Pregnancy and neonatal outcomes in COVID-19: study protocol for a global registry of women with suspected or confirmed SARS-CoV-2 infection in pregnancy and their neonates, understanding natural history to guide treatment and prevention

ntroduction Previous novel COVID-19 pandemics, SARS and middle east respiratory syndrome observed an association of infection in pregnancy with preterm delivery, stillbirth and increased maternal mortality. COVID-19, caused by SARS-CoV-2 infection, is the largest pandemic in living memory. Rapid accrual of robust case data on women in pregnancy and their babies affected by suspected COVID-19 or confirmed SARS-CoV-2 infection will inform clinical management and preventative strategies in the current pandemic and future outbreaks. Methods and analysis The pregnancy and neonatal outcomes in COVID-19 (PAN-COVID) registry are an observational study collecting focused data on outcomes of pregnant mothers who have had suspected COVID-19 in pregnancy or confirmed SARS-CoV-2 infection and their neonates via a web-portal. Among the women recruited to the PAN-COVID registry, the study will evaluate the incidence of: (1) miscarriage and pregnancy loss, (2) fetal growth restriction and stillbirth, (3) preterm delivery, (4) vertical transmission (suspected or confirmed) and early onset neonatal SARS-CoV-2 infection. Data will be centre based and collected on individual women and their babies. Verbal consent will be obtained, to reduce face-to-face contact in the pandemic while allowing identifiable data collection for linkage. Statistical analysis of the data will be carried out on a pseudonymised data set by the study statistician. Regular reports will be distributed to collaborators on the study research questions. Ethics and dissemination This study has received research ethics approval in the UK. For international centres, evidence of appropriate local approval will be required to participate, prior to entry of data to the database. The reports will be published regularly. The outputs of the study will be regularly disseminated to participants and collaborators on the study website (https://pan-covid.org) and social media channels as well as dissemination to scientific meetings and journals

A national cohort study and confidential enquiry to investigate ethnic disparities in maternal mortality

Background Ethnic disparities in maternal mortality were first documented in the UK in the early 2000s but are known to be widening. This project aimed to describe the women who died in the UK during or up to a year after the end of pregnancy, to compare the quality of care received by women from different aggregated ethnic groups, and to identify any structural or cultural biases or discrimination affecting their care. Methods National surveillance data was used to identify all 1894 women who died during or up to a year after the end of pregnancy between 2009 and 18 in the UK. Their characteristics and causes of death were described. A Confidential Enquiry was undertaken to describe the quality of care women received. The care of a stratified random sample of 54 women who died during or up to a year after the end of pregnancy between 2009 and 18, (18 from the aggregated group of Black women, 19 from the Asian aggregated group and 17 from the White aggregated group) was re-examined specifically to describe any structural or cultural biases or discrimination identified. Findings There were no major differences causes of death between women from different aggregated ethnic groups, with cardiovascular disease the leading cause of death in all groups. Multiple areas of bias were identified in the care women received, including lack of nuanced care (notable amongst women from Black aggregated ethnic groups who died), microaggressions (most prominent in the care of women from Asian aggregated ethnic groups who died) and clinical, social and cultural complexity (evident across all ethnic groups). Interpretation This confidential enquiry suggests that multiple structural and other biases exist in UK maternity care. Further research on the role of microaggressions is warranted. Funding This research is funded by the National Institute for Health Research (NIHR) Policy Research Programme, conducted through the Policy Research Unit in Maternal and Neonatal Health and Care, PR-PRU-1217–21,202. MK is an NIHR Senior Investigator. SK is part funded and FCS fully funded by the National Institute for Health Research (NIHR) Applied Research Centre (ARC) West Midlands. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care

Effect of the Growth Assessment Protocol on the DEtection of Small for GestatioNal age fetus: process evaluation from the DESiGN cluster randomised trial

BACKGROUND: Reducing the rate of stillbirth is an international priority. At least half of babies stillborn in high-income countries are small for gestational-age (SGA). The Growth Assessment Protocol (GAP), a complex antenatal intervention that aims to increase the rate of antenatal detection of SGA, was evaluated in the DESiGN type 2 hybrid effectiveness-implementation cluster randomised trial (n = 13 clusters). In this paper, we present the trial process evaluation. METHODS: A mixed-methods process evaluation was conducted. Clinical leads and frontline healthcare professionals were interviewed to inform understanding of context (implementing and standard care sites) and GAP implementation (implementing sites). Thematic analysis of interview text used the context and implementation of complex interventions framework to understand acceptability, feasibility, and the impact of context. A review of implementing cluster clinical guidelines, training and maternity records was conducted to assess fidelity, dose and reach. RESULTS: Interviews were conducted with 28 clinical leads and 27 frontline healthcare professionals across 11 sites. Staff at implementing sites generally found GAP to be acceptable but raised issues of feasibility, caused by conflicting demands on resource, and variable beliefs among clinical leaders regarding the intervention value. GAP was implemented with variable fidelity (concordance of local guidelines to GAP was high at two sites, moderate at two and low at one site), all sites achieved the target to train > 75% staff using face-to-face methods, but only one site trained > 75% staff using e-learning methods; a median of 84% (range 78–87%) of women were correctly risk stratified at the five implementing sites. Most sites achieved high scores for reach (median 94%, range 62–98% of women had a customised growth chart), but generally, low scores for dose (median 31%, range 8–53% of low-risk women and median 5%, range 0–17% of high-risk women) were monitored for SGA as recommended. CONCLUSIONS: Implementation of GAP was generally acceptable to staff but with issues of feasibility that are likely to have contributed to variation in implementation strength. Leadership and resourcing are fundamental to effective implementation of clinical service changes, even when such changes are well aligned to policy mandated service-change priorities. TRIAL REGISTRATION: Primary registry and trial identifying number: ISRCTN 67698474. Registered 02/11/16. https://doi.org/10.1186/ISRCTN67698474

Pravastatin for early-onset pre-eclampsia:a randomised, blinded, placebo-controlled trial

Objective: Women with pre-eclampsia have elevated circulating levels of soluble fms-like tyrosine kinase-1 (sFlt-1). Statins can reduce sFlt-1 from cultured cells and improve pregnancy outcome in animals with a pre-eclampsia-like syndrome. We investigated the effect of pravastatin on plasma sFlt-1 levels during pre-eclampsia. Design: Blinded (clinician and participant), proof of principle, placebo-controlled trial. Setting: Fifteen UK maternity units. Population: We used a minimisation algorithm to assign 62 women with early-onset pre-eclampsia (24 +0–31 +6 weeks of gestation) to receive pravastatin 40 mg daily (n = 30) or matched placebo (n = 32), from randomisation to childbirth. Primary outcome: Difference in mean plasma sFlt-1 levels over the first 3 days following randomisation. Results: The difference in the mean maternal plasma sFlt-1 levels over the first 3 days after randomisation between the pravastatin (n = 27) and placebo (n = 29) groups was 292 pg/ml (95% CI −1175 to 592; P = 0.5), and over days 1–14 was 48 pg/ml (95% CI −1009 to 913; P = 0.9). Women who received pravastatin had a similar length of pregnancy following randomisation compared with those who received placebo (hazard ratio 0.84; 95% CI 0.50–1.40; P = 0.6). The median time from randomisation to childbirth was 9 days [interquartile range (IQR) 5–14 days] for the pravastatin group and 7 days (IQR 4–11 days) for the placebo group. There were three perinatal deaths in the placebo-treated group and no deaths or serious adverse events attributable to pravastatin. Conclusions: We found no evidence that pravastatin lowered maternal plasma sFlt-1 levels once early-onset pre-eclampsia had developed. Pravastatin appears to have no adverse perinatal effects. Tweetable abstract: Pravastatin does not improve maternal plasma sFlt-1 or placental growth factor levels following a diagnosis of early preterm pre-eclampsia #clinicaltrial finds

Basic science232. Certolizumab pegol prevents pro-inflammatory alterations in endothelial cell function

Background: Cardiovascular disease is a major comorbidity of rheumatoid arthritis (RA) and a leading cause of death. Chronic systemic inflammation involving tumour necrosis factor alpha (TNF) could contribute to endothelial activation and atherogenesis. A number of anti-TNF therapies are in current use for the treatment of RA, including certolizumab pegol (CZP), (Cimzia ®; UCB, Belgium). Anti-TNF therapy has been associated with reduced clinical cardiovascular disease risk and ameliorated vascular function in RA patients. However, the specific effects of TNF inhibitors on endothelial cell function are largely unknown. Our aim was to investigate the mechanisms underpinning CZP effects on TNF-activated human endothelial cells. Methods: Human aortic endothelial cells (HAoECs) were cultured in vitro and exposed to a) TNF alone, b) TNF plus CZP, or c) neither agent. Microarray analysis was used to examine the transcriptional profile of cells treated for 6 hrs and quantitative polymerase chain reaction (qPCR) analysed gene expression at 1, 3, 6 and 24 hrs. NF-κB localization and IκB degradation were investigated using immunocytochemistry, high content analysis and western blotting. Flow cytometry was conducted to detect microparticle release from HAoECs. Results: Transcriptional profiling revealed that while TNF alone had strong effects on endothelial gene expression, TNF and CZP in combination produced a global gene expression pattern similar to untreated control. The two most highly up-regulated genes in response to TNF treatment were adhesion molecules E-selectin and VCAM-1 (q 0.2 compared to control; p > 0.05 compared to TNF alone). The NF-κB pathway was confirmed as a downstream target of TNF-induced HAoEC activation, via nuclear translocation of NF-κB and degradation of IκB, effects which were abolished by treatment with CZP. In addition, flow cytometry detected an increased production of endothelial microparticles in TNF-activated HAoECs, which was prevented by treatment with CZP. Conclusions: We have found at a cellular level that a clinically available TNF inhibitor, CZP reduces the expression of adhesion molecule expression, and prevents TNF-induced activation of the NF-κB pathway. Furthermore, CZP prevents the production of microparticles by activated endothelial cells. This could be central to the prevention of inflammatory environments underlying these conditions and measurement of microparticles has potential as a novel prognostic marker for future cardiovascular events in this patient group. Disclosure statement: Y.A. received a research grant from UCB. I.B. received a research grant from UCB. S.H. received a research grant from UCB. All other authors have declared no conflicts of interes

Macroprolactinomas and Nonfunctioning Pituitary Adenomas and Pregnancy Outcomes

Objective To examine the monitoring, management, and outcomes of pituitary tumors in pregnancy. Methods A national, prospective, observational, population-based case series study was conducted in all UK consultant-led obstetric units over 3 years using the UK Obstetric Surveillance System. In order to evaluate rates of adverse pregnancy outcomes, women with a macroprolactinoma (≥10mm) or non-functioning pituitary adenoma, diagnosed before or during pregnancy, were compared to 2 comparison groups: 1) a UKOSS cohort with singleton (n=2205) or twin (n=27) pregnancy and 2) data from the Office of National Statistics (n=2,703,102). Main outcome measures were the incidence, management, and frequency of adverse maternal and offspring outcomes of pituitary tumors in pregnancy. Results There were 71 confirmed cases of pituitary tumors in pregnancy (49 macrolactinoma, 16 non-functioning adenomas, 3 acromegaly, 3 Cushing’s disease). The women with pituitary tumors were 4 years older than comparison women (P<0.001). None of the 9 women treated with surgery or radiotherapy prior to pregnancy had symptomatic tumor expansion. This occurred in 6 out of 40 women with macroprolactinomas and 1 out of 7 non-functioning adenomas diagnosed before conception, and in 3 out of 5 women with non-functioning adenomas diagnosed in pregnancy. Two women had pituitary apoplexy, both of whom also had symptoms of expansion of tumor or surrounding pituitary tissue. To within the level of accuracy possible, there was no evidence that pituitary tumors were associated with adverse pregnancy outcomes (pregnancy-induced hypertension, preeclampsia, preterm labor, stillbirth). Women with non-functioning adenomas were more likely to have cesarean section compared to controls (RR 2.06, CI 1.26-3.36, p = 0.035). Conclusions The majority of women with macroprolactinomas and non-functioning adenomas have good pregnancy outcomes. Non-functioning pituitary adenomas occur more commonly in pregnancy than previously thought, and can present de novo with symptoms of pituitary expansion in pregnancy

Rheumatic mitral valve disease in pregnancy

A 32-year-old Nepalese woman with known rheumatic mitral valve disease presented 17 weeks into her first pregnancy with exertional breathlessness and wheezing, leading to expectoration of foamy pink liquid. Her history included percutaneous balloon mitral valvotomy at the age of 25 years, after which she had remained asymptomatic and fully active. She had three episodes of acute pulmonary oedema and was transferred to a tertiary centre for further management. An echocardiogram suggested severe mitral stenosis (mitral valve area 1.0 cm2) and pulmonary hypertension (mean pulmonary artery pressure 87 mmHg). She had further episodes of pulmonary oedema despite maximal medical therapy with diuretics, cardioselective beta blockers (dose limited because of systolic hypotension), digoxin, nitrates and anticoagulation. At 21 weeks' gestation, an emergency St Jude metallic valve was implanted. Unfortunately, intrauterine death occurred 2 days postoperatively, likely caused by pre-eclampsia or haemolysis, elevated liver enzymes and low platelets (HELLP) syndrome. The patient recovered well and continues on warfarin and a small dose of beta blocker. </jats:p

Myasthenia in pregnancy:best practice guidelines from a UK multispecialty working group

A national UK workshop to discuss practical clinical management issues related to pregnancy in women with myasthenia gravis was held in May 2011. The purpose was to develop recommendations to guide general neurologists and obstetricians and facilitate best practice before, during and after pregnancy. The main conclusions were (1) planning should be instituted well in advance of any potential pregnancy to allow time for myasthenic status and drug optimisation; (2) multidisciplinary liaison through the involvement of relevant specialists should occur throughout pregnancy, during delivery and in the neonatal period; (3) provided that their myasthenia is under good control before pregnancy, the majority of women can be reassured that it will remain stable throughout pregnancy and the postpartum months; (4) spontaneous vaginal delivery should be the aim and actively encouraged; (5) those with severe myasthenic weakness need careful, multidisciplinary management with prompt access to specialist advice and facilities; (6) newborn babies born to myasthenic mothers are at risk of transient myasthenic weakness, even if the mother's myasthenia is wellcontrolled, and should have rapid access to neonatal high-dependency support