Title: STOP-OHSS (Shaping and Trialling Outpatient Protocols for Ovarian HyperStimulation Syndrome): A randomised controlled trial to assess the clinical and cost-effectiveness of active outpatient management of Ovarian HyperStimulation Syndrome
Funder: Department of Health and Social Care

Abstract: 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). If too many eggs develop, the ovaries can become large and painful. It can affect women who are recovering from the effects of the medication given during their fertility treatment, and those who have become pregnant after treatment. Symptoms are often more severe in pregnant women._x000D_ _x000D_ OHSS can range in severity and can be categorised as mild, moderate or severe. Mild symptoms are common, whereby the woman feels unwell and experiences shortness of breath, abdominal pain and bloating. This is usually resolved quickly, but for 3-8% of women undergoing IVF, these symptoms can worsen to moderate or severe OHSS. Severe OHSS can lead to serious health complications needing treatment in hospital for several days or weeks, and in a small number of women can be life-threatening._x000D_ _x000D_ Current management of OHSS is conservative; fertility teams monitor the condition, and if severe symptoms develop the woman is admitted to hospital for intensive monitoring and/or treatment. This treatment can include a procedure called paracentesis, which involves a needle being inserted through the vagina or abdomen to drain the fluid that has collected to relieve the OHSS symptoms. Paracentesis is normally performed in an inpatient setting._x000D_ _x000D_ The aim of this study is to understand whether carrying out the same paracentesis procedure but early and as an outpatient (and including additional monitoring) can stop OHSS symptoms from worsening, and can prevent women from having to be admitted to hospital. Women deemed at risk of OHSS will be informed about the study and monitored. If OHSS develops, they will be asked to take part in the study. If they agree, a computer will randomly determine whether they receive either outpatient paracentesis, or usual care. The women will be followed up to see how quickly their symptoms resolve and whether hospital admission is needed. We will also compare the safety, acceptability and cost of the treatment._x000D_ _x000D_ We aim to recruit 224 women with moderate or severe (early or late) OHSS, who will receive either early outpatient paracentesis, or usual care. We will primarily be looking at any OHSS-related hospital admissions of at least 24 hours, within 28 days of randomisation. This information will be collected by staff at fertility units by contacting the participant by telephone, at patient visits, or from hospital notes after 28 days. Participants will then be followed up at 90 days to review medical notes and collect data on DVT, significant infections, hospitalisations and pregnancy. If pregnant at 90 days, they will be followed up again at 13.5 months to review the medical notes and collect data on live birth information, pregnancy outcomes, neonatal death and serious adverse events for the baby._x000D_ _x000D_ We will involve former patients throughout the study to help inform the design and delivery of the research. The Sheffield Reproductive Health Research Public Advisory Panel will contribute to the study and assist in presenting the results of the research to a wide audience. The results of the study will be disseminated to patients and clinicians via reports sent to key organisations (e.g. British Fertility Society, Fertility Network UK) and publication in journals.

Lay abstract: Background_x000D_ Ovarian hyperstimulation syndrome (OHSS) is a side-effect of assisted reproductive treatments (ARTs) and is caused by overstimulation of the ovaries, resulting in fluid retention in the abdomen (ascites), dehydration and in critical cases, respiratory distress and disturbed renal and liver functions. _x000D_ OHSS can be classified as early or late. Early OHSS is caused by the ovarian stimulation drugs given during ARTs and occurs usually within 7 days after the final drug (hCG) is given. Late OHSS usually occurs 10 days or more after the administration of hCG and is caused by endogenous hCG of a resulting pregnancy. _x000D_ Currently, treatment is only usually provided once OHSS has progressed to a severe state and the patient requires intensive inpatient treatment. Prior to this, patients are monitored and provided with medication and advice to enable rehydration. In uncontrolled, small studies, paracentesis (drainage of the ascites) provided in the outpatient setting has been shown to prevent the need for hospitalisation if administered soon after OHSS develops; this needs to be confirmed by high quality trials. _x000D_ _x000D_ Aims_x000D_ The study aims to establish the clinical and cost-effectiveness, safety, and acceptability of outpatient paracentesis (OP) as an active management for women with moderate or severe OHSS, in a multi-centre adaptive randomised controlled trial (RCT) with internal pilot to assess the feasibility of conducting the RCT._x000D_ Research question_x000D_ What is the clinical and cost effectiveness, safety profile and acceptability of OP compared to conventional conservative management (usual care) of women with moderate or severe OHSS? We hypothesise that the use of OP in the management of moderate or severe OHSS will result in earlier resolution of symptoms and avoid the need for hospital admission, when compared with usual care._x000D_ _x000D_ Methods_x000D_ In phase 1, qualitative interviews were undertaken with clinicians and patients to explore the feasibility and acceptability of the earlier active management protocols and RCTs. The results of these interviews were fed back to clinicians during a consensus event in order to confirm protocols. In parallel, a retrospective review of patient notes was undertaken at the proposed RCT centres in order to validate the parameters used for the RCTs. _x000D_ In phase 2, the study will undergo a pragmatic, two-arm, parallel-group, adaptive, open label, superiority, confirmatory, group sequential, individual RCT with one interim analysis for futility early stopping. A total of 224 women with moderate or severe (early or late) OHSS will be randomised to the trial. The women will be undergoing In vitro fertilisation (IVF) including intracytoplasmic sperm injection (ICSI) and intrauterine insemination (IUI). Participants will be randomised (1:1) to receive outpatient paracentesis (OP) plus increased self-monitoring, or conservative management (usual care). The primary outcome measure will be OHSS related hospitalisations for at least 24 hours within 28 days of randomisation. _x000D_ The trial will include an internal pilot after 15 months of recruitment to assess the feasibility of conducting the RCT. An interim analysis will be performed for futility early stopping when 65% (73 per arm) of the maximum required participants have accrued primary outcome data on hospitalisation. _x000D_ _x000D_ Anticipated impact and dissemination_x000D_ If effective, earlier active management of OHSS will prevent the more serious complications of OHSS and avoid inpatient hospital admission, reducing burden on patients and saving the NHS an estimated £2.62 million per year. Findings will be directly disseminated to key stakeholders (fertility charities, clinical bodies and patients) and published in high-quality journals.

Research activity codes: 7.3 MANAGEMENT AND DECISION MAKING;8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH