Title: A feasibility trial of serial prophylactic exchange blood transfusion (SPEBT) in pregnant women with sickle cell disease (SCD) aiming to improve maternal and infant outcomes.
Funder: Department of Health and Social Care

Abstract: Background: Pregnancies in women with SCD are associated with a higher risk of sickle and pregnancy complications. There are limited options for treating SCD during pregnancy. Serial prophylactic exchange blood transfusion (SPEBT) has shown to be effective in treating SCD outside pregnancy, but there is a lack of evidence regarding its use during pregnancy. Evidence from observational studies suggests that SPEBT may be beneficial, but a recent Cochrane review identified only one small and underpowered randomised controlled trial (RCT), reporting indeterminate results. There is a clear need for a rigorous multicentre RCT to determine the safety and efficacy of SPEBT during pregnancy. Aims and research question: The aim of this study is to assess the feasibility and acceptability of conducting a RCT to establish the clinical and cost effectiveness of serial prophylactic exchange blood transfusion in pregnant women with SCD. The overarching research question is how effective is SPEBT for improving maternal and infant outcomes in pregnant women with SCD. Design: An individually randomised two-arm feasibility trial. Duration: 24 months Setting: Five hospitals in England, four in inner London and one in central Manchester. Outcomes: The primary outcome for this study will be the recruitment rate (women eligible: women randomised) to determine feasibility of an RCT in women with this rare condition. Data on other feasibility outcomes (reasons for refusal; acceptability and patient experience) will be collected. We will also record clinical outcomes for the woman (hospital admissions; length of stay; frequency of painful crisis; frequency of other symptoms) and infant (birthweight; preterm delivery; NICU admission; stillbirth) with a focus on improving design and implementation of a future RCT. Methods: Women aged 18 or over with SCD and a singleton pregnancy who are at 18 weeks or below gestation will be recruited from either the SCD clinics or antenatal booking clinics at the five maternity units. Women will be individually randomised to the intervention or control arm. Women allocated to the intervention will receive SPEBT starting between 6-18 weeks of gestation. SPEBT will be performed using automated erythrocytopheresis, approximately every 6-8 weeks, aiming to maintain HbS% below 30%. All recruited women will receive usual NHS care for pregnant women with SCD based on the NICE Accredited RCOG Guidelines. Women in the control group will only receive transfusion if clinically indicated. All participating women will complete a baseline questionnaire on previous medical and obstetric history. Women will be monitored at least monthly throughout pregnancy to assess maternal, sickle, and fetal complications. Detailed information about adverse events (including hospital admission) and delivery outcomes will be extracted from medical records. A process evaluation will be conducted, including the collection of qualitative data (interviews, focus groups) from both participating and non-participating women to assess patient experience and acceptability. An embedded health economic study will collect and assess economic and QoL data. We will also test data capture methods on NHS resource use (inpatient, outpatient, test/procedures, etc.). Sample size: We will aim to recruit 50 women in total, at a minimum rate of three women a month. Allowing for loss to follow-up, this should result in complete data on 40 women (20 in each arm). We will estimate maternal and infant clinical outcomes with a focus on estimates of means and standard deviations necessary for the estimation of sample size for the definitive RCT. Potential benefit to patients and the NHS: This feasibility study is the first step towards rigorously evaluating SPEBT as a treatment for SCD in pregnancy to improve maternal and infant outcomes. The study will address an important knowledge and safety gaps highlighted by a 2016 Cochrane review and recent meta-analyses.

Lay abstract: Sickle Cell Disease (SCD) is a serious inherited blood disorder affecting red blood cells. When oxygen levels drop the red cells become abnormally shaped and unable to move through the blood vessels easily. Blood and oxygen do not reach body organs, resulting in episodes of severe pain and other complications. Pregnant women with SCD have an increased risk of both sickle and pregnancy complications, including raised blood pressure. Their babies may grow more slowly in the womb, are more likely to be born early and need special care, and have a higher risk of dying. The only treatments currently available for women with SCD are Hydroxycarbamide (which cannot be used during pregnancy) and blood transfusion. Currently, blood transfusion is only used during pregnancy to treat emergency complications. We believe giving blood transfusions throughout pregnancy could improve outcomes for both mother and babies. In Serial Prophylactic Exchange Blood Transfusion (SPEBT), sickle blood is mechanically removed and simultaneously replaced with donor red cells. We wish to conduct a trial of SPEBT given every 6-8 weeks, starting before 18 weeks of pregnancy, compared to standard care. We will measure outcomes in the woman (e.g. hospital admission, frequency of crisis) and their infants (e.g. early delivery, birthweight). Before we embark on a large multi-centre study we need to know if this is feasible and safe. We will therefore undertake a feasibility study in which we will randomly allocate participants to have either SPEBT or standard care. The study will be carried out in five centres and last two years. We will assess how many pregnant women are willing to join the study and how many participants remain part of the study until the end. This will give us an indication of how many participants we may be able to recruit in our future trial.

Research activity codes: 3.3 NUTRITION AND CHEMOPREVENTION
Health categories: BLOOD;REPRODUCTIVE HEALTH AND CHILDBIRTH