Effectiveness of nitric oxide agents in preventing the early onset of pre-eclampsia and possible modification of metabolic factors in high-risk pregnancies:

Objectives: To determine the effectiveness of nitric oxide agents in modifying the metabolic factors of pre-eclampsia and its effectiveness in preventing the onset of pre-eclampsia in high-risk pregnancies. Introduction: Pre-eclampsia is a major cause of maternal death during the prenatal and neonatal periods. Nitric oxide is a vasodilator and platelet aggregation inhibitor responsible for the vascular adaptation of the placenta. Although various studies have established that nitric oxide is effective in preventing complications from pre-eclampsia, there is limited evidence to show that administering nitric oxide agents to the high-risk women before 20 weeks’ gestation will prevent the onset of pre-eclampsia. Inclusion criteria: This review will consider randomized controlled trials that compare nitric oxide donors and precursors with a placebo or no intervention on pregnant women (18 to 44 years) with ≤ 20-week gestational age that are at high risk of pre-eclampsia. The primary outcome of interest will be the onset of pre-eclampsia. Secondary outcomes include increased systolic and diastolic blood pressure, elevated asymmetric dimethylarginine levels, decreased endothelial nitric oxide synthase activity, reduced maternal placental vasculature, and abnormal Doppler ultrasound waveforms. Methods: Data sources will be drawn up from MEDLINE, CINAHL, ProQuest (Health and Medicine) and Web of Science from inception till current date. No language restrictions will be applied in the search strategy. Selected studies will be assessed against the JBI critical appraisal checklist, and the certainty of evidence and strength of recommendations from findings will also be ascertained. Systematic review registration number: CRD4201809929

Ophthalmic artery Doppler for prediction of pre‐eclampsia: systematic review and meta‐analysis

Objective To determine the accuracy of ophthalmic artery Doppler in pregnancy for the prediction of pre‐eclampsia (PE). Methods MEDLINE, EMBASE, CINAHL and The Cochrane Library were searched for relevant citations without language restrictions. Two reviewers independently selected studies that evaluated the accuracy of ophthalmic artery Doppler to predict the development of PE and extracted data to construct 2 × 2 tables. Individual patient data were obtained from the authors if available. A bivariate random‐effects model was used for the quantitative synthesis of data. Logistic regression analysis was employed to generate receiver–operating characteristics (ROC) curves and obtain optimal cut‐offs for each investigated parameter, and a bivariate analysis was employed using predetermined cut‐offs to obtain sensitivity and specificity values and generate summary ROC curves. Results A total of 87 citations matched the search criteria of which three studies, involving 1119 pregnancies, were included in the analysis. All included studies had clear description of the index and reference tests, avoidance of verification bias and adequate follow‐up. Individual patient data were obtained for all three included studies. First diastolic peak velocity of ophthalmic artery Doppler at a cut‐off of 23.3 cm/s showed modest sensitivity (61.0%; 95% CI, 44.2–76.1%) and specificity (73.2%; 95% CI, 66.9–78.7%) for the prediction of early‐onset PE (area under the ROC curve (AUC), 0.68; 95% CI, 0.61–0.76). The first diastolic peak velocity had a much lower sensitivity (39.0%; 95% CI, 20.6–61.0%), a similar specificity (73.2%; 95% CI, 66.9–78.7%) and a lower AUC (0.58; CI, 0.52–0.65) for the prediction of late‐onset PE. The pulsatility index of the ophthalmic artery did not show a clinically useful sensitivity or specificity at any cut‐off for early‐ or late‐onset PE. Peak ratio above 0.65 showed a similar diagnostic accuracy to that of the first diastolic peak velocity with an AUC of 0.67 (95% CI, 0.58–0.77) for early‐onset PE and 0.57 (95% CI, 0.51–0.63) for late‐onset disease. Conclusions Ophthalmic artery Doppler is a simple, accurate and objective technique with a standalone predictive value for the development of early‐onset PE equivalent to that of uterine artery Doppler evaluation. The relationship between ophthalmic Doppler indices and PE cannot be a consequence of trophoblast invasion and may be related to maternal hemodynamic adaptation to pregnancy. The findings of this review justify efforts to elucidate the effectiveness and underlying mechanism whereby two seemingly unrelated maternal vessels can be used for the prediction of a disease considered a ‘placental disorder’

External validation, update and development of prediction models for pre-eclampsia using an Individual Participant Data (IPD) meta-analysis: the International Prediction of Pregnancy Complication Network (IPPIC pre-eclampsia) protocol.

Background: Pre-eclampsia, a condition with raised blood pressure and proteinuria is associated with an increased risk of maternal and offspring mortality and morbidity. Early identification of mothers at risk is needed to target management. Methods/design: We aim to systematically review the existing literature to identify prediction models for pre-eclampsia. We have established the International Prediction of Pregnancy Complication Network (IPPIC), made up of 72 researchers from 21 countries who have carried out relevant primary studies or have access to existing registry databases, and collectively possess data from more than two million patients. We will use the individual participant data (IPD) from these studies to externally validate these existing prediction models and summarise model performance across studies using random-effects meta-analysis for any, late (after 34 weeks) and early (before 34 weeks) onset pre-eclampsia. If none of the models perform well, we will recalibrate (update), or develop and validate new prediction models using the IPD. We will assess the differential accuracy of the models in various settings and subgroups according to the risk status. We will also validate or develop prediction models based on clinical characteristics only; clinical and biochemical markers; clinical and ultrasound parameters; and clinical, biochemical and ultrasound tests. Discussion: Numerous systematic reviews with aggregate data meta-analysis have evaluated various risk factors separately or in combination for predicting pre-eclampsia, but these are affected by many limitations. Our large-scale collaborative IPD approach encourages consensus towards well developed, and validated prognostic models, rather than a number of competing non-validated ones. The large sample size from our IPD will also allow development and validation of multivariable prediction model for the relatively rare outcome of early onset pre-eclampsia. Trial registration: The project was registered on Prospero on the 27 November 2015 with ID: CRD42015029349

External validation of prognostic models to predict stillbirth using the International Prediction of Pregnancy Complications (IPPIC) Network database: an individual participant data meta-analysis

Objective Stillbirth is a potentially preventable complication of pregnancy. Identifying women at high risk of stillbirth can guide decisions on the need for closer surveillance and timing of delivery in order to prevent fetal death. Prognostic models have been developed to predict the risk of stillbirth, but none has yet been validated externally. In this study, we externally validated published prediction models for stillbirth using individual participant data (IPD) meta-analysis to assess their predictive performance. Methods MEDLINE, EMBASE, DH-DATA and AMED databases were searched from inception to December 2020 to identify studies reporting stillbirth prediction models. Studies that developed or updated prediction models for stillbirth for use at any time during pregnancy were included. IPD from cohorts within the International Prediction of Pregnancy Complications (IPPIC) Network were used to validate externally the identified prediction models whose individual variables were available in the IPD. The risk of bias of the models and cohorts was assessed using the Prediction study Risk Of Bias ASsessment Tool (PROBAST). The discriminative performance of the models was evaluated using the C-statistic, and calibration was assessed using calibration plots, calibration slope and calibration-in-the-large. Performance measures were estimated separately in each cohort, as well as summarized across cohorts using random-effects meta-analysis. Clinical utility was assessed using net benefit. Results Seventeen studies reporting the development of 40 prognostic models for stillbirth were identified. None of the models had been previously validated externally, and the full model equation was reported for only one-fifth (20%, 8/40) of the models. External validation was possible for three of these models, using IPD from 19 cohorts (491 201 pregnant women) within the IPPIC Network database. Based on evaluation of the model development studies, all three models had an overall high risk of bias, according to PROBAST. In the IPD meta-analysis, the models had summary C-statistics ranging from 0.53 to 0.65 and summary calibration slopes ranging from 0.40 to 0.88, with risk predictions that were generally too extreme compared with the observed risks. The models had little to no clinical utility, as assessed by net benefit. However, there remained uncertainty in the performance of some models due to small available sample sizes. Conclusions The three validated stillbirth prediction models showed generally poor and uncertain predictive performance in new data, with limited evidence to support their clinical application. The findings suggest methodological shortcomings in their development, including overfitting. Further research is needed to further validate these and other models, identify stronger prognostic factors and develop more robust prediction models. (c) 2021 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.Peer reviewe

Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Background: In this study, we aimed to evaluate the effects of tocilizumab in adult patients admitted to hospital with COVID-19 with both hypoxia and systemic inflammation. Methods: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. Those trial participants with hypoxia (oxygen saturation <92% on air or requiring oxygen therapy) and evidence of systemic inflammation (C-reactive protein ≥75 mg/L) were eligible for random assignment in a 1:1 ratio to usual standard of care alone versus usual standard of care plus tocilizumab at a dose of 400 mg–800 mg (depending on weight) given intravenously. A second dose could be given 12–24 h later if the patient's condition had not improved. The primary outcome was 28-day mortality, assessed in the intention-to-treat population. The trial is registered with ISRCTN (50189673) and ClinicalTrials.gov (NCT04381936). Findings: Between April 23, 2020, and Jan 24, 2021, 4116 adults of 21 550 patients enrolled into the RECOVERY trial were included in the assessment of tocilizumab, including 3385 (82%) patients receiving systemic corticosteroids. Overall, 621 (31%) of the 2022 patients allocated tocilizumab and 729 (35%) of the 2094 patients allocated to usual care died within 28 days (rate ratio 0·85; 95% CI 0·76–0·94; p=0·0028). Consistent results were seen in all prespecified subgroups of patients, including those receiving systemic corticosteroids. Patients allocated to tocilizumab were more likely to be discharged from hospital within 28 days (57% vs 50%; rate ratio 1·22; 1·12–1·33; p<0·0001). Among those not receiving invasive mechanical ventilation at baseline, patients allocated tocilizumab were less likely to reach the composite endpoint of invasive mechanical ventilation or death (35% vs 42%; risk ratio 0·84; 95% CI 0·77–0·92; p<0·0001). Interpretation: In hospitalised COVID-19 patients with hypoxia and systemic inflammation, tocilizumab improved survival and other clinical outcomes. These benefits were seen regardless of the amount of respiratory support and were additional to the benefits of systemic corticosteroids. Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

Background: Many patients with COVID-19 have been treated with plasma containing anti-SARS-CoV-2 antibodies. We aimed to evaluate the safety and efficacy of convalescent plasma therapy in patients admitted to hospital with COVID-19. Methods: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]) is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. The trial is underway at 177 NHS hospitals from across the UK. Eligible and consenting patients were randomly assigned (1:1) to receive either usual care alone (usual care group) or usual care plus high-titre convalescent plasma (convalescent plasma group). The primary outcome was 28-day mortality, analysed on an intention-to-treat basis. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936. Findings: Between May 28, 2020, and Jan 15, 2021, 11558 (71%) of 16287 patients enrolled in RECOVERY were eligible to receive convalescent plasma and were assigned to either the convalescent plasma group or the usual care group. There was no significant difference in 28-day mortality between the two groups: 1399 (24%) of 5795 patients in the convalescent plasma group and 1408 (24%) of 5763 patients in the usual care group died within 28 days (rate ratio 1·00, 95% CI 0·93–1·07; p=0·95). The 28-day mortality rate ratio was similar in all prespecified subgroups of patients, including in those patients without detectable SARS-CoV-2 antibodies at randomisation. Allocation to convalescent plasma had no significant effect on the proportion of patients discharged from hospital within 28 days (3832 [66%] patients in the convalescent plasma group vs 3822 [66%] patients in the usual care group; rate ratio 0·99, 95% CI 0·94–1·03; p=0·57). Among those not on invasive mechanical ventilation at randomisation, there was no significant difference in the proportion of patients meeting the composite endpoint of progression to invasive mechanical ventilation or death (1568 [29%] of 5493 patients in the convalescent plasma group vs 1568 [29%] of 5448 patients in the usual care group; rate ratio 0·99, 95% CI 0·93–1·05; p=0·79). Interpretation: In patients hospitalised with COVID-19, high-titre convalescent plasma did not improve survival or other prespecified clinical outcomes. Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research