Marcus Green

BACKGROUND: The ratio of sFlt-1 (soluble fms-like tyrosine kinase 1) to PlGF (placental growth factor) is an established biomarker for preeclampsia diagnostic triage. GlyFn (glycosylated fibronectin) measured by point-of-care testing is an alternative rapid assessment from finger-stick blood samples. This study was designed to test the hypothesis that the sensitivity of GlyFn is noninferior to that of the sFlt-1/PlGF ratio in women with suspected preeclampsia. METHODS: This prospective observational study evaluated the diagnostic accuracy of both tests for preeclampsia in high-risk participants presenting between 24 ⁺⁰ and 36 ⁺⁶ weeks of gestation at 5 hospitals from January 2024 to July 2025. Participants underwent simultaneous point-of-care GlyFn testing (Lumella) and laboratory sFlt-1/PlGF ratio measurements. The primary outcome was birth for preeclampsia within 28 days of testing. Thresholds were set at GlyFn ≥350 μg/mL and sFlt-1/PlGF ratio ≥38. The noninferiority margin was predefined at 5%. RESULTS: Among 397 participants, 59 (14.9%) had an indicated birth for preeclampsia within 28 days. GlyFn showed a sensitivity of 86.44% (95% CI, 75.02%–93.96%) compared with sFlt-1/PlGF 84.75% (95% CI, 73.01%–92.78%). Although sensitivities were numerically similar ( P =0.79), the CI around the difference was too wide to establish noninferiority at the 5% margin. Negative predictive values were 96.40% and 96.59%, respectively. However, GlyFn had a lower specificity (63.31% versus 75.44%, P <0.01). CONCLUSIONS: Point-of-care GlyFn testing showed similar sensitivity and negative predictive value to the sFlt-1/PlGF ratio for predicting an indicated birth for preeclampsia within 28 days. The point-of-care nature of the GlyFn test may facilitate immediate clinical decision-making in diverse healthcare settings. REGISTRATION: URL: https://doi.org/10.1186/ISRCTN13430018 ; Unique identifier: ISRCTN13430018.

Background: Raised blood pressure affects 10% of pregnancies worldwide, of which around half develop pre-eclampsia including proteinuria, causing maternal and perinatal morbidity and mortality. Objectives: To develop and test interventions for self-monitoring of blood pressure designed to improve the detection and management of hypertension in pregnancy. Additionally, to test the accuracy of self-testing of urine for protein, a key marker of pre-eclampsia. Design and methods: Development phase, a pilot trial, two large randomised controlled trials of self-monitoring of blood pressure interventions with integrated economic evaluations, linked qualitative work, a large survey and a diagnostic accuracy study of self-testing for proteinuria, and finally economic modelling. Setting and participants: Antenatal clinics in 16 English hospitals. Participants were pregnant women and antenatal healthcare professionals. Patient and public involvement: Comprehensive involvement from initial development through to dissemination, with collaboration from both individuals and relevant charities and organisations. Interventions: Self-monitoring of blood pressure supported by app to improve the detection (BUMP1) and management (BUMP2) of raised blood pressure in pregnancy (WS3.2.1 and 2). Proteinuria self-testing by pregnant hypertensive women (UDIP, WS4). Main outcome measures: Qualitative data informed the development of the BUMP App and trial (WS1). Feasibility of self-monitoring of blood pressure in hypertensive pregnancy (recruitment, retention, adherence and intervention persistence) (WS2). Prevalence of self-monitoring of blood pressure during pregnancy (WS3.1). Time to diagnosis of hypertension defined in routinely recorded clinical data (BUMP1, WS3.2.1) and difference in mean systolic blood pressure recorded by healthcare professionals between randomisation and birth (BUMP2, WS3.2.2). WS3.3 and 4.2 evaluated experiences with the trial and UDIP respectively using inductive and deductive thematic analysis. Within-trial cost–consequence analysis and long-term cost-effectiveness modelling (WS3.4 and WS5). Proteinuria testing accuracy (WS4.1). Results: WS1 : Areas important to staff included providing clear patient information and supporting them in decision-making in the context of discrepant readings. The intervention was optimised iteratively with pregnant women. WS2 : A feasibility trial showed that the self-monitoring of blood pressure intervention was feasible and acceptable. WS3.1 : Data from a survey of 5181 women showed that 19% of pregnant women were currently self-monitoring blood pressure but only 482/983 (49%) shared this information with healthcare professionals. WS3.2.1 : Self-monitoring of blood pressure in addition to usual care did not lead to an earlier diagnosis of clinic hypertension in routinely recorded clinical data with no evidence of differences in maternal or perinatal outcomes or serious adverse events (BUMP1). WS3.2.2: Self-monitoring of blood pressure in pregnancy hypertension did not improve clinic blood pressure control, with no difference in maternal or perinatal outcomes or serious adverse events (BUMP2). WS3.3: Self-monitoring was generally accepted by women and professionals with differences in views of which blood pressure data to give precedence. Women found self-monitoring empowering, provided health professionals considered home readings in their management. On occasion self-monitoring proved unsettling due to uncertainty. WS3.4: Within trial economic analyses revealed no significant difference in overall total costs between trial arms in either BUMP1 or BUMP2. Women’s health-related quality of life (EQ-5D-5L) was similar between groups in both trials. WS4 : Self-testing for proteinuria had a sensitivity of 0.71 (95% confidence interval 0.62 to 0.79) and a specificity of 0.89 (95% confidence interval 0.84 to 0.92) compared to laboratory protein–creatinine ratio testing and this was not clinically or statistically different when compared to healthcare professionals or a colorimetric monitor (UDIP, WS4.1). Self-testing was generally acceptable (WS4.2). WS5 : Model frameworks capable of facilitating exploration of the long-term cost-effectiveness of combining self-monitoring of blood pressure with blood pressure treatment and management policies were developed for use in future research projects in the area. Implementation : Self-monitoring was rapidly and widely implemented during the pandemic but has yet to become fully embedded in clinical pathways. Limitations: Self-monitoring of blood pressure by women in the control groups; difficulties in testing self-monitoring of blood pressure in clinical pathways in the absence of evidence or accepted treatment thresholds; process evaluation suggested women and professionals privileged different information. Conclusions: Self-monitoring of blood pressure during higher risk or hypertensive pregnancy was feasible, acceptable, safe, and no more expensive, but did not improve the detection of hypertension or blood pressure control in those with hypertension when used alongside usual care. During the programme, self-monitoring of blood pressure entered common practice in pregnancy, a process accelerated by the pandemic. Pregnant women can read a dipstick for urinary protein with similar accuracy to healthcare professionals or colorimetric testing, and find this acceptable, suggesting that self-testing could be included in clinical pathways. Future work: Future trials of interventions including self-monitoring of blood pressure should test strategies in the context of novel clinical pathways. Study registration: This study is registered as Current Controlled Trials ISRCTN16018898. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Programme Grants for Applied Research programme (NIHR award ref.: RP-PG-0614-20005) and is published in full in Programme Grants for Applied Research ; Vol. 14, No. 3. See the NIHR Funding and Awards website for further award information.

Background: For women with chronic or gestational hypertension who remain well, early term birth (at 37–38 weeks’ gestation) may reduce maternal complications, caesareans and stillbirths, but it may increase neonatal morbidity compared with expectant care. Expectant care may increase costs. There are no high-quality data to guide care, which currently involves maternal–fetal surveillance and intervention for maternal or fetal compromise, which may be rapid or unexpected. Objective: To investigate optimal timing of birth for women with chronic or gestational hypertension who reach term and remain well. Design: Pragmatic, unmasked, multicentre randomised trial with a health economic analysis. Setting: Fifty United Kingdom hospitals. Participants: Inclusion: maternal age ≥ 16 years, chronic or gestational hypertension, singleton pregnancy, live fetus, 36 ⁺⁰ –37 ⁺⁶ weeks’ gestation and able to give documented informed consent. Exclusion: contraindication to either trial arm (e.g. pre-eclampsia), blood pressure ≥ 160/110 mmHg until controlled, major fetal anomaly anticipated to require neonatal care unit admission or participation in another timed birth trial. Interventions: Planned early term birth at 38 ^+0–3 weeks’ (intervention) or ‘usual care at term’ (control, revised from ‘expectant care until at least 40 ⁺⁰ weeks’, August 2022). Main outcome measures: Maternal coprimary: composite of ‘poor maternal outcome’ (severe hypertension, maternal death or maternal morbidity and superiority hypothesis). Neonatal coprimary: neonatal care unit admission ≥ 4 hours (non-inferiority hypothesis). Each coprimary is measured until primary hospital discharge or 28 days post birth (whichever is earlier). Key secondary: caesarean birth. Randomisation: 1 : 1 ratio, minimised for key prognostic variables: site, hypertension type and prior caesarean. Blinding: It was not possible to mask care providers or participants to the intervention. For the coprimary maternal outcome, there was local site principal investigator/delegate sign-off based on review, masked to allocated group, of primary case notes. Results: From 2019 to 2022, 403 participants were randomised (37% of target 1080) to intervention ( n = 201) or control ( n = 202). The funder stopped the trial during the coronavirus disease discovered in 2019 pandemic for delayed recruitment. In the intervention (vs. control) group, birth was a median of 0.9 weeks earlier (38.4, interquartile range 38.3–38.6 vs. 39.3, interquartile range 38.7–39.9 weeks). There was no evidence of a difference in ‘poor maternal outcome’ (13% vs. 12%, respectively; adjusted risk ratio 1.16, 95% confidence interval 0.72 to 1.87). For ‘neonatal care unit admission ≥ 4 hours’, the intervention was considered to be non-inferior to control, as the adjusted risk difference, 95% confidence interval upper bound did not cross the 8% pre-specified non-inferiority margin (7% vs. 7%, respectively; adjusted risk difference 0.003, 95% confidence interval −0.05 to +0.06), although event rates were lower than estimated. There was no evidence of a difference in caesarean (29% vs. 36%, respectively; adjusted risk ratio 0.81, 95% confidence interval 0.61 to 1.08). Limitations: Recruitment was 37% of the anticipated sample size (as above). Conclusions: Despite being unable to recruit to target in this study, we observed that most women with chronic or gestational hypertension required labour induction and planned birth at 38 ^0–3 weeks (vs. usual care), which resulted in birth an average of 6 days earlier and there were no differences in poor maternal outcome or neonatal morbidity. Our findings provide reassurance about planned birth at 38 ^0–3 weeks as a clinical option for these women. Future work: An individual participant data meta-analysis is planned to address whether the intervention (vs. control) reduces caesarean; low adverse event rates would make unfeasible mounting another randomised trial. Funding: This synopsis presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number 16/167/123.

Background: Chronic or gestational hypertension complicates approximately 7% of pregnancies, half of which reach 37 weeks’ gestation. Early term birth (at 37 to 38 weeks) may reduce maternal complications, cesareans, stillbirths, and costs but may increase neonatal morbidity. In the WILL Trial (When to Induce Labour to Limit risk in pregnancy hypertension), we aimed to establish optimal timing of birth for women with chronic or gestational hypertension who reach term and remain well. Methods and findings: This 50-centre, open-label, randomised trial in the United Kingdom included an economic analysis. WILL randomised women with chronic or gestational hypertension at 36 to 37 weeks and a singleton fetus, and who provided documented informed consent to “Planned early term birth at 38^+0–3 weeks” (intervention) or “usual care at term” (control). The coprimary outcomes were “poor maternal outcome” (composite of severe hypertension, maternal death, or maternal morbidity; superiority hypothesis) and “neonatal care unit admission for ≥4 hours” (noninferiority hypothesis). The key secondary was cesarean. Follow-up was to 6 weeks postpartum. The planned sample size was 540/group. Analysis was by intention-to-treat. A total of 403 participants (37.3% of target) were randomised to the intervention (n = 201) or control group (n = 202), from 3 June 2019 to 19 December 2022, when the funder stopped the trial for delayed recruitment. In the intervention (versus control) group, losses to follow-up were 18/201 (9%) versus 15/202 (7%). In each group, maternal age was about 30 years, about one-fifth of women were from ethnic minorities, over half had obesity, approximately half had chronic hypertension, and most were on antihypertensives with normal blood pressure. In the intervention (versus control) group, birth was a median of 0.9 weeks earlier (38.4 [38.3 to 38.6] versus 39.3 [38.7 to 39.9] weeks). There was no evidence of a difference in “poor maternal outcome” (27/201 [13%] versus 24/202 [12%], respectively; adjusted risk ratio [aRR] 1.16, 95% confidence interval [CI] 0.72 to 1.87). For “neonatal care unit admission for ≥4 hours,” the intervention was considered noninferior to the control as the adjusted risk difference (aRD) 95% CI upper bound did not cross the 8% prespecified noninferiority margin (14/201 [7%] versus 14/202 [7%], respectively; aRD 0.003, 95% CI −0.05 to +0.06), although event rates were lower-than-estimated. The intervention (versus control) was associated with no difference in cesarean (58/201 [29%] versus 72/202 [36%], respectively; aRR 0.81, 95% CI 0.61 to 1.08. There were no serious adverse events. Limitations include our smaller-than-planned sample size, and lower-than-anticipated event rates, so the findings may not be generalisable to where hypertension is not treated with antihypertensive therapy. Conclusions: In this study, we observed that most women with chronic or gestational hypertension required labour induction, and planned birth at 38^+0–3 weeks (versus usual care) resulted in birth an average of 6 days earlier, and no differences in poor maternal outcome or neonatal morbidity. Our findings provide reassurance about planned birth at 38^+0–3 weeks as a clinical option for these women. Trial registration: isrctn.com ISRCTN77258279.

BACKGROUND: PlGF (placental growth factor)-based testing reduces severe maternal adverse outcomes. Repeat PlGF-based testing is not associated with improved perinatal or maternal outcomes. This planned secondary analysis aimed to determine whether there is a subgroup of women who benefit from repeat testing. METHODS: Pregnant individuals with suspected preterm preeclampsia were randomized to repeat revealed PlGF-based testing, compared with usual care where testing was concealed. Perinatal and maternal outcomes were stratified by trial group, by initial PlGF-based test result, and by PlGF-based test type (PlGF or sFlt-1 [soluble fms-like tyrosine kinase-1]/PlGF ratio). RESULTS: A total of 1252 pregnant individuals were included. Abnormal initial PlGF-based test identified a more severe phenotype of preeclampsia, at increased risk of adverse maternal and perinatal outcomes. Repeat testing was not significantly associated with clinical benefit in women with abnormal initial results. Of women with a normal initial result, 20% developed preeclampsia, with the majority at least 3 to 4 weeks after initial presentation. Repeat test results were more likely to change from normal to abnormal in symptomatic women (112/415; 27%) compared with asymptomatic women (163/890; 18%). A higher proportion of symptomatic women who changed from normal to abnormal were diagnosed with preeclampsia, compared with asymptomatic women. CONCLUSIONS: Our results do not demonstrate evidence of the clinical benefit of repeating PlGF-based testing if the initial result is abnormal. Judicious use of repeat PlGF-based testing to stratify risk may be considered at least 2 weeks after a normal initial test result, particularly in women who have symptoms or signs of preeclampsia. REGISTRATION: URL: XXX; Unique identifier: ISRCTN85912420.

BACKGROUND: Pregnancy hypertension continues to cause maternal and perinatal morbidity. Two linked UK randomized trials showed adding self-monitoring of blood pressure (SMBP) with automated telemonitoring to usual antenatal care did not result in earlier detection or better control of pregnancy hypertension. This article reports the trials’ integrated cost analyses. METHODS: Two cost analyses. SMBP with usual care was compared with usual care alone in pregnant individuals at risk of hypertension (BUMP 1 trial [Blood Pressure Monitoring in High Risk Pregnancy to Improve the Detection and Monitoring of Hypertension], n=2441) and with hypertension (BUMP 2 trial, n=850). Clinical notes review identified participant-level antenatal, intrapartum, and postnatal care and these were costed. Comparisons between trial arms used means and 95% CIs. Within BUMP 2, chronic and gestational hypertension cohorts were analyzed separately. Telemonitoring system costs were reported separately. RESULTS: In BUMP 1, mean (SE) total costs with SMBP and with usual care were £7200 (£323) and £7063 (£245), respectively, mean difference (95% CI), £151 (−£633 to £936). For the BUMP 2 chronic hypertension cohort, corresponding figures were £13 384 (£1230), £12 614 (£1081), mean difference £323 (−£2904 to £3549) and for the gestational hypertension cohort were £11 456 (£901), £11 145 (£959), mean difference £41 (−£2486 to £2567). The per-person cost of telemonitoring was £6 in BUMP 1 and £29 in BUMP 2. CONCLUSIONS: SMBP was not associated with changes in the cost of health care contacts for individuals at risk of, or with, pregnancy hypertension. This is reassuring as SMBP in pregnancy is widely prevalent, particularly because of the COVID-19 pandemic. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03334149.

Objective: To assess the diagnostic performance of angiogenic biomarkers in determining need for delivery in seven days in women with late preterm preeclampsia. Study design: In a prospective observational cohort study in 36 maternity units across England and Wales, we studied the diagnostic accuracy of placental growth factor (PlGF) and sFlt-1 in determining the risk of complications requiring delivery in late preterm (34⁺⁰ to 36⁺⁶ weeks' gestation) preeclampsia. Angiogenic biomarkers were measured using the Quidel (PlGF) and Roche (sFlt-1 : PlGF ratio) assays. Additional clinical data was obtained for use within the established ʻPrediction of complications in early-onset pre-eclampsiaʼ (PREP)-S prognostic model. Biomarkers were assessed using standard methods (sensitivity, specificity, Receiver Operator Curve areas). Estimated probability of early delivery from PREP-S was compared to actual event rates. Main outcome measures: Clinically indicated need for delivery for pre-eclampsia within seven days. Results: PlGF (Quidel) testing had high sensitivity (97.9%) for delivery within seven days, but negative predictive value was only 71.4%, with low specificity (8.4%), with similar results from sFlt-1/PlGF assay. The area under the curve for PlGF was 0.60 (SE 0.03), and 0.65 (0.03), and 0.64 (0.03) for PREP-S in combination with PlGF, and sFlt-1 : PlGF, respectively. Conclusions: Angiogenic biomarkers do not add to clinical assessment to help determine need for delivery for women with late preterm pre-eclampsia. Existing models developed in women with early-onset pre-eclampsia to predict complications cannot be used to predict clinically indicated need for delivery in women with late preterm pre-eclampsia.

Objective: We evaluated the best time to initiate delivery in late preterm pre-eclampsia in order to optimise long-term infant and maternal outcomes. Design: Parallel-group, non-masked, randomised controlled trial. Setting: 46 UK maternity units. Population: Women with pre-eclampsia between 34⁺⁰ and 36⁺⁶ weeks’ gestation, without severe disease, were randomised to planned delivery or expectant management. Primary long-term outcome: Infant neurodevelopmental outcome at 2 years of age, using the PARCA-R (Parent Report of Children’s Abilities-Revised) composite score. Results: Between 29 September 2014 and 10 December 2018, 901 women were enrolled in the trial, with 450 allocated to planned delivery and 451 to expectant management. At 2-year follow-up, the intention-to-treat analysis population included 276 women (290 infants) allocated to planned delivery and 251 women (256 infants) to expectant management. The mean composite standardised PARCA-R scores were 89.5 [standard deviation (SD) 18.2] in the planned delivery group and 91.9 (SD 18.4) in the expectant management group, with an adjusted mean difference of −2.4 (95% CI −5.4 to 0.5) points. Conclusion: In infants of women with late preterm pre-eclampsia, average neurodevelopmental assessment at 2 years lies within the normal range, regardless of whether planned delivery or expectant management is pursued. Because of lower than anticipated follow-up, there was limited power to demonstrate these scores were not different, but the small between-group difference in PARCA-R scores is unlikely to be clinically important.