Publications by authors named "Paul T Seed"

173 Publications

Cervicovaginal microbiota and metabolome predict preterm birth risk in an ethnically diverse cohort.

JCI Insight 2021 Jul 13. Epub 2021 Jul 13.

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

The syndrome of spontaneous preterm birth (sPTB) presents a challenge to mechanistic understanding, effective risk stratification, and management. Individual associations between sPTB, ethnicity, vaginal microbiota, metabolome and innate immune response are known, but not fully understood and knowledge has yet to impact clinical practice. Here we use multi-data type integration and composite statistical models to gain insight into sPTB risk by exploring the cervicovaginal environment of an ethnically heterogenous pregnant population (n=346 women; n=60 sPTB <37 weeks' gestation, including n=27 sPTB <34 weeks). Analysis of cervicovaginal samples (10-15+6 weeks) identified novel interactions between risk of sPTB and microbiota, metabolite, and maternal host defense molecules. Statistical modelling identified a composite of metabolites (leucine, tyrosine, aspartate, lactate, betaine, acetate and Ca2+) associated with risk of sPTB <37 weeks (Area Under the Curve - AUC 0.752). A combination of glucose, aspartate, Ca2+ and Lactobacillus crispatus and L. acidophilus relative abundance, identified risk of early sPTB <34 weeks, (AUC 0.758); improved by ethnicity stratification (AUC 0.835). Increased relative abundance of L. acidophilus appeared protective against sPTB <34 weeks. By using cervicovaginal fluid samples, we demonstrate the potential of multi-datatype integration for developing composite models towards understanding the contribution of the vaginal environment to risk of sPTB.
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http://dx.doi.org/10.1172/jci.insight.149257DOI Listing
July 2021

Evaluating the use of the QUiPP app and its impact on the management of threatened preterm labour: A cluster randomised trial.

PLoS Med 2021 Jul 6;18(7):e1003689. Epub 2021 Jul 6.

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

Background: Preterm delivery (before 37 weeks of gestation) is the single most important contributor to neonatal death and morbidity, with lifelong repercussions. However, the majority of women who present with preterm labour (PTL) symptoms do not deliver imminently. Accurate prediction of PTL is needed in order ensure correct management of those most at risk of preterm birth (PTB) and to prevent the maternal and fetal risks incurred by unnecessary interventions given to the majority. The QUantitative Innovation in Predicting Preterm birth (QUIPP) app aims to support clinical decision-making about women in threatened preterm labour (TPTL) by combining quantitative fetal fibronectin (qfFN) values, cervical length (CL), and significant PTB risk factors to create an individualised percentage risk of delivery.

Methods And Findings: EQUIPTT was a multi-centre cluster randomised controlled trial (RCT) involving 13 maternity units in South and Eastern England (United Kingdom) between March 2018 and February 2019. Pregnant women (n = 1,872) between 23+0 and 34+6 weeks' gestation with symptoms of PTL in the analysis period were assigned to either the intervention (762) or control (1,111). The mean age of the study population was 30.2 (+/- SD 5.93). A total of 56.0% were white, 19.6% were black, 14.2% were Asian, and 10.2% were of other ethnicities. The intervention was the use of the QUiPP app with admission, antenatal corticosteroids (ACSs), and transfer advised for women with a QUiPP risk of delivery >5% within 7 days. Control sites continued with their conventional management of TPTL. Unnecessary management for TPTL was a composite primary outcome defined by the sum of unnecessary admission decisions (admitted and delivery interval >7 days or not admitted and delivery interval ≤7 days) and the number of unnecessary in utero transfer (IUT) decisions/actions (IUT that occurred or were attempted >7 days prior to delivery) and ex utero transfers (EUTs) that should have been in utero (attempted and not attempted). Unnecessary management of TPTL was 11.3% (84/741) at the intervention sites versus 11.5% (126/1094) at control sites (odds ratio [OR] 0.97, 95% confidence interval [CI] 0.66-1.42, p = 0.883). Control sites frequently used qfFN and did not follow UK national guidance, which recommends routine treatment below 30 weeks without testing. Unnecessary management largely consisted of unnecessary admissions which were similar at intervention and control sites (10.7% versus 10.8% of all visits). In terms of adverse outcomes for women in TPTL <36 weeks, 4 women from the intervention sites and 12 from the control sites did not receive recommended management. If the QUiPP percentage risk was used as per protocol, unnecessary management would have been 7.4% (43/578) versus 9.9% (134/1,351) (OR 0.72, 95% CI 0.45-1.16). Our external validation of the QUiPP app confirmed that it was highly predictive of delivery in 7 days; receiver operating curve area was 0.90 (95% CI 0.85-0.95) for symptomatic women. Study limitations included a lack of compliance with national guidance at the control sites and difficulties in implementation of the QUiPP app.

Conclusions: This cluster randomised trial did not demonstrate that the use of the QUiPP app reduced unnecessary management of TPTL compared to current management but would safely improve the management recommended by the National Institute for Health and Care Excellence (NICE). Interpretation of qfFN, with or without the QUiPP app, is a safe and accurate method for identifying women most likely to benefit from PTL interventions.

Trial Registration: ISRCTN Registry ISRCTN17846337.
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http://dx.doi.org/10.1371/journal.pmed.1003689DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8291648PMC
July 2021

Modifiable Determinants of Postpartum Weight Loss in Women with Obesity: A Secondary Analysis of the UPBEAT Trial.

Nutrients 2021 Jun 9;13(6). Epub 2021 Jun 9.

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

Pregnancy can alter a woman's weight gain trajectory across the life course and contribute to the development of obesity through retention of weight gained during pregnancy. This study aimed to identify modifiable determinants associated with postpartum weight retention (PPWR; calculated by the difference in pre-pregnancy and 6 month postpartum weight) in 667 women with obesity from the UPBEAT study. We examined the relationship between PPWR and reported glycaemic load, energy intake, and smoking status in pregnancy, excessive gestational weight gain (GWG), mode of delivery, self-reported postpartum physical activity (low, moderate, and high), and mode of infant feeding (breast, formula, and mixed). At the 6 month visit, 48% ( = 320) of women were at or above pre-pregnancy weight. Overall, PPWR was negative (-0.06 kg (-42.0, 40.4)). Breastfeeding for ≥4 months, moderate or high levels of physical activity, and GWG ≤9 kg were associated with negative PPWR. These three determinants were combined to provide a modifiable factor score (range 0-3); for each added variable, a further reduction in PPWR of 3.0 kg (95% confidence interval 3.76, 2.25) occurred compared to women with no modifiable factors. This study identified three additive determinants of PPWR loss. These provide modifiable targets during pregnancy and the postnatal period to enable women with obesity to return to their pre-pregnancy weight.
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http://dx.doi.org/10.3390/nu13061979DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8227672PMC
June 2021

Validation of the BPro radial pulse waveform acquisition device in pregnancy and gestational hypertensive disorders.

Blood Press Monit 2021 Jun 14. Epub 2021 Jun 14.

Maternity Services, Guy's and St. Thomas' Hospital NHS Trust, St. Thomas' Hospital School of Life Course Sciences, King's College London, London, UK.

Objective: To validate the BPro blood pressure (BP) wrist device for use in pregnancy and preeclampsia according to the Universal Standard protocol.

Participants And Methods: BP was measured sequentially in 45 pregnant women (including 15 with preeclampsia, 15 with gestational hypertension and 15 who remained normotensive) alternating between a mercury sphygmomanometer and BPro device.

Results: The BPro is accurate in pregnancy with a mean device-observer difference of -1.7 ± 6.1 and 0.1 ± 4.6 mmHg for SBP and DBP, respectively. In women with preeclampsia, BPro also met the validation criteria for the Universal Standard protocol with a mean device-observer difference of -2.7 ± 7.1 and 0.3 ± 4.7 mmHg for SBP and DBP, respectively. However, the number of absolute BP differences within 5 mmHg was considerably fewer in those with preeclampsia when compared to the other two subgroups.

Conclusion: The BPro device can be recommended for BP measurement in pregnancy but should be used with caution in those with confirmed preeclampsia.
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http://dx.doi.org/10.1097/MBP.0000000000000552DOI Listing
June 2021

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

Health Technol Assess 2021 May;25(30):1-32

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

Background: Pre-eclampsia affects around 2-3% of all pregnancies, and is associated with potential serious complications for the woman and the baby. Once diagnosed, progression of the syndrome can be unpredictable, and decisions around timing of delivery need to take into account evolving maternal complications and perinatal morbidity. Novel prognostic models and blood biomarkers for determination of need for delivery in pregnancies with pre-eclampsia are now emerging.

Objective: The objective of the study was to establish a prognostic model to inform optimal timing of delivery in women with late preterm pre-eclampsia (34 to 36 weeks' gestation), comparing novel candidate biomarkers (e.g. placental growth factor) with clinical and routinely collected blood/urinary parameters [incorporated into the PREP-S (Prediction models for Risk of Early-onset Pre-eclampsia - Survival) model] to determine clinically indicated need for delivery for pre-eclampsia (or related complications) within 7 days of assessment.

Methods: Prospective recruitment of women in whom blood samples for placental growth factor and soluble fms-like tyrosine kinase-1 testing was obtained, alongside clinical data, for use within the PREP-S model. Candidate variables were compared using standard methods (sensitivity, specificity, receiver operator curve areas). Estimated probability of early delivery from PREP-S was compared with actual event rates by calibration.

Setting: The PEACOCK (Prognostic indicators of severe disEAse in women with late preterm pre-eClampsia tO guide deCision maKing on timing of delivery) study was a prospective cohort study, nested within the PHOENIX (Pre-eclampsia in HOspital: Early iNductIon or eXpectant management) trial.

Participants: Women between 34 and 36 weeks' gestation, with a diagnosis of pre-eclampsia, in whom a plasma (ethylenediaminetetraacetic acid) blood sample for placental growth factor testing was obtained, alongside clinical data for the assessment of variables in a prognostic model.

Main Outcome Measures: Clinically indicated need for delivery for pre-eclampsia within 7 days of assessment. Statistical analysis: both PREP-S and placental growth factor were assessed and compared using standard methods (sensitivity and specificity for placental growth factor thresholds of 100 pg/ml and < 12 pg/ml, and receiver operating characteristic areas for continuous measurements). The estimated probability of early delivery from PREP-S was compared with actual event rates for women with similar probabilities by calibration. Calibration using logistic regression was also used.

Results: Between 27 April 2016 and 24 December 2018, 501 women were recruited to the study. Although placental growth factor testing had high sensitivity (97.9%) for delivery within 7 days, the negative predictive value was only 71.4% and the specificity was low (8.4%). The area under the curve for the clinical prediction model (PREP-S) and placental growth factor in this cohort in determining need for delivery within 7 days was 0.64 (standard error 0.03) and 0.60 (standard error 0.03), respectively, and 0.65 (standard error 0.03) in combination.

Limitations: A high proportion of women in this cohort already had low placental growth factor concentrations at the time of confirmed diagnosis, which reduced the ability of the biomarker to further predict adverse outcomes.

Conclusions: In this group of women with late preterm pre-eclampsia, placental growth factor measurement is not likely to add to the current clinical assessment to help plan care for late preterm pre-eclampsia regarding timing of delivery. Existing models developed in women with early-onset pre-eclampsia to predict complications cannot be used to predict clinically indicated need for delivery in women with late preterm pre-eclampsia.

Future Work: Further statistical modelling and subgroup analysis is being considered to assess if improved model performance in the whole cohort or a subgroup can be achieved. Addition of other biomarkers to the model may also be of use and will be explored.

Trial Registration: Current Controlled Trials ISRCTN01879376.

Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in ; Vol. 25, No. 30. See the NIHR Journals Library website for further project information.
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http://dx.doi.org/10.3310/hta25300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8182444PMC
May 2021

Modifiable early life exposures associated with adiposity and obesity in 3-year old children born to mothers with obesity.

Pediatr Obes 2021 May 17:e12801. Epub 2021 May 17.

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

Background: Children born to mothers with obesity are at increased risk of obesity. Influences underlying this predisposition include in-utero exposures, genetic predisposition and a shared family environment. Effective intervention strategies are needed to prevent obesity in these high-risk children; this requires evaluation of modifiable pregnancy and early-life risk factors.

Objectives: To assess the individual and cumulative contributions of maternal and early-life modifiable exposures on childhood adiposity and obesity outcomes in 3-year-old children born to women with obesity.

Methods: We used adjusted regression to assess the individual and cumulative contributions of six exposures (early pregnancy BMI, excessive gestational weight gain, mode of infant feeding and three measures of childhood eating habits [food responsiveness, slowness in eating and a processed/snacking dietary pattern score]) on body composition in 495 three-year-old children. Outcomes included BMI z-score, arm circumference and overweight/obesity (BMI≥25.0 kg/m ).

Results: While the UPBEAT intervention did not influence adiposity outcomes in 3-year-old children, the six modifiable exposures combined incrementally to increase childhood adiposity and obesity. For each additional exposure, children had a higher BMI z-score (β = 0.35SD [95% confidence interval: 0.23, 0.47]), arm circumference (β = 0.59 cm [0.40, 0.79]) and risk of overweight/obesity (relative risk 1.49 [1.26, 1.77]). Compared to no exposures, children with four or more exposures had a higher BMI z-score (1.11SD [0.65, 1.58]), arm circumference (2.15 cm [1.41, 2.89]) and risk of overweight/obesity (3.01 [1.67, 5.41]) (all P < 0.001).

Conclusion: Our findings suggest that complex interventions targeting preconception, pregnancy, perinatal and early childhood exposures offer a potential strategy for prevention of pre-school obesity.
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http://dx.doi.org/10.1111/ijpo.12801DOI Listing
May 2021

Folate and vitamin B12 status: associations with maternal glucose and neonatal DNA methylation sites related to dysglycaemia, in pregnant women with obesity.

J Dev Orig Health Dis 2021 May 11:1-9. Epub 2021 May 11.

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

Recent studies implicate maternal gestational diabetes mellitus (GDM) in differential methylation of infant DNA. Folate and vitamin B12 play a role in DNA methylation, and these vitamins may also influence GDM risk. The aims of this study were to determine folate and vitamin B12 status in obese pregnant women and investigate associations between folate and vitamin B12 status, maternal dysglycaemia and neonatal DNA methylation at cytosine-phosphate-guanine sites previously observed to be associated with dysglycaemia. Obese pregnant women who participated in the UK Pregnancies Better Eating and Activity Trial were included. Serum folate and vitamin B12 were measured at the oral glucose tolerance test (OGTT) visit. Cord blood DNA methylation was assessed using the Infinium MethylationEPIC BeadChip. Regression models with adjustment for confounders were used to examine associations. Of the 951 women included, 356 (37.4%) were vitamin B12 deficient, and 44 (4.6%) were folate deficient. Two-hundred and seventy-one women (28%) developed GDM. Folate and vitamin B12 concentrations were not associated with neonatal DNA methylation. Higher folate was positively associated with 1-h plasma glucose after OGTT (β = 0.031, 95% CI 0.001-0.061, p = 0.045). There was no relationship between vitamin B12 and glucose concentrations post OGTT or between folate or vitamin B12 and GDM. In summary, we found no evidence to link folate and vitamin B12 status with the differential methylation of neonatal DNA previously observed in association with dysglycaemia. We add to the evidence that folate status may be related to maternal glucose homoeostasis although replication in other maternal cohorts is required for validation.
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http://dx.doi.org/10.1017/S2040174421000246DOI Listing
May 2021

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

Lancet Gastroenterol Hepatol 2021 Jul 27;6(7):547-558. Epub 2021 Apr 27.

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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8192305PMC
July 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

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

Pregnancy Hypertens 2021 Jun 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
June 2021

Placental and endothelial biomarkers for the prediction of superimposed pre-eclampsia in chronic kidney disease.

Pregnancy Hypertens 2021 Jun 23;24:58-64. Epub 2021 Feb 23.

Department of Women and Children's Health, King's College London, London, United Kingdom; Guy's and St. Thomas' NHS Foundation Trust, United Kingdom.

Objectives: To evaluate PlGF, sFlt-1, and novel endothelial biomarkers hyaluronan and vascular cell adhesion molecule (VCAM), for the prediction of superimposed pre-eclampsia in women with chronic kidney disease (CKD).

Study Design: Prospective cohort study of pregnant women with CKD in UK.

Main Outcome Measures: Outcomes including superimposed pre-eclampsia were based on predetermined criteria. Test performances of plasma PlGF, serum sFlt-1:PlGF, hyaluronan and VCAM concentrations were evaluated as area under the receiver-operating curve and at established and exploratory threshold concentrations.

Results: There were 232 pregnancies in 221 women with CKD. One third (76/232) developed superimposed pre-eclampsia. From 21 to 37 weeks' gestation, plasma PlGF was decreased among women that developed superimposed preeclampsia. Plasma PlGF levels < 150 pg/ml had the highest sensitivity (79% 95% CI: 58-91%) and negative predictive value (97%, 95% CI: 93-99%) for the prediction of delivery with superimposed pre-eclampsia within 14 days. Predictive performances of hyaluronan and VCAM were lower than for plasma PlGF. Low plasma PlGF, high hyaluronan and high VCAM concentrations had lower predictive performance in women with pre-pregnancy CKD stages 3-5 compared to stages 1-2. sFlt-1:PlGF > 38 did not usefully predict the need to deliver in women with CKD when measured in serum.

Conclusions: Increased surveillance for the need for delivery should take place in women with CKD and plasma PlGF below 150 pg/ml after 20 weeks' gestation, with awareness that predictive value is reduced as excretory kidney function declines. Maternal endothelial dysfunction may alter the PlGF threshold at which superimposed pre-eclampsia manifests in women with CKD.
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http://dx.doi.org/10.1016/j.preghy.2021.02.010DOI Listing
June 2021

Placental magnetic resonance imaging in chronic hypertension: A case-control study.

Placenta 2021 01 13;104:138-145. Epub 2020 Dec 13.

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

Introduction: We aimed to explore the use of magnetic resonance imaging (MRI) in vivo as a tool to elucidate the placental phenotype in women with chronic hypertension.

Methods: In case-control study, women with chronic hypertension and those with uncomplicated pregnancies were imaged using either a 3T Achieva or 1.5T Ingenia scanner. T2-weighted images, diffusion weighted and T1/T2* relaxometry data was acquired. Placental T2*, T1 and apparent diffusion coefficient (ADC) maps were calculated.

Results: 129 women (43 with chronic hypertension and 86 uncomplicated pregnancies) were imaged at a median of 27.7 weeks' gestation (interquartile range (IQR) 23.9-32.1) and 28.9 (IQR 26.1-32.9) respectively. Visual analysis of T2-weighted imaging demonstrated placentae to be either appropriate for gestation or to have advanced lobulation in women with chronic hypertension, resulting in a greater range of placental mean T2* values for a given gestation, compared to gestation-matched controls. Both skew and kurtosis (derived from histograms of T2* values across the whole placenta) increased with advancing gestational age at imaging in healthy pregnancies; women with chronic hypertension had values overlapping those in the control group range. Upon visual assessment, the mean ADC declined in the third trimester, with a corresponding decline in placental mean T2* values and showed an overlap of values between women with chronic hypertension and the control group.

Discussion: A combined placental MR examination including T2 weighted imaging, T2*, T1 mapping and diffusion imaging demonstrates varying placental phenotypes in a cohort of women with chronic hypertension, showing overlap with the control group.
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http://dx.doi.org/10.1016/j.placenta.2020.12.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7921773PMC
January 2021

Validation and development of models using clinical, biochemical and ultrasound markers for predicting pre-eclampsia: an individual participant data meta-analysis.

Health Technol Assess 2020 12;24(72):1-252

Background: Pre-eclampsia is a leading cause of maternal and perinatal mortality and morbidity. Early identification of women at risk is needed to plan management.

Objectives: To assess the performance of existing pre-eclampsia prediction models and to develop and validate models for pre-eclampsia using individual participant data meta-analysis. We also estimated the prognostic value of individual markers.

Design: This was an individual participant data meta-analysis of cohort studies.

Setting: Source data from secondary and tertiary care.

Predictors: We identified predictors from systematic reviews, and prioritised for importance in an international survey.

Primary Outcomes: Early-onset (delivery at < 34 weeks' gestation), late-onset (delivery at ≥ 34 weeks' gestation) and any-onset pre-eclampsia.

Analysis: We externally validated existing prediction models in UK cohorts and reported their performance in terms of discrimination and calibration. We developed and validated 12 new models based on clinical characteristics, clinical characteristics and biochemical markers, and clinical characteristics and ultrasound markers in the first and second trimesters. We summarised the data set-specific performance of each model using a random-effects meta-analysis. Discrimination was considered promising for -statistics of ≥ 0.7, and calibration was considered good if the slope was near 1 and calibration-in-the-large was near 0. Heterogeneity was quantified using and τ. A decision curve analysis was undertaken to determine the clinical utility (net benefit) of the models. We reported the unadjusted prognostic value of individual predictors for pre-eclampsia as odds ratios with 95% confidence and prediction intervals.

Results: The International Prediction of Pregnancy Complications network comprised 78 studies (3,570,993 singleton pregnancies) identified from systematic reviews of tests to predict pre-eclampsia. Twenty-four of the 131 published prediction models could be validated in 11 UK cohorts. Summary -statistics were between 0.6 and 0.7 for most models, and calibration was generally poor owing to large between-study heterogeneity, suggesting model overfitting. The clinical utility of the models varied between showing net harm to showing minimal or no net benefit. The average discrimination for IPPIC models ranged between 0.68 and 0.83. This was highest for the second-trimester clinical characteristics and biochemical markers model to predict early-onset pre-eclampsia, and lowest for the first-trimester clinical characteristics models to predict any pre-eclampsia. Calibration performance was heterogeneous across studies. Net benefit was observed for International Prediction of Pregnancy Complications first and second-trimester clinical characteristics and clinical characteristics and biochemical markers models predicting any pre-eclampsia, when validated in singleton nulliparous women managed in the UK NHS. History of hypertension, parity, smoking, mode of conception, placental growth factor and uterine artery pulsatility index had the strongest unadjusted associations with pre-eclampsia.

Limitations: Variations in study population characteristics, type of predictors reported, too few events in some validation cohorts and the type of measurements contributed to heterogeneity in performance of the International Prediction of Pregnancy Complications models. Some published models were not validated because model predictors were unavailable in the individual participant data.

Conclusion: For models that could be validated, predictive performance was generally poor across data sets. Although the International Prediction of Pregnancy Complications models show good predictive performance on average, and in the singleton nulliparous population, heterogeneity in calibration performance is likely across settings.

Future Work: Recalibration of model parameters within populations may improve calibration performance. Additional strong predictors need to be identified to improve model performance and consistency. Validation, including examination of calibration heterogeneity, is required for the models we could not validate.

Study Registration: This study is registered as PROSPERO CRD42015029349.

Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in ; Vol. 24, No. 72. See the NIHR Journals Library website for further project information.
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http://dx.doi.org/10.3310/hta24720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780127PMC
December 2020

The impact of chronic kidney disease Stages 3-5 on pregnancy outcomes.

Nephrol Dial Transplant 2020 Dec 12. Epub 2020 Dec 12.

Imperial College Healthcare NHS Trust, London, UK.

Background: Contemporaneous data are required for women with chronic kidney disease (CKD) Stages 3-5 to inform pre-pregnancy counselling and institute appropriate antenatal surveillance.

Methods: A retrospective cohort study in women with CKD Stages 3-5 after 20 weeks' gestation was undertaken in six UK tertiary renal centres in the UK between 2003 and 2017. Factors predicting adverse outcomes and the impact of pregnancy in accelerating the need for renal replacement therapy (RRT) were assessed.

Results: There were 178 pregnancies in 159 women, including 43 women with renal transplants. The live birth rate was 98%, but 56% of babies were born preterm (before 37 weeks' gestation). Chronic hypertension was the strongest predictor of delivery before 34 weeks' gestation. Of 121 women with known pre-pregnancy hypertension status, the incidence of delivery before 34 weeks was 32% (31/96) in women with confirmed chronic hypertension compared with 0% (0/25) in normotensive women. The risk of delivery before 34 weeks doubled in women with chronic hypertension from 20% [95% confidence interval (CI) 9-36%] to 40% (95% CI 26-56%) if the gestational fall in serum creatinine was <10% of pre-pregnancy concentrations. Women with a urinary protein:creatinine ratio >100 mg/mmol prior to pregnancy or before 20 weeks' gestation had an increased risk for birthweight below the 10th centile (odds ratio 2.57, 95% CI 1.20-5.53). There was a measurable drop in estimated glomerular filtration rate (eGFR) between pre-pregnancy and post-partum values (4.5 mL/min/1.73 m2), which was greater than the annual decline in eGFR prior to pregnancy (1.8 mL/min/1.73 m2/year). The effect of pregnancy was, therefore, equivalent to 1.7, 2.1 and 4.9 years of pre-pregnancy renal disease in CKD Stages 3a, 3b and 4-5, respectively. The pregnancy-associated decline in renal function was greater in women with chronic hypertension and in those with a gestational fall in serum creatinine of <10% of pre-pregnancy concentrations. At 1 year post-partum, 46% (58/126) of women had lost ≥25% of their pre-pregnancy eGFR or required RRT. Most women with renal transplants had CKD Stage 3 and more stable renal function prior to pregnancy. Renal transplantation was not independently associated with adverse obstetric or renal outcomes.

Conclusions: Contemporary pregnancies in women with CKD Stages 3-5 are complicated by preterm delivery, low birthweight and loss of maternal renal function. Chronic hypertension, pre- or early pregnancy proteinuria and a gestational fall in serum creatinine of <10% of pre-pregnancy values are more important predictors of adverse obstetric and renal outcome than CKD Stages 3-5. Pregnancy in women with CKD Stages 3-5 advances the need for dialysis or transplantation by 2.5 years.
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http://dx.doi.org/10.1093/ndt/gfaa247DOI Listing
December 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

Placental growth factor for the prognosis of women with preeclampsia (fullPIERS model extension): context matters.

BMC Pregnancy Childbirth 2020 Nov 5;20(1):668. Epub 2020 Nov 5.

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

Background: The fullPIERS risk prediction model was developed to identify which women admitted with confirmed diagnosis of preeclampsia are at highest risk of developing serious maternal complications. The model discriminates well between women who develop (vs. those who do not) adverse maternal outcomes. It has been externally validated in several populations. We assessed whether placental growth factor (PlGF), a biomarker associated with preeclampsia risk, adds incremental value to the fullPIERS model.

Methods: Using a cohort of women admitted into tertiary hospitals in well-resourced settings (the USA and Canada), between May 2010 to February 2012, we evaluated the incremental value of PlGF added to fullPIERS for prediction of adverse maternal outcomes within 48 h after admission with confirmed preeclampsia. The discriminatory performance of PlGF and the fullPIERS model were assessed in this cohort using the area under the receiver's operating characteristic curve (AUROC) while the extended model (fullPIERS +PlGF) was assessed based on net reclassification index (NRI) and integrated discrimination improvement (IDI) performances.

Results: In a cohort of 541 women delivered shortly (< 1 week) after presentation, 8.1% experienced an adverse maternal outcome within 48 h of admission. Prediction of adverse maternal outcomes was not improved by addition of PlGF to fullPIERS (NRI: -8.7, IDI - 0.06). Discriminatory performance (AUROC) was 0.67 [95%CI: 0.59-0.75] for fullPIERS only and 0.67 [95%CI: 0.58-0.76]) for fullPIERS extended with PlGF, a performance worse than previously documented in fullPIERS external validation studies (AUROC > 0.75).

Conclusions: While fullPIERS model performance may have been affected by differences in healthcare context between this study cohort and the model development and validation cohorts, future studies are required to confirm whether PlGF adds incremental benefit to the fullPIERS model for prediction of adverse maternal outcomes in preeclampsia in settings where expectant management is practiced.
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http://dx.doi.org/10.1186/s12884-020-03332-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7643272PMC
November 2020

Maternal dysglycaemia, changes in the infant's epigenome modified with a diet and physical activity intervention in pregnancy: Secondary analysis of a randomised control trial.

PLoS Med 2020 11 5;17(11):e1003229. Epub 2020 Nov 5.

Biological Sciences, Institute of Developmental Sciences, Faculty of Environmental and Life Sciences, University of Southampton, Southampton, United Kingdom.

Background: Higher maternal plasma glucose (PG) concentrations, even below gestational diabetes mellitus (GDM) thresholds, are associated with adverse offspring outcomes, with DNA methylation proposed as a mediating mechanism. Here, we examined the relationships between maternal dysglycaemia at 24 to 28 weeks' gestation and DNA methylation in neonates and whether a dietary and physical activity intervention in pregnant women with obesity modified the methylation signatures associated with maternal dysglycaemia.

Methods And Findings: We investigated 557 women, recruited between 2009 and 2014 from the UK Pregnancies Better Eating and Activity Trial (UPBEAT), a randomised controlled trial (RCT), of a lifestyle intervention (low glycaemic index (GI) diet plus physical activity) in pregnant women with obesity (294 contol, 263 intervention). Between 27 and 28 weeks of pregnancy, participants had an oral glucose (75 g) tolerance test (OGTT), and GDM diagnosis was based on diagnostic criteria recommended by the International Association of Diabetes and Pregnancy Study Groups (IADPSG), with 159 women having a diagnosis of GDM. Cord blood DNA samples from the infants were interrogated for genome-wide DNA methylation levels using the Infinium Human MethylationEPIC BeadChip array. Robust regression was carried out, adjusting for maternal age, smoking, parity, ethnicity, neonate sex, and predicted cell-type composition. Maternal GDM, fasting glucose, 1-h, and 2-h glucose concentrations following an OGTT were associated with 242, 1, 592, and 17 differentially methylated cytosine-phosphate-guanine (dmCpG) sites (false discovery rate (FDR) ≤ 0.05), respectively, in the infant's cord blood DNA. The most significantly GDM-associated CpG was cg03566881 located within the leucine-rich repeat-containing G-protein coupled receptor 6 (LGR6) (FDR = 0.0002). Moreover, we show that the GDM and 1-h glucose-associated methylation signatures in the cord blood of the infant appeared to be attenuated by the dietary and physical activity intervention during pregnancy; in the intervention arm, there were no GDM and two 1-h glucose-associated dmCpGs, whereas in the standard care arm, there were 41 GDM and 160 1-h glucose-associated dmCpGs. A total of 87% of the GDM and 77% of the 1-h glucose-associated dmCpGs had smaller effect sizes in the intervention compared to the standard care arm; the adjusted r2 for the association of LGR6 cg03566881 with GDM was 0.317 (95% confidence interval (CI) 0.012, 0.022) in the standard care and 0.240 (95% CI 0.001, 0.015) in the intervention arm. Limitations included measurement of DNA methylation in cord blood, where the functional significance of such changes are unclear, and because of the strong collinearity between treatment modality and severity of hyperglycaemia, we cannot exclude that treatment-related differences are potential confounders.

Conclusions: Maternal dysglycaemia was associated with significant changes in the epigenome of the infants. Moreover, we found that the epigenetic impact of a dysglycaemic prenatal maternal environment appeared to be modified by a lifestyle intervention in pregnancy. Further research will be needed to investigate possible medical implications of the findings.

Trial Registration: ISRCTN89971375.
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http://dx.doi.org/10.1371/journal.pmed.1003229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7643947PMC
November 2020

External validation of prognostic models predicting pre-eclampsia: individual participant data meta-analysis.

BMC Med 2020 11 2;18(1):302. Epub 2020 Nov 2.

Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Background: Pre-eclampsia is a leading cause of maternal and perinatal mortality and morbidity. Early identification of women at risk during pregnancy is required to plan management. Although there are many published prediction models for pre-eclampsia, few have been validated in external data. Our objective was to externally validate published prediction models for pre-eclampsia using individual participant data (IPD) from UK studies, to evaluate whether any of the models can accurately predict the condition when used within the UK healthcare setting.

Methods: IPD from 11 UK cohort studies (217,415 pregnant women) within the International Prediction of Pregnancy Complications (IPPIC) pre-eclampsia network contributed to external validation of published prediction models, identified by systematic review. Cohorts that measured all predictor variables in at least one of the identified models and reported pre-eclampsia as an outcome were included for validation. We reported the model predictive performance as discrimination (C-statistic), calibration (calibration plots, calibration slope, calibration-in-the-large), and net benefit. Performance measures were estimated separately in each available study and then, where possible, combined across studies in a random-effects meta-analysis.

Results: Of 131 published models, 67 provided the full model equation and 24 could be validated in 11 UK cohorts. Most of the models showed modest discrimination with summary C-statistics between 0.6 and 0.7. The calibration of the predicted compared to observed risk was generally poor for most models with observed calibration slopes less than 1, indicating that predictions were generally too extreme, although confidence intervals were wide. There was large between-study heterogeneity in each model's calibration-in-the-large, suggesting poor calibration of the predicted overall risk across populations. In a subset of models, the net benefit of using the models to inform clinical decisions appeared small and limited to probability thresholds between 5 and 7%.

Conclusions: The evaluated models had modest predictive performance, with key limitations such as poor calibration (likely due to overfitting in the original development datasets), substantial heterogeneity, and small net benefit across settings. The evidence to support the use of these prediction models for pre-eclampsia in clinical decision-making is limited. Any models that we could not validate should be examined in terms of their predictive performance, net benefit, and heterogeneity across multiple UK settings before consideration for use in practice.

Trial Registration: PROSPERO ID: CRD42015029349 .
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http://dx.doi.org/10.1186/s12916-020-01766-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7604970PMC
November 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

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

Acta Obstet Gynecol Scand 2021 06 24;100(6):1040-1050. Epub 2020 Sep 24.

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
June 2021

Impact of smoking on coronavirus disease 19 severity.

J Med Virol 2021 03 29;93(3):1195-1197. Epub 2020 Sep 29.

Department of Surgery and Cancer, Imperial College London, London, UK.

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http://dx.doi.org/10.1002/jmv.26456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7461439PMC
March 2021

The effect of smoking on COVID-19 severity: A systematic review and meta-analysis.

J Med Virol 2021 02 13;93(2):1045-1056. Epub 2020 Aug 13.

Department of Surgery and Cancer, Imperial College London, London, UK.

Various comorbidities represent risk factors for severe coronavirus disease 2019 (COVID-19). The impact of smoking on COVID-19 severity has been previously reported in several meta-analyses limited by small sample sizes and poor methodology. We aimed to rigorously and definitively quantify the effects of smoking on COVID-19 severity. MEDLINE, Embase, CENTRAL, and Web of Science were searched between 1 December 2019 and 2 June 2020. Studies reporting smoking status of hospitalized patients with different severities of disease and/or at least one clinical endpoint of interest (disease progression, intensive care unit admission, need for mechanical ventilation, and mortality) were included. Data were pooled using a random-effects model. This study was registered on PROSPERO: CRD42020180920. We analyzed 47 eligible studies reporting on 32 849 hospitalized COVID-19 patients, with 8417 (25.6%) reporting a smoking history, comprising 1501 current smokers, 5676 former smokers, and 1240 unspecified smokers. Current smokers had an increased risk of severe COVID-19 (risk ratios [RR]: 1.80; 95% confidence interval [CI]: 1.14-2.85; P = .012), and severe or critical COVID-19 (RR: 1.98; CI: 1.16-3.38; P = .012). Patients with a smoking history had a significantly increased risk of severe COVID-19 (RR: 1.31; CI: 1.12-1.54; P = .001), severe or critical COVID-19 (RR: 1.35; CI: 1.19-1.53; P < .0001), in-hospital mortality (RR: 1.26; CI: 1.20-1.32; P < .0001), disease progression (RR: 2.18; CI: 1.06-4.49; P = .035), and need for mechanical ventilation (RR: 1.20; CI: 1.01-1.42; P = .043). Patients with any smoking history are vulnerable to severe COVID-19 and worse in-hospital outcomes. In the absence of current targeted therapies, preventative, and supportive strategies to reduce morbidity and mortality in current and former smokers are crucial.
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http://dx.doi.org/10.1002/jmv.26389DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7436545PMC
February 2021

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

The UK Pregnancies Better Eating and Activity Trial (UPBEAT); Pregnancy Outcomes and Health Behaviours by Obesity Class.

Int J Environ Res Public Health 2020 06 30;17(13). Epub 2020 Jun 30.

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.

The effectiveness of antenatal intervention in women with increasing obesity is unknown. This study investigated whether there was a differential effect of antenatal intervention on diet, physical activity and pregnancy outcomes in women stratified by obesity class using data from the UK Pregnancies Better Eating and Activity Trial (UPBEAT) ( = 1555). The stratification was by World Health Organization classifications: Class I, II and III (30-34.9 kg/m, 35-39.9 kg/m and ≥40 kg/m). Using linear and logistic regression, adjusted for confounders, outcomes were assessed post-intervention (27-28 weeks' gestation) and in late pregnancy (34-36 weeks' gestation). Interactions between obesity class and the intervention were explored. Compared to the standard care arm, class III intervention women had lower gestational weight gain (GWG) (-1.87 kg; 95% CI -3.29 to -0.47, = 0.009), and the effect of the intervention was greater in class III compared to class I, by -2.01 kg (95% CI -3.45 to -0.57, = 0.006). Class I and II intervention women reported significantly lower dietary glycaemic load and saturated fat intake across their pregnancy. This differential effect of the intervention suggests antenatal interventions for women with obesity should stratify outcomes by obesity severity. This would inform evidence-based antenatal strategies for high-risk groups, including women with a BMI ≥ 40 kg/m.
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http://dx.doi.org/10.3390/ijerph17134712DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7370059PMC
June 2020

Rule-in thresholds for DELFIA Xpress PlGF 1-2-3 test for suspected pre-eclampsia.

Pregnancy Hypertens 2020 Jul 22;21:35-37. Epub 2020 Apr 22.

Women's Health Academic Centre, St Thomas' Hospital, King's College London, United Kingdom. Electronic address:

We aimed to establish a rule-in threshold for the DELFIA Xpress placental growth factor (PlGF) 1-2-3 test. Plasma EDTA samples from 305 women presenting with suspected pre-eclampsia before 35 weeks' gestation were analysed using three different PlGF-based tests: PlGF 1-2-3 test (Perkin Elmer); Triage PlGF test (Quidel); Elecsys immunoassay sFlt-1/PlGF ratio (Roche). The rule-in threshold for PlGF 1-2-3 test created with equivalent specificity of the Quidel and Roche tests was 50 pg/ml. This can be used as a rule-in test for diagnosis of preterm pre-eclampsiarequiring delivery within 14 days (specificity 95.0% (95% CI 91.7-97.2%), positive predictive value50 (95% CI 30.6-69.4%), positive likelihood ratio 10.7 (5.8-20).
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http://dx.doi.org/10.1016/j.preghy.2020.04.005DOI Listing
July 2020

Pulmonary complications for women with sickle cell disease in pregnancy: systematic review and meta-analysis.

Thorax 2020 07 28;75(7):568-575. Epub 2020 Apr 28.

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

Background: Sickle cell disease (SCD) is a multisystem disease characterised by vaso-occlusive crisis, chronic anaemia and a shorter lifespan. More patients with SCD are living till reproductive age and contemplating pregnancy. Pulmonary complications in pregnancy are significant causes of maternal morbidity and mortality but yet this has not been systematically quantified. A systematic review and meta-analysis were conducted to quantify the association between SCD and pulmonary complications in pregnancy.

Methods: MEDLINE, EMBASE, Web of Science, Cochrane and Maternity and Infant Care databases were searched for publications between January 1998 and April 2019. Observational studies involving at least 30 participants were included. Random-effects models were used for statistical meta-analysis.

Findings: Twenty-two studies were included in the systematic review and 18 in the quantitative analysis. The meta-analysis included 3964 pregnancies with SCD and 336 559 controls. Compared with women without SCD, pregnancies complicated by SCD were at increased risk of pulmonary thromboembolism (relative risk (RR) 7.74; 95% CI 4.65 to 12.89). The estimated prevalence of acute chest syndrome and pneumonia was 6.46% (95% CI 4.66% to 8.25%), with no significant difference between the HbSS and HbSC genotypes (RR 1.42; 95% CI 0.90 to 2.23).

Interpretation: This meta-analysis highlighted a strong association between SCD and maternal pulmonary complications. Understanding the risks of and the factors associated with pulmonary complications would aid preconceptual counselling and optimal management of the condition in pregnancy, thereby reducing associated maternal morbidity and mortality.

Prospero Registration Number: CRD42019124708.
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http://dx.doi.org/10.1136/thoraxjnl-2019-213796DOI Listing
July 2020

T2* Placental Magnetic Resonance Imaging in Preterm Preeclampsia: An Observational Cohort Study.

Hypertension 2020 06 27;75(6):1523-1531. Epub 2020 Apr 27.

From the Department of Women and Children's Health, School of Life Course Sciences (A.E.P.H., P.S., L.S., L.C.C.), King's College London, United Kingdom.

Placental dysfunction underlies the cause of pregnancies complicated by preeclampsia. The use of placental magnetic resonance imaging to provide an insight into the pathophysiology of preeclampsia and thus assess its potential use to inform prognosis and clinical management was explored. In this prospective observational cohort study, 14 women with preterm preeclampsia and 48 gestation-matched controls using 3-Tesla magnetic resonance imaging at median of 31.6 weeks (interquartile range [IQR], 28.6-34.6) and 32.2 weeks (IQR, 28.6-33.8), respectively, were imaged. The acquired data included T2-weighted images and T2* maps of the placenta, the latter an indicative measure of placental oxygenation. Placentae in women with preeclampsia demonstrated advanced lobulation, varied lobule sizes, high granularity, and substantial areas of low-signal intensity on T2-weighted imaging, with reduced entire placental mean T2* values for gestational age (2 sample test, t=7.49) correlating with a reduction in maternal PlGF (placental growth factor) concentrations (Spearman rank correlation coefficient 0.76) and increased lacunarity values (t=3.26). Median mean T2* reduced from 67 ms (IQR, 54-73) at 26.0 to 29.8 weeks' gestation to 38 ms (IQR, 28-40) at 34.0 to 37.9 weeks' gestation in the control group. In women with preeclampsia, median T2* was 23 ms (IQR, 20-23) at 26.0 to 29.8 weeks' gestation and remained low (22 ms [IQR, 20-26] at 34.0-37.8 weeks' gestation). Histological features of maternal vascular malperfusion were only found in placentae from women with preeclampsia. Placental volume did not differ between the control group and women with preeclampsia. Placental magnetic resonance imaging allows both objective quantification of placental function in vivo and elucidation of the complex mechanisms underlying preeclampsia development.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.14701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7682790PMC
June 2020

Quantitative fetal fibronectin for prediction of preterm birth in asymptomatic twin pregnancy.

Acta Obstet Gynecol Scand 2020 09 20;99(9):1191-1197. Epub 2020 Apr 20.

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

Introduction: To evaluate cervicovaginal fluid quantitative fetal fibronectin, measured by a bedside analyzer, to predict spontaneous preterm birth in twin pregnancy before 30 weeks of gestation.

Material And Methods: In a prospective cohort study, we studied the accuracy of quantitative fetal fibronectin measured between 18 and 27 weeks of gestation in high-risk asymptomatic women with twin pregnancies, to predict spontaneous preterm birth before 30 weeks of gestation. Predefined fetal fibronectin thresholds were ≥10, ≥50 and ≥200 ng/mL. Predictive statistics were also calculated to evaluate accuracy of "early" tests, performed between 18 and 21 weeks and "standard" tests performed between 22 and 27 weeks of gestation in the same cohort. Subgroup analysis was performed according to cervical length measurement. In addition, we compared accuracy of prediction with quantitative fetal fibronectin measured during the standard test period in asymptomatic twin pregnancy with no additional risk factors, to twin pregnancies with one or more additional risk factors for spontaneous preterm birth.

Results: Of 130 eligible women identified with quantitative fetal fibronectin tests undertaken during the standard testing period, 9% delivered before 30 weeks of gestation. Quantitative fetal fibronectin was significantly related to outcome before 30/40 (ROC curves of 0.8 [95% CI 0.7-1]). Early tests were not significantly predictive; ROC area 0.53 (95% CI 0.29-0.81). There was a trend towards better predictive accuracy when one or more additional risk factors for spontaneous preterm birth or cervical length were considered.

Conclusions: Quantitative fetal fibronectin measured from 22 to 27 weeks of gestation accurately predicts spontaneous preterm birth at <30 weeks of gestation. Tests undertaken earlier are of limited value. Consideration of cervical length or prior history in addition to quantitative fetal fibronectin strengthens prediction.
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http://dx.doi.org/10.1111/aogs.13861DOI Listing
September 2020
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