Late Preterm Pre-eclampsia Research Articles

Planned Delivery or Expectant Management for Late Preterm Pre-Eclampsia in Low-Income and Middle-Income Countries (CRADLE-4): A Multicenter, Open-Label, Randomized Controlled Trial

(Lancet. 2023;402:386–396) Pre-eclampsia is a relatively common condition and poses a disproportionately high risk to women in low-income and middle-income countries where it is a leading cause of maternal morbidity and mortality, estimated to have caused more than 42,000 deaths. The only known treatment is delivery, but there are also risks associated with preterm delivery that can contribute to both maternal and neonatal outcomes. Evidence suggests delivery at 37 weeks optimizes outcomes for both mother and infant, but there is little evidence about delivery in the late preterm gestational period leading up to that, between 34 and 36 and 6/7 weeks. Research in higher income settings has shown that fetal death in these cases is rare, but there are factors in such settings that are unavailable or unrealistic in low-income and middle-income settings. This study aimed to address the gap in knowledge by assessing outcomes related to planned delivery between 34 and 37 weeks in women with pre-eclampsia compared with expectant management during the same gestational period in India and Zambia.

Planned Delivery or Expectant Management for Late Preterm Pre-eclampsia in Low-Income and Middle-Income Countries (CRADLE-4): A Multicentre, Open-Label, Randomized Controlled Trial

(Abstracted from Lancet 2023; 402:386–396) Preeclampsia is a disorder of pregnancy that proposes a disproportionately high risk to women in low- and middle-income countries (LMICs); it is one of the leading causes of maternal morbidity and mortality worldwide and is estimated to have an annual death toll of greater than 40,000. The only treatment with proven effectiveness for preeclampsia is delivery, but there are risks to both mother and infant associated with preterm delivery that contribute to both of their short- and long-term outcomes.

Prognostic indicators of severe disease in late preterm pre-eclampsia to guide decision making on timing of delivery: the PEACOCK study

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.

Project publication: Two-year follow-up of infant and maternal outcomes after planned early delivery or expectant management for late preterm pre-eclampsia (PHOENIX): a randomised controlled trial

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.

Project publication: Planned early delivery or expectant management for late preterm pre-eclampsia (PHOENIX): a randomised controlled trial

This article consists of a citation of a published article describing research funded by the Health Technology Assessment programme under project number 12/25/03, and is provided as as part of the complete record of research outputs for this project. The original publication is available at: https://doi.org/10.1016/S0140-6736(19)31963-4

Planned delivery or expectant management for late preterm pre-eclampsia in low-income and middle-income countries (CRADLE-4): a multicentre, open-label, randomised controlled trial

Pre-eclampsia is a leading cause of maternal and perinatal mortality. Evidence regarding interventions in a low-income or middle-income setting is scarce. We aimed to evaluate whether planned delivery between 34+ 0 and 36+ 6 weeks' gestation can reduce maternal mortality and morbidity without increasing perinatal complications in India and Zambia. In this parallel-group, multicentre, open-label, randomised controlled trial, we compared planned delivery versus expectant management in women with pre-eclampsia from 34+ 0 to 36+ 6 weeks' gestation. Participants were recruited from nine hospitals and referral facilities in India and Zambia and randomly assigned to planned delivery or expectant management in a 1:1 ratio by a secure web-based randomisation facility hosted by MedSciNet. Randomisation was stratified by centre and minimised by parity, single-fetus pregnancy or multi-fetal pregnancy, and gestational age. The primary maternal outcome was a composite of maternal mortality or morbidity with a superiority hypothesis. The primary perinatal outcome was a composite of one or more of: stillbirth, neonatal death, or neonatal unit admission of more than 48 h with a non-inferiority hypothesis (margin of 10% difference). Analyses were by intention to treat, with an additional per-protocol analysis for the perinatal outcome. The trial was prospectively registered with ISRCTN, 10672137. The trial is closed to recruitment and all follow-up has been completed. Between Dec 19, 2019, and March 31, 2022, 565 women were enrolled. 284 women (282 women and 301 babies analysed) were allocated to planned delivery and 281 women (280 women and 300 babies analysed) were allocated to expectant management. The incidence of the primary maternal outcome was not significantly different in the planned delivery group (154 [55%]) compared with the expectant management group (168 [60%]; adjusted risk ratio [RR] 0·91, 95% CI 0·79 to 1·05). The incidence of the primary perinatal outcome by intention to treat was non-inferior in the planned delivery group (58 [19%]) compared with the expectant management group (67 [22%]; adjusted risk difference -3·39%, 90% CI -8·67 to 1·90; non-inferiority p<0·0001). The results from the per-protocol analysis were similar. There was a significant reduction in severe maternal hypertension (adjusted RR 0·83, 95% CI 0·70 to 0·99) and stillbirth (0·25, 0·07 to 0·87) associated with planned delivery. There were 12 serious adverse events in the planned delivery group and 21 in the expectant management group. Clinicians can safely offer planned delivery to women with late preterm pre-eclampsia, in a low-income or middle-income country. Planned delivery reduces stillbirth, with no increase in neonatal unit admissions or neonatal morbidity and reduces the risk of severe maternal hypertension. Planned delivery from 34 weeks' gestation should therefore be considered as an intervention to reduce pre-eclampsia associated mortality and morbidity in these settings. UK Medical Research Council and Indian Department of Biotechnology.

Planned delivery for pre-eclampsia between 34 and 37 weeks of gestation: the PHOENIX RCT.

In women with late preterm pre-eclampsia (i.e. at 34+0 to 36+6 weeks' gestation), the optimal delivery time is unclear because limitation of maternal-fetal disease progression needs to be balanced against infant complications. The aim of this trial was to determine whether or not planned earlier initiation of delivery reduces maternal adverse outcomes without substantial worsening of perinatal or infant outcomes, compared with expectant management, in women with late preterm pre-eclampsia. We undertook an individually randomised, triple non-masked controlled trial in 46 maternity units across England and Wales, with an embedded health economic evaluation, comparing planned delivery and expectant management (usual care) in women with late preterm pre-eclampsia. The co-primary maternal outcome was a maternal morbidity composite or recorded systolic blood pressure of ≥ 160 mmHg (superiority hypothesis). The co-primary short-term perinatal outcome was a composite of perinatal deaths or neonatal unit admission (non-inferiority hypothesis). Analyses were by intention to treat, with an additional per-protocol analysis for the perinatal outcome. The primary 2-year infant neurodevelopmental outcome was measured using the PARCA-R (Parent Report of Children's Abilities-Revised) composite score. The planned sample size of the trial was 900 women; the trial is now completed. We undertook two linked substudies. Between 29 September 2014 and 10 December 2018, 901 women were recruited; 450 women [448 women (two withdrew consent) and 471 infants] were allocated to planned delivery and 451 women (451 women and 475 infants) were allocated to expectant management. The incidence of the co-primary maternal outcome was significantly lower in the planned delivery group [289 (65%) women] than in the expectant management group [338 (75%) women] (adjusted relative risk 0.86, 95% confidence interval 0.79 to 0.94; p = 0.0005). The incidence of the co-primary perinatal outcome was significantly higher in the planned delivery group [196 (42%) infants] than in the expectant management group [159 (34%) infants] (adjusted relative risk 1.26, 95% confidence interval 1.08 to 1.47; p = 0.0034), but indicators of neonatal morbidity were similar in both groups. At 2-year follow-up, the mean PARCA-R scores were 89.5 points (standard deviation 18.2 points) for the planned delivery group (290 infants) and 91.9 points (standard deviation 18.4 points) for the expectant management group (256 infants), both within the normal developmental range (adjusted mean difference -2.4 points, 95% confidence interval -5.4 to 0.5 points; non-inferiority p = 0.147). Planned delivery was significantly cost-saving (-£2711, 95% confidence interval -£4840 to -£637) compared with expectant management. There were nine serious adverse events in the planned delivery group and 12 in the expectant management group. In women with late preterm pre-eclampsia, planned delivery reduces short-term maternal morbidity compared with expectant management, with more neonatal unit admissions related to prematurity but no indicators of greater short-term neonatal morbidity (such as need for respiratory support). At 2-year follow-up, around 60% of parents reported follow-up scores. Average infant development was within the normal range for both groups; the small between-group mean difference in PARCA-R scores is unlikely to be clinically important. Planned delivery was significantly cost-saving to the health service. These findings should be discussed with women with late preterm pre-eclampsia to allow shared decision-making on timing of delivery. Limitations of the trial include the challenges of finding a perinatal outcome that adequately represented the potential risks of both groups and a maternal outcome that reflects the multiorgan manifestations of pre-eclampsia. The incidences of maternal and perinatal primary outcomes were higher than anticipated on the basis of previous studies, but this did not limit interpretation of the analysis. The trial was limited by a higher loss to follow-up rate than expected, meaning that the extent and direction of bias in outcomes (between responders and non-responders) is uncertain. A longer follow-up period (e.g. up to 5 years) would have enabled us to provide further evidence on long-term infant outcomes, but this runs the risk of greater attrition and increased expense. We identified a number of further questions that could be prioritised through a formal scoping process, including uncertainties around disease-modifying interventions, prognostic factors, longer-term follow-up, the perspectives of women and their families, meta-analysis with other studies, effect of a similar intervention in other health-care settings, and clinical effectiveness and cost-effectiveness of other related policies around neonatal unit admission in late preterm birth. The trial was prospectively registered as ISRCTN01879376. This project was funded by the National Institute for Health and Care Research ( NIHR ) Health Technology Assessment programme and will be published in Health Technology Assessment. See the NIHR Journals Library website for further project information.

Cost-utility analysis of planned early delivery or expectant management for late preterm pre-eclampsia (PHOENIX)

Aim There is currently limited evidence on the costs associated with late preterm pre-eclampsia beyond antenatal care and post-natal discharge from hospital. The aim of this analysis is to evaluate the 24-month cost-utility of planned delivery for women with late preterm pre-eclampsia at 34+0 and 36+6 weeks’ gestation compared to expectant management from an English National Health Service perspective using participant-level data from the PHOENIX trial. Methods Women between 34+0 and 36+6 weeks' gestation in 46 maternity units in England and Wales were individually randomised to planned delivery or expectant management. Resource use was collected from hospital records between randomisation and primary hospital discharge following birth. Women were followed up at 6 months and 24 months following birth and self-reported resource use for themselves and their infant(s) covering the previous 6 months. Women completed the EQ-5D-5L at randomisation and follow-up. Results A total of 450 women were randomised to planned delivery, 451 to expectant management: 187 and 170 women, respectively, had complete data at 24 months. Planned delivery resulted in a significantly lower mean cost per woman and infant(s) over 24 months [−£2711, 95% confidence interval (CI) −4840 to −637], with a mean incremental difference in QALYs of 0.019 (95% CI −0.039 to 0.063). Short-term and 24-month infant costs were not significantly different between the intervention arms. There is a 99% probability that planned delivery is cost-effective at all thresholds below £37,000 per QALY gained. Conclusion There is a high probability that planned delivery is cost-effective compared to expectant management. These results need to be considered alongside clinical outcomes and in the wider context of maternity care. Trial registration ISRCTN registry ISRCTN01879376. Registered 25 November 2013.

Cost-Utility Analysis of Planned Early Delivery or Expectant Management for Late Preterm Pre-eclampsia (PHOENIX)

AimThere is currently limited evidence on the costs associated with late preterm pre-eclampsia beyond antenatal care and post-natal discharge from hospital. The aim of this analysis is to evaluate the 24-month cost-utility of planned delivery for women with late preterm pre-eclampsia at 34+0–36+6 weeks’ gestation compared to expectant management from an English National Health Service perspective using participant-level data from the PHOENIX trial.MethodsWomen between 34+0 and 36+6 weeks’ gestation in 46 maternity units in England and Wales were individually randomised to planned delivery or expectant management. Resource use was collected from hospital records between randomisation and primary hospital discharge following birth. Women were followed up at 6 months and 24 months following birth and self-reported resource use for themselves and their infant(s) covering the previous 6 months. Women completed the EQ-5D 5L at randomisation and follow-up.ResultsA total of 450 women were randomised to planned delivery, 451 to expectant management: 187 and 170 women, respectively, had complete data at 24 months. Planned delivery resulted in a significantly lower mean cost per woman and infant(s) over 24 months (− £2711, 95% confidence interval (CI) − 4840 to − 637), with a mean incremental difference in QALYs of 0.019 (95% CI − 0.039 to 0.063). Short-term and 24-month infant costs were not significantly different between the intervention arms. There is a 99% probability that planned delivery is cost-effective at all thresholds below £37,000 per QALY gained.ConclusionThere is a high probability that planned delivery is cost-effective compared to expectant management. These results need to be considered alongside clinical outcomes and in the wider context of maternity care.Trial registration: ISRCTN registry ISRCTN01879376. Registered 25 November 2013.Supplementary InformationThe online version contains supplementary material available at 10.1007/s41669-022-00355-1.

Two-year follow-up of infant and maternal outcomes after planned early delivery or expectant management for late preterm pre-eclampsia (PHOENIX): A randomised controlled trial.

ObjectiveWe evaluated the best time to initiate delivery in late preterm pre‐eclampsia in order to optimise long‐term infant and maternal outcomes.DesignParallel‐group, non‐masked, randomised controlled trial.SettingForty‐six maternity units in the UK.PopulationWomen with pre‐eclampsia between 34+0 and 36+6 weeks of gestation, without severe disease, were randomised to planned delivery or expectant management.Main outcome measuresInfant neurodevelopmental outcome at 2 years of age, using the Parent Report of Children’s Abilities – Revised (PARCA‐R) composite score.ResultsBetween 29 September 2014 and 10 December 2018, 901 women were enrolled in the trial, with 450 women allocated to planned delivery and 451 women allocated to expectant management. At the 2‐year follow‐up, the intention‐to‐treat analysis population included 276 women (290 infants) allocated to planned delivery and 251 women (256 infants) allocated to expectant management. The mean composite standardised PARCA‐R scores were 89.5 (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 points (95% CI −5.4 to 0.5 points).ConclusionsIn infants of women with late preterm pre‐eclampsia, the average neurodevelopmental assessment at 2 years lies within the normal range, regardless of whether planned delivery or expectant management was pursued. With the lower than anticipated follow‐up rate there was limited power to demonstrate that these scores did not differ, but the small between‐group difference in PARCA‐R scores is unlikely to be clinically important.

Defer or deliver? Two‐year outcomes after late preterm pre‐eclampsia

Linked article: This is a mini commentary on Alice Beardmore‐Gray et al., pp. 1654–1663 in this issue. To view this article visit https://doi.org/10.1111/1471-0528.17167

Early Delivery or Expectant Management for Late Preterm Preeclampsia: A Meta-Analysis of Randomized Controlled Trials

(Abstracted from Acta Obstet Gynecol Scand 2021;100:1392–1400) Worldwide, preeclampsia affects approximately 4.5% of pregnancies. Weighing the maternal benefit of immediate delivery with the risk of severe neonatal complications is important to determine the appropriate time to deliver in cases of preeclampsia.

Factors influencing perinatal outcomes in women with preterm preeclampsia: A secondary analysis of the PHOENIX trial.

This secondary analysis of the PHOENIX trial (evaluating planned delivery against expectant management in late preterm preeclampsia) demonstrates that in women who started induction of labour, 63% of women delivered vaginally (56% at 34weeks' gestation). Compared to expectant management, planned delivery was associated with higher rates of neonatal unit admission for prematurity (but lower proportions of small-for-gestational age infants); length of neonatal unit stay and neonatal morbidity (including respiratory support) were similar across both intervention groups at all gestational windows. Neonatal unit admission was increased by earlier gestation at delivery, development of severe preeclampsia, and being small-for-gestational age.

Planned delivery to improve postpartum cardiac function in women with preterm pre-eclampsia: the PHOEBE mechanisms of action study within the PHOENIX RCT

Background Women whose pregnancies are affected by hypertensive disorders of pregnancy, in particular preterm pre-eclampsia, are at increased risk of long-term cardiovascular morbidity and mortality. Objectives To investigate the hypothesis that prolongation of a pregnancy affected by preterm pre-eclampsia managed by expectant management compared with planned early delivery would result in worse cardiovascular function 6 months postpartum. Design A randomised controlled trial. Setting 28 maternity hospitals in England and Wales. Participants Women who were eligible for the Pre-eclampsia in HOspital: Early iNductIon or eXpectant management (PHOENIX) study were approached and recruited for the PHOEBE study. The PHOENIX (Pre-eclampsia in HOspital: Early iNductIon or eXpectant management) study was a parallel-group, non-masked, multicentre, randomised controlled trial that was carried out in 46 maternity units across England and Wales. This study compared planned early delivery with expectant management (usual care) with individual randomisation in women with late preterm pre-eclampsia who were 34 weeks’ gestation to less than 37 weeks’ gestation and having a singleton or dichorionic diamniotic twin pregnancy. Interventions Postpartum follow-up included medical history, blood pressure assessment and echocardiography. All women had blood sampling performed on at least two time points from recruitment to the 6-month follow-up for assessment of cardiac necrosis markers. Main outcome measures Primary outcome was a composite of systolic and/or diastolic dysfunction (originally by 2009 guidelines then updated by 2016 guidelines, with an amended definition of diastolic dysfunction). Analyses were by intention to treat, together with a per-protocol analysis for the primary and secondary outcomes. Results Between 27 April 2016 and 30 November 2018, 623 women were found to be eligible, of whom 420 (67%) were recruited across 28 maternity units in England and Wales. A total of 133 women were allocated to planned delivery, 137 women were allocated to expectant management and a further 150 received non-randomised expectant management within usual care. The mean time from enrolment to delivery was 2.5 (standard deviation 1.9) days in the planned delivery group compared with 6.8 (standard deviation 5.3) days in the expectant management group. There were no differences in the primary outcome between women in the planned delivery group and those in the expectant management group using either the 2009 (risk ratio 1.06, 95% confidence interval 0.80 to 1.40) or the 2016 definition (risk ratio 0.78, 95% confidence interval 0.33 to 1.86). Overall, 10% (31/321) of women had a left ventricular ejection fraction &lt; 55% and 71% of the cohort remained hypertensive at 6 months postpartum. No differences were observed between groups in cardiorespiratory outcomes prior to discharge from hospital or in systolic or diastolic blood pressure measurements. Variables associated with the primary outcome (2009 definition) at 6 months postpartum were maternal body mass index (adjusted odds ratio 1.33 per 5 kg/m2, 95% confidence interval 1.12 to 1.59 per 5 kg/m2) and maternal age (adjusted odds ratio 2.16, 95% confidence interval 1.44 to 3.22 per 10 years). Limitations include changing definitions regarding systolic and/or diastolic dysfunction. Conclusions Preterm pre-eclampsia results in persistence of hypertension in the majority of women with late preterm pre-eclampsia at 6 months postpartum and systolic dysfunction in 10%. Pre-eclampsia should not be considered a self-limiting disease of pregnancy alone. Future work Interventions aimed at reducing cardiovascular dysfunction. Trial registration Current Controlled Trials ISRCTN01879376. Funding This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a Medical Research Council and National Institute for Health Research (NIHR) partnership. This will be published in full in Efficacy and Mechanism Evaluation; Vol. 8, No. 12. See the NIHR Journals Library website for further project information.

SY5-1. Timing of delivery in late preterm pre-eclampsia

SY5-1. Timing of delivery in late preterm pre-eclampsia

Y-014. Two-year infant and maternal outcomes after planned delivery or expectant management for late preterm pre-eclampsia (PHOENIX): a randomised controlled trial

Introduction: Safety is a critical factor in promoting sustainable urban non-motorized travel modes like bicycles. Helmets have shown to be effective in reducing injury severity in bicycle crashes, however, their effects on bicyclists’ behaviors still requires deeper understanding, especially amid the emerging trend of using shared bicycles. Risk compensation effects suggest that bicyclists may offset perceived gains in safety from wearing a helmet by increasing risk-taking behaviors. A better understanding of these compensation effects can be useful in assessing various bicycle safety related programs. Method: Using a sample of 131 bicyclists from the San Francisco Bay area, this research studies how bicyclists respond with respect to risk-taking behaviors under various urban-street conditions, as a function of helmet use. Study participants were each shown 12 videos, shot in Berkeley, California, from the perspective of a bicyclist riding behind another bicyclist. A fractional factorial experiment design was used to systematically vary contextual attributes (e.g., speed, bike lane facilities, on-street parking, passing vehicles) across the videos. After each video, participants were asked to indicate if they would overtake the bicyclist in the video. With the help of data adaptive estimation techniques, targeted maximum likelihood estimation (TMLE) was applied to estimate the average risk difference between helmeted users and non-users, controlling for self-selection effects. Individual-based nonparametric bootstrap was performed to assess the uncertainty associated with the estimator. Results: Our findings suggest, on average, individuals more likely to wear a helmet are 15.6% more likely to undertake a risky overtaking maneuver. Practical Applications: This study doesn’t try to oppose mandatory helmet laws, but rather serves as a cautionary warning that road safety programs may need to consider strategies in which unintended impact of bicycle helmet use can be mitigated. Moreover, our findings also provide additional evaluation component when it comes to the cost-benefit assessment of helmet-related laws.

Planned early delivery for late preterm pre-eclampsia in a low- and middle-income setting: a feasibility study

BackgroundPre-eclampsia is a leading cause of maternal and perinatal mortality and morbidity globally. Planned delivery between 34+0 and 36+6 weeks may reduce adverse pregnancy outcomes but is yet to be evaluated in a low and middle-income setting. Prior to designing a randomised controlled trial to evaluate this in India and Zambia, we carried out a 6-month feasibility study in order to better understand the proposed trial environment and guide development of our intervention.MethodsWe used mixed methods to understand the disease burden and current management of pre-eclampsia at our proposed trial sites and explore the acceptability of the intervention. We undertook a case notes review of women with pre-eclampsia who delivered at the proposed trial sites over a 3-month period, alongside facilitating focus group discussions with women and partners and conducting semi-structured interviews with healthcare providers. Descriptive statistics were used to analyse audit data. A thematic framework analysis was used for qualitative data.ResultsCase notes data (n = 326) showed that in our settings, 19.5% (n = 44) of women with pre-eclampsia delivering beyond 34 weeks experienced an adverse outcome. In women delivering between 34+0 and 36+6 weeks, there were similar numbers of antenatal stillbirths [n = 3 (3.3%)] and neonatal deaths [n = 3 (3.4%)]; median infant birthweight was 2.2 kg and 1.9 kg in Zambia and India respectively. Lived experience of women and healthcare providers was an important facilitator to the proposed intervention, highlighting the serious consequences of pre-eclampsia. A preference for spontaneous labour and limited neonatal resources were identified as potential barriers.ConclusionsThis study demonstrated a clear need to evaluate the intervention and highlighted several challenges relating to trial context that enabled us to adapt our protocol and design an acceptable intervention. Our study demonstrates the importance of assessing feasibility when developing complex interventions, particularly in a low-resource setting. Additionally, it provides a unique insight into the management of pre-eclampsia at our trial settings and an understanding of the knowledge, attitudes and beliefs underpinning the acceptability of planned early delivery.

A prognostic model to guide decision-making on timing of delivery in late preterm pre-eclampsia: the PEACOCK prospective cohort study.

Pre-eclampsia affects around 2-3% of all pregnancies, and is associated with potential serious complications for the woman and the baby. Once diagnosed, progression of the syndrome can be unpredictable, and decisions around timing of delivery need to take into account evolving maternal complications and perinatal morbidity. Novel prognostic models and blood biomarkers for determination of need for delivery in pregnancies with pre-eclampsia are now emerging. The objective of the study was to establish a prognostic model to inform optimal timing of delivery in women with late preterm pre-eclampsia (34+ 0 to 36+ 6 weeks' gestation), comparing novel candidate biomarkers (e.g. placental growth factor) with clinical and routinely collected blood/urinary parameters [incorporated into the PREP-S (Prediction models for Risk of Early-onset Pre-eclampsia - Survival) model] to determine clinically indicated need for delivery for pre-eclampsia (or related complications) within 7 days of assessment. Prospective recruitment of women in whom blood samples for placental growth factor and soluble fms-like tyrosine kinase-1 testing was obtained, alongside clinical data, for use within the PREP-S model. Candidate variables were compared using standard methods (sensitivity, specificity, receiver operator curve areas). Estimated probability of early delivery from PREP-S was compared with actual event rates by calibration. The PEACOCK (Prognostic indicators of severe disEAse in women with late preterm pre-eClampsia tO guide deCision maKing on timing of delivery) study was a prospective cohort study, nested within the PHOENIX (Pre-eclampsia in HOspital: Early iNductIon or eXpectant management) trial. Women between 34+ 0 and 36+ 6 weeks' gestation, with a diagnosis of pre-eclampsia, in whom a plasma (ethylenediaminetetraacetic acid) blood sample for placental growth factor testing was obtained, alongside clinical data for the assessment of variables in a prognostic model. Clinically indicated need for delivery for pre-eclampsia within 7 days of assessment. Statistical analysis: both PREP-S and placental growth factor were assessed and compared using standard methods (sensitivity and specificity for placental growth factor thresholds of 100 pg/ml and < 12 pg/ml, and receiver operating characteristic areas for continuous measurements). The estimated probability of early delivery from PREP-S was compared with actual event rates for women with similar probabilities by calibration. Calibration using logistic regression was also used. Between 27 April 2016 and 24 December 2018, 501 women were recruited to the study. Although placental growth factor testing had high sensitivity (97.9%) for delivery within 7 days, the negative predictive value was only 71.4% and the specificity was low (8.4%). The area under the curve for the clinical prediction model (PREP-S) and placental growth factor in this cohort in determining need for delivery within 7 days was 0.64 (standard error 0.03) and 0.60 (standard error 0.03), respectively, and 0.65 (standard error 0.03) in combination. A high proportion of women in this cohort already had low placental growth factor concentrations at the time of confirmed diagnosis, which reduced the ability of the biomarker to further predict adverse outcomes. In this group of women with late preterm pre-eclampsia, placental growth factor measurement is not likely to add to the current clinical assessment to help plan care for late preterm pre-eclampsia regarding timing of delivery. 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. Further statistical modelling and subgroup analysis is being considered to assess if improved model performance in the whole cohort or a subgroup can be achieved. Addition of other biomarkers to the model may also be of use and will be explored. Current Controlled Trials ISRCTN01879376. This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 30. See the NIHR Journals Library website for further project information.

Early delivery or expectant management for late preterm preeclampsia: A meta-analysis of randomized controlled trials.

Currently, there is no consensus regarding the timing of delivery in women with non-severe preeclampsia at the late preterm period. The aim of the present meta-analysis is to compare expectant management with immediate delivery in pregnant women with preeclampsia between 34+0 and 36+6 gestational weeks, in terms of maternal and neonatal outcomes. A search was conducted until October 1, 2020 and eligible studies were identified in MEDLINE, Scopus, Cochrane Central Register of Controlled Trials (Central), the US Registry of clinical trials (www.clinicaltrials.gov), and sources of gray literature without limitations concerning the publication dates and languages. Randomized controlled trials, comparing planned delivery vs expectant management in women with preeclampsia at 34-37weeks were included. The primary outcomes were neonatal intensive care unit (NICU) admission and progression to eclampsia. Secondary outcomes were HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome, severe preeclampsia, composite adverse maternal outcome (defined by the presence of any of the potential preeclampsia-related complications, ranging from severe hypertension to maternal death), neonatal respiratory disease, and respiratory distress syndrome. Relative risks (RRs) and mean differences with 95% CI were used for the estimation of the effect sizes; the quality of the evidence was assessed per GRADE guidelines. The electronic search yielded 10721 potential studies, of which six were fully reviewed and three (1773 participants) were included in the meta-analysis. Immediate delivery increased the risk for NICU admission, (RR 1.23, 95% CI 1.05-1.45) and decreased the risk for the composite adverse maternal outcome (RR 0.86, 95% CI 0.78-0.93). There were no differences for eclampsia (RR 0.55, 95% CI 0.16-1.85), HELLP syndrome (RR 0.58, 95% CI 0.25-1.33), severe preeclampsia (RR 0.27, 95% CI 0.02-3.52), respiratory disease of neonate (RR 1.04, 95% CI 0.75-1.44), and respiratory distress syndrome (RR 2.3, 95% CI 0.73-7.25). Immediate delivery of women with non-severe preeclampsia at the period of late prematurity decreases the risk of a composite adverse maternal outcome by 14%, at the cost of an increase in NICU admissions by 23%. The overall quality of the evidence for these outcomes is high, indicating a high degree of certainty for the results.

Placental growth factor testing in the management of late preterm preeclampsia without severe features: a multicenter, randomized, controlled trial

In women with late preterm preeclampsia, the optimal time for delivery remains a controversial topic, because of the fine balance between the maternal benefits from early delivery and the risks for prematurity. It remains challenging to define prognostic markers to identify women at highest risk for complications, in which case a selective, planned delivery may reduce the adverse maternal and perinatal outcomes. This trial aimed to determine whether using an algorithm based on the maternal levels of placental growth factor in women with late preterm preeclampsia to evaluate the best time for delivery reduced the progression to preeclampsia with severe features without increasing the adverse perinatal outcomes. This parallel-group, open-label, multicenter, randomized controlled trial was conducted at 7 maternity units across Spain. We compared selective planned deliveries based on maternal levels of placental growth factor at admission (revealed group) and expectant management under usual care (concealed group) with individual randomization in singleton pregnancies with late preterm preeclampsia from 34 to 36+6 weeks' gestation. The coprimary maternal outcome was the progression to preeclampsia with severe features. The coprimary neonatal outcome was morbidity at infant hospital discharge with a noninferiority hypothesis (noninferiority margin of 10% difference in incidence). Analyses were conducted according to intention-to-treat. Between January 1, 2016, and December 31, 2019, 178 women were recruited. Of those women, 88 were assigned to the revealed group and 90 were assigned to the concealed group. The data analysis was performed before the completion of the required sample size. The proportion of women with progression to preeclampsia with severe features was significantly lower in the revealed group than in the concealed group (adjusted relative risk, 0.5; 95% confidence interval, 0.33-0.76; P=.001). The proportion of infants with neonatal morbidity was not significantly different between groups (adjusted relative risk, 0.77; 95% confidence interval, 0.39-1.53; P=.45). There is evidence to suggest that the use of an algorithm based on placental growth factor levels in women with late preterm preeclampsia leads to a lower rate of progression to preeclampsia with severe features and reduces maternal complications without worsening the neonatal outcomes. This trade-off should be discussed with women with late preterm preeclampsia to allow shared decision making about the timing of delivery.