Eugene Oteng-Ntim

Background: Pregnancy in women living with sickle cell disease (SCD) is associated with increased risk of morbidity and mortality for mother and baby. Outside of pregnancy, serial prophylactic exchange blood transfusion (SPEBT) has proven efficacy as a treatment for acute SCD complications, however, there is inadequate evidence for the safety and benefit for SCD during pregnancy. Aim: To explore health professionals and women’s view on the acceptability and feasibility of a randomised control trial of SPEBT versus usual care in pregnant women with SCD (Transfusion Antenatally in Pregnant women with SCD—TAPS2). Methods: Semi-structured telephone interviews were conducted with TAPS2 trial participants, trial decliners and clinical staff working on the TAPS2 trial. Interviews were analysed using reflexive thematic analysis. Results: We interviewed 19 trial participants, 12 trial decliners and 15 clinical staff. Three overarching themes were identified. First, factors affecting patient decisions on participation. These included personal benefit, particularly the hope that SPEBT would lead to a healthier pregnancy—and altruistic motivations to help other women with SCD. Factors deterring women from participating included concerns about potential risks of SPEBT, for example infection, side effects, or transfusion reactions. Second, experiences of the TAPS2 trial varied. Participants allocated to SPEBT recounted perceived health benefits as well as ‘expected’ side effects. The time and cost involved in attending transfusion sessions had been difficult for some. Clinical staff at some sites reported that pressures on local apheresis capacity made delivering the intervention challenging. Third, interviews provided recommendations to inform the design of a future definitive RCT of SPEBT versus usual care, including suggestions to maximise participant recruitment. Suggested strategies included the provision of accessible, evidenced-based patient education to patients, partners and families to enable informed decision-making. There was strong support for including an observational arm in any future trial to enable patients unwilling, or unable, to be randomised to take part. Conclusion: Patients’ views on blood transfusions emerged as a key determinant in whether they chose to take part in this feasibility trial. Addressing pregnant SCD women’s treatment concerns and preferences is key to maximising recruitment and retention in future trials. Addressing information gaps or misinformation through accessible patient education is needed. Including an observational study arm as part of a future definitive RCT, along with other highlighted strategies, will ensure that the evidence base and understanding of clinical outcomes in pregnant women with SCD is maximised for future research. Trial registration: NIH registry ( www.clinicaltrials.gov ), registration number NCT03975894 (registered 05/06/19); ISRCTN ( www.isrctn.com ), registration number ISRCTN52684446 (retrospectively registered 02/08/19).

Introduction: Sickle cell disease (SCD) poses significant risks during pregnancy. Transfusions are the only recommended treatment, but there is no strong evidence of its efficacy. The aim of this study was to evaluate prophylactic transfusion on pregnancy outcomes.Methods: We performed a systematic review and meta‐analysis (PROSPERO‐CRD42024510511), using MEDLINE, EMBASE, Cochrane, Web of Science, and Maternity and Infant Care. No date or language restrictions were applied. Inclusion criteria comprised randomised‐controlled trials (RCTs) involving SCD pregnancy, comparing maternal and foetal outcomes for prophylactic versus on‐demand transfusions. Two independent reviewers performed screening, selection, and data extraction, following PRISMA. Two authors independently assessed certainty and risk‐of‐bias. Data were pooled using random‐effects model. Primary outcomes included mortality, vaso‐occlusive crisis (VOC), acute chest syndrome, venous thromboembolism and preterm delivery. The measure of the effect was the unadjusted odds ratio (OR), calculated from numbers of events.Results: Ninety‐one studies were identified and two RCTs (106 patients) were included, with uncertain and low risk of bias. Prophylactic transfusions reduced VOC, OR of 0.197 (95% CI 0.08–0.49). However, due to the small number of patients, this meta‐analysis was underpowered to evaluate other outcomes.Conclusion: A larger RCT is needed to comprehensively assess the impact of prophylactic transfusion in SCD pregnancy.

Serial prophylactic exchange blood transfusion (SPEBT) is increasingly used in sickle cell disease (SCD) pregnancy, despite a lack of robust evidence. The Transfusion Antenatally in Pregnant Women with Sickle Cell Disease (TAPS2) study assessed the feasibility and acceptability of conducting a definitive randomized controlled trial of SPEBT (intervention) vs standard care (control) in this population. Women aged ≥18 years with SCD, between 6+0 and 18+6 weeks of singleton gestation, were randomized 1:1 every 6 -10 weeks throughout pregnancy in 7 hospitals in England. The main outcomes were recruitment rate (primary outcome), acceptability, and retention. Secondary outcomes were safety and maternal/infant outcomes. In total, 194 women were screened over 42 months (extended because of the pandemic), 88 were eligible, and 35 (39.8%) consented to participate; 18 participants were randomized to intervention, and 17 to control. Follow-up data were collected on all participants. Twelve patients in the intervention group received at least 1 SPEBT, of these, 11 received ≥3. The remaining patient was withdrawn from SPEBT because of transfusion reaction. Sixteen control participants required at least 1 transfusion. There were no statistically significant differences in maternal, infant, and postnatal outcomes. A trend toward a lower incidence of vaso-occlusive crisis, preterm delivery, and improved birthweight was observed in the intervention. The study achieved satisfactory recruitment and retention, confirming its acceptability to participants. TAPS2 demonstrates that it is feasible to perform a definitive international trial of SPEBT in SCD pregnancy. These trials were registered at www.ClinicalTrials.gov as #NCT03975894 and International Standard Randomized Controlled Trial Number (www.isrctn.com; #ISRCTN52684446).

Summary: There are limited data on contemporary outcomes for women with sickle cell disease (SCD) in pregnancy. We conducted a single‐site matched cohort study, comparing 131 pregnancies to women with SCD between 2007 and 2017 to a comparison group of 1310 pregnancies unaffected by SCD. Restricting our analysis to singleton pregnancies that reached 24 weeks of gestation, we used conditional Poisson regression to estimate adjusted risk ratios (aRRs) for perinatal outcomes. Infants born to mothers with SCD were more likely to be small for gestational age [aRR 1·69, 95% confidence interval (CI) 1·13–2·48], preterm (aRR 2·62, 95% CI 1·82–3·78) and require Neonatal Unit (NNU) admission (aRR 3·59, 95% CI 2·18–5·90). Pregnant women with SCD were at higher risk of pre‐eclampsia/eclampsia (aRR 3·53, 95% CI 2·00–6·24), more likely to receive induction of labour (aRR 2·50, 95% CI 1·82–1·76) and caesarean birth (aRR 1·44, 95% CI 1·18–1·76). In analysis stratified by genotype, the risk of adverse outcomes was highest in haemoglobin SS (HbSS) pregnancies (n = 80). There was no strong evidence that haemoglobin SC (HbSC) pregnancies (n = 46) were at higher risk of preterm birth, caesarean delivery, or NNU admission. Pre‐eclampsia/eclampsia was more frequently observed in HbSC pregnancies. Despite improvements in the care of pregnant women with SCD, the increased risk of adverse perinatal outcomes remains.

Sickle cell disease (SCD) patients are commonly affected by pulmonary complications such as acute chest syndrome (ACS), pulmonary embolism (PE) and pneumonia that contribute to significant mortality risks. With a greater susceptibility to infection, they are deemed to be vulnerable patients during the current COVID‐19 pandemic. In emerging small case studies of SCD patients with COVID‐19 and further complicated by pneumonia, ACS, and/or PE, the clinical benefits of early exchange transfusion and Tocilizumab are evident. However, further clinical trials and larger cohort studies are essential to evaluate effective diagnostic and management options for this high‐risk group.

Summary: To review the cumulative outcome of pre‐implantation genetic diagnosis (PGD) cycles performed for prevention of sickle cell disease (SCD). Couples referred for PGD for SCD between April 2012 and October 2017 were included. Ovarian stimulation was performed using a short gonadotrophin‐releasing hormone (GnRH) antagonist protocol and follicle‐stimulating hormone injections. The GnRH agonist was used to trigger oocyte maturation. Oocytes were fertilised using intracytoplasmic sperm injection. Trophectoderm biopsy was performed on day 5 or 6 followed by vitrification. Genetic testing was done using pre‐implantation genetic haplotyping. A total of 60 couples started 70 fresh PGD cycles (mean 1·2 cycles/couple) and underwent a total of 74 frozen‐embryo‐transfer (FET) cycles (mean 1·3 FET/couple). The mean (SD) female age was 33 (4·4) years and the mean (SD) anti‐müllerian hormone level was 22·9 (2·8) pmol/l. The cumulative live‐birth rate was 54%/PGD cycle started and 63%/couple embarking on PGD. The rate of multiple births was 8%. The cumulative outcome of PGD treatment for prevention of SCD transmission is high and PGD treatment should be offered to all at‐risk couples.

Background: Increasing numbers of UK women have overweight or obese body mass index scores when they become pregnant, or gain excessive weight in pregnancy, increasing their risk of adverse outcomes. Failure to manage postnatal weight is linked to smoking, non-healthy dietary choices, lack of regular exercise and poorer longer-term health. Women living in areas of higher social deprivation are more likely to experience weight management problems postnatally.Objectives: The objectives were to assess the feasibility of conducting a definitive randomised controlled trial to determine the clinical effectiveness and cost-effectiveness of lifestyle information and access to a commercial weight management group focusing on self-monitoring, goal-setting and motivation to achieve dietary change commencing 8–16 weeks postnatally to achieve and maintain weight management and positive lifestyle behaviour.Design: The design was a randomised two-arm feasibility trial with a nested mixed-methods process evaluation.Setting: The setting was a single centre in an inner city setting in the south of England.Participants: Participants were women with body mass index scores of > 25 kg/m²at antenatal ‘booking’ and women with normal body mass index scores (18.0–24.9 kg/m²) at antenatal booking who developed excessive gestational weight gain as assessed at 36 weeks’ gestation.Main outcome measures: Recruitment, retention, acceptability of trial processes and identification of relevant economic data were the feasibility objectives. The proposed primary outcome was difference between groups in weight at 12 months postnatally, expressed as percentage weight change and weight loss from antenatal booking. Other proposed outcomes included assessment of diet, physical activity, smoking, alcohol consumption, body image, maternal esteem, mental health, infant feeding and NHS costs.Results: Most objectives were achieved. A total of 193 women were recruited, 98 allocated to the intervention arm and 95 to the control arm. High follow-up rates (> 80%) were achieved to 12 months. There was an 8.8% difference in weight loss at 12 months between women allocated to the intervention arm and women allocated to the control arm (13.0% vs. 4.2%, respectively;p = 0.062); 47% of women in the intervention arm attended at least one weight management session, with low risk of contamination between arms. The greatest benefit was among women who attended ≥ 10 sessions. Barriers to attending sessions included capability, opportunity and motivation issues. Data collection tools were appropriate to support economic evaluation in a definitive trial, and economic modelling is feasible to quantify resource impacts and outcomes not directly measurable within a trial.Limitations: The trial recruited from only one site. It was not possible to recruit women with normal body mass index scores who developed excessive pregnancy weight gain.Conclusions: It was feasible to recruit and retain women with overweight or obese body mass index scores at antenatal booking to a trial comparing postnatal weight management plus standard care with standard care only and collect relevant data to assess outcomes. Approaches to recruit women with normal body mass index scores who gain excessive gestational weight need to be considered. Commercial weight management groups could support women’s weight management as assessed at 12 months postnatally, with probable greater benefit from attending ≥ 10 sessions. Process evaluation findings highlighted the importance of providing more information about the intervention on trial allocation, extended duration of time to commence sessions following birth and extended number of sessions offered to enhance uptake and retention. Results support the conduct of a future randomised controlled trial.Trial registration: Current Controlled Trials ISRCTN39186148.Funding: This project was funded by the National Institute for Health Research (NIHR) Public Health Research programme and will be published in full inPublic Health Research; Vol. 8, No. 9. See the NIHR Journals Library website for further project information.

Background Sickle cell disease (SCD) is a multisystem disease characterised by vaso-occlusive crisis, chronic anaemia and a shorter lifespan. More patients with SCD are living till reproductive age and contemplating pregnancy. Pulmonary complications in pregnancy are significant causes of maternal morbidity and mortality but yet this has not been systematically quantified. A systematic review and meta-analysis were conducted to quantify the association between SCD and pulmonary complications in pregnancy. Methods MEDLINE, EMBASE, Web of Science, Cochrane and Maternity and Infant Care databases were searched for publications between January 1998 and April 2019. Observational studies involving at least 30 participants were included. Random-effects models were used for statistical meta-analysis. Findings Twenty-two studies were included in the systematic review and 18 in the quantitative analysis. The meta-analysis included 3964 pregnancies with SCD and 336 559 controls. Compared with women without SCD, pregnancies complicated by SCD were at increased risk of pulmonary thromboembolism (relative risk (RR) 7.74; 95% CI 4.65 to 12.89). The estimated prevalence of acute chest syndrome and pneumonia was 6.46% (95% CI 4.66% to 8.25%), with no significant difference between the HbSS and HbSC genotypes (RR 1.42; 95% CI 0.90 to 2.23). Interpretation This meta-analysis highlighted a strong association between SCD and maternal pulmonary complications. Understanding the risks of and the factors associated with pulmonary complications would aid preconceptual counselling and optimal management of the condition in pregnancy, thereby reducing associated maternal morbidity and mortality. PROSPERO registration number CRD42019124708.

Objective To assess whether levels of first‐trimester pregnancy‐associated plasma protein A (PAPP‐A) differ between women with and without sickle cell disease (SCD). Methods Retrospective study of 101 singleton pregnancies in women with SCD (including 55 with genotype HbSS, 37 with genotype HbSC and 9 with other genotypes). Measured levels of PAPP‐A were converted to multiple of the median (MoM) values corrected for gestational age and maternal characteristics. Median PAPP‐A MoM in the SCD group was compared to that of 1010 controls. Results In the SCD group median PAPP‐A MoM was lower than in the non‐SCD group (0.72, interquartile range [IQR] 0.54‐1.14 versus 1.09, IQR 0.74‐1.49; p<0.001). Within the SCD group median PAPP‐A MoM was lower for those with genotype HbSS than HbSC (0.62, IQR 0.44‐1.14 versus 0.94, IQR 0.72‐1.25; p=0.006). In 7.3% (4/55) of the HbSS group there was stillbirth and in these cases PAPP‐A was ≤0.5 MoM; in the control group the incidence of stillbirth was lower (1%; p<0.001). In HbSS disease the incidence of small for gestational age (SGA) neonates was increased. Conclusion Pregnancies with HbSS have lower PAPP‐A MoM values and higher incidence of stillbirth and birth of SGA neonates than in non‐SCD controls.