Repeat Placental Growth Factor-Based Testing in Women With Suspected Preterm Preeclampsia: A Stratified Analysis of the PARROT-2 Trial.

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: https://www.isrctn.com/ISRCTN85912420; Unique identifier: ISRCTN85912420.

Repeat placental growth factor-based testing in women with suspected preterm pre-eclampsia (PARROT-2): a multicentre, parallel-group, superiority, randomised controlled trial.

BACKGROUND: Placental growth factor (PlGF)-based testing has high diagnostic accuracy for predicting pre-eclampsia needing delivery, significantly reducing time to diagnosis and severe maternal adverse outcomes. The clinical benefit of repeat PlGF-based testing is unclear. We aimed to determine whether repeat PlGF-based testing (using a clinical management algorithm and nationally recommended thresholds) reduces adverse perinatal outcomes in pregnant individuals with suspected preterm pre-eclampsia. METHODS: In this multicentre, parallel-group, superiority, randomised controlled trial, done in 22 maternity units across England, Scotland, and Wales, we recruited women aged 18 years or older with suspected pre-eclampsia between 22 weeks and 0 days of gestation and 35 weeks and 6 days of gestation. Women were randomly assigned (1:1) to revealed repeat PlGF-based testing or concealed repeat testing with usual care. The intervention was not masked to women or partners, or clinicians or data collectors, due to the nature of the trial. The trial statistician was masked to intervention allocation. The primary outcome was a perinatal composite of stillbirth, early neonatal death, or neonatal unit admission. The primary analysis was by the intention-to-treat principle, with a per-protocol analysis restricted to women managed according to their allocation group. The trial was prospectively registered with the ISRCTN registry, ISRCTN 85912420. FINDINGS: Between Dec 17, 2019, and Sept 30, 2022, 1253 pregnant women were recruited and randomly assigned treatment; one patient was excluded due to randomisation error. 625 women were allocated to revealed repeat PlGF-based testing and 627 women were allocated to usual care with concealed repeat PlGF-based testing (mean age 32·3 [SD 5·7] years; 879 [70%] white). One woman in the concealed repeat PlGF-based testing group was lost to follow-up. There was no significant difference in the primary perinatal composite outcome between the revealed repeat PlGF-based testing group (195 [31·2%]) of 625 women) compared with the concealed repeat PlGF-based testing group (174 [27·8%] of 626 women; relative risk 1·21 [95% CI 0·95-1·33]; p=0·18). The results from the per-protocol analysis were similar. There were four serious adverse events in the revealed repeat PlGF-based testing group and six in the concealed repeat PlGF-based testing group; all serious adverse events were deemed unrelated to the intervention by the site principal investigators and chief investigator. INTERPRETATION: Repeat PlGF-based testing in pregnant women with suspected pre-eclampsia was not associated with improved perinatal outcomes. In a high-income setting with a low prevalence of adverse outcomes, universal, routine repeat PlGF-based testing of all individuals with suspected pre-eclampsia is not recommended. FUNDING: Tommy's Charity, Jon Moulton Charitable Trust, and National Institute for Health and Care Research Guy's and St Thomas' Biomedical Research Centre.

CRADLE-5: a stepped-wedge type 2 hybrid implementation-effectiveness cluster randomised controlled trial to evaluate the real-world scale-up of the CRADLE Vital Signs Alert intervention into routine maternity care in Sierra Leone-study protocol.

BACKGROUND: The CRADLE Vital Signs Alert intervention (an accurate easy-to-use device that measures blood pressure and pulse with inbuilt traffic-light early warning system, and focused training package) was associated with reduced rates of eclampsia and maternal death when trialled in urban areas in Sierra Leone. Subsequently, implementation was successfully piloted as evidenced by measures of fidelity, feasibility and adoption. The CRADLE-5 trial will examine whether national scale-up, including in the most rural areas, will reduce a composite outcome of maternal and fetal mortality and maternal morbidity and will evaluate how the CRADLE package can be embedded sustainably into routine clinical pathways. METHODS: CRADLE-5 is a stepped-wedge cluster-randomised controlled trial of the CRADLE intervention compared to routine maternity care across eight rural districts in Sierra Leone (Bonthe, Falaba, Karene, Kailahun, Koinadugu, Kono, Moyamba, Tonkolili). Each district will cross from control to intervention at six-weekly intervals over the course of 1 year (May 2022 to June 2023). All women identified as pregnant or within six-weeks postpartum presenting for maternity care in the district are included. Primary outcome data (composite rate of maternal death, stillbirth, eclampsia and emergency hysterectomy) will be collected. A mixed-methods process and scale-up evaluation (informed by Medical Research Council guidance for complex interventions and the World Health Organization ExpandNet tools) will explore implementation outcomes of fidelity, adoption, adaptation and scale-up outcomes of reach, maintenance, sustainability and integration. Mechanisms of change and contextual factors (barriers and facilitators) will be assessed. A concurrent cost-effectiveness analysis will be undertaken. DISCUSSION: International guidance recommends that all pregnant and postpartum women have regular blood pressure assessment, and healthcare staff are adequately trained to respond to abnormalities. Clinical effectiveness to improve maternal and perinatal health in more rural areas, and ease of integration and sustainability of the CRADLE intervention at scale has yet to be investigated. This trial will explore whether national scale-up of the CRADLE intervention reduces maternal and fetal mortality and severe maternal adverse outcomes and understand the strategies for adoption, integration and sustainability in low-resource settings. If successful, the aim is to develop an adaptable, evidence-based scale-up roadmap to improve maternal and infant outcomes. TRIAL REGISTRATION: ISRCTN 94429427. Registered on 20 April 2022.

Optimising timing of steroid administration in preterm pre-eclampsia.

Antenatal corticosteroids (ACS) are an established intervention to improve outcomes in preterm birth. ACS are optimally timed if the administration-to-birth interval is greater than 24 h and <7 days. Evidence has emerged suggesting harm associated with administration-to-birth intervals greater than seven days, or with repeated courses of ACS. Pre-eclampsia is a leading cause of iatrogenic preterm birth, as delivery of the fetus and placenta remains the only cure. This study investigated optimal ACS use in women delivering before 35 weeks' gestation in the United Kingdom with a diagnosis of preterm pre-eclampsia. Of 1,632 women with suspected pre-eclampsia, 250 delivered before 35 weeks' gestation with pre-eclampsia. 31 % (78/250) received optimally timed ACS, 49 % (122/250) received ACS more than seven days pre-delivery and 20 % (50/250) did not receive ACS. There were no significant differences in gestational age, mean birthweight, respiratory distress syndrome, neonatal unit admission or neonatal death between groups. There was a higher rate of intrauterine fetal death in the group of women who did not receive ACS (p < 0.05), and a corresponding increase in vaginal delivery and reduction in caesarean section (p < 0.05). Optimal ACS administration is poor in women delivering preterm with pre-eclampsia and the largest group of mistimed ACS administration were those given more than 7 days prior to birth. Clinicians should defer ACS until a decision for delivery has been made, at which point ACS should be prioritised. Judicious use of ACS may improve outcomes.

Placental growth fActor Repeat sampling for Reduction of adverse perinatal Outcomes in women with suspecTed pre-eclampsia: study protocol for a randomised controlled trial (PARROT-2).

BACKGROUND: Pre-eclampsia is a complex pregnancy disorder, characterised by new or worsening hypertension associated with multi-organ dysfunction. Adverse outcomes include eclampsia, liver rupture, stroke, pulmonary oedema, and acute kidney injury in the mother, and stillbirth, foetal growth restriction, and iatrogenic preterm delivery for the foetus. Angiogenic biomarkers, including placental growth factor (PlGF) and soluble fms-like tyrosine kinase 1 (sFlt-1), have been identified as valuable biomarkers for preterm pre-eclampsia, accelerating diagnosis and reducing maternal adverse outcomes by risk stratification, with enhanced surveillance for high-risk women. PlGF-based testing for suspected preterm pre-eclampsia has been incorporated into national guidance. The role of repeat PlGF-based testing and its effect on maternal and perinatal adverse outcomes have yet to be evaluated. METHODS: The PARROT-2 trial is a multi-centre randomised controlled trial of repeat revealed PlGF-based testing compared to repeat concealed testing, in women presenting with suspected pre-eclampsia between 22+0 and 35+6 weeks' gestation. The primary objective is to establish whether repeat PlGF-based testing decreases a composite of perinatal severe adverse outcomes (stillbirth, early neonatal death, or neonatal unit admission). All women prior to enrolment in the trial will have an initial revealed PlGF-based test. Repeat PlGF-based tests will be performed weekly or two-weekly, depending on the initial PlGF-based test result, with results randomised to revealed or concealed. DISCUSSION: National guidance recommends that all women presenting with suspected preterm pre-eclampsia should have a single PlGF-based test when disease is first suspected, to help rule out pre-eclampsia. Clinical and cost-effectiveness of repeat PlGF-based testing has yet to be investigated. This trial aims to address whether repeat PlGF-based testing reduces severe maternal and perinatal adverse outcomes and whether repeat testing is cost-effective. TRIAL REGISTRATION: ISRCTN 85912420 . Registered on 25 November 2019.

The assessment of blood pressure in pregnant women: pitfalls and novel approaches.

Accurate assessment of blood pressure is fundamental to the provision of safe obstetrical care. It is simple, cost effective, and life-saving. Treatments for preeclampsia, including antihypertensive drugs, magnesium sulfate, and delivery, are available in many settings. However, the instigation of appropriate treatment relies on prompt and accurate recognition of hypertension. There are a number of different techniques for blood pressure assessment, including the auscultatory method, automated oscillometric devices, home blood pressure monitoring, ambulatory monitoring, and invasive monitoring. The auscultatory method with a mercury sphygmomanometer and the use of Korotkoff sounds was previously recommended as the gold standard technique. Mercury sphygmomanometers have been withdrawn owing to safety concerns and replaced with aneroid devices, but these are particularly prone to calibration errors and regular calibration is imperative to ensure accuracy. Automated oscillometric devices are straightforward to use, but the physiological changes in healthy pregnancy and pathologic changes in preeclampsia may affect the accuracy of a device and monitors must be validated. Validation protocols classify pregnant women as a "special population," and protocols must include 15 women in each category of normotensive pregnancy, hypertensive pregnancy, and preeclampsia. In addition to a scarcity of devices validated for pregnancy and preeclampsia, other pitfalls that cause inaccuracy include the lack of training and poor technique. Blood pressure assessment can be affected by maternal position, inappropriate cuff size, conversation, caffeine, smoking, and irregular heart rate. For home blood pressure monitoring, appropriate instruction should be given on how to use the device. The classification of hypertension and hypertensive disorders of pregnancy has recently been revised. These are classified as preeclampsia, transient gestational hypertension, gestational hypertension, white-coat hypertension, masked hypertension, chronic hypertension, and chronic hypertension with superimposed preeclampsia. Blood pressure varies across gestation and by ethnicity, but gestation-specific thresholds have not been adopted. Hypertension is defined as a sustained systolic blood pressure of ≥140 mm Hg or a sustained diastolic blood pressure of ≥90 mm Hg. In some guidelines, the threshold of diagnosis depends on the setting in which blood pressure measurement is taken, with a threshold of 140/90 mm Hg in a healthcare setting, 135/85 mm Hg at home, or a 24-hour average blood pressure on ambulatory monitoring of >126/76 mm Hg. Some differences exist among organizations with respect to the criteria for the diagnosis of preeclampsia and the correct threshold for intervention and target blood pressure once treatment has been instigated. Home blood pressure monitoring is currently a focus for research. Novel technologies, including early warning devices (such as the CRADLE Vital Signs Alert device) and telemedicine, may provide strategies that prompt earlier recognition of abnormal blood pressure and therefore improve management. The purpose of this review is to provide an update on methods to assess blood pressure in pregnancy and appropriate technique to optimize accuracy. The importance of accurate blood pressure assessment is emphasized with a discussion of preeclampsia prediction and treatment of severe hypertension. Classification of hypertensive disorders and thresholds for treatment will be discussed, including novel developments in the field.

Prescribing for pregnancy: managing diabetes.

Topics for DTB review articles are selected by DTB's editorial board to provide concise overviews of medicines and other treatments to help patients get the best care. Articles include a summary of key points and a brief overview for patients. Articles may also have a series of multiple choice CME questions.

Recent advances in the diagnosis and management of pre-eclampsia.

Pre-eclampsia is an elusive condition to diagnose and a complex disease to manage. There have been recent developments in prediction, prevention, diagnosis, and management. Risk modelling has been used to identify women at highest risk of developing pre-eclampsia as well as predicting maternal adverse outcomes in confirmed disease. New evidence has shown that aspirin prophylaxis significantly reduces early onset pre-eclampsia as well as preterm birth. The criteria for the diagnosis of pre-eclampsia are evolving, and proteinuria is no longer a pre-requisite to make a diagnosis. Angiogenic biomarker testing accelerates diagnosis as well as minimises adverse maternal outcomes and has been incorporated into national guidelines. Emerging evidence demonstrates that expedited delivery in late preterm pre-eclampsia may be protective against maternal adverse outcomes but increase the risk of neonatal unit admission. Both women and their offspring are at increased risk of long-term health complications following pre-eclampsia, and it is important that postnatal health is optimised. This article summarises recent developments in the field of pre-eclampsia research, evaluating the impact on clinical care for women at risk of, or with suspected or confirmed, pre-eclampsia.

Coronary artery dissection in the puerperium: A case report and literature review.

Spontaneous coronary artery dissection is a rare but important cause of acute coronary syndrome. Its relevance for women during the puerperium mandates awareness and understanding amongst obstetric healthcare professionals. The aetiology of the increased risk in pregnancy has not been fully elucidated, but include medial eosinophilic angitis, pregnancy-induced degeneration of collagen in conjunction with the stresses of parturition, and rupture of the vasa vasorum. The risk of mortality necessitates prompt diagnosis, usually by angiography. There is no one-size-fits-all treatment; management must be individualised according to haemodynamic status and affected vessel(s) and includes conservative management, percutaneous coronary intervention, or bypass grafting. Recovery complications include extension of the haematoma or false lumen, valvular pathology secondary to ischaemia, and sudden cardiac death. Close post-operative surveillance is mandatory. We present a 41-year-old lady with post-partum spontaneous coronary artery dissection, complicated by ischaemic papillary rupture and mitral regurgitation requiring valve replacement. Additionally, we present a literature review, including guidance on management and critical analysis of potential complications.

Recurrent ectopic pregnancy as a unique clinical sub group: a case control study.

BACKGROUND: Women with recurrent ectopic pregnancy (EP) represent a unique cohort of patients in whom diagnostic expertise is paramount. We determined whether recurrent EP is associated with significant differences in patient demographics, clinical presentation, risk factors and surgical findings when compared with primary EP. METHODS: A retrospective case-control study of all EPs diagnosed from 2003 to 2014, at Whipps Cross University Hospital, London. RESULTS: In the above period 849 EPs were surgically managed (758 primary EPs and 91 recurrent EPs). Recurrent EPs were significantly older than primary EPs (32.2 ± 5.08 vs. 30.5 ± 5.83 years, p < 0.05). They presented at a significantly earlier gestation (5.99 ± 1.08 vs. 6.52 ± 1.81 weeks, p < 0.05) and with a significantly lower primary ßHCG (3176 ± 7350 vs. 6243 ± 12,282, p < 0.05). Recurrent EPs were significantly more likely to have a positive history of tubal or pelvic surgery (61.5 % vs. 3.5 %, p < 0.05 and 53.8 vs. 14 %, p < 0.05). At surgery, primary EPs had a significantly greater volume of hemoperitoneum (592 ± 850 vs. 249 ± 391 ml, p < 0.05), whereas recurrent EPs were significantly more likely to have contralateral pathology (31.1 vs. 9.8 %, p < 0.05). Regression analysis showed that the parameters of age, gestational age at presentation, first ßHCG level, positive history of previous tubal surgery and previous ectopic pregnancy differ in women at risk of a recurrent EP when compared to women not at risk of a recurrent ectopic (AUC, 0.844). CONCLUSIONS: We conclude that recurrent EPs may represent a unique sub-group of patients with EP.

Evaluation of the selective use of abdomino-pelvic drains at laparoscopic myomectomy: in enhanced recovery, do drains delay discharge home?

OBJECTIVE: To assess whether the use of abdominal drains at laparoscopic myomectomy (LM) influences length of hospital stay. The primary outcome was to determine whether the use of intra-abdominal drains after LM was associated with prolonged hospital stay after surgery. Secondary outcomes were to identify factors that influence the use of abdomino-pelvic drains during LM. STUDY DESIGN: Retrospective cohort study of 217 consecutive single surgeon LMs in a London university teaching hospital. Abdominal drains were used selectively after LM. Of the 217 patients, 123 (57%) had a drain left in situ at the end of the operation. RESULTS: The two cohorts of patients were not significantly different in their demographics. The use of a drain was significantly associated with an increased number of fibroids (4.6±3.8 vs. 2.8±2.1, p<0.0001), increased weight of fibroids (277±211 g vs. 133±153 g, p<0.0001), increased surgical time (133±40 min vs. 90±35 min, p<0.0001) and increased estimated blood loss (406±265 ml vs. 199±98 ml, p<0.0001). There was no statistically significant difference in length of hospital stay (mean duration of admission 2.1 days±0.98 with drain, vs. 2.1 days±0.97 without a drain, p=0.98). CONCLUSION: We conclude that although the use of a drain may be associated with a more complex operation, this does not delay the patient's discharge.