Publications by authors named "Andrew Shennan"

271 Publications

Development and rapid rollout of The QUiPP App Toolkit for women who arrive in threatened preterm labour.

BMJ Open Qual 2021 05;10(2)

Department of Women and Children's Health, School of Life Course Sciences, King's College London, London, UK.

Background: Often the first opportunity for clinicians to assess risk of preterm birth is when women present with threatened preterm labour symptoms (such as period-like pain, tightening's or back ache). However, threatened preterm labour symptoms are not a strong predictor of imminent birth. Clinicians are then faced with a complex clinical dilemma, the need to ameliorate the consequences of preterm birth requires consideration with the side-effects and costs. The QUiPP app is a validated app which can aid clinicians when they triage a women who is in threatened preterm labour.

Aim: Our aim was to produce a toolkit to promote a best practice pathway for women who arrive in threatened preterm labour.

Methods: We worked with two hospitals in South London. This included the aid of a toolkit midwife at each hospital. We also undertook stakeholder focus groups and worked with two Maternity Voice Partnership groups to ensure a diverse range of voices was heard in the toolkit development. While we aimed to produce the toolkit in September 2020, we rapidly rolled out and produced the first version of the toolkit in April 2020 due to COVID-19. As the QUiPP app can reduce admissions and hospital transfers, there was a need to enable all hospitals in England to have access to the toolkit as soon as possible.

Results: While the rapid rollout of The QUiPP App Toolkit due to COVID-19 was not planned, it has demonstrated that toolkits to improve clinical practice can be produced promptly. Through actively welcoming continued feedback meant the initial version of the toolkit could be continually and iteratively refined. The toolkit has been recommended nationally, with National Health Service England recommending the app and toolkit in their COVID-19 update to the Saving Babies Lives Care Bundle and in the British Association of Perinatal Medicine Antenatal Optimisation Toolkit.
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http://dx.doi.org/10.1136/bmjoq-2020-001272DOI Listing
May 2021

Ursodeoxycholic acid in intrahepatic cholestasis of pregnancy: a systematic review and individual participant data meta-analysis.

Lancet Gastroenterol Hepatol 2021 Apr 26. Epub 2021 Apr 26.

Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA.

Background: Ursodeoxycholic acid is commonly used to treat intrahepatic cholestasis of pregnancy, yet its largest trial detected minimal benefit for a composite outcome (stillbirth, preterm birth, and neonatal unit admission). We aimed to examine whether ursodeoxycholic acid affects specific adverse perinatal outcomes.

Methods: In this systematic review and individual participant data meta-analysis, we searched PubMed, Web of Science, Embase, MEDLINE, CINAHL, Global Health, MIDIRS, and Cochrane without language restrictions for relevant articles published between database inception, and Jan 1, 2020, using search terms referencing intrahepatic cholestasis of pregnancy, ursodeoxycholic acid, and perinatal outcomes. Eligible studies had 30 or more study participants and reported on at least one individual with intrahepatic cholestasis of pregnancy and bile acid concentrations of 40 μmol/L or more. We also included two unpublished cohort studies. Individual participant data were collected from the authors of selected studies. The primary outcome was the prevalence of stillbirth, for which we anticipated there would be insufficient data to achieve statistical power. Therefore, we included a composite of stillbirth and preterm birth as a main secondary outcome. A mixed-effects meta-analysis was done using multi-level modelling and adjusting for bile acid concentration, parity, and multifetal pregnancy. Individual participant data analyses were done for all studies and in different subgroups, which were produced by limiting analyses to randomised controlled trials only, singleton pregnancies only, or two-arm studies only. This study is registered with PROSPERO, CRD42019131495.

Findings: The authors of the 85 studies fulfilling our inclusion criteria were contacted. Individual participant data from 6974 women in 34 studies were included in the meta-analysis, of whom 4726 (67·8%) took ursodeoxycholic acid. Stillbirth occurred in 35 (0·7%) of 5097 fetuses among women with intrahepatic cholestasis of pregnancy treated with ursodeoxycholic acid and in 12 (0·6%) of 2038 fetuses among women with intrahepatic cholestasis of pregnancy not treated with ursodeoxycholic acid (adjusted odds ratio [aOR] 1·04, 95% CI 0·35-3·07; p=0·95). Ursodeoxycholic acid treatment also had no effect on the prevalence of stillbirth when considering only randomised controlled trials (aOR 0·29, 95% CI 0·04-2·42; p=0·25). Ursodeoxycholic acid treatment had no effect on the prevalence of the composite outcome in all studies (aOR 1·28, 95% CI 0·86-1·91; p=0·22), but was associated with a reduced composite outcome when considering only randomised controlled trials (0·60, 0·39-0·91; p=0·016).

Interpretation: Ursodeoxycholic acid treatment had no significant effect on the prevalence of stillbirth in women with intrahepatic cholestasis of pregnancy, but our analysis was probably limited by the low overall event rate. However, when considering only randomised controlled trials, ursodeoxycholic acid was associated with a reduction in stillbirth in combination with preterm birth, providing evidence for the clinical benefit of antenatal ursodeoxycholic acid treatment.

Funding: Tommy's, the Wellcome Trust, ICP Support, and the National Institute for Health Research.
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http://dx.doi.org/10.1016/S2468-1253(21)00074-1DOI Listing
April 2021

Effect of the CRADLE vital signs alert device intervention on referrals for obstetric haemorrhage in low-middle income countries: a secondary analysis of a stepped- wedge cluster-randomised control trial.

BMC Pregnancy Childbirth 2021 Apr 21;21(1):317. Epub 2021 Apr 21.

Department of Women and Children's Health, School of Life Course Sciences, Faculty of Life Sciences and Medicine, King's College London, London, SE1 7EH, UK.

Background: Obstetric haemorrhage is the leading cause of maternal death worldwide, 99% of which occur in low and middle income countries. The majority of deaths and adverse events are associated with delays in identifying compromise and escalating care. Management of severely compromised pregnant women may require transfer to tertiary centres for specialised treatment, therefore early recognition is vital for efficient management. The CRADLE vital signs alert device accurately measures blood pressure and heart rate, calculates the shock index (heart rate divided by systolic blood pressure) and alerts the user to compromise through a traffic light system reflecting previously validated shock index thresholds.

Methods: This is a planned secondary analysis of data from the CRADLE-3 trial from ten clusters across Africa, India and Haiti where the device and training package were randomly introduced. Referral data were prospectively collected for a 4-week period before, and a 4-week period 3 months after implementation. Referrals from primary or secondary care facilities to higher level care for any cause were recorded. The denominator was the number of women seen for maternity care in these facilities.

Results: Between April 1 2016 and Nov 30th, 2017 536,223 women attended maternity care facilities. Overall, 3.7% (n = 2784/74,828) of women seen in peripheral maternity facilities were referred to higher level care in the control period compared to 4.4% (n = 3212/73,371) in the intervention period (OR 0.89; 0.39-2.05) (data for nine sites that were able to collect denominator). Of these 0.29% (n = 212) pre-intervention and 0.16% (n = 120) post-intervention were referred to higher-level facilities for maternal haemorrhage. Although overall referrals did not significantly reduce there was a significant reduction in referrals for obstetric haemorrhage (OR 0.56 (0.39-0.65) following introduction of the device with homogeneity (i-squared 26.1) between sites. There was no increase in any bleeding-related morbidity (maternal death or emergency hysterectomy).

Conclusions: Referrals for obstetric haemorrhage reduced following implementation of the CRADLE Vital Signs Alert Device, occurring without an increase in maternal death or emergency hysterectomy. This demonstrates the potential benefit of shock index in management pathways for obstetric haemorrhage and targeting limited resources in low- middle- income settings.

Trial Registration: This study is registered with the ISRCTN registry, number ISRCTN41244132 (02/02/2016).
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http://dx.doi.org/10.1186/s12884-021-03796-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8061003PMC
April 2021

Experiences of maternity care among women at increased risk of preterm birth receiving midwifery continuity of care compared to women receiving standard care: Results from the POPPIE pilot trial.

PLoS One 2021 21;16(4):e0248588. Epub 2021 Apr 21.

Department of Women and Children's Health, Faculty of Life Science and Medicine, King's College London, London, United Kingdom.

Background: Midwifery continuity of care models for women at low and mixed risk of complications have been shown to improve women's experiences of care. However, there is limited research on care experiences among women at increased risk of preterm birth. We aimed to explore the experiences of care among women with risk factors for preterm birth participating in a pilot trial (POPPIE) of a midwifery continuity of care model which included a specialist obstetric clinic.

Methods: A total of 334 pregnant women identified at increased risk of preterm birth were randomly allocated to either midwifery continuity of care (POPPIE group) or standard maternity care. Women in both groups were followed up at six-to-eight weeks postpartum and were invited to complete a postnatal survey either online or by post. An equal status exploratory sequential mixed method design was chosen to collect and analyse the quantitative postnatal survey data and qualitative interviews data. The postnatal survey included measures of social support, trust, perceptions of safety, quality of care, control during childbirth, bonding and quality of life. Categorical data were analysed with chi-squared tests and continuous data were analysed with t-tests and/or Mann-Whitney U test to measure differences in measures scores among groups. The qualitative interview data were subjected to a thematic framework analysis. Data triangulation brought quantitative and qualitative data together at the interpretation stage.

Findings: A total of 166 women completed the survey and 30 women were interviewed (90 and 16 in POPPIE group; 76 and 14 in standard group). We found survey respondents in the POPPIE group, compared to respondents in the standard group, were significantly more likely to report greater trust in midwives (Mann-Whitney U, p<0.0001), greater perceptions of safety during the antenatal care (t-test, p = 0.0138), have a particular midwife to contact when they needed during their pregnancy (t-test, p<0.0001) and the postnatal period (chi-squared, p<0.0001). They reported increased involvement in decisions regarding antenatal, intrapartum and postnatal care (t-test, p = 0.002; p = 0.008; p = 0.006 respectively); and greater postnatal support and advice about: feeding the baby (chi-squared, p<0.0001), handling, settling and looking after the baby (chi-squared, p<0.0001), baby's health and progress (chi-squared, p = 0.039), their own health and recovery (chi-squared, p = 0.006) and who to contact about any emotional changes (chi-squared, p = 0.005). There were no significant differences between groups in the reporting of perceptions of safety during birth and the postnatal period, concerns raised during labour and birth taken seriously, being left alone during childbirth at a time of worries, control during labour, bonding, social support, and physical and mental health related quality of life after birth. Results from qualitative interviews provided insight and depth into many of these findings, with women in the POPPIE group reporting more positive experiences of bonding towards their babies and more positive physical health postnatally.

Conclusions: Compared with standard maternity care, women at increased risk of PTB who received midwifery continuity of care were more likely to report increased perceptions of trust, safety and quality of care.

Trial Registration: ISRCTN (Number: 37733900); UK CRN (ID: 31951).
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0248588PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8059847PMC
April 2021

Brain volumetry in fetuses that deliver very preterm: An MRI pilot study.

Neuroimage Clin 2021 Mar 29;30:102650. Epub 2021 Mar 29.

Centre for the Developing Brain, King's College London, London, UK.

Background: Infants born preterm are at increased risk of neurological complications resulting in significant morbidity and mortality. The exact mechanism and the impact of antenatal factors has not been fully elucidated, although antenatal infection/inflammation has been implicated in both the aetiology of preterm birth and subsequent neurological sequelae. It is therefore hypothesized that processes driving preterm birth are affecting brain development in utero. This study aims to compare MRI derived regional brain volumes in fetuses that deliver < 32 weeks with fetuses that subsequently deliver at term.

Methods: Women at high risk of preterm birth, with gestation 19.4-32 weeks were recruited prospectively. A control group was obtained from existing study datasets. Fetal MRI was performed on a 1.5 T or 3 T MRI scanner: T2-weighted images were obtained of the fetal brain. 3D brain volumetric datsets were produced using slice to volume reconstruction and regional segmentations were produced using multi-atlas approaches for supratentorial brain tissue, lateral ventricles, cerebellum cerebral cortex and extra-cerebrospinal fluid (eCSF). Statistical comparison of control and high-risk for preterm delivery fetuses was performed by creating normal ranges for each parameter from the control datasets and then calculating gestation adjusted z scores. Groups were compared using t-tests.

Results: Fetal image datasets from 24 pregnancies with delivery < 32 weeks and 87 control pregnancies that delivered > 37 weeks were included. Median gestation at MRI of the preterm group was 26.8 weeks (range 19.4-31.4) and control group 26.2 weeks (range 21.7-31.9). No difference was found in supra-tentorial brain volume, ventricular volume or cerebellar volume but the eCSF and cerebral cortex volumes were smaller in fetuses that delivered preterm (p < 0.001 in both cases).

Conclusion: Fetuses that deliver preterm have a reduction in cortical and eCSF volumes. This is a novel finding and needs further investigation. If alterations in brain development are commencing antenatally in fetuses that subsequently deliver preterm, this may present a window for in utero therapy in the future.
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http://dx.doi.org/10.1016/j.nicl.2021.102650DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8045030PMC
March 2021

Evaluation of the Arabin cervical pessary for prevention of preterm birth in women with a twin pregnancy and short cervix (STOPPIT-2): An open-label randomised trial and updated meta-analysis.

PLoS Med 2021 Mar 29;18(3):e1003506. Epub 2021 Mar 29.

Multiple Births Foundation, London, United Kingdom.

Background: Preterm-labour-associated preterm birth is a common cause of perinatal mortality and morbidity in twin pregnancy. We aimed to test the hypothesis that the Arabin pessary would reduce preterm-labour-associated preterm birth by 40% or greater in women with a twin pregnancy and a short cervix.

Methods And Findings: We conducted an open-label randomised controlled trial in 57 hospital antenatal clinics in the UK and Europe. From 1 April 2015 to 14 February 2019, 2,228 women with a twin pregnancy underwent cervical length screening between 18 weeks 0 days and 20 weeks 6 days of gestation. In total, 503 women with cervical length ≤ 35 mm were randomly assigned to pessary in addition to standard care (n = 250, mean age 32.4 years, mean cervical length 29 mm, with pessary inserted in 230 women [92.0%]) or standard care alone (n = 253, mean age 32.7 years, mean cervical length 30 mm). The pessary was inserted before 21 completed weeks of gestation and removed at between 35 and 36 weeks or before birth if earlier. The primary obstetric outcome, spontaneous onset of labour and birth before 34 weeks 0 days of gestation, was present in 46/250 (18.4%) in the pessary group compared to 52/253 (20.6%) following standard care alone (adjusted odds ratio [aOR] 0.87 [95% CI 0.55-1.38], p = 0.54). The primary neonatal outcome-a composite of any of stillbirth, neonatal death, periventricular leukomalacia, early respiratory morbidity, intraventricular haemorrhage, necrotising enterocolitis, or proven sepsis, from birth to 28 days after the expected date of delivery-was present in 67/500 infants (13.4%) in the pessary group compared to 76/506 (15.0%) following standard care alone (aOR 0.86 [95% CI 0.54-1.36], p = 0.50). The positive and negative likelihood ratios of a short cervix (≤35 mm) to predict preterm birth before 34 weeks were 2.14 and 0.83, respectively. A meta-analysis of data from existing publications (4 studies, 313 women) and from STOPPIT-2 indicated that a cervical pessary does not reduce preterm birth before 34 weeks in women with a short cervix (risk ratio 0.74 [95% CI 0.50-1.11], p = 0.15). No women died in either arm of the study; 4.4% of babies in the Arabin pessary group and 5.5% of babies in the standard treatment group died in utero or in the neonatal period (p = 0.53). Study limitations include lack of power to exclude a smaller than 40% reduction in preterm labour associated preterm birth, and to be conclusive about subgroup analyses.

Conclusions: These results led us to reject our hypothesis that the Arabin pessary would reduce the risk of the primary outcome by 40%. Smaller treatment effects cannot be ruled out.

Trial Registration: ISRCTN Registry ISRCTN 02235181. ClinicalTrials.gov NCT02235181.
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http://dx.doi.org/10.1371/journal.pmed.1003506DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8041194PMC
March 2021

Pregnancy Outcomes and Blood Pressure Visit-to-Visit Variability and Level in Three Less-Developed Countries.

Hypertension 2021 May 29;77(5):1714-1722. Epub 2021 Mar 29.

Department of Women and Children's Health, School of Life Course Sciences, Faculty of Life Sciences and Medicine (L.A.M., H.L.N., A.H.S., P.v.D.), King's College London, United Kingdom.

[Figure: see text].
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.16851DOI Listing
May 2021

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

Pregnancy Hypertens 2021 Mar 3;24:90-95. Epub 2021 Mar 3.

Department of Women and Children's Health, School of Life Course Sciences, King's College London, UK.

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 to 36 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 'Prediction of complications in early-onset pre-eclampsia' (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.
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http://dx.doi.org/10.1016/j.preghy.2021.02.012DOI Listing
March 2021

A realist review to explore how midwifery continuity of care may influence preterm birth in pregnant women.

Birth 2021 Mar 21. Epub 2021 Mar 21.

Department of Women & Children's Health, School of Life Course Sciences, King's College London, London, UK.

Background: Midwifery continuity of care models are the only health system intervention associated with both a reduction in preterm birth (PTB) and an improvement in perinatal survival; however, questions remain about the mechanisms by which such positive outcomes are achieved. We aimed to uncover theories of change by which we can postulate how and why continuity of midwifery care models might affect PTB.

Methods: We followed Pawson's guidance for conducting a realist review and performed a comprehensive search to identify existing literature exploring the impact of continuity models on PTB in all pregnant women. A realist methodology was used to uncover the context (C), mechanisms (M), and outcomes (O) and to develop a group of CMO configurations to illuminate middle-range theories.

Results: Eleven papers were included from a wide variety of settings in the United Kingdom, Australia, and the United States. The majority of study participants had low socioeconomic status or social risk factors and received diverse models of midwifery continuity of care. Three themes-woman-midwife partnership, maternity pathways and processes, and system resources-encompassed ten CMO configurations. Building relationships, trust, confidence, and advocacy resulted in women feeling safer, less stressed, and more secure and respected, and encouraged them to access and engage in antenatal care with more opportunities for early prevention and diagnosis of complications, which facilitated effective management when compliance to guidelines was ensured. Organizational infrastructure, innovative partnerships, and robust community systems are crucial to overcome barriers, address women's complex needs, ensure quality of care, and reduce PTB risk.

Conclusions: Pregnant women living in different contexts in the United Kingdom, Australia, and the United States at low and mixed risk of complications and with low socioeconomic status or social risk factors experienced continuity models in similar ways, and similar underlying mechanisms may have influenced PTB outcomes. Further research is required to understand how continuity models may influence behavioral change, physiological stress levels, ethnic disparities in PTB and care coordination, and navigation of health services.
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http://dx.doi.org/10.1111/birt.12547DOI Listing
March 2021

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

Fac Rev 2020 16;9:10. Epub 2020 Nov 16.

Women's Health Academic Centre, King's College London, Westminster Bridge Road, London, SE1 7EH, UK.

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.
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http://dx.doi.org/10.12703/b/9-10DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7886065PMC
November 2020

Optimal timing of cervical cerclage removal following preterm premature rupture of membranes; a retrospective analysis.

Eur J Obstet Gynecol Reprod Biol 2021 Apr 6;259:75-80. Epub 2021 Feb 6.

Department of Women and Children's Health, King's College London, St Thomas' Hospital, London, SE1 7EH, United Kingdom.

Objective: Preterm prelabour rupture of membranes occurs in over one third of pregnant women with a cervical cerclage in situ. In the setting of preterm prelabour rupture of membranes, clinicians are faced with the difficult decision of the optimal timing for removing the cerclage. We compared the maternal and neonatal outcomes following immediate removal or retention of the cervical cerclage.

Study Design: Women were retrospectively identified from St Thomas's Hospital Preterm Surveillance clinic database. Asymptomatic women with preterm prelabour rupture of membranes were identified and separated into those that had the cerclage removed and those that had the cerclage retained within 24 h of presentation. Women who were symptomatic at presentation and who delivered within 24 h of presentation were excluded from the analysis. Maternal outcomes measured were latency between preterm prelabour rupture of membranes and delivery, gestation at delivery and maternal chorioamnionitis and infection markers. Neonatal outcomes including birthweight and Apgar scores were also measured.

Results: 43 women with cerclage retained for over 24 h following preterm prelabour rupture of membranes were compared to 25 women in whom the cerclage was removed. The latency between preterm prelabour rupture of membranes and delivery was on average 70.4 h longer in women who had their cerclage retained compared to the removed group (p = 0.009). Rates of chorioamnionitis, maternal blood results, neonatal birthweight and Apgar scores did not differ significantly between the two groups, however a trend towards higher rates of chorioamnionitis (60 % vs 45 %) were seen in the retained group.

Conclusion: Cervical cerclage retention in women following preterm prelabour rupture of membranes was associated with a longer latency period to delivery and was not significantly associated with any adverse obstetric, maternal or neonatal outcomes. Therefore, in women at risk of spontaneous preterm birth, cerclage retention may be beneficial, however these women and their babies should be monitored closely for any signs of infection. Further prospective randomised controlled studies assessing these outcomes as well as longer-term outcomes in these women and their children are needed.
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http://dx.doi.org/10.1016/j.ejogrb.2021.02.002DOI Listing
April 2021

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

Am J Obstet Gynecol 2020 Nov 20. Epub 2020 Nov 20.

Department of Women and Children's Health, School of Life Course Sciences, King's College London, London, United Kingdom. Electronic address:

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.
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http://dx.doi.org/10.1016/j.ajog.2020.10.026DOI Listing
November 2020

Development of a video to teach clinicians how to perform a transabdominal cerclage.

Am J Obstet Gynecol MFM 2020 11;2(4):100238

Department of Women and Children's Health, School of Life Course Sciences, King's College London, London, United Kingdom.

Background: A transabdominal cerclage has been shown in a recent randomized controlled trial to be superior to a low vaginal cerclage in reducing the risk of early preterm birth (8% [3/39] vs 33% [11/33]; relative risk, 0.23; 95% confidence interval, 0.07-0.76; P=.01570) and fetal loss (3% [1/39] vs 21% [7/33]; relative risk, 0.12; 95% confidence interval, 0.016-0.930) in women with a previous failed vaginal cerclage. OBJECTIVE: We sought to create a video illustrating a transabdominal cerclage procedure for use as a teaching resource and describing this uncommon but important procedure for dissemination among clinicians.

Study Design: Transabdominal cerclage insertion in a non-gravid and gravid uterus (less than 14 weeks' gestation) via laparotomy and laparoscopy was filmed with patients' and clinicians' consent in main theatres at St Thomas' Hospital and University College London Hospital. The film footage was edited, and an audio narration by the surgeon was included to provide a description of the procedures.

Results: We developed an 8-minute video with an audio narration describing the insertion and management issues of an abdominal cerclage for free dissemination among clinicians who wish to learn how to perform this procedure.

Conclusion: An abdominal cerclage has been shown to significantly reduce early preterm birth and fetal loss more effectively than a low vaginal cerclage in women with a previous failed cerclage. More obstetricians and gynecologists need to be trained on how to perform the transabdominal cerclage procedure to increase its availability to suitable women. This procedure is technically straightforward and can be taught via video, which can easily be shared among clinicians at a low cost.
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http://dx.doi.org/10.1016/j.ajogmf.2020.100238DOI Listing
November 2020

Planned early delivery versus expectant management to reduce adverse pregnancy outcomes in pre-eclampsia in a low- and middle-income setting: study protocol for a randomised controlled trial (CRADLE-4 Trial).

Trials 2020 Nov 23;21(1):960. Epub 2020 Nov 23.

Department of Women and Children's Health, School of Life Course Sciences, King's College London, London, UK.

Background: Pre-eclampsia is a pregnancy complication characterised by high blood pressure and multi-organ dysfunction in the mother. It is a leading contributor to maternal and perinatal mortality, with 99% of these deaths occurring in low- and middle-income countries (LMIC). Whilst clear guidelines exist for management of early-onset (< 34 weeks) and term (≥ 37 weeks) disease, the optimal timing of delivery in pre-eclampsia between 34 and 36 weeks is less clear. In a high-income setting, delivery may improve maternal outcomes without detriment to the baby, but this intervention is yet to be evaluated in LMIC.

Methods: The CRADLE-4 Trial is a non-masked, randomised controlled trial comparing planned early delivery (initiation of delivery within 48 h of randomisation) with routine care (expectant management) in women with pre-eclampsia between 34 and 36 weeks' gestation in India and Zambia. The primary objective is to establish whether a policy of planned early delivery can reduce adverse maternal outcomes, without increasing severe neonatal morbidity.

Discussion: The World Health Organization recommends delivery for all women with pre-eclampsia from 37 weeks onwards, based on evidence showing clear maternal benefit without increased neonatal risk. Before 34 weeks, watchful waiting is preferred, with delivery recommended only when there is severe maternal or fetal compromise, due to the neonatal risks associated with early preterm delivery. Currently, there is a lack of guidance for clinicians managing women with pre-eclampsia between 34 and 36 weeks. Early delivery benefits the mother but may increase the need for neonatal unit admission in the infant (albeit without serious morbidity at this gestation). On the other hand, waiting to deliver may increase the risk of stillbirth, fetal growth restriction and hypoxic brain injury in the neonate as a result of severe maternal complications. This is especially true for LMIC where there is a higher prevalence of adverse events. The balance of risks and benefits therefore needs to be carefully assessed before making firm recommendations. This is the first trial evaluating the optimal timing of delivery in pre-eclampsia in LMIC, where resources and disease burden are considerably different.

Trial Registration: ISRCTN 10672137 . Registered on 28 November 2019.
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http://dx.doi.org/10.1186/s13063-020-04888-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7684962PMC
November 2020

Placental growth factor measurements in the assessment of women with suspected Preeclampsia: A stratified analysis of the PARROT trial.

Pregnancy Hypertens 2021 Mar 18;23:41-47. Epub 2020 Oct 18.

Department of Women and Children's Health, School of Life Course Sciences, King's College London (KED, PTS, AHS, LCC), United Kingdom; The Division of Developmental Biology and Medicine, University of Manchester, United Kingdom; Neonatal Medicine, School of Public Health, Faculty of Medicine, Chelsea and Westminster Campus, Imperial College London, United Kingdom. Electronic address:

Objective: Placental growth factor testing decreases time to recognition of preeclampsia and may reduce severe maternal adverse outcomes. This analysis aims to describe the clinical phenotype of women by PlGF concentration, and to determine the mechanism(s) underpinning the reduction in severe maternal adverse outcomes in the PARROT trial, in order to inform how PlGF testing may be optimally used within clinical management algorithms.

Study Design: This was a planned secondary analysis from the PARROT trial that compared revealed PlGF testing and management guidance with usual care in the assessment of women with suspected preterm preeclampsia.

Main Outcome Measures: Maternal and perinatal outcomes following stratification of women by trial group, and measured PlGF concentration.

Results: 1006 women were included. PlGF < 100 pg/ml identified women with more marked hypertension, increased adverse maternal outcomes and preterm delivery rates, and higher rates of small for gestational age infants. There was a reduction in adverse maternal outcomes in women whose results were revealed when PlGF levels were 12-100 pg/ml compared to usual care (3.8% vs 6.9%; aOR 0.15(95% CI 0.03-0.92). There was no significant difference in gestation at delivery between concealed or revealed groups in any PlGF categories.

Conclusion: Low PlGF concentrations are associated with severe preeclampsia. The reduction in severe adverse maternal outcomes may be mediated through quicker diagnosis and intensive surveillance, as recommended by the management algorithm for those at increased risk. PlGF is particularly beneficial in those who test 12-100 pg/ml, as these may be women with silent multi-organ disease who otherwise may go undetected.
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http://dx.doi.org/10.1016/j.preghy.2020.10.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7909322PMC
March 2021

CRAFT (Cerclage after full dilatation caesarean section): protocol of a mixed methods study investigating the role of previous in-labour caesarean section in preterm birth risk.

BMC Pregnancy Childbirth 2020 Nov 16;20(1):698. Epub 2020 Nov 16.

Department of Women and Children's Health, School of Life Course Sciences, King's College London, 10th Floor, North Wing, St Thomas' Hospital, Westminster Bridge Road, London, SE1 7EH, UK.

Background: Full dilatation caesarean sections are associated with recurrent early spontaneous preterm birth and late miscarriage. The risk following first stage caesarean sections, are less well defined, but appears to be increased in late-first stage of labour. The mechanism for this increased risk of late miscarriage and early spontaneous preterm birth in these women is unknown and there are uncertainties with regards to clinical management. Current predictive models of preterm birth (based on transvaginal ultrasound and quantitative fetal fibronectin) have not been validated in these women and it is unknown whether the threshold to define a short cervix (≤25 mm) is reliable in predicting the risk of preterm birth. In addition the efficacy of standard treatments or whether benefit may be derived from prophylactic interventions such as a cervical cerclage is unknown.

Methods: There are three distinct components to the CRAFT project (CRAFT-OBS, CRAFT-RCT and CRAFT-IMG).

Craft-obs: Observational Study; To evaluate subsequent pregnancy risk of preterm birth in women with a prior caesarean section in established labour. This prospective study of cervical length and quantitative fetal fibronectin data will establish a predictive model of preterm birth.

Craft-rct: Randomised controlled trial arm; To assess treatment for short cervix in women at high risk of preterm birth following a fully dilated caesarean section.

Craft-img: Imaging sub-study; To evaluate the use of MRI and transvaginal ultrasound imaging of micro and macrostructural cervical features which may predispose to preterm birth in women with a previous fully dilated caesarean section, such as scar position and niche.

Discussion: The CRAFT project will quantify the risk of preterm birth or late miscarriage in women with previous in-labour caesarean section, define the best management and shed light on pathological mechanisms so as to improve the care we offer to women and their babies.

Trial Registration: CRAFT was prospectively registered on 25th November 2019 with the ISRCTN registry ( https://doi.org/10.1186/ISRCTN15068651 ).
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http://dx.doi.org/10.1186/s12884-020-03375-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7667480PMC
November 2020

Population-level data on antenatal screening for proteinuria; India, Mozambique, Nigeria, Pakistan.

Bull World Health Organ 2020 Oct 9;98(10):661-670. Epub 2020 Sep 9.

Department of Women and Children's Health, King's College London, Becket House, 1 Lambeth Palace Road, SE1 7EU, London, England.

Objective: To estimate the prevalence and prognosis of proteinuria at enrolment in the 27 intervention clusters of the Community-Level Interventions for Pre-eclampsia cluster randomized trials.

Methods: We identified pregnant women eligible for inclusion in the trials in their communities in four countries (2013-2017). We included women who delivered by trial end and received an intervention antenatal care visit. The intervention was a community health worker providing supplementary hypertension-oriented care, including proteinuria assessment by visual assessment of urinary dipstick at the first visit and all subsequent visits when hypertension was detected. In a multilevel regression model, we compared baseline prevalence of proteinuria (≥ 1+ or ≥ 2+) across countries. We compared the incidence of subsequent complications by baseline proteinuria.

Findings: Baseline proteinuria was detected in less than 5% of eligible pregnancies in each country (India: 234/6120; Mozambique: 94/4234; Nigeria: 286/7004; Pakistan: 315/10 885), almost always with normotension (India: 225/234; Mozambique: 93/94; Nigeria: 241/286; Pakistan: 264/315). There was no consistent relationship between baseline proteinuria (either ≥ 1+ or ≥ 2+) and progression to hypertension, maternal mortality or morbidity, birth at < 37 weeks, caesarean section delivery or perinatal mortality or morbidity. If proteinuria testing were restricted to women with hypertension, we projected annual cost savings of 153 223 981 United States dollars (US$) in India, US$ 9 055 286 in Mozambique, US$ 53 181 933 in Nigeria and US$ 38 828 746 in Pakistan.

Conclusion: Our findings question the recommendations to routinely evaluate proteinuria at first assessment in pregnancy. Restricting proteinuria testing to pregnant women with hypertension has the potential to save resources.
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http://dx.doi.org/10.2471/BLT.19.248898DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7652559PMC
October 2020

Midwifery continuity of care versus standard maternity care for women at increased risk of preterm birth: A hybrid implementation-effectiveness, randomised controlled pilot trial in the UK.

PLoS Med 2020 10 6;17(10):e1003350. Epub 2020 Oct 6.

Department of Women and Children's Health, Faculty of Life Science and Medicine, King's College London, London, United Kingdom.

Background: Midwifery continuity of care is the only health system intervention shown to reduce preterm birth (PTB) and improve perinatal survival, but no trial evidence exists for women with identified risk factors for PTB. We aimed to assess feasibility, fidelity, and clinical outcomes of a model of midwifery continuity of care linked with a specialist obstetric clinic for women considered at increased risk for PTB.

Methods And Findings: We conducted a hybrid implementation-effectiveness, randomised, controlled, unblinded, parallel-group pilot trial at an inner-city maternity service in London (UK), in which pregnant women identified at increased risk of PTB were randomly assigned (1:1) to either midwifery continuity of antenatal, intrapartum, and postnatal care (Pilot study Of midwifery Practice in Preterm birth Including women's Experiences [POPPIE] group) or standard care group (maternity care by different midwives working in designated clinical areas). Pregnant women attending for antenatal care at less than 24 weeks' gestation were eligible if they fulfilled one or more of the following criteria: previous cervical surgery, cerclage, premature rupture of membranes, PTB, or late miscarriage; previous short cervix or short cervix this pregnancy; or uterine abnormality and/or current smoker of tobacco. Feasibility outcomes included eligibility, recruitment and attrition rates, and fidelity of the model. The primary outcome was a composite of appropriate and timely interventions for the prevention and/or management of preterm labour and birth. We analysed by intention to treat. Between 9 May 2017 and 30 September 2018, 334 women were recruited; 169 women were allocated to the POPPIE group and 165 to the standard group. Mean maternal age was 31 years; 32% of the women were from Black, Asian, and ethnic minority groups; 70% were in employment; and 46% had a university degree. Nearly 70% of women lived in areas of social deprivation. More than a quarter of women had at least one pre-existing medical condition and multiple risk factors for PTB. More than 75% of antenatal and postnatal visits were provided by a named/partner midwife, and a midwife from the POPPIE team was present at 80% of births. The incidence of the primary composite outcome showed no statistically significant difference between groups (POPPIE group 83.3% versus standard group 84.7%; risk ratio 0.98 [95% confidence interval (CI) 0.90 to 1.08]; p = 0.742). Infants in the POPPIE group were significantly more likely to have skin-to-skin contact after birth, to have it for a longer time, and to breastfeed immediately after birth and at hospital discharge. There were no differences in other secondary outcomes. The number of serious adverse events was similar in both groups and unrelated to the intervention (POPPIE group 6 versus standard group 5). Limitations of this study included the limited power and the nonmasking of group allocation; however, study assignment was masked to the statistician and researchers who analysed the data.

Conclusions: In this study, we found that it is feasible to set up and achieve fidelity of a model of midwifery continuity of care linked with specialist obstetric care for women at increased risk of PTB in an inner-city maternity service in London (UK), but there is no impact on most outcomes for this population group. Larger appropriately powered trials are needed, including in other settings, to evaluate the impact of relational continuity and hypothesised mechanisms of effect based on increased trust and engagement, improved care coordination, and earlier referral on disadvantaged communities, including women with complex social factors and social vulnerability.

Trial Registration: We prospectively registered the pilot trial on the UK Clinical Research Network Portfolio Database (ID number: 31951, 24 April 2017). We registered the trial on the International Standard Randomised Controlled Trial Number (ISRCTN) (Number: 37733900, 21 August 2017) and before trial recruitment was completed (30 September 2018) when informed that prospective registration for a pilot trial was also required in a primary clinical trial registry recognised by WHO and the International Committee of Medical Journal Editors (ICMJE). The protocol as registered and published has remained unchanged, and the analysis conforms to the original plan.
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http://dx.doi.org/10.1371/journal.pmed.1003350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7537886PMC
October 2020

All the right moves: why transfer is both important for the baby and difficult to achieve and new strategies for change.

F1000Res 2020 13;9. Epub 2020 Aug 13.

Guy's and St Thomas NHS Foundation Trust, London, UK.

The best way to ensure that preterm infants benefit from relevant neonatal expertise as soon as they are born is to transfer the mother and baby to an appropriately specialised neonatal facility before birth (" "). This review explores the evidence surrounding the importance of being born in the right unit, the advantages of transfers compared to transfers, and how to accurately assess which women are at most risk of delivering early and the challenges of transfers. Accurate identification of the women most at risk of preterm birth is key to prioritising who to transfer antenatally, but the administrative burden and pathway variation of transfer in the UK are likely to compromise optimal clinical care. Women reported the impact that transfers have on them, including the emotional and financial burdens of being transferred and the anxiety surrounding domestic and logistical concerns related to being away from home. The final section of the review explores new approaches to reforming the transfer process, including learning from outside the UK and changing policy and guidelines. Examples of collaborative regional guidance include the recent Pan-London guidance on transfers. Reforming the transfer process can also be aided through technology, such as utilising the CotFinder app. transfer is an unavoidable aspect of maternity and neonatal care, and the burden will increase if preterm birth rates continue to rise in association with increased rates of multiple pregnancy, advancing maternal age, assisted reproductive technologies, and obstetric interventions. As funding and capacity pressures on health services increase because of the COVID-19 pandemic, better prioritisation and sustained multi-disciplinary commitment are essential to maximise better outcomes for babies born too soon.
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http://dx.doi.org/10.12688/f1000research.25923.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429922PMC
September 2020

Antenatal thymus volumes in fetuses that delivered <32 weeks gestation: An MRI pilot study.

Acta Obstet Gynecol Scand 2020 Aug 31. Epub 2020 Aug 31.

Centre for the Developing Brain and Centre for Medical Engineering, King's College London, London, UK.

Introduction: Infection and inflammation have been implicated in the etiology and subsequent morbidity associated with preterm birth. At present, there are no tests to assess for fetal compartment infection. The thymus, a gland integral in the fetal immune system, has been shown to involute in animal models of antenatal infection, but its response in human fetuses has not been studied. This study aims: (a) to generate magnetic resonance imaging (MRI) -derived fetal thymus volumes standardized for fetal weight; (b) to compare standardized thymus volumes from fetuses that delivered before 32 weeks of gestation with fetuses that subsequently deliver at term; (c) to assess thymus size as a predictor of preterm birth; and (d) to correlate the presence of chorioamnionitis and funisitis at delivery with thymic volumes in utero in fetuses that subsequently deliver preterm.

Material And Methods: Women at high-risk of preterm birth at 20-32 weeks of gestation were recruited. A control group was obtained from existing data sets acquired as part of three research studies. A fetal MRI was performed on a 1.5T or 3T MRI scanner: T2 weighted images were obtained of the entire uterine content and specifically the fetal thorax. A slice-to-volume registration method was used for reconstruction of three-dimensional images of the thorax. Thymus segmentations were performed manually. Body volumes were calculated by manual segmentation and thymus:body volume ratios were generated. Comparison of groups was performed using multiple regression analysis. Normal ranges were created for thymus volume and thymus:body volume ratios using the control data. Receiver operating curves (ROC) curves were generated for thymus:body volume ratio and gestation-adjusted thymus volume centiles as predictors of preterm birth. Placental histology was analyzed where available from pregnancies that delivered very preterm and the presence of chorioamnionitis/funisitis was noted.

Results: Normative ranges were created for thymus volume, and thymus volume was standardized for fetal size from fetuses that subsequently delivered at term, but were imaged at 20-32 weeks of gestation. Image data sets from 16 women that delivered <32 weeks of gestation (ten with ruptured membranes and six with intact membranes) and 80 control women that delivered >37 weeks were included. Mean gestation at MRI of the study group was 28  weeks (SD 3.2) and for the control group was 25  weeks (SD 2.4). Both absolute fetal thymus volumes and thymus:body volume ratios were smaller in fetuses that delivered preterm (P < .001). Of the 16 fetuses that delivered preterm, 13 had placental histology, 11 had chorioamnionitis, and 9 had funisitis. The strongest predictors of prematurity were the thymus volume Z-score and thymus:body volume ratio Z-score (ROC areas 0.915 and 0.870, respectively).

Conclusions: We have produced MRI-derived normal ranges for fetal thymus and thymus:body volume ratios between 20 and 32 weeks of gestation. Fetuses that deliver very preterm had reduced thymus volumes when standardized for fetal size. A reduced thymus volume was also a predictor of spontaneous preterm delivery. Thymus volume may be a suitable marker of the fetal inflammatory response, although further work is needed to assess this, increasing the sample size to correlate the extent of chorioamnionitis with thymus size.
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http://dx.doi.org/10.1111/aogs.13983DOI Listing
August 2020

Community-level interventions for pre-eclampsia (CLIP) in Pakistan: A cluster randomised controlled trial.

Pregnancy Hypertens 2020 Oct 28;22:109-118. Epub 2020 Jul 28.

the CLIP Pakistan Trial Working Group (Table S1).

Objectives: To reduce all-cause maternal and perinatal mortality and major morbidity through Lady Health Worker (LHW)-facilitated community engagement and early diagnosis, stabilization and referral of women with preeclampsia, an important contributor to adverse maternal and perinatal outcomes given delays in early detection and initial management.

Study Design: In the Pakistan Community-Level Interventions for Pre-eclampsia (CLIP) cluster randomized controlled trial (NCT01911494), LHWs engaged the community, recruited pregnant women from 20 union councils (clusters), undertook mobile health-guided clinical assessment for preeclampsia, and referral to facilities after stabilization.

Main Outcome Measures: The primary outcome was a composite of maternal, fetal and newborn mortality and major morbidity.

Findings: We recruited 39,446 women in intervention (N = 20,264) and control clusters (N = 19,182) with minimal loss to follow-up (3∙7% vs. 4∙5%, respectively). The primary outcome did not differ between intervention (26·6%) and control (21·9%) clusters (adjusted odds ratio, aOR, 1∙20 [95% confidence interval 0∙84-1∙72]; p = 0∙31). There was reduction in stillbirths (0·89 [0·81-0·99]; p = 0·03), but no impact on maternal death (1·08 [0·69, 1·71]; p = 0·74) or morbidity (1·12 [0·57, 2·16]; p = 0·77); early (0·95 [0·82-1·09]; p = 0·46) or late neonatal deaths (1·23 [0·97-1·55]; p = 0·09); or neonatal morbidity (1·22 [0·77, 1·96]; p = 0·40). Improvements in outcome rates were observed with 4-7 (p = 0·015) and ≥8 (p < 0·001) (vs. 0) CLIP contacts.

Interpretation: The CLIP intervention was well accepted by the community and implemented by LHWs. Lack of effects on adverse outcomes could relate to quality care for mothers with pre-eclampsia in health facilities. Future strategies for community outreach must also be accompanied by health facility strengthening.

Funding: The University of British Columbia (PRE-EMPT), a grantee of the Bill & Melinda Gates Foundation (OPP1017337).
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http://dx.doi.org/10.1016/j.preghy.2020.07.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7694879PMC
October 2020

Efficacy of transvaginal cervical cerclage in women at risk of preterm birth following previous emergency cesarean section.

Acta Obstet Gynecol Scand 2020 11 2;99(11):1486-1491. Epub 2020 Sep 2.

Department of Women and Children's Health, King's College London, London, UK.

Introduction: Emergency cesarean sections (EMCS) are associated with subsequent preterm birth, particularly at full dilation (FDCS), which is a cause of both second trimester miscarriages and early, recurrent spontaneous preterm birth (sPTB). The optimal management for these women in subsequent pregnancies is currently unknown. This study aims to assess efficacy of transvaginal cervical cerclage (TVC) in prevention of preterm birth among women who have had an EMCS followed by a subsequent late miscarriage or sPTB.

Material And Methods: A historical cohort study was performed assessing outcomes of women attending the Preterm Surveillance Clinic at St Thomas' Hospital, London, who received TVC, with a history of EMCS (pregnancy A) followed by a sPTB/late miscarriage (pregnancy B) and a subsequent pregnancy (pregnancy C). A historical reference group managed in the same clinic was identified comprising women with any risk factor for sPTB, who required TVC. Incidence of delivery >24 to <30 weeks' gestation was compared with relative risk and 95% confidence intervals (CI). Subgroup analysis was carried out assessing women who had a previous FDCS.

Results: 209 women with a previous EMCS during labor (50 with FDCS), followed by sPTB/late miscarriage were identified. 178 progressed beyond 24 weeks; of these, 56 received TVC and formed the study group. 905 high-risk women were identified; of these, 154 received TVC and formed the reference group. Despite TVC treatment, 17/56 (30%) of the study group delivered <30 weeks' gestation compared with 5/154 (3%) of the reference group (RR 9.4, 95% CI 3.6-24.2, P < .001). In the subset of 17 women in the study group with a previous FDCS, followed by sPTB/late miscarriage, 6/17 (35%) delivered <30 weeks' gestation, significantly higher than the reference group (P < .001) but similar to EMCS at less than full dilation (35% vs 28%, P = .596). Overall, 33/72 (46%) women receiving cerclage with prior EMCS had either a mid-trimester loss or delivery <30 weeks.

Conclusions: Transvaginal cervical cerclage appears less effective in preventing preterm birth among pregnant women who have had an EMCS followed by a sPTB/late miscarriage compared with other high-risk women. The lack of efficacy in the subgroup with an FDCS was similar.
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http://dx.doi.org/10.1111/aogs.13972DOI Listing
November 2020

Setting and techniques for monitoring blood pressure during pregnancy.

Cochrane Database Syst Rev 2020 07 23;8:CD012739. Epub 2020 Jul 23.

Department of Women and Children's Health, King's College London, London, UK.

Background: Regular blood pressure (BP) measurement is crucial for the diagnosis and management of hypertensive disorders in pregnancy, such as pre-eclampsia. BP can be measured in various settings, such as conventional clinics or self-measurement at home, and with different techniques, such as using auscultatory or automated BP devices. It is important to understand the impact of different settings and techniques of BP measurement on important outcomes for pregnant women.

Objectives: To assess the effects of setting and technique of BP measurement for diagnosing hypertensive disorders in pregnancy on subsequent maternal and perinatal outcomes, women's quality of life, or use of health service resources.

Search Methods: We searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) on 22 April 2020, and reference lists of retrieved studies.

Selection Criteria: Randomised controlled trials (RCTs) involving pregnant women, using validated BP devices in different settings or using different techniques.

Data Collection And Analysis: Two authors independently extracted data, assessed risk of bias, and used the GRADE approach to assess the certainty of the evidence.

Main Results: Of the 21 identified studies, we included three, and excluded 11; seven were ongoing. Of the three included RCTs (536,607 women), one was a cluster-RCT, with a substantially higher number of participants (536,233 deliveries) than the other two trials, but did not provide data for most of our outcomes. We generally judged the included studies at low risk of bias, however, the certainty of the evidence was low, due to indirectness and imprecision. Meta-analysis was not possible because each study investigated a different comparison. None of the included studies reported our primary outcome of systolic BP greater than or equal to 150 mmHg. None of the studies reported any of these important secondary outcomes: antenatal hospital admissions, neonatal unit length of stay, or neonatal endotracheal intubation and use of mechanical ventilation. Setting of BP measurement: self-measurement versus conventional clinic measurement (one study, 154 women) There were no maternal deaths in either the self-monitoring group or the usual care group. The study did not report perinatal mortality. Self-monitoring may lead to slightly more diagnoses of pre-eclampsia compared with usual care (risk ratio (RR) 1.49, 95% confidence interval (CI) 0.87 to 2.54; 154 women; 1 study; low-certainty evidence) but the wide 95% CI is consistent with possible benefit and possible harm. Self-monitoring may have little to no effect on the likelihood of induction of labour compared with usual care (RR 1.09, 95% CI 0.82 to 1.45; 154 women; 1 study; low-certainty evidence). We are uncertain if self-monitoring BP has any effect on maternal admission to intensive care (RR 1.54, 95% CI 0.06 to 37.25; 154 women; 1 study; low-certainty evidence), stillbirth (RR 2.57, 95% CI 0.13 to 52.63; 154 women; 1 study; low-certainty evidence), neonatal death (RR 1.54, 95% CI 0.06 to 37.25; 154 women; 1 study; low-certainty evidence) or preterm birth (RR 1.15, 95% CI 0.37 to 3.55; 154 women; 1 study; low-certainty evidence), compared with usual care because the certainty of evidence is low and the 95% CI is consistent with appreciable harms and appreciable benefits. Self-monitoring may lead to slightly more neonatal unit admissions compared with usual care (RR 1.53, 95% CI 0.65 to 3.62; 154 women; 1 study; low-certainty evidence) but the wide 95% CI includes the possibility of slightly fewer admissions with self-monitoring. Technique of BP measurement: Korotkoff phase IV (K4, muffling sound) versus Korotkoff phase V (K5, disappearance of sound) to represent diastolic BP (one study, 220 women) There were no maternal deaths in either the K4 or K5 group. There may be little to no difference in the diagnosis of pre-eclampsia between using K4 or K5 for diastolic BP (RR 1.16; 95% CI 0.89 to 1.49; 1 study; 220 women; low-certainty evidence), since the wide 95% CI includes the possibility of more diagnoses with K4. We are uncertain if there is a difference in perinatal mortality between the groups because the quality of evidence is low and the 95% CI is consistent with appreciable harm and appreciable benefit (RR 1.14, 95% CI 0.16 to 7.92; 1 study, 220 women; low-certainty evidence). The trial did not report data on maternal admission to intensive care, induction of labour, stillbirth, neonatal death, preterm birth, or neonatal unit admissions. Technique of BP measurement: CRADLE intervention (CRADLE device, a semi-automated BP monitor with additional features, and an education package) versus usual care (one study, 536,233 deliveries) There may be little to no difference between the use of the CRADLE device and usual care in the number of maternal deaths (adjusted RR 0.80, 95% CI 0.30 to 2.11; 536,233 women; 1 study; low-certainty evidence), but the 95% CI is consistent with appreciable harm and appreciable benefit. The trial did not report pre-eclampsia, induction of labour, perinatal mortality, preterm birth, or neonatal unit admissions. Maternal admission to intensive care and perinatal outcomes (stillbirths and neonatal deaths) were only collected for a small proportion of the women, identified by an outcome not by baseline characteristics, thereby breaking the random allocation. Therefore, any differences between the groups could not be attributed to the intervention, and we did not extract data for these outcomes.

Authors' Conclusions: The benefit, if any, of self-monitoring BP in hypertensive pregnancies remains uncertain, as the evidence is limited to one feasibility study. Current practice of using K5 to measure diastolic BP is supported for women with pregnancy hypertension. The benefit, if any, of using the CRADLE device to measure BP in pregnancy remains uncertain, due to the limitations and instability of the trial study design.
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http://dx.doi.org/10.1002/14651858.CD012739.pub2DOI Listing
July 2020

Managing late preterm pre-eclampsia - Authors' reply.

Lancet 2020 08;396(10247):308-309

Department of Women and Children's Health, School of Life Course Sciences, King's College London, London SE1 7EH, UK.

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http://dx.doi.org/10.1016/S0140-6736(20)30620-6DOI Listing
August 2020

Cervicovaginal natural antimicrobial expression in pregnancy and association with spontaneous preterm birth.

Sci Rep 2020 07 21;10(1):12018. Epub 2020 Jul 21.

Department of Women and Children's Health, School of Life Course Sciences, King's College London, St Thomas' Hospital, London, SE1 7EH, UK.

There is much interest in the role of innate immune system proteins (antimicrobial peptides) in the inflammatory process associated with spontaneous preterm birth (sPTB). After promising pilot work, we aimed to validate the association between the antimicrobial peptides/proteins elafin and cathelicidin and sPTB. An observational cohort study of 405 women at high-risk, and 214 women at low-risk of sPTB. Protein concentrations of elafin and cathelicidin, and the enzyme human neutrophil elastase (HNE) were measured in over 1,000 cervicovaginal fluid (CVF) samples (10 to 24 weeks' gestation). Adjusted CVF cathelicidin and HNE concentrations (but not elafin) were raised in high-risk women who developed cervical shortening and who delivered prematurely and were predictive of sPTB < 37 weeks, with an area under the curve (AUC) of 0.75 (95% CI 0.68 to 0.81) for cathelicidin concentration at 14 to 15 weeks. Elafin concentrations were affected by gestation, body mass index and smoking. CVF elafin in early pregnancy was modestly predictive of sPTB < 34 weeks (AUC 0.63, 0.56-0.70). Alterations in innate immune response proteins in early pregnancy are predictive of sPTB. Further investigation is warranted to understand the drivers for this, and their potential to contribute towards clinically useful prediction techniques.
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http://dx.doi.org/10.1038/s41598-020-68329-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7374562PMC
July 2020

Authors' reply re: Incidence and characteristics of pregnancy-related death across ten low- and middle-income geographical regions: secondary analysis of a cluster randomised controlled trial: The underestimated incidence of eclampsia in low-income countries: variation between regions.

BJOG 2020 09 16;127(10):1302-1303. Epub 2020 Jul 16.

Department of Women and Children's Health, School of Life Course Sciences, Faculty of Life Sciences and Medicine, King's College London, London, UK.

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http://dx.doi.org/10.1111/1471-0528.16353DOI Listing
September 2020

Community level interventions for pre-eclampsia (CLIP) in India: A cluster randomised controlled trial.

Pregnancy Hypertens 2020 Jul 19;21:166-175. Epub 2020 May 19.

Department of Obstetrics and Gynaecology, Faculty of Medicine, University of British Columbia, Suite 930, 1125 Howe Street, Vancouver, BC V6Z 2K8, Canada; Department of Women and Children's Health, School of Life Course Sciences, Faculty of Life Sciences and Medicine, King's College London, St. Thomas' Hospital, Westminster Bridge Road, London SE1 7EH, UK.

Objectives: Pregnancy hypertension is associated with 7.1% of maternal deaths in India. The objective of this trial was to assess whether task-sharing care might reduce adverse pregnancy outcomes related to delays in triage, transport, and treatment.

Study Design: The Indian Community-Level Interventions for Pre-eclampsia (CLIP) open-label cluster randomised controlled trial (NCT01911494) recruited pregnant women in 12 clusters (initial four-cluster internal pilot) in Belagavi and Bagalkote, Karnataka. The CLIP intervention (6 clusters) consisted of community engagement, community health workers (CHW) provided mobile health (mHeath)-guided clinical assessment, initial treatment, and referral to facility either urgently (<4 h) or non-urgently (<24 h), dependent on algorithm-defined risk. Treatment effect was estimated by multi-level logistic regression modelling, adjusted for prognostically-significant baseline variables. Predefined secondary analyses included safety and evaluation of the intensity of mHealth-guided CHW-provided contacts.

Main Outcome Measures: 20% reduction in composite of maternal, fetal, and newborn mortality and major morbidity.

Results: All 14,783 recruited pregnancies (7839 intervention, 6944 control) were followed-up. The primary outcome did not differ between intervention and control arms (adjusted odds ratio (aOR) 0.92 [95% confidence interval 0.74, 1.15]; p = 0.47; intraclass correlation coefficient 0.013). There were no intervention-related safety concerns following administration of either methyldopa or MgSO, and 401 facility referrals. Compared with intervention arm women without CLIP contacts, those with ≥8 contacts suffered fewer stillbirths (aOR 0.19 [0.10, 0.35]; p < 0.001), at the probable expense of survivable neonatal morbidity (aOR 1.39 [0.97, 1.99]; p = 0.072).

Conclusions: As implemented, solely community-level interventions focussed on pre-eclampsia did not improve outcomes in northwest Karnataka.
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http://dx.doi.org/10.1016/j.preghy.2020.05.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7471838PMC
July 2020

Community-level interventions for pre-eclampsia (CLIP) in Mozambique: A cluster randomised controlled trial.

Pregnancy Hypertens 2020 Jul 14;21:96-105. Epub 2020 May 14.

Department of Obstetrics and Gynaecology, University of British Columbia, Suite 930, 1125 Howe Street, Vancouver V6Z 2K8, Canada; Department of Women and Children's Health, School of Life Course Sciences, Faculty of Medicine and Life Sciences, King's College London, 1 Lambeth Place Road, London SE1 7EH, UK.

Objectives: Pregnancy hypertension is the third leading cause of maternal mortality in Mozambique and contributes significantly to fetal and neonatal mortality. The objective of this trial was to assess whether task-sharing care might reduce adverse pregnancy outcomes related to delays in triage, transport, and treatment.

Study Design: The Mozambique Community-Level Interventions for Pre-eclampsia (CLIP) cluster randomised controlled trial (NCT01911494) recruited pregnant women in 12 administrative posts (clusters) in Maputo and Gaza Provinces. The CLIP intervention (6 clusters) consisted of community engagement, community health worker-provided mobile health-guided clinical assessment, initial treatment, and referral to facility either urgently (<4hrs) or non-urgently (<24hrs), dependent on algorithm-defined risk. Treatment effect was estimated by multi-level logistic regression modelling, adjusted for prognostically-significant baseline variables. Predefined secondary analyses included safety and evaluation of the intensity of CLIP contacts.

Main Outcome Measures: 20% reduction in composite of maternal, fetal, and newborn mortality and major morbidity.

Results: 15,013 women (15,123 pregnancies) were recruited in intervention (N = 7930; 2·0% loss to follow-up (LTFU)) and control (N = 7190; 2·8% LTFU) clusters. The primary outcome did not differ between intervention and control clusters (adjusted odds ratio (aOR) 1·31, 95% confidence interval (CI) [0·70, 2·48]; p = 0·40). Compared with intervention arm women without CLIP contacts, those with ≥8 contacts experienced fewer primary outcomes (aOR 0·79 (95% CI 0·63, 0·99); p = 0·041), primarily due to improved maternal outcomes (aOR 0·72 (95% CI 0·53, 0·97); p = 0·033).

Interpretation: As generally implemented, the CLIP intervention did not improve pregnancy outcomes; community implementation of the WHO eight contact model may be beneficial.

Funding: The University of British Columbia (PRE-EMPT), a grantee of the Bill & Melinda Gates Foundation (OPP1017337).
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http://dx.doi.org/10.1016/j.preghy.2020.05.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7471842PMC
July 2020