predicted macrosomia.

• Chief investigator: Professor Siobhan Quenby, University Hospitals Coventry and Warwickshire NHS Trust
• Funder: National Institute for Health and Care Research (NIHR)

Difficulty in delivering the shoulders of a baby after the head has already come out can be a serious complication during birth. Most babies that get into such trouble are larger than average. It has been suggested that if we can predict by ultrasound scan in the last weeks of pregnancy which babies are large and at increased risk, then we could deliver them a week or so earlier and reduce the chance of such complications. However the available evidence is not clear, and can be interpreted in different ways. To know if delivering large babies earlier is the right thing to do for baby and mother an objective clinical trial is needed to see whether it is really of benefit. This study will help decide what the safest method is to care for pregnancies where, because of the large size of the baby, complications may occur during labour.

For more information please visit https://warwick.ac.uk/fac/sci/med/research/ctu/trials/bigbaby

In Scotland, this trial recruited in NHS Ayrshire & Arran, Grampian and Lanarkshire, it is now in follow-up.

The PARROT-2 Trial. Placental growth fActor Repeat sampling for Reduction of adverse perinatal Outcomes in women with suspecTed preeclampsia.

• Chief investigator: Professor Lucy Chappell, King's College London
• Funder: Moulton Charitable Trust

Pre-eclampsia is a condition, occurring only in pregnancy, thought to be caused by the placenta. Women with pre-eclampsia can suffer from high blood pressure, problems with their kidneys, liver and blood clotting. The problems with the placenta can mean that the baby’s growth is affected; in some cases the baby can be stillborn. Once diagnosed, the only cure is to deliver the baby.  If pre-eclampsia occurs before 37 weeks of pregnancy, women may need to be admitted to hospital to have treatment and monitoring for complications, whilst planning for safe delivery of the baby. Some women become unwell very quickly and need to have their babies delivered; others have long stays in hospital. It can be difficult to identify women at high-risk of severe complications of pre-eclampsia.

This study will look at blood levels of proteins produced by the placenta, such as Placenta Growth Factor (PlGF) to see if using repeated blood samples can help to reduce severe complications for babies, and for women.

For more information: Welcome | Parrot 2 (medscinet.com)

PARROT-2 Follow on study assesses impact of PlGF tests - Action on Pre-eclampsia (action-on-pre-eclampsia.org.uk)

In Scotland, this trial recruited in NHS Lothian and it is now in follow-up.

BabyBreathe Trial. A randomised controlled trial of a complex intervention to prevent return to smoking postpartum.

• Chief Investigator: Professor Caitlin Notley, University of East Anglia
• Funder: National Institute for Health and Care Research (NIHR)

BabyBreathe aims to provide pre- and post-natal support for women who have stopped smoking in pregnancy and wish to remain smoke free after giving birth. This support will come from health visitors, tailored experiences through online, app and text messages as well as support to use alternatives to smoking or e-cigarettes as ways to remain smoke free. As part of the BabyBreathe trial women who have recently quit smoking will be identified through their routine pregnancy appointments across four areas of the UK (Norfolk, London, Scotland, and Newcastle). If they agree to be part of the trial, they will then be put into one of two groups, receiving the support of BabyBreathe, or usual care, with the same chance of being in either group. We will measure how many women receiving the BabyBreathe support package are smoke free at 12 months following the birth of their baby compared to those not receiving support. We will assess the value for money of the package of support. We will also look into which parts of the package are most used, ‘liked’ and appear most effective by talking in depth to women, partners and health visitors.

For more information: https://www.uea.ac.uk/groups-and-centres/addiction-research-group/babybreathe

In Scotland this trial is recruiting in NHS Lothian.

ESPriT2. A multi-centre randomised controlled trial to determine the effectiveness of laparoscopic removal of isolated superficial peritoneal endometriosis for the management of chronic pelvic pain in women.

• Chief investigators: Professor Andrew Horne and Dr Lucy Whitaker, University of Edinburgh
• Funder: National Institute for Health and Care Research (NIHR) HTA

Endometriosis affects 1 in 10 women and is associated with debilitating pelvic pain and infertility. The most common type of endometriosis, superficial peritoneal endometriosis (SPE), is diagnosed by keyhole surgery (laparoscopy) and gynaecologists usually surgically treat it (excise and/or ablate) at the time. Unfortunately, many women do not get good pain relief from treatment of SPE and some have complications from surgery. Despite thousands of surgeries annually, there is little scientific evidence as to whether surgical treatment of SPE improves overall symptoms and quality of life more than not surgically treating the endometriosis, or whether surgery could exacerbate symptoms, or even cause harm.

ESPriT2 is a major UK NIHR/HTA-funded randomised controlled trial to determine if removal of SPE is effective in the treatment of chronic pelvic pain. We aim to randomise 400 women who have been SPE alone identified at diagnostic laparoscopy within 70 NHS hospitals across the UK. At laparoscopy, participants will be randomised to either having their endometriosis removed or to diagnostic laparoscopy only. All participants will be informed of the findings at laparoscopy but they will not be told if the endometriosis was removed or not. 

Participants will be asked to complete pain and quality of life questionnaires before their operation and then at 3, 6 and 12 months post laparoscopy.  Data on pain, quality of life, further surgical treatment and fertility outcomes will also be captured at 2 and 5 years by repeat questionnaires and data linkage.

For more information: https://www.ed.ac.uk/centre-reproductive-health/esprit2

In Scotland, this trial is open to recruitment in NHS Ayrshire & Arran, Borders, Fife, Forth Valley, Grampian, Greater Glasgow & Clyde, Highland, Lanarkshire, Lothian and Tayside.  

DIAMOND. Deep infiltrating endometriosis: management by medical treatment versus early surgery.

• Chief investigator: Professor Kevin Cooper, University of Aberdeen.
• Funder: National Institute for Health and Care Research (NIHR) Health Technology Assessment (HTA)

Endometriosis affects up to 10% of women of reproductive age and involves the growth of endometrial tissue in sites other than the uterine cavity, causing inflammation and adhesions, leading to pain and infertility. Deep endometriosis is its most severe form affecting up to 2% of women. It is characterised by the presence of endometrial deposits measuring more than 5mm under the peritoneum or in any of the following locations: between the rectum and the vagina (recto-vaginal endometriosis), the Pouch of Douglas, uterosacral ligaments, bowel, appendix, ureter, bladder, uterovesical fold and the pelvic side wall. Women with endometriosis have been shown to have significantly impaired quality of life. A global survey in 2013 revealed that endometriosis affected work, relationships and education in 51%, 50% and 16% women respectively.

This is a multi-centre randomised controlled trial, with an internal pilot phase, to compare medical management alone versus early planned laparoscopic surgery (first attempt at definitive surgery) with or without adjuvant medical treatment) in women with deep endometriosis. The internal pilot phase will monitor recruitment and assess the willingness of patients to participate in DIAMOND.

For more information: https://w3.abdn.ac.uk/hsru/DIAMOND/Public/Public/index.cshtml, DIAMOND (abdn.ac.uk)

In Scotland, this trial is open to recruitment in NHS Grampian and Lothian, and going through the process of approval in Greater Glasgow & Clyde.

REGAL trial. Recurrence of Endometriosis: A randomised controlled trial of clinical and cost-effectiveness of Gonadotrophin Releasing Hormone Analogues with add-back hormone replacement therapy versus repeat Laparoscopic surgery.

• Chief investigator: Dr Lucky Saraswat, University of Aberdeen.
• Funder: National Institute for Health and Care Research (NIHR) Central Commissioning Facility (CCF)

Endometriosis is a common condition which affects one in ten women from puberty to menopause. It causes pelvic pain, poor quality of life and reduces work productivity. It occurs when cells similar to those lining the womb grow outside it, generally within the pelvis. These cells cause internal bleeding at the time of periods, scarring and pain. The condition is diagnosed by laparoscopy (key hole surgery) to identify areas of endometriosis which can be destroyed or removed. Surgery may not provide lasting relief and pain can return in up to half of treated women within five years. Following surgery, women who are not trying to get pregnant are offered the combined oral contraceptive pill or other contraceptives containing hormones called progestogens. Despite surgery and hormonal contraceptives, about two in three women will require further surgery to treat pain due to endometriosis that has come back. A less invasive way of shrinking endometriosis is to use a drug called gonadotrophin releasing hormone analogue (GnRHa) which temporarily stops the ovaries from producing oestrogen. While very effective in terms of reducing pain, this treatment is generally only used for six months to a year because of side effects such as hot flushes and night sweats caused by the lack of oestrogen, and concerns about osteoporosis (thinning of the bones). Recent research has shown that adding small doses of hormone replacement therapy (HRT) in women on GnRHa reduces the risk of side effects and osteoporosis without causing pain to return. An effective long-term non-surgical treatment for endometriosis has been identified as a research priority by patients and clinicians, but to date there have been no long-term comparisons. The REGAL trial will compare long-term (two years) GnRHa with added HRT to key hole surgery in women who experience recurrence of pain after endometriosis surgery.

For more information: Regal (abdn.ac.uk), https://w3.abdn.ac.uk/hsru/REGAL/Public/Public/index.cshtml

In Scotland, this trial is recruiting in NHS Ayrshire & Arran, Grampian, Greater Glasgow & Clyde and Lothian.

PEtAL. Understanding local mechanisms involved in uterine bleeding and endometrial function.

• Chief investigator: Professor Hilary Critchley, University of Edinburgh
• Funder: Wellbeing of Women, Scottish Government Chief Scientist Office (CSO)

Abnormal uterine bleeding (AUB) is a condition where a woman's monthly menstrual blood loss (MBL) changes in amount/frequency of the bleed, often becoming heavier and/or more frequent. This debilitating condition affects 25% of all women before the menopause and significantly impacts them socially, mentally and financially. The mechanisms which cause the lining of the womb (endometrium) to bleed abnormally are not yet known, but may relate to “progesterone resistance” i.e. the endometrium has an altered response to progesterone. This means treatment options are not specific, leading almost a third of patients to resort to major surgery to remove the womb.

This study forms the human part of a national/international collaboration to understand uterine bleeding and endometrial function. It aims to investigate tissue samples from women with AUB. Recruitment will occur from gynaecology services within NHS Lothian. Tissue samples are routinely collected as part of standard clinical care during the investigation/treatment of patients. The majority of samples will therefore be surplus tissue to what is needed for clinical diagnosis. Groups of patients will be carefully categorised according to cause of AUB, e.g. fibroids, adenomyosis and the impact of age. To corroborate this categorisation, objective measurements of MBL may be taken in some women. Laboratory tests (cellular/molecular) will be conducted at the MRC Centre for Reproductive Health (University of Edinburgh). Tests will aim to understand if the endometrium is different in women with AUB, the impact of age and if there are signs of progesterone resistance. Testing will also investigate if treatments can be better targeted in the future, providing a better outcome for women, improving quality of life and reducing the need for surgery. Anonymised data will be shared between national/international collaborators as part of the analyses of this study. This study will take approximately five years to complete.

This study is recruiting in NHS Lothian.

IMAGEN, Version 1. The impact of androgens on endometrial health.

• Chief investigator: Dr Jacqueline Maybin, University of Edinburgh
• Funder: Wellcome Trust

Gender reassignment procedures alter a transgender person's physical appearance and/or the function of their existing sexual characteristics to resemble that socially associated with their identified gender. It is part of a treatment for gender dysphoria in transgender people. For those wishing to transition to male gender, this involves administration of androgens (hormones) to facilitate development of male secondary sexual characteristics. Many of these individuals will then opt to have a hysterectomy procedure (removal of uterus) with removal of their ovaries and Fallopian tubes.

Androgen hormone receptors are present in the endometrium (lining of the womb). Androgens are known to have an important role in cell growth and cell repair in the endometrium, and also in establishment of pregnancy. However the effect of high doses of androgens on the health of the uterus is not fully understood. The high dose androgen therapy used during gender reassignment may impact endometrial health. Data are required to establish the effects of these androgens on endometrial function to ensure safety, particularly for those who opt to delay or cancel hysterectomy procedures. In addition, the endometrium exposed to these high levels of androgens will inform our studies on endometrial function, providing important high dose androgen-exposed endometrium to compare with endometrium from those not taking hormones. This will provide high-quality in vivo data on the role of androgens in endometrial physiology. People undergoing hysterectomy procedures as part of their female-to-male gender reassignment, or undergoing a hysterectomy for benign conditions, will be asked to participate. With informed consent, pipelle samples and/or “wedge” samples of endometrium and the underlying muscle layer will be taken from the uterus after removal. The study will not alter the surgical procedure in any way.

This study is recruiting in NHS Lothian.

GEM3. Combination of methotrexate and gefitinib vs methotrexate alone for ectopic pregnancy.

• Chief investigator: Professor Andrew Horne, University of Edinburgh
• Funder: National Institute for Health and Care Research (NIHR)

Ectopic pregnancy (EP) occurs when an embryo implants in a Fallopian tube. A methotrexate (MTX) injection causes serum pregnancy hormone [hCG] levels to fall and is a suitable treatment for stable EP. This is standard care. However, in 30% of women, MTX is unsuccessful (with surgery required); and in 15%, it is partially effective (2nd dose of MTX required); and for many women, treatment is prolonged (many hospital visits). We have performed studies giving MTX and gefitinib (lung cancer drug) to women with EP. We found that giving MTX and gefitinib together may reduce the need for surgery and hospital visits without causing any important side effects. These findings now require further study in a large trial and we need to understand how gefitinib works. This clinical trial (‘main study’) will compare MTX and either a seven-day course of gefitinib or placebo (dummy) tablets. We will assess whether the two drugs together are better at treating the EP without the need for surgery; reducing hCG levels, hospital visits and need for further MTX; and look at safety and patient satisfaction. Treatment response will be monitored according to local standard protocols. The study will recruit 328 women from ~50 UK hospitals. To examine how MTX and gefitinib affects the pregnancy tissue (‘mechanistic study’), we will also ask 30 women who opt to have their EP treated surgically to take medication pre-operatively (gefitinib and MTX) and collect their EP tissues at time of surgery. We will also ask women in whom the treatment has failed and who require ‘rescue’ surgery for permission to collect their pregnancy tissues.

For more information: https://www.ed.ac.uk/centre-reproductive-health/gem3-trial/welcome

This trial is now completed. In Scotland, this study was open to recruitment in NHS Ayrshire & Arran, Borders, Fife, Forth Valley, Grampian, Greater Glasgow & Clyde, Highland, Lanarkshire, Lothian and Tayside. 

LOCI. Letrozole Or Clomifene for Ovulation Induction.

• Chief investigator: Professor Arri Coomarasamy, University of Birmingham
• Funder: National Institute for Health and Care Research (NIHR) HTA

Polycystic ovary syndrome (PCOS) affects 20% of women. Women with PCOS may not release eggs from their ovaries; this is called anovulation. The first line treatment for anovulation is a medicine called clomifene (formerly known as clomiphene). Current clinical guidelines in the UK recommend the use of clomifene with or without another medicine, metformin, for a maximum of 6 menstrual cycles. Clomifene treatment does not result in pregnancy for approximately 70% of women despite prolonged treatment. Furthermore, clomifene is associated with numerous side effects and a 10-fold increase in the risk of multiple pregnancy. Recently there has been growing interest in the use of another medicine, letrozole, to treat infertility in women with PCOS. Letrozole works differently to clomifene and has fewer side effects, including a lower risk of multiple pregnancy. A recent review of studies involving all available medicines for women with PCOS and infertility has indicated that letrozole may be more effective than clomifene when used alone, and there may be additional value when it is combined with metformin.

This trial has been developed in consultation with two patient representation groups, Fertility Network UK and the Women’s Network of the RCOG. We plan to ask women diagnosed with PCOS seeking fertility treatment to participate in this study. Participants will be allocated to clomifene or letrozole, which they will take for 5 days at the beginning of each menstrual cycle. Participants will also be given metformin or a dummy drug to be used alongside clomifene or letrozole but this use will continue up until the first 14 weeks of pregnancy. Clomifene or letrozole treatment will be offered for up to 6 treatment cycles, to match the current guidelines. The allocation of treatment will be decided at random by a computer, and neither the participants nor the researchers will know what treatment a patient is receiving; this arrangement is necessary to test the treatments fairly. The main outcome evaluated will be whether a participant has a live birth. A number of other key outcomes such as ovulation rate, miscarriage, multiple pregnancy and new born outcomes will also be assessed.

For further details please visit: https://www.birmingham.ac.uk/research/bctu/trials/womens/locitrial/index.aspx

In Scotland, this trial is recruiting in NHS Ayrshire & Arran, Forth Valley, Grampian, Greater Glasgow & Clyde, Lothian and Tayside.

STOP-OHSS. Shaping and Trialling Outpatient Protocols for Ovarian HyperStimulation Syndrome): A randomised controlled trial to assess the clinical and cost-effectiveness of active management of Ovarian HyperStimulationSyndrome.

• Chief investigator: Mr Mostafa Metwally, Sheffield Teaching Hospitals NHS Foundation Trust
• Funder: National Institute for Health and Care Research (NIHR)

Ovarian hyperstimulation syndrome (OHSS) is a condition that can affect women undergoing fertility treatment. OHSS is caused by the medication taken to increase egg production during ovulation induction or In Vitro Fertilisation (IVF). Too many eggs can develop, and the ovaries can become large and painful. It can affect both women who are pregnant and women who have not become pregnant but are still recovering from the effects of this medication given during their fertility treatment. Currently, OHSS is managed conservatively. Doctors/fertility teams monitor the condition and if the symptoms worsen, admit the woman to hospital for intensive monitoring or treatment. The aim of the STOP-OHSS trial is to establish the clinical and cost-effectiveness, safety and acceptability of outpatient paracentesis as an earlier active management for women with moderate or severe OHSS. STOP-OHSS is a pragmatic, parallel open-label, multi-centre, superiority, adaptive, group sequential, confirmatory RCT with an internal pilot to assess feasibility aspects. Participants will be individually allocated 1:1 to receive outpatient paracentesis or conservative management. A qualitative study will be conducted during the internal pilot phase to facilitate the feasibility of conducting the RCT by identifying problems so that solutions can be instigated rapidly. A total of 224 women with moderate or severe OHSS will be randomised to the trial. A 0% withdrawal rate is assumed as the primary outcome is short term, occurring at 28 days, and can be collected directly from patient notes (consent will be obtained). Approximately 20 private and NHS Fertility Units are expected to take part from England and Scotland.

For more information: https://www.sheffield.ac.uk/scharr/research/centres/ctru/stop-ohss

In Scotland, NHS Grampian is participating in this study.

HELP Fertility? Hysteroscopic Excision of Leiomyoma and Polyp in Infertility - two randomised controlled trials.

• Chief Investigator: Mr Mostafa Metwally, Sheffield Teaching Hospitals NHS Foundation Trust
• Funder: National Institute for Health and Care Research (NIHR) HTA

This trial aims to determine the clinical and cost-effectiveness of hysteroscopic removal of submucosal fibroids and endometrial polyps, in women presenting with infertility and recurrent pregnancy loss. 

Submucous fibroids and endometrial polyps are commonly detected in women seeking treatment for infertility and recurrent miscarriage. Currently, such uterine abnormalities are routinely removed by hysteroscopic resection, but there is limited evidence to suggest that their removal improves the chances of the woman achieving a pregnancy and live birth. The trial aims to examine the clinical and cost effectiveness of hysteroscopic resection of submucous fibroids and endometrial polyps in women presenting with infertility and recurrent miscarriage. This will be an 'umbrella' randomised controlled trial (RCT) in which there are two multicentre RCTs running in parallel; one where women with polyps of less than 3cm are randomly allocated to either have their polyps removed by hysteroscopic resection (intervention arm) or not removed (control arm with no hysterscopic resection). Within the second trial, women with fibroids of less than 3cm are randomised into the same intervention and control arms i.e. hysteroscopic resection of fibroids versus no hysteroscopic resection. Participants will be recruited from approximately 30 centres within the United Kingdom (e.g. general gynaecology units, recurrent miscarriage and IVF clinics and smaller District General Hospitals). There is current uncertainty whether resection of fibroids and polyps is beneficial or indeed possibly harmful to patients wishing to conceive. Given how common fibroids and polyps are in this population, there is a potential for wide spread benefit to patients and the wider NHS to be gained from the findings of this study.

For more information https://www.sheffield.ac.uk/scharr/research/centres/ctru/help-fertility

This trial is now closed to recruitment, in follow-up. In Scotland, this trial recruited in NHS Grampian and Tayside.

Understanding sperm function and dysfunction.

• Chief investigator: Dr Sarah Martins da Silva, University of Dundee
• Funder: Bill and Melinda Gates Foundation, Scottish Government Chief Scientist Office (CSO)

Infertility is estimated to affect 1:6 couples globally. Male factor is the underlying cause in over half of all cases, yet there are very limited treatment options for affected couples, other than undertaking IVF / ICSI, which is expensive, invasive and without guarantee of success. Poor sperm motility is the commonest underlying factor in male infertility, however, the processes defining and controlling sperm function are not fully understood.

This project has several areas of research focus: Firstly, we hope to understand normal sperm function, by examining how sperm work (moving and swimming), calcium responses to chemicals normally encountered in the female (for example, progesterone), protein expression and cell membrane properties. Secondly, we hope to understand why sperm don't work, by examining similar properties of sperm from patients undertaking fertility treatment as well from those affected by low (<25%) or failed fertilisation following IVF treatment. Thirdly, we hope to develop new treatment options for infertile men, using drug discovery techniques. Lastly, we also aim to use the knowledge we gain to improve patient diagnostics to improve clinical care for male infertility.

This study is recruiting in NHS Tayside.

Male contraception study. Clinical Evaluation of Daily Application of Nestorone® (NES) and Testosterone (T) Combination Gel for Male Contraception.

• Chief investigator: Professor Richard Anderson, University of Edinburgh
• Funder: National Institutes of Health- Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), USA

The subject of this clinical trial is an experimental gel that is being developed as a possible new method for male family planning. Currently, no safe, highly effective, reversible method of contraception is available to men who are interested in sharing the responsibility of family planning.

Men who join the study with their female sexual partner, should be healthy and between the ages of 18-50 years old. Women who join the study with their male sexual partner should be healthy and between the ages of 18-34 years old. The partners should be in a stable mutually monogamous relationship for at least 1 year prior to screening and intend to remain in the relationship for the duration of the study. The study will take approximately two years to complete. During this time, the male partners will have to come to the clinic for approximately 31 visits, the female partners for approximately 10 visits.

The clinical trial will be conducted at selected competence centres in reproductive medicine in Chile, Italy, Kenya, Sweden, the United Kingdom and the United States of America.

This trial is now in follow-up. In Scotland, this trial recruited in NHS Lothian.

DAISy-PCOS Phenome Study. Dissecting androgen excess and metabolic dysfunction for an integrated systems approach to polycystic ovary syndrome through the assessment of detailed phenome and metabolome data.

• Chief investigator: Professor Wiebke Arlt, University of Birmingham
• Funder: Wellcome Trust

Polycystic ovary syndrome (PCOS) affects 10% of all women and usually presents with irregular menstrual periods and difficulties conceiving. However, PCOS is also a lifelong metabolic disorder and affected women have an increased risk of type 2 diabetes, high blood pressure, and heart disease. Increased blood levels of male hormones, also termed androgens, are found in most PCOS patients. Androgen excess appears to impair the ability of the body to respond to the sugar-regulating hormone insulin (=insulin resistance). We found that fat tissue of PCOS patients overproduces androgens and that this can result in a build-up of toxic fat, which increases insulin resistance and could cause liver damage. In a large cohort of women registered in a GP database, we have found that androgen excess increases the risk of fatty liver disease.

We aim to identify those women with PCOS who are at the highest risk of developing metabolic disease, which would allow for early detection and potentially prevention of type 2 diabetes, high blood pressure, fatty liver and cardiovascular disease. We will assess clinical presentation, androgen production and metabolic function in women with PCOS to use similarities and differences in these parameters for the identification of subsets (=clusters) of women who are at the highest risk of metabolic disease. We will do this by using a standardised set of questions to scope PCOS-related signs and symptoms and the patient’s medical history and measure body composition and blood pressure. This standardised recording of a patient’s clinical presentation (=clinical phenotype) is called Phenome analysis. We will collect blood and urine samples for the systematic measurement of steroid hormones including a very detailed androgen profile (=steroid metabolome analysis) and of thousands of substances produced by human metabolism (=global metabolome analysis). Phenome and metabolome data will then undergo integrated computational analysis for the detection of clusters predictive of metabolic risk.

For further details please visit https://daisypcos.com/

In Scotland, this study is recruiting in NHS Lothian.

The PROTECT study. Reproductive function in teenagers and young adults (TYA) cancer survivors.

• Chief investigator: Professor Richard Anderson, University of Edinburgh
• Funder: Merck Serono Ltd; Scottish Government, Children and Families Directorate

This study will undertake analysis of the effects of cancer treatments on reproductive function in teenagers and young adults (TYA) to address our hypothesis that cancer diagnosis, cancer treatment and age at treatment effect fertility related biomarkers and hence long-term fertility/reproductive health in survivors. This is a multi-centre clinical prospective observational cohort study open to clinical centres directly involved in the care of TYA (aged 13-25) with cancer. Previous studies are retrospective thus assessing historical treatments, and mostly rely on questionnaire-based self-reported outcomes, introducing the opportunity for bias and inaccuracy. Additionally, there is a need for data specific to this post-pubertal age group, distinct from children. For individual patients, a personal assessment of post-recovery reproductive function following new and emerging treatment regimens is essential, and individualised prediction of that risk is necessary for accurate information provision at the time of diagnosis to allow informed decision-making regarding the need for fertility preservation interventions. Currently, understanding of reproductive physiology allows biomarkers to be used with confidence to reflect and predict gonadal function and fertility in oncologic practice, with the potential for a more detailed detection of partial loss of gonadal function, but this requires validation in larger prospective patient groups. This prospective study will combine biomarker and clinical analysis pre-treatment as well as post-treatment, with the generation of accurate risk assessment for rarer diagnoses/treatments as well as the more common ones, and of new treatments as they emerge: at present there are almost no data on the potential reproductive effects of targeted therapies. This study will recruit TYA patients from UK cancer centres, providing detailed individual assessment and long-term follow-up to address the need for prospective data on well-characterised patients, encompassing the rapid changes in oncological practice.

In Scotland, this study is open to recruitment in NHS Lothian and Greater Glasgow & Clyde.

PURSUIT. Proper Understanding of Recurrent Stress Urinary Incontinence Treatment in Women: A Randomised Controlled Trial of Endoscopic and Surgical Treatment.

• Chief investigator: Professor Marcus Drake, University of Bristol
• Funder: National Institute for Health and Care Research (NIHR)

Women with recurrent stress urinary incontinence (SUI) experience urine leakage with physical activity. Currently the interventions for recurrent SUI are surgical, or endoscopic bulking injection, procedures. These procedures are not always successful and there are longstanding symptoms and distress associated with a failed treatment. The current research in this field is not conclusive about the best therapy for recurrent SUI.

The NIHR-HTA funded PURSUIT trial will investigate whether the surgical operations of colposuspension, autologus urethral sling, midurethral tape or artificial urinary sphincter are a better treatment in terms of symptom severity than the endoscopic therapy of urethral bulking injections in women with recurrent SUI at one year after randomisation. In the surgery arm of the study the participants will receive one of the four operations mentioned above. Which operation they receive will depend on the underlying mechanism which caused their SUI (as determined by urodynamic/cystoscopy assessment) and the patient's preference following discussion with their surgeon. In the endoscopy arm, participants will receive injections of bulking agents. Adult women with bothersome stress urinary incontinence symptoms after failed primary SUI surgery or bulking injections, where recurrent SUI is confirmed by urodynamic/cystoscopy testing will be recruited. Women will be recruited from urology and urogynaecology secondary/tertiary units in the UK. The study duration is 6 years, comprising 6 months set-up/site initiation, 2 years recruitment, 3 years follow-up, 6 months analysis/dissemination. The 6 month internal pilot phase at the start of recruitment will test ability to recruit/randomise (trial sites and women), with clear progression criteria to the main trial.

For further details please visit https://pursuit.blogs.bristol.ac.uk/

This trial is closed to recruitment. In Scotland, this trial recruited in NHS Ayrshire and Arran.

A Phase 2/3 Study to Evaluate the Safety, Tolerability, and Immunogenicity of a SARS-CoV-2 RNA Vaccine Candidate (BNT162b2) Against COVID-19 in Healthy Pregnant Women 18 Years of Age and Older.

• Chief investigator: Dr Christine Jones, University Hospital Southampton
• Funder: Pfizer-BioNTech

The purpose of this study is to describe the safety, tolerability, and immunogenicity of the Pfizer BNT162b2 RNA-based vaccine against COVID-19 in healthy pregnant women and their infants. It will assess the immunogenicity of BNT162b2 in pregnant women, the transfer of antibody to their infants, and the kinetics of antibody transfer in the infant.

Since first reported as the unknown cause of a pneumonia outbreak in Wuhan, China, in December 2019, the infections caused by the novel virus, later named, SARS-CoV-2 and the resulting disease, COVID-19, have spread globally.

Pregnant women are at risk of acquiring SARS-CoV-2 infection and COVID-19. Pregnancy may confer increased risk of severe COVID-19 because of physiological changes during pregnancy that can increase susceptibility to respiratory infections and subsequent rapid progression to respiratory failure. Additionally, pregnant women with COVID-19 have been reported to have higher rates of preterm birth, caesarean delivery, fetal distress, and infants requiring neonatal intensive care. Prevention of SARS-CoV-2 infection and COVID-19 is critically important in pregnant women.

This is a global Phase 2/3, randomized, placebo-controlled, observer-blind study evaluating the safety, tolerability, and immunogenicity of BNT162b2 or placebo (normal saline solution) administered in 2 doses, 21 days apart. There will be approximately 4000 healthy women, 18 years of age or older, vaccinated at 24 to 34 weeks’ gestation, and their unborn babies taking part in this study worldwide and approximately 235 participants involved throughout the UK.

This study is in follow-up. In Scotland, NHS Lothian participated in this trial.

RSV MAT-009. A Phase III, randomized, double-blind, placebo controlled multi-country study to demonstrate efficacy of a single dose of unadjuvanted RSV Maternal vaccine, administered IM to pregnant women 18 to 49 years of age, for prevention of RSV associated LRTI in their infants up to 6 months of age.

• Chief investigator: Dr Asma Khalil, St George's Hospital, London
• Funder: GlaxoSmithKline Biologicals

Respiratory Syncytial Virus (RSV) is a common respiratory virus that can cause infections of the airways. Whilst most infections of RSV present as a simple cold, in young babies RSV can cause difficulty in breathing and can be dangerous. RSV infection is one of the most common reasons for young babies to be admitted to hospital. For protection against RSV, babies rely upon antibodies given to them from their mothers during pregnancy. A vaccine is one way to increase the antibodies in pregnant women.

This study, funded by GlaxoSmithKline, will assess safety and efficacy of an RSV Maternal vaccine in pregnant women and their babies. It will check: how well the vaccine can boost antibodies in pregnant women; how well the antibodies are passed from the pregnant woman to their babies; how long it stays in the babies’ blood; if pregnant women visit a doctor less often for cold-like illnesses and if the RSV caused their illness.

The study will include around 10,000 participants worldwide. Six hospitals in the UK will take part. Women aged 18 to 49 years, between weeks 24 and 34 of uncomplicated pregnancies will be included. Mothers will have: up to 5 study visits; receive a single dose of active vaccine or placebo (a dummy vaccine); general and obstetrical examinations; heath questions; blood collected from their arm and umbilical cord; monthly contacts; and will be followed for 6 months after delivery. Babies will have: 5 planned visits; a physical examination; health questions; at least one monthly contact; blood collected if umbilical cord could not be collected. Approximately 1,500 infants will have one blood sample taken. All babies will be followed for 12 months after birth. Safety will be monitored for mothers and babies. They may have extra visits for cold-like illnesses, where nasal swabs will be collected.

This trial is closed to recruitment, no follow-up. In Scotland this trial recruited in NHS Lothian.